Papers - KAIKITA Koichi
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Effect of Antihypertensive Drugs on Rapid Decline in Estimated Glomerular Filtration Rate in Japanese Patients with Chronic Kidney Disease. Reviewed
Fujimoto K, Kikuchi M, Nakai M, Konta T, Iseki K, Tsuruya K, Yamagata K, Narita I, Moriyama T, Shibagaki Y, Kasahara M, Kondo M, Asahi K, Watanabe T, Kaikita K, Fujimoto S
American journal of hypertension 2025.3
Language：English Publishing type：Research paper (scientific journal)
DOI： 10.1093/ajh/hpaf041
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A case of rapidly progressive Salmonella aortic aneurysm with acute pericarditis manifesting as a precursor. Reviewed
Harada K, Kawagoe K, Matsuura Y, Kawano M, Suiko Y, Tanaka H, Moribayashi K, Ishii H, Ideguchi T, Furukawa K, Kaikita K
Journal of cardiology cases 31 ( 3 ) 76 - 79 2025.3
Authorship：Last author Language：English Publishing type：Research paper (scientific journal)
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Inflammatory stimuli and hypoxia on atherosclerotic plaque thrombogenicity: Linking macrophage tissue factor and glycolysis. Reviewed
Maekawa K, Nakamura E, Saito Y, Matsuura Y, Gi T, Nishihira K, Oguri N, Moriguchi-Goto S, Sato Y, Hatakeyama K, Shibata Y, Komohara Y, Kaikita K, Asada Y, Yamashita A
PloS one 20 ( 3 ) e0316474 2025
Language：English Publishing type：Research paper (scientific journal)
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5-Aminolevulinic acid combined with ferrous iron ameliorates myocardial ischemia/reperfusion injury by increasing heme oxygenase-1. Reviewed
Nakanishi N, Kaikita K, Oimatsu Y, Ishii M, Kuyama N, Arima Y, Araki S, Nakamura T, Yamamoto E, Tsujita K
Heart and vessels 2024.11
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)
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Uninephrectomy and sodium-glucose cotransporter 2 inhibitor administration delay the onset of hyperglycemia. Reviewed
Ishizaki YS, Kikuchi M, Kaikita K, Fujimoto S
Physiological reports 12 ( 21 ) e70121 2024.11
Language：English Publishing type：Research paper (scientific journal)
DOI： 10.14814/phy2.70121
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Optical coherence tomography imaging of coronary thrombosis developed after rotational atherectomy despite appropriate antithrombotic therapy. Reviewed
Komaki S, Moribayashi K, Matsuura Y, Tanaka H, Kaikita K
Cardiovascular intervention and therapeutics 39 ( 4 ) 493 - 494 2024.10
Authorship：Last author Language：English Publishing type：Research paper (scientific journal)
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Antiplatelets for Cardiovascular Disease in Non-valvular AF with Rivaroxaban: A Subanalysis of the EXPAND Study. Reviewed
Kaikita K, Uchiyama S, Atarashi H, Inoue H, Kitazono T, Yamashita T, Shimizu W, Ikeda T, Kamouchi M, Fukuda K, Origasa H, Shimokawa H
Journal of atherosclerosis and thrombosis 2024.9
Authorship：Lead author, Corresponding author Language：English Publishing type：Research paper (scientific journal)
DOI： 10.5551/jat.64681
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Mineralocorticoid Receptor Blocker Prevents Mineralocorticoid Receptor-Mediated Inflammation by Modulating Transcriptional Activity of Mineralocorticoid Receptor-p65-Signal Transducer and Activator of Transcription 3 Complex. Reviewed
Kuyama N, Araki S, Kaikita K, Nakanishi N, Nakashima N, Hanatani S, Arima Y, Yamamoto M, Nakamura T, Yamamoto E, Matsushita K, Matsui K, Tsujita K
Journal of the American Heart Association 13 ( 18 ) e030941 2024.9
Language：English Publishing type：Research paper (scientific journal)
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Basal inferoseptal segment is highly susceptible to deformation in the clinical spectrum of transthyretin-derived amyloid cardiomyopathy. Reviewed
Tsuruda T, Nakada H, Yamamura Y, Matsuura Y, Ogata M, Tanaka M, Suiko Y, Komaki S, Tanaka H, Moribayashi K, Ideguchi T, Terada T, Ota T, Yamamoto K, Nishihira K, Shibata Y, Kaikita K
European heart journal open 4 ( 5 ) oeae076 2024.9
Authorship：Last author Language：English Publishing type：Research paper (scientific journal)
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Differential impact of diabetes mellitus on in-hospital mortality based on the circadian variation in acute myocardial infarction. Reviewed
Matsushita K, Kojima S, Hirakawa K, Tabata N, Ito M, Yamanaga K, Fujisue K, Hoshiyama T, Hanatani S, Sueta D, Kanazawa H, Takashio S, Arima Y, Araki S, Usuku H, Suzuki S, Yamamoto E, Nakamura T, Soejima H, Kaikita K, Tsujita K
Hellenic journal of cardiology : HJC = Hellenike kardiologike epitheorese 2024.8
Language：English Publishing type：Research paper (scientific journal)
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Subclinical leaflet thrombus in patients with severe aortic stenosis and atrial fibrillation -ENRICH-AF TAVI study. Reviewed
Otsuka Y, Ishii M, Tabata N, Oda S, Kidoh M, Shirahama Y, Egashira K, Kuyama N, Rokutanda T, Noda K, Horio E, Sakamoto T, Kudo T, Shimomura H, Ikemoto T, Tsunoda R, Nakamura T, Matsui K, Kaikita K, Tsujita K, ENRICH AF TAVI Investigators
Scientific reports 14 ( 1 ) 14902 2024.6
Language：English Publishing type：Research paper (scientific journal)
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An Unusual Contrast Computed Tomography Scan Finding in a Patient with Immune Checkpoint Inhibitor-Associated AKI. Reviewed
Ochiai S, Kikuchi M, Kaikita K
Kidney360 5 ( 6 ) 927 - 928 2024.6
Authorship：Last author Language：English Publishing type：Research paper (scientific journal)
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Mitral regurgitation is associated with similar loss of von Willebrand factor large multimers but lower frequency of anemia compared with aortic stenosis. Reviewed
Takiguchi H, Miura M, Shirai SI, Soga Y, Hanyu M, Sakaguchi G, Soga Y, Arai Y, Watanabe S, Kimura T, Takahama H, Yasuda S, Nakayoshi T, Fukumoto Y, Yaoita N, Shimokawa H, Sakatsume K, Saiki Y, Kaikita K, Tsujita K, Tamura T, Doman T, Yamashita M, Suzuki M, Eura Y, Kokame K, Hayakawa M, Matsumoto M, Okubo N, Sugawara S, Fujimaki SI, Kawate Y, Ando K, Horiuchi H
Research and practice in thrombosis and haemostasis 8 ( 4 ) 102431 2024.5
Language：English Publishing type：Research paper (scientific journal)
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Antithrombotic therapy for stable coronary artery disease and atrial fibrillation in patients with and without revascularisation: the AFIRE trial. Reviewed
Noda T, Nochioka K, Kaikita K, Akao M, Ako J, Matoba T, Nakamura M, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa H, Yasuda S, Afire Investigators OBOT
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 20 ( 7 ) e425 - e435 2024.4
Language：English Publishing type：Research paper (scientific journal)
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Non-Contrast Magnetic Resonance Imaging of Isolated Superior Mesenteric Artery Dissection. Reviewed
Uchida A, Matsuura Y, Kuroiwa Y, Kaikita K
Circulation reports 6 ( 2 ) 34 - 35 2024.2
Authorship：Last author Language：English Publishing type：Research paper (scientific journal)
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Rapidly progressive glomerulonephritis due to IgA nephropathy accompanied by collagenofibrotic glomerulopathy. A nephrology picture. Reviewed
Ochiai S, Kikuchi M, Kaikita K, Fujimoto S
Journal of nephrology 2024.2
Language：English Publishing type：Research paper (scientific journal)
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Guideline-Directed Medical Therapy for Elderly Patients With Acute Myocardial Infarction Who Undergo Percutaneous Coronary Intervention - Insights From a Retrospective Observational Study. Reviewed
Nishihira K, Nakai M, Kuriyama N, Kadooka K, Honda Y, Emori H, Yamamoto K, Nishino S, Kudo T, Ogata K, Kimura T, Kaikita K, Shibata Y
Circulation journal : official journal of the Japanese Circulation Society 2024.1
Language：English Publishing type：Research paper (scientific journal)
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Nitroglycerin use and adverse clinical outcomes in elderly patients with acute coronary syndrome. Reviewed
Komaki S, Matsuura Y, Tanaka H, Moribayashi K, Yamamura Y, Kurogi K, Ideguchi T, Yamamoto N, Nakai M, Tsuruda T, Kaikita K
Open heart 11 ( 1 ) 2024.1
Authorship：Last author Language：English Publishing type：Research paper (scientific journal)
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von Willebrand factor Ristocetin co-factor activity to von Willebrand factor antigen level ratio for diagnosis of acquired von Willebrand syndrome caused by aortic stenosis. Reviewed
Okubo N, Sugawara S, Fujiwara T, Sakatsume K, Doman T, Yamashita M, Goto K, Tateishi M, Suzuki M, Shirakawa R, Eura Y, Kokame K, Hayakawa M, Matsumoto M, Kawate Y, Miura M, Takiguchi H, Soga Y, Shirai S, Ando K, Arai Y, Nakayoshi T, Fukumoto Y, Takahama H, Yasuda S, Tamura T, Watanabe S, Kimura T, Yaoita N, Shimokawa H, Saiki Y, Kaikita K, Tsujita K, Yoshii S, Nakase H, Fujimaki SI, Horiuchi H
Research and practice in thrombosis and haemostasis 8 ( 1 ) 102284 2024.1
Language：English Publishing type：Research paper (scientific journal)
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Periprocedural Thrombogenicity Change Is Associated With Subclinical Leaflet Thrombosis Progression in Patients Undergoing Transcatheter Aortic Valve Implantation. Reviewed
Kuyama N, Kaikita K, Ishii M, Tabata N, Oda S, Otsuka Y, Egashira K, Shirahama Y, Hanatani S, Takashio S, Matsuzawa Y, Yamamoto E, Hirai T, Tsujita K
Circulation reports 5 ( 12 ) 450 - 458 2023.12
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)
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BNP level predicts bleeding event in patients with heart failure after percutaneous coronary intervention. Reviewed
Otsuka Y, Ishii M, Ikebe S, Nakamura T, Tsujita K, Kaikita K, Matoba T, Kohro T, Oba Y, Kabutoya T, Kario K, Imai Y, Kiyosue A, Mizuno Y, Nochioka K, Nakayama M, Iwai T, Miyamoto Y, Sato H, Akashi N, Fujita H, Nagai R, CLIDAS research group
Open heart 10 ( 2 ) 2023.12
Language：English Publishing type：Research paper (scientific journal)
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Effectiveness and safety of reduced-dose rivaroxaban for elderly patients with non-valvular atrial fibrillation: A subanalysis of the EXPAND study. Reviewed
Shimizu W, Uchiyama S, Atarashi H, Inoue H, Kitazono T, Yamashita T, Ikeda T, Kamouchi M, Kaikita K, Fukuda K, Origasa H, Shimokawa H
International journal of cardiology 391 131290 2023.11
Language：English Publishing type：Research paper (scientific journal)
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Prognostic impact of diabetes mellitus on in-hospital mortality in patients with acute myocardial infarction complicating renal dysfunction according to age and sex. Reviewed
Matsushita K, Kojima S, Hirakawa K, Tabata N, Ito M, Yamanaga K, Fujisue K, Hoshiyama T, Hanatani S, Sueta D, Kanazawa H, Takashio S, Arima Y, Araki S, Usuku H, Suzuki S, Yamamoto E, Nakamura T, Soejima H, Kaikita K, Tsujita K
Hellenic journal of cardiology : HJC = Hellenike kardiologike epitheorese 2023.11
Language：English Publishing type：Research paper (scientific journal)
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Increasing baseline aortic valve peak flow velocity is associated with progression of aortic valve stenosis in osteoporosis patients-a possible link to low vitamin D status. Reviewed
Tsuruda T, Funamoto T, Suzuki C, Yamamura Y, Nakai M, Chosa E, Kaikita K
Archives of osteoporosis 18 ( 1 ) 129 2023.10
Authorship：Last author Language：English Publishing type：Research paper (scientific journal)
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Very Late Stent Thrombosis Complicating Immune Thrombocytopenia: Insights From Optical Coherence Tomography and Thrombopathology. Reviewed
Shimazu H, Matsuura Y, Moribayashi K, Gi T, Suiko Y, Tanaka H, Komaki S, Ishikawa T, Yamashita A, Kaikita K
JACC. Case reports 24 102017 2023.10
Authorship：Last author Language：English Publishing type：Research paper (scientific journal)
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Thrombocytopenia as a Bleeding Risk Factor in Atrial Fibrillation and Coronary Artery Disease: Insights From the AFIRE Study. Reviewed
Iijima R, Tokue M, Nakamura M, Yasuda S, Kaikita K, Akao M, Ako J, Matoba T, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa H, AFIRE Investigators
Journal of the American Heart Association 12 ( 20 ) e031096 2023.10
Language：English Publishing type：Research paper (scientific journal)
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Sex- and Age-Based Disparities in Public Access Defibrillation, Bystander Cardiopulmonary Resuscitation, and Neurological Outcome in Cardiac Arrest. Reviewed
Ishii M, Tsujita K, Seki T, Okada M, Kubota K, Matsushita K, Kaikita K, Yonemoto N, Tahara Y, Ikeda T, Japanese Circulation Society with Resuscitation Science Study (JCS-ReSS) Investigators
JAMA network open 6 ( 7 ) e2321783 2023.7
Language：English Publishing type：Research paper (scientific journal)
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Natriuretic peptides potentiate cardiac hypertrophic response to noradrenaline in rats. Reviewed
Jiang D, Matsuzaki M, Ida T, Kitamura K, Tsuruda T, Kaikita K, Kato J
Peptides 166 171035 2023.5
Language：English Publishing type：Research paper (scientific journal)
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Risk prediction score for clinical outcome in atrial fibrillation and stable coronary artery disease. Reviewed
Ishii M, Kaikita K, Yasuda S, Akao M, Ako J, Matoba T, Nakamura M, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Nishihara E, Nakamura S, Matsui K, Ogawa H, Tsujita K, AFIRE Investigators
Open heart 10 ( 1 ) 2023.5
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)
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A case of primary aldosteronism with excessive secretion of renin that was unmasked by kidney transplantation. Reviewed
Fujimoto K, Hisanaga S, Kuroda S, Kodama K, Sugiyama F, Kikuchi M, Kita T, Yamashita A, Nagai T, Kamimura T, Kaikita K, Imamura T, Fujimoto S
CEN case reports 2023.4
Language：English Publishing type：Research paper (scientific journal)
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JCS/CVIT/JCC 2023 Guideline Focused Update on Diagnosis and Treatment of Vasospastic Angina (Coronary Spastic Angina) and Coronary Microvascular Dysfunction. Reviewed
Hokimoto S, Kaikita K, Yasuda S, Tsujita K, Ishihara M, Matoba T, Matsuzawa Y, Mitsutake Y, Mitani Y, Murohara T, Noda T, Node K, Noguchi T, Suzuki H, Takahashi J, Tanabe Y, Tanaka A, Tanaka N, Teragawa H, Yasu T, Yoshimura M, Asaumi Y, Godo S, Ikenaga H, Imanaka T, Ishibashi K, Ishii M, Ishihara T, Matsuura Y, Miura H, Nakano Y, Ogawa T, Shiroto T, Soejima H, Takagi R, Tanaka A, Tanaka A, Taruya A, Tsuda E, Wakabayashi K, Yokoi K, Minamino T, Nakagawa Y, Sueda S, Shimokawa H, Ogawa H, Japanese Circulation Society and Japanese Association of Cardiovascular Intervention and Therapeutics and Japanese College of Cardiology Joint Working Group
Circulation journal : official journal of the Japanese Circulation Society 2023.3
Language：English Publishing type：Research paper (scientific journal)
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Japanese high bleeding risk criteria status predicts low thrombogenicity and bleeding events in patients undergoing percutaneous coronary intervention. Reviewed
Nakanishi N, Kaikita K, Ishii M, Kuyama N, Tabata N, Ito M, Yamanaga K, Fujisue K, Hoshiyama T, Kanazawa H, Hanatani S, Sueta D, Takashio S, Arima Y, Araki S, Usuku H, Nakamura T, Yamamoto E, Soejima H, Matsushita K, Tsujita K
Cardiovascular intervention and therapeutics 2023.3
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)
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Relationship between coronary artery calcium score and bleeding events after percutaneous coronary intervention in chronic coronary syndrome. Reviewed
Komaki S, Ishii M, Kaichi R, Takae M, Mori T, Toida R, Kurogi K, Matsuura Y, Yamamoto N, Tsujita K, Tsuruda T, Kaikita K
Heart and vessels 2023.2
Authorship：Last author Language：English Publishing type：Research paper (scientific journal)
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Analysis of Mechanisms for Increased Blood Pressure Variability in Rats Continuously Infused with Angiotensin II. Reviewed
Jiang D, Matsuzaki M, Kawagoe Y, Kitamura K, Tsuruda T, Kaikita K, Asada Y, Kato J
Journal of the renin-angiotensin-aldosterone system : JRAAS 2023 4201342 2023.1
Language：English Publishing type：Research paper (scientific journal)
DOI： 10.1155/2023/4201342
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Utility of the Total Thrombus-Formation Analysis System as a Tool for Evaluating Thrombogenicity and Monitoring Antithrombotic Therapy in Pediatric Fontan Patients. Reviewed
Matsuo O, Ishii M, Kaikita K, Morinaga J, Miyamura F, Matsumoto S, Tsujita K, Nakamura K
Pediatric cardiology 2022.12
Language：English Publishing type：Research paper (scientific journal)
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Differential effects of overweight/obesity depending on the severity of heart failure complicating acute myocardial infarction in Japan. Reviewed
Matsushita K, Kojima S, Hirakawa K, Tabata N, Ito M, Yamanaga K, Fujisue K, Hoshiyama T, Hanatani S, Sueta D, Kanazawa H, Takashio S, Arima Y, Araki S, Usuku H, Suzuki S, Yamamoto E, Nakamura T, Soejima H, Kaikita K, Tsujita K
Progress in cardiovascular diseases 2022.12
Language：English Publishing type：Research paper (scientific journal)
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Rivaroxaban Monotherapy in Atrial Fibrillation and Stable Coronary Artery Disease Across Body Mass Index Categories. Reviewed
Ishii M, Kaikita K, Yasuda S, Akao M, Ako J, Matoba T, Nakamura M, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa H, Tsujita K, AFIRE Investigators
JACC. Asia 2 ( 7 ) 882 - 893 2022.12
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)
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Rivaroxaban Monotherapy in Patients With Atrial Fibrillation and Coronary Stenting at Multiple Vessels or the Left Main Trunk: The AFIRE Trial Subanalysis. Reviewed
Ishii M, Akao M, Yasuda S, Kaikita K, Ako J, Matoba T, Nakamura M, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa H, AFIRE Investigators.
Journal of the American Heart Association 11 ( 21 ) e027107 2022.10
Language：English Publishing type：Research paper (scientific journal)
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Optimal Antithrombotic Therapy in Patients Undergoing Percutaneous Coronary Intervention: A Focused Review on High Bleeding Risk. Reviewed
Matsuura Y, Moribayashi K, Kaikita K
Journal of atherosclerosis and thrombosis 29 ( 10 ) 1409 - 1420 2022.10
Authorship：Last author Language：English Publishing type：Research paper (scientific journal)
DOI： 10.5551/jat.RV17066
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Validation of the obesity paradox by body mass index and waist circumference in patients undergoing percutaneous coronary intervention. Reviewed
Shirahama Y, Tabata N, Sakamoto K, Sato R, Yamanaga K, Fujisue K, Sueta D, Araki S, Takashio S, Arima Y, Hokimoto S, Sato K, Sakamoto T, Nakao K, Shimomura H, Matsumura T, Tayama S, Fujimoto K, Oshima S, Nakamura S, Tsunoda R, Hirose T, Kikuta K, Sakaino N, Yamamoto N, Kajiwara I, Suzuki S, Yamamoto E, Kaikita K, Matsushita K, Tsujita K, Kumamoto Intervention Conference Study (KICS) Investigators.
International journal of obesity (2005) 46 ( 10 ) 1840 - 1848 2022.10
Language：English Publishing type：Research paper (scientific journal)
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Bystander-witnessed cardiopulmonary resuscitation by nonfamily is associated with neurologically favorable survival after out-of-hospital cardiac arrest in Miyazaki City District. Reviewed
Tsuruda T, Hamahata T, Endo GJ, Tsuruda Y, Kaikita K
PloS one 17 ( 10 ) e0276574 2022.10
Authorship：Last author Language：English Publishing type：Research paper (scientific journal)
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Fujisue K, Yamamoto E, Sueta D, Arima Y, Hirakawa K, Tabata N, Ishii M, Ito M, Yamanaga K, Hanatani S, Hoshiyama T, Kanazawa H, Takashio S, Araki S, Usuku H, Nakamura T, Soejima H, Kaikita K, Kawano H, Matsushita K, Tsujita K
Journal of atherosclerosis and thrombosis 29 ( 9 ) 1285 - 1294 2022.9
Language：English Publishing type：Research paper (scientific journal) Publisher：一般社団法人 日本動脈硬化学会
<b>Aims: </b>Royal jelly, a creamy substance secreted by honeybees, has been reported to have beneficial effects against dyslipidemia and metabolic syndrome. However, the effects of royal jelly on atherogenesis remain unknown. Hence, we prospectively evaluated whether royal jelly augments vascular endothelial function, which can reflect early atherogenesis, in healthy volunteers.<b> </b><b>Methods: </b>This was a single-center, double-blind, 1:1 randomized placebo-controlled study conducted from October 2018 to December 2019. A total of 100 healthy volunteers were randomly assigned to receive either royal jelly 690 mg or placebo daily for 4 weeks. The primary endpoint was augmentation in vascular endothelial function as assessed using the change in the reactive hyperemia peripheral arterial tonometry index (RH-PAT) index, and the secondary endpoints were the changes in liver function and lipid profiles between baseline and 4 weeks after enrollment.<b> </b><b>Results: </b>The mean age of the participants was 35.0±9.3 years in the placebo group and 36.1±9.1 years in the royal jelly groups; 45% and 50% of the placebo and the royal jelly groups, respectively, were male. The percentage relative change in the RH-PAT index was significantly higher in the royal jelly group than in the placebo group (21.4%±53.1% vs. 0.05%±40.9%, <i>P</i>=0.037). The percentage relative changes in alanine aminotransferase and γ-glutamyl transpeptidase were significantly lower in the royal jelly group than in the placebo group (alanine aminotransferase: −6.06%±22.2% vs. 11.6%±46.5%, <i>P</i>=0.02; γ-glutamyl transpeptidase: −3.45%±17.8% vs. 4.62%±19.4%, <i>P</i>=0.045). Lipid profiles were not significantly different between the two groups.<b> </b><b>Conclusions: </b>Royal jelly might have antiatherogenic property by improving vascular endothelial function. It also augmented liver functions in healthy volunteers.
DOI： 10.5551/jat.63044
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Apical flow and wall motion dynamics in left ventricular outflow obstruction: a case report. Reviewed
Misumi I, Sato K, Nagano M, Haba K, Ohba K, Kaikita K, Tsujita K
Journal of echocardiography 20 ( 3 ) 178 - 179 2022.9
Language：English Publishing type：Research paper (scientific journal)
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Attempt of quality management seminar for clinical research by visitation in clinical departments at the University of Miyazaki Hospital: results from questionnaire survey Reviewed
Hitomi Morita, Toshihiko Yanagita, Koichiro Itai, Sosuke Iwae, Koichi Kaikita, Hideo Takeshima
50 ( suppl. 1 ) s62 - s66 2022.8
Authorship：Lead author Language：Japanese Publishing type：Research paper (scientific journal)
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Rivaroxaban Monotherapy vs Combination Therapy With Antiplatelets on Total Thrombotic and Bleeding Events in Atrial Fibrillation With Stable Coronary Artery Disease: A Post Hoc Secondary Analysis of the AFIRE Trial. Reviewed
Naito R, Miyauchi K, Yasuda S, Kaikita K, Akao M, Ako J, Matoba T, Nakamura M, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa H, AFIRE Investigators.
JAMA cardiology 7 ( 8 ) 787 - 794 2022.6
Language：English Publishing type：Research paper (scientific journal)
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Rivaroxaban Underdose for Atrial Fibrillation with Stable Coronary Disease: The AFIRE Trial Findings. Reviewed
Arashi H, Yamaguchi J, Hagiwara N, Yasuda S, Kaikita K, Akao M, Ako J, Matoba T, Nakamura M, Miyauchi K, Kimura K, Hirayama A, Matsui K, Ogawa H
Thrombosis and haemostasis 122 ( 9 ) 1584 - 1593 2022.6
Language：English Publishing type：Research paper (scientific journal)
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Impact of statins in patients with vasospastic angina: A multicenter registry study of the Japanese Coronary Spasm Association. Reviewed
Mori H, Takahashi J, Sato K, Miyata S, Takagi Y, Tsunoda R, Sumiyoshi T, Matsui M, Tanabe Y, Sueda S, Momomura SI, Kaikita K, Yasuda S, Ogawa H, Shimokawa H, Suzuki H, Japanese Coronary Spasm Association.
Journal of cardiology 80 ( 3 ) 226 - 231 2022.5
Language：English Publishing type：Research paper (scientific journal)
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Takotsubo cardiomyopathy after vaccination for coronavirus disease 2019 in a patient on maintenance hemodialysis. Reviewed
Toida R, Uezono S, Komatsu H, Toida T, Imamura A, Fujimoto S, Kaikita K
CEN case reports 11 ( 2 ) 220 - 224 2022.5
Authorship：Last author Language：English Publishing type：Research paper (scientific journal)
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Nakanishi N., Kaikita K., Ishii M., Kuyama N., Tabata N., Ito M., Yamanaga K., Fujisue K., Hoshiyama T., Kanazawa H., Hanatani S., Sueta D., Takashio S., Arima Y., Araki S., Usuku H., Nakamura T., Suzuki S., Yamamoto E., Soejima H., Matsushita K., Tsujita K.
Nutrition, Metabolism and Cardiovascular Diseases 32 ( 5 ) 1227 - 1235 2022.5
Authorship：Corresponding author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Nutrition, Metabolism and Cardiovascular Diseases
Background and aims: Although antithrombotic treatments are established for coronary artery disease (CAD), they increase the bleeding risk, especially in malnourished patients. The total thrombus-formation analysis system (T-TAS) is useful for the assessment of thrombogenicity in CAD patients. Here, we examined the relationships among malnutrition, thrombogenicity and 1-year bleeding events in patients undergoing percutaneous coronary intervention (PCI). Methods and results: This was a retrospective analysis of 300 consecutive CAD patients undergoing PCI. Blood samples obtained on the day of PCI were used in the T-TAS to compute the thrombus formation area under the curve. We assigned patients to two groups based on the geriatric nutritional risk index (GNRI): 102 patients to the lower GNRI group (≤98), 198 patients to the higher GNRI group (98<). The primary endpoint was the incidence of 1-year bleeding events defined by Bleeding Academic Research Consortium criteria types 2, 3, or 5. The T-TAS levels were lower in the lower GNRI group than in the higher GNRI group. Kaplan-Meier analysis showed worse 1-year bleeding event-free survival in the lower GNRI group compared with the higher GNRI group. The combined model of the GNRI and the Academic Research Consortium for High Bleeding Risk (ARC-HBR) had good calibration and discrimination for bleeding risk prediction. In addition, having a lower GNRI and ARC-HBR positivity was associated with 1-year bleeding events. Conclusion: A lower GNRI could reflect low thrombogenicity evaluated by the T-TAS and determine bleeding risk in combination with ARC-HBR positivity.
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Increased thrombogenicity is associated with revascularization outcomes in patients with chronic limb-threatening ischemia. Reviewed
Kuyama N, Kaikita K, Ishii M, Mitsuse T, Nakanishi N, Fujisue K, Otsuka Y, Hanatani S, Sueta D, Takashio S, Araki S, Yamamoto E, Matsushita K, Tsujita K
Journal of vascular surgery 76 ( 2 ) 513 - 522 2022.4
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)
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Aberrant Expression of Cardiac Troponin-T in Lung Cancer Tissues in Association With Pathological Severity. Reviewed
Tsuruda T, Sato Y, Tomita M, Tanaka H, Hatakeyama K, Otsu M, Kawano A, Nagatomo K, Yoshikawa N, Ikeda R, Asada Y, Kaikita K
Frontiers in cardiovascular medicine 9 833649 2022.4
Language：English Publishing type：Research paper (scientific journal)
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Kurogi K, Ishii M, Ikebe S, Kaichi R, Mori T, Komaki S, Yamamoto N, Yamanaga K, Arima Y, Yamamoto E, Kaikita K, Matsushita K, Tsujita K
Cardiovascular intervention and therapeutics 37 ( 2 ) 312 - 323 2022.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Cardiovascular Intervention and Therapeutics
Optical coherence tomography (OCT) has a higher resolution than intravascular ultrasound (IVUS) and enables a more precise evaluation of calcium severity. We investigated the impact of the imaging method (OCT versus IVUS) on stent expansion during intravascular imaging-guided percutaneous coronary intervention (PCI) in calcified lesions. In this single-center, retrospective, observational study, 145 lesions with moderate to severe calcification were divided into four groups: 40 IVUS-guided rotational atherectomy (RA), 38 IVUS-guided non-RA, 35 OCT-guided RA, and 32 OCT-guided non-RA. Lesions without pre-procedural intravascular imaging were excluded. OCT-guided RA was associated with greater stent expansion at the target calcium compared with IVUS-guided RA (median 88.0%, interquartile range [78.0–96.0] vs. 76.5% [71.0–84.3], P = 0.008). Furthermore, stent expansion in OCT-guided non-RA was similar to OCT-guided RA. OCT-guided RA used a larger burr compared to IVUS-guided RA (1.75 mm [1.50–2.0] vs. 1.50 mm [1.50–1.75], P = 0.004). In OCT-guided RA, the median minimum calcium thickness was significantly reduced from 800 (640–980) µm to 550 (350–680) µm (P < 0.001). There was no significant difference in the incidence of ischemia driven target lesion revascularization between the four groups (P = 0.37). By determining the indication and endpoint of lesion modification by RA based on the thickness of calcium, OCT-guided PCI was associated with significantly greater stent expansion compared with IVUS-guided PCI.
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Myocardial Tissue Characterization by Combining Extracellular Volume Fraction and T2 Mapping. Reviewed
Kidoh M, Oda S, Nakaura T, Nagayama Y, Funama Y, Takashio S, Kaikita K, Tsujita K, Hirai T
JACC. Cardiovascular imaging 15 ( 4 ) 700 - 704 2022.4
Language：English Publishing type：Research paper (scientific journal) Publisher：JACC: Cardiovascular Imaging
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Stratifying Bleeding Risk and Beyond - Predicting Where Bleeding Will Occur. Reviewed
Moribayashi K, Matsuura Y, Kaikita K
Circulation journal : official journal of the Japanese Circulation Society 86 784 - 786 2022.3
Language：English Publishing type：Research paper (scientific journal)
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Misumi I, Sato K, Nagano M, Korogi W, Usuku H, Kaikita K, Tsujita K
Journal of echocardiography 20 ( 1 ) 59 - 61 2022.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Echocardiography
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The impact of kidney function in patients on antithrombotic therapy: a post hoc subgroup analysis focusing on recurrent bleeding events from the AFIRE trial. Reviewed
Matsui K, Yasuda S, Kaikita K, Akao M, Ako J, Matoba T, Nakamura M, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Ogawa H
BMC medicine 20 ( 1 ) 69 2022.2
Language：English Publishing type：Research paper (scientific journal)
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Increased soluble programed cell death-ligand 1 is associated with acute coronary syndrome. Reviewed
Fujisue K, Yamamoto E, Sueta D, Takae M, Nishihara T, Komorita T, Usuku H, Yamanaga K, Ito M, Hoshiyama T, Kanazawa H, Takashio S, Arima Y, Araki S, Soejima H, Kaikita K, Matsushita K, Tsujita K
International journal of cardiology 349 1 - 6 2022.2
Language：English Publishing type：Research paper (scientific journal)
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Dose-Dependent Inhibitory Effect of Rosuvastatin in Japanese Patients with Acute Myocardial Infarction on Serum Concentration of Matrix Metalloproteinases-INVITATION Trial. Reviewed
Shirakawa T, Fujisue K, Nakamura S, Yamamoto N, Oshima S, Matsumura T, Tsunoda R, Hirai N, Koide S, Tayama S, Kikuta K, Hirose T, Maruyama H, Fujimoto K, Kajiwara I, Sakamoto T, Nakao K, Sakaino N, Nagayoshi Y, Hokamaki J, Shimomura H, Sakamoto K, Yamamoto E, Izumiya Y, Kaikita K, Hokimoto S, Ogawa H, Tsujita K
Journal of atherosclerosis and thrombosis 29 ( 2 ) 229 - 241 2022.2
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Effect of the ALDH2 Variant on the Prevalence of Atrial Fibrillation in Habitual Drinkers. Reviewed
Yamashita T, Arima Y, Hoshiyama T, Tabata N, Sueta D, Kawahara Y, Ito M, Kanazawa H, Ishii M, Yamanaga K, Hanatani S, Takashio S, Araki S, Suzuki S, Yamamoto E, Kaikita K, Oniki K, Saruwatari J, Matsushita K, Tsujita K
JACC. Asia 2 ( 1 ) 62 - 70 2022.2
Language：English Publishing type：Research paper (scientific journal)
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Malnutrition-associated high bleeding risk with low thrombogenicity in patients undergoing percutaneous coronary intervention. Reviewed
Nakanishi N, Kaikita K, Ishii M, Kuyama N, Tabata N, Ito M, Yamanaga K, Fujisue K, Hoshiyama T, Kanazawa H, Hanatani S, Sueta D, Takashio S, Arima Y, Araki S, Usuku H, Nakamura T, Suzuki S, Yamamoto E, Soejima H, Matsushita K, Tsujita K
Nutrition, metabolism, and cardiovascular diseases : NMCD 32 ( 5 ) 1227 - 1235 2022.1
Language：English Publishing type：Research paper (scientific journal)
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Impact of cerebrovascular comorbidity on prognosis in Japanese patients undergoing PCI: 1-year data from Japanese multicenter registry (KICS). Reviewed
Ahmed K, Arima Y, Tabata N, Ishii M, Sato R, Yamashita T, Yamanaga K, Takizawa H, Hokimoto S, Sueta D, Araki S, Fujisue K, Takashio S, Fujimoto K, Shimomura H, Tsunoda R, Hirose T, Sato K, Kikuta K, Sakaino N, Nakamura S, Yamamoto N, Matsumura T, Kajiwara I, Tayama S, Sakamoto T, Nakao K, Oshima S, Yamamoto E, Sakamoto K, Kaikita K, Matsushita K, Tsujita K
Heart and vessels 37 ( 6 ) 911 - 918 2022.1
Language：English Publishing type：Research paper (scientific journal)
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Lotus Root-Like Appearance of a Lipid-Rich Plaque in a Patient With Acute Myocardial Infarction - Findings From Near-Infrared Spectroscopy and Optical Coherence Tomography. Reviewed
Nishihira K, Shibata Y, Kaikita K
Circulation reports 4 ( 1 ) 66 - 67 2022.1
Language：English Publishing type：Research paper (scientific journal)
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Balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension. Reviewed
Hirakawa K, Yamamoto E, Takashio S, Hanatani S, Araki S, Suzuki S, Kaikita K, Matsushita K, Ogo T, Tsujita K
Cardiovascular intervention and therapeutics 37 ( 1 ) 60 - 65 2022.1
Language：English Publishing type：Research paper (scientific journal)
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HFA-PEFF scores: prognostic value in heart failure with preserved left ventricular ejection fraction. Reviewed
Egashira K, Sueta D, Komorita T, Yamamoto E, Usuku H, Tokitsu T, Fujisue K, Nishihara T, Oike F, Takae M, Hanatani S, Takashio S, Ito M, Yamanaga K, Araki S, Soejima H, Kaikita K, Matsushita K, Tsujita K
The Korean journal of internal medicine 37 ( 1 ) 96 - 108 2022.1
Language：English Publishing type：Research paper (scientific journal)
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Development of anti-thrombotic vaccine against human S100A9 in rhesus monkey Reviewed
Shimamura M., Kaikita K., Nakagami H., Kawano T., Ju N., Hayashi H., Nakamaru R., Yoshida S., Sasaki T., Mochizuki H., Tsujita K., Morishita R.
Scientific Reports 11 ( 1 ) 11472 2021.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports
In post-stroke patients, a decreased adherence to antiplatelet drugs is a major challenge in the prevention of recurrent stroke. Previously, we reported an antiplatelet vaccine against S100A9 in mice, but the use of Freund’s adjuvant and the difference in amino acid sequences in epitopes between mice and humans were problematic for clinical use. Here, we redesigned the S100A9 vaccine for the common sequence in both humans and monkeys and examined its effects in cynomolgus monkeys with Alum adjuvant. First, we assessed several candidate epitopes and selected 102 to 112 amino acids as the suitable epitope, which could produce antibodies. When this peptide vaccine was intradermally injected into 4 cynomolgus monkeys with Alum, the antibody against human S100A9 was successfully produced. Anti-thrombotic effects were shown in two monkeys in a mixture of vaccinated serum and fresh whole blood from another cynomolgus monkey. Additionally, the anti-thrombotic effects were partially inhibited by the epitope peptide, indicating the feasibility of neutralizing anti-thrombotic effects of produced antibodies. Prolongation of bleeding time was not observed in vaccinated monkeys. Although further studies on increasing the effect of vaccine and safety are necessary, this vaccine will be a promising approach to improve adherence to antiplatelet drugs in clinical settings.
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Sirt7 Deficiency Attenuates Neointimal Formation Following Vascular Injury by Modulating Vascular Smooth Muscle Cell Proliferation. Reviewed
Kimura Y, Izumiya Y, Araki S, Yamamura S, Hanatani S, Onoue Y, Ishida T, Arima Y, Nakamura T, Yamamoto E, Senokuchi T, Yoshizawa T, Sata M, Kim-Mitsuyama S, Nakagata N, Bober E, Braun T, Kaikita K, Yamagata K, Tsujita K
Circulation journal : official journal of the Japanese Circulation Society 85 ( 12 ) 2232 - 2240 2021.11
Language：English Publishing type：Research paper (scientific journal)
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Associations of cardiovascular risk factors with survival outcomes in a cancer registration: Findings from the KUMAMON registry. Reviewed
Maki Y, Sueta D, Ishii M, Yamanouchi Y, Fujisue K, Yamanaga K, Nakamura T, Tabata N, Arima Y, Araki S, Yamamoto E, Kaikita K, Chikamoto A, Matsushita K, Matsuoka M, Usuku K, Tsujita K
Medicine 100 ( 47 ) e27921 2021.11
Language：English Publishing type：Research paper (scientific journal)
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重症再生不良性貧血を合併した不安定狭心症に対し人工心肺非使用冠動脈バイパス術を施行した1例
廣田貴史, 定永達明, 高木淳, 西川幸作, 吉永隆, 岡本健, 海北幸一, 辻田賢一, 福井寿啓.
心臓 53 ( 11 ) 1213 - 1219 2021.11
Publishing type：Research paper (scientific journal)
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Rivaroxaban Monotherapy in Patients With Atrial Fibrillation After Coronary Stenting: Insights From the AFIRE Trial. Reviewed
Matoba T, Yasuda S, Kaikita K, Akao M, Ako J, Nakamura M, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa H, AFIRE Investigators.
JACC. Cardiovascular interventions 14 ( 21 ) 2330 - 2340 2021.11
Language：English Publishing type：Research paper (scientific journal)
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Aspirin versus P2Y<inf>12</inf>inhibitors with anticoagulation therapy for atrial fibrillation Reviewed
Fukaya H., Ako J., Yasuda S., Kaikita K., Akao M., Matoba T., Nakamra M., Miyauchi K., Hagiwara N., Kimura K., Hirayama A., Matsui K., Ogawa H.
Heart 107 ( 21 ) 1731 - 1738 2021.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Heart
Objective: Patients with coronary artery disease (CAD) and atrial fibrillation (AF) can be treated with multiple antithrombotic therapies including antiplatelet and anticoagulant therapies; however, this has the potential to increase bleeding risk. Here, we aimed to evaluate the efficacy and safety of P2Y12 inhibitors and aspirin in patients also receiving anticoagulant therapy. Methods: We evaluated patients from the Atrial Fibrillation and Ischaemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial who received rivaroxaban plus an antiplatelet agent; the choice of antiplatelet agent was left to the physician's discretion. The primary efficacy and safety end points, consistent with those of the AFIRE trial, were compared between P2Y12 inhibitors and aspirin groups. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularisation or death from any cause. The primary safety end point was major bleeding according to the International Society on Thrombosis and Haemostasis criteria. Results: A total of 1075 patients were included (P2Y12 inhibitor group, n=297; aspirin group, n=778). Approximately 60% of patients were administered proton pump inhibitors (PPIs) and there was no significant difference in PPI use in the groups. There were no significant differences in the primary end points between the groups (efficacy: HR 1.31; 95% CI 0.88 to 1.94; p=0.178; safety: HR 0.79; 95% CI 0.43 to 1.47; p=0.456). Conclusions: There were no significant differences in cardiovascular and bleeding events in patients with AF and stable CAD taking rivaroxaban with P2Y12 inhibitors or aspirin in the chronic phase. Trial registration number: UMIN000016612; NCT02642419.
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Clinical Outcomes of Rivaroxaban Monotherapy in Heart Failure Patients With Atrial Fibrillation and Stable Coronary Disease: Insights From the AFIRE Trial. Reviewed
Yazaki Y, Nakamura M, Iijima R, Yasuda S, Kaikita K, Akao M, Ako J, Matoba T, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa H, AFIRE Investigators.
Circulation 144 ( 17 ) 1449 - 1451 2021.10
Language：English Publishing type：Research paper (scientific journal)
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Ishii M., Seki T., Kaikita K., Sakamoto K., Nakai M., Sumita Y., Nishimura K., Miyamoto Y., Noguchi T., Yasuda S., Kanaoka K., Terasaki S., Saito Y., Tsutsui H., Komuro I., Ogawa H., Tsujita K., Kawakami K.
European Journal of Preventive Cardiology 28 ( 13 ) 1435 - 1444 2021.10
Language：English Publishing type：Research paper (scientific journal) Publisher：European Journal of Preventive Cardiology
Background: Air pollution including particulate matter with an aerodynamic diameter ≤2.5 µm (PM ) increases the risk of acute myocardial infarction. However, whether short-term exposure to PM triggers the onset of myocardial infarction with nonobstructive coronary arteries, compared with myocardial infarction with coronary artery disease, has not been elucidated. This study aimed to estimate the association between short-term exposure to PM and admission for acute myocardial infarction, myocardial infarction with coronary artery disease, and myocardial infarction with nonobstructive coronary arteries. Design: This was a time-stratified case-crossover study and multicenter validation study. Methods: This study used a nationwide administrative database in Japan between April 2012–March 2016. Of 137,678 acute myocardial infarction cases, 123,633 myocardial infarction with coronary artery disease and 14,045 myocardial infarction with nonobstructive coronary arteries were identified by a validated algorithm combined with International Classification of Disease (10th revision), diagnostic, and procedure codes. Air pollutants and meteorological data were obtained from the monitoring station nearest to the admitting hospital. Results: In spring (March–May), the short-term increase of 10 µg/m in PM 2 days before admission was significantly associated with admission for acute myocardial infarction, myocardial infarction with nonobstructive coronary arteries, and myocardial infarction with coronary artery disease after adjustment for meteorological variables (odds ratio 1.060, 95% confidence interval 1.038–1.082; odds ratio 1.151, 1.079–1.227; odds ratio 1.049, 1.026–1.073, respectively), while the association was not significant in other variables. These associations were also observed after adjustment for other co-pollutants. The risk for myocardial infarction with nonobstructive coronary arteries (vs myocardial infarction with coronary artery disease) was associated with an even lower concentration of PM under the current environmental standards. Conclusions: This study showed the seasonal difference of acute myocardial infarction risk attributable to PM and the difference in the threshold of triggering the onset of acute myocardial infarction subtype. 2.5 2.5 2.5 2.5 2.5 2.5 3
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Antithrombotic Therapy for Atrial Fibrillation and Coronary Artery Disease in Patients With Prior Atherothrombotic Disease: A Post Hoc Analysis of the AFIRE Trial. Reviewed
Matsuzawa Y, Kimura K, Yasuda S, Kaikita K, Akao M, Ako J, Matoba T, Nakamura M, Miyauchi K, Hagiwara N, Hirayama A, Matsui K, Ogawa H, AFIRE Investigators.
Journal of the American Heart Association e020907 2021.10
Language：English Publishing type：Research paper (scientific journal)
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Hanatani S., Izumiya Y., Yamamoto M., Araki S., Fujisue K., Arima Y., Takashio S., Yamamoto E., Kaikita K., Matsushita K., Tsujita K.
International Journal of Obesity 45 ( 10 ) 2214 - 2220 2021.10
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Obesity
Background: Although sarcopenic obesity is associated with a higher risk of cardiovascular events compared with obesity without sarcopenia, it is difficult to diagnose sarcopenia in daily clinical settings. Recently, a simple scoring system has been developed to identify sarcopenia patients based on three variables (age, hand grip strength, and calf circumference). However, the utility of this score for cardiovascular risk stratification in patients with abdominal obesity is unknown. Methods: We calculated the sarcopenia score in 262 patients with abdominal obesity, defined as a waist circumference ≥90 cm in women or ≥85 cm in men. The composite endpoint of this study was cardiovascular mortality, nonfatal myocardial infarction, stroke, unstable angina, and heart failure hospitalization. Results: Of the 262 patients, 108 had a high sarcopenia score based on previously established criteria (≥105 in men and ≥120 in women). The patients with a high sarcopenia score had a significantly higher plasma level of B-type natriuretic peptide compared with those with a low sarcopenia score (median 56.7, interquartile range [28.2–142.9] vs. 37.9 [13.8–76.1] pg/mL; p < 0.0001). Kaplan–Meier curves revealed a significantly lower event-free survival rate in those with a high compared with a low sarcopenia score (log-rank test p = 0.001), even after adjustment for confounding factors using propensity score matching (log-rank test p = 0.009). Multivariate Cox proportional hazard analysis identified a high sarcopenia score (hazard ratio: 2.46; 95% confidence interval: 1.31–4.64, p = 0.005) as an independent predictor of the primary endpoints. The combination of a high sarcopenia score and low body mass index (<25 kg/m2) predicted a significantly higher risk of future adverse events (p = 0.005). Furthermore, patients with a high sarcopenia score and high B-type natriuretic peptide level (≥200 pg/mL) had the poorest prognosis (p < 0.0001). Conclusions: This simple screening test for sarcopenia can predict future adverse cardiovascular events in patients with abdominal obesity.
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Takae M., Fujisue K., Yamamoto E., Egashira K., Komorita T., Oike F., Nishihara T., Yamamoto M., Hirakawa K., Tabata N., Tokitsu T., Yamanaga K., Sueta D., Hanatani S., Nakamura T., Usuku H., Araki S., Arima Y., Takashio S., Suzuki S., Kaikita K., Matsushita K., Tsujita K.
ESC Heart Failure 8 ( 5 ) 3809 - 3821 2021.10
Language：English Publishing type：Research paper (scientific journal) Publisher：ESC Heart Failure
Background: Heart failure (HF)-related congestive hepatopathy is a well-recognized problem in management of HF. The fibrosis-4 (FIB4) index calculated by [age × aspartate aminotransferase (IU/L)/platelet count (109/L) × square root of alanine aminotransferase (IU/L)] is useful for evaluating liver stiffness. We aimed to investigate the impact of the FIB4 index on prognosis in patients with HF. Methods and results: Consecutive HF patients referred for hospitalization at Kumamoto University Hospital, Japan, were registered between 2006 and 2015. We observed cardiovascular outcomes in each type of HF [HF with reduced left ventricular ejection fraction (LVEF) (HFrEF), HF with mid-range LVEF (HFmrEF) and with preserved LVEF (HFpEF)] according to their FIB4 index; Group 1 (FIB4 index <1.3), Group 2 (FIB4 index: 1.3–2.67), and Group 3 (FIB4 index >2.67). This study enrolled 83 HFrEF patients, 117 HFmrEF patients, and 504 HFpEF patients. In HFpEF patients, the Kaplan–Meier curve revealed that Group 3 had a significantly higher rate of total cardiovascular events compared with the other two groups. By contrast, the occurrences of total cardiovascular events were not different among three groups in HFrEF and HFmrEF patients. Multivariate Cox proportional hazard analysis with significant factors in univariate analysis identified that the FIB4 index as an independent and significant predictor for future total cardiovascular events in HFpEF patients (hazard ratio: 1.09, 95% confidence interval: 1.03–1.15, P = 0.001). Conclusions: The FIB4 index was a significant predictor for total cardiovascular events in HFpEF.
DOI： 10.1002/ehf2.13351
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Bleeding and Subsequent Cardiovascular Events and Death in Atrial Fibrillation With Stable Coronary Artery Disease: Insights From the AFIRE Trial. Reviewed
Kaikita K, Yasuda S, Akao M, Ako J, Matoba T, Nakamura M, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa H, AFIRE Investigators.
Circulation. Cardiovascular interventions 14 ( 11 ) CIRCINTERVENTIONS120010476 2021.9
Authorship：Lead author, Corresponding author Language：English Publishing type：Research paper (scientific journal)
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Atarashi H., Uchiyama S., Inoue H., Kitazono T., Yamashita T., Shimizu W., Ikeda T., Kamouchi M., Kaikita K., Fukuda K., Origasa H., Shimokawa H.
Heart and Vessels 36 ( 9 ) 1410 - 1420 2021.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Heart and Vessels
The EXPAND Study demonstrated the effectiveness and safety of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF) in routine clinical practice in Japan. This sub-analysis was conducted to reveal the effectiveness and safety of rivaroxaban in Japanese NVAF patients according to baseline creatinine clearance (CrCl) levels and rivaroxaban doses in the EXPAND Study. We examined 6806 patients whose baseline CrCl data were available and classified them into 2 groups: normal renal function group with CrCl ≥ 50 mL/min (n = 5326, 78%) and renal dysfunction group with CrCl < 50 mL/min (n = 1480, 22%). In the normal renal function group, 1609 (30%) received 10 mg/day (under-dose), while in the renal dysfunction group, 108 (7%) received 15 mg/day (over-dose). In the normal renal function group, under-dose of rivaroxaban was associated with higher all-cause mortality, while in the renal dysfunction group, over-dose was associated with higher incidence of major bleeding. In contrast, the incidence of stroke or systemic embolism was not different between the 2 groups regardless of the dose of rivaroxaban. In the propensity score matched analysis to adjust the difference in characteristics according to doses of rivaroxaban, the incidences of clinical outcomes were comparable between the 2 dose groups in both renal function groups. These results indicate that the dose of rivaroxaban should be reduced depending on the renal function, considering the balance between risks of bleeding and ischemia.
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Kanazawa H., Kaikita K., Ito M., Kawahara Y., Hoshiyama T., Kanemaru Y., Kiyama T., Iwashita S., Tabata N., Yamanaga K., Fujisue K., Sueta D., Takashio S., Arima Y., Araki S., Usuku H., Nakamura T., Izumiya Y., Sakamoto K., Suzuki S., Yamamoto E., Soejima H., Matsushita K., Tsujita K.
Journal of the American Heart Association 10 ( 17 ) e021551 2021.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American Heart Association
BACKGROUND: The clinical implication of vascular endothelial dysfunction in patients with atrial fibrillation (AF) remains un-clear. This study aimed to elucidate the correlation between changes in vascular endothelial function assessed by reactive hyperemia-peripheral arterial tonometry and the effect of sinus rhythm restoration after catheter ablation (CA) for AF. METHODS AND RESULTS: Consecutive 214 patients who underwent CA for AF were included in this single center, retrospective study. The natural logarithmic transformed reactive hyperemia-peripheral arterial tonometry index (LnRHI) of all patients was measured before CA as well as 3 and 6 months after CA. LnRHI in sinus rhythm was significantly higher than that in AF before CA. Multivariate logistic regression analysis revealed that the presence of AF was an independent risk factor for lowering of LnRHI (odds ratio, 4.092; P=0.002) before CA. The LnRHI was significantly improved 3 and 6 months after CA in patients without AF recurrence. Multivariate Cox hazard analysis revealed that changes in LnRHI from before to 3 months after CA independently correlated with recurrence of AF (hazard ratio, 0.106; P=0.001). Receiver operating characteristic analysis showed the decrease in LnRHI levels from before to 3 months after CA as a significant marker that suspects AF recurrence (area under the curve, 0.792; log-rank test, P<0.001). CONCLUSIONS: The presence of AF was independently correlated with the impaired vascular endothelial function assessed by the reactive hyperemia-peripheral arterial tonometry. Long-term sinus rhythm restoration after CA for AF might contribute to the improvement of vascular endothelial function, which may reflect the nonrecurrence of AF.
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Validation of the Khorana Venous Thromboembolism Risk Score in Japanese Cancer Patients. Reviewed
Akasaka-Kihara F, Sueta D, Ishii M, Maki Y, Hirakawa K, Tabata N, Ito M, Yamanaga K, Fujisue K, Hoshiyama T, Hanatani S, Kanazawa H, Takashio S, Arima Y, Araki S, Usuku H, Nakamura T, Suzuki S, Yamamoto E, Soejima H, Kaikita K, Matsushita K, Matsuoka M, Usuku K, Tsujita K
JACC. Asia 1 ( 2 ) 259 - 270 2021.9
Language：English Publishing type：Research paper (scientific journal)
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HE4 predicts progressive fibrosis and cardiovascular events in patients with dilated cardiomyopathy Reviewed
Yamamoto M., Hanatani S., Araki S., Izumiya Y., Yamada T., Nakanishi N., Ishida T., Yamamura S., Kimura Y., Arima Y., Nakamura T., Takashio S., Yamamoto E., Sakamoto K., Kaikita K., Matsushita K., Morimoto S., Ito T., Tsujita K.
Journal of the American Heart Association 10 ( 15 ) e021069 2021.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American Heart Association
BACKGROUND: Cardiac fibrosis plays a crucial role in the pathogenesis of dilated cardiomyopathy (DCM). HE4 (human epididymis protein 4) is a secretory protein expressed in activated fibroblasts that exacerbates tissue fibrosis. In the present study, we investigated the clinical utility of HE4 measurement in patients with DCM and its pathophysiological role in preclinical experi-ments in vivo and in vitro. METHODS AND RESULTS: We measured serum HE4 levels of 87 patients with DCM. Endomyocardial biopsy expressed severe fibrosis only in the high HE4 group (P<0.0001). Echocardiography showed that left ventricular end-diastolic diameter tends to decrease over time (58±7.3 to 51±6.6 mm; P<0.0001) in the low HE4 group (<59.65 pmol/L [median value]). HE4 was significantly associated with risk reduction of mortality and cardiovascular hospitalization in multivariate Cox model. In vivo, HE4 was highly expressed in kidney and lung tissue of mouse, and scarcely expressed in heart. In genetically induced DCM mouse model, HE4 expression increased in kidney but not in heart and lung. In vitro, supernatant from HE4-transfected human em-bryonic kidney 293T cells enhanced transdifferentiation of rat neonatal fibroblasts and increased expression of fibrosis-related genes, and this was accompanied by the activation of extracellular signal-regulated kinase signaling in cardiac fibroblasts. Treatment with an inhibitor of upstream signal of extracellular signal-regulated kinase or a neutralizing HE4 antibody canceled the profibrotic properties of HE4. CONCLUSIONS: HE4 functions as a secretory factor, activating cardiac fibroblasts, thereby inducing cardiac interstitial fibrosis. HE4 could be a promising biomarker for assessing ongoing fibrosis and a novel therapeutic target in DCM. REGISTRATION: URL: https://upload.umin.ac.jp/cgi-open-bin/ctr; Unique identifier: UMIN000043062.
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East Asian variant aldehyde dehydrogenase type 2 genotype exacerbates ischemia/reperfusion injury with ST-elevation myocardial infarction in men: possible sex differences. Reviewed
Ishida T, Arima Y, Mizuno Y, Harada E, Yamashita T, Sueta D, Sakamoto K, Suzuki S, Kaikita K, Yamada Y, Shimomura H, Oniki K, Saruwatari J, Hokimoto S, Yasue H, Tsujita K
Heart and vessels 37 ( 2 ) 184 - 193 2021.7
Language：English Publishing type：Research paper (scientific journal)
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Kumamoto Intervention Conference Study (KICS) Investigators. Imaging‑guided PCI for event suppression in Japanese acute coronary syndrome patients: community‑based observational cohort registry Reviewed
Yamashita T, Sakamoto K, Tabata N, Ishii M, Sato R, Nagamatsu S, Motozato K, Yamanaga K, Sueta D, Araki S, Arima Y, Yamamoto E, Takashio S, Fujisue K, Fujimoto K, Shimomura H, Tsunoda R, Maruyama H, Nakamura N, Sakaino N, Nakamura S, Yamamoto N, Matsumura T, Kajiwara I, Tayama S, Sakamoto T, Nakao K, Oshima S, Kaikita K, Hokimoto S, Tsujita K
Cardiovascular Intervention and Therapeutics 36 ( 1 ) 81 - 90 2021.7
Language：English Publishing type：Research paper (scientific journal)
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Akao M., Yasuda S., Kaikita K., Ako J., Matoba T., Nakamura M., Miyauchi K., Hagiwara N., Kimura K., Hirayama A., Matsui K., Ogawa H.
American Heart Journal 236 59 - 68 2021.6
Language：English Publishing type：Research paper (scientific journal) Publisher：American Heart Journal
Background: In the AFIRE trial, rivaroxaban monotherapy was noninferior to combination therapy with rivaroxaban and an antiplatelet agent for thromboembolic events or death, and superior for major bleeding in patients with atrial fibrillation (AF) and stable coronary artery disease. Little is known about impacts of stroke and bleeding risks on the efficacy and safety of rivaroxaban monotherapy. Methods: In this subanalysis of the AFIRE trial, we assessed the risk of stroke and bleeding by the CHADS2, CHA2DS2-VASc, and HAS-BLED scores. The primary efficacy end point was the composite of stroke, systemic embolism, myocardial infarction (MI), unstable angina requiring revascularization, or death from any cause. The primary safety end point was major bleeding defined by the International Society on Thrombosis and Haemostasis. Results: Rivaroxaban monotherapy significantly reduced the primary efficacy and safety end points with no evidence of differential effects by stroke risk (CHADS2, p for interaction = 0.727 for efficacy, 0.395 for safety; CHA2DS2-VASc, p for interaction = 0.740 for efficacy, 0.265 for safety) or bleeding risk (HAS-BLED, p for interaction = 0.581 for efficacy, 0.225 for safety). There was also no evidence of statistical heterogeneity across patient risk categories for other end points; stroke or systemic embolism, ischemic stroke, hemorrhagic stroke, MI, MI or unstable angina, death from any cause, any bleeding, or net adverse clinical events. Conclusions: The advantages of rivaroxaban monotherapy compared with those of combination therapy with respect to all prespecified end points, including thromboembolism, bleeding, and mortality were similar across patients with AF and stable coronary artery disease, irrespective of their risk for stroke and bleeding. Clinical Trial Registration: UMIN Clinical Trials Registry number, UMIN000016612, and ClinicalTrials.gov number, NCT02642419.
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Egashira K., Sueta D., Tomiguchi M., Kidoh M., Oda S., Usuku H., Hidaka K., Goto-Yamaguchi L., Sueta A., Komorita T., Takae M., Oike F., Fujisue K., Yamamoto E., Hanatani S., Takashio S., Arima Y., Araki S., Kaikita K., Matsushita K., Yamamoto Y., Hirai T., Tsujita K.
IJC Heart and Vasculature 34 100797 2021.6
Language：English Publishing type：Research paper (scientific journal) Publisher：IJC Heart and Vasculature
Cardiotoxicity in the late phase after anthracycline drugs administration remains to be defined. Of the 44 patients who received anthracycline treatment, 7 were found to have cancer therapeutics–related cardiac dysfunction (CTRCD). The global longitudinal strain determined by echocardiography and myocardial extracellular volume fraction (ECV) determined by cardiac computed tomography (CCT) of the CTRCD(+) group were significantly higher than those of the control group and CTRCD(-) group, whereas there were no significant differences between the control and CTRCD(-) groups. Our findings indicated that CCT may be a tool comparable to echocardiography, indicating the effective evaluation of CTRCD by CCT.
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A Coronary Artery-Left Ventricular Fistula Through the Sinusoid. Reviewed
Sato K, Misumi I, Nagano M, Arima R, Ehara S, Sakamoto T, Usuku H, Kaikita K, Tsujita K
Internal medicine (Tokyo, Japan) 60 ( 23 ) 3755 - 3758 2021.5
Language：English Publishing type：Research paper (scientific journal) Publisher：一般社団法人 日本内科学会
A 78-year-old woman was referred to our hospital because of repetitive suppurative arthritis at the artificial left knee joint. Her plasma brain natriuretic peptide level was 122 pg/mL. A 12-lead electrocardiogram showed a QS pattern in the inferior leads. A two-dimensional echocardiogram revealed hypokinesis at the inferior wall and hypertrophy at the apical lateral wall. Color flow imaging revealed this hypertrophic region to be a myocardial sinusoid, demonstrating diastolic coronary to left ventricular flow and early systolic flow vice versa. This was a very rare case of coronary to left ventricular fistula through a sinusoid without cyanotic congenital heart disease or severe coronary artery disease.
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Emoto T., Oda S., Kidoh M., Nakaura T., Nagayama Y., Sakabe D., Kakei K., Goto M., Funama Y., Hatemura M., Takashio S., Kaikita K., Tsujita K., Ikeda O.
Academic Radiology 28 ( 5 ) e119 - e126 2021.5
Language：English Publishing type：Research paper (scientific journal) Publisher：Academic Radiology
Rationale and Objectives: To clarify the accuracy of two measurement methods for myocardial extracellular volume (ECV) quantification (ie, the standard subtraction method [ECV ] and the dual-energy iodine method [ECV ]) with the use of cardiac CT in comparison to cardiac magnetic resonance imaging (CMR) as a reference standard. Materials and Methods: Equilibrium phase cardiac images of 21 patients were acquired with a dual-layer spectral detector CT and CMR, and the images were retrospectively analyzed. CT-ECV was calculated using ECV and ECV . The correlation between the ECV values measured by each method was assessed. Bland-Altman analysis was used to identify systematic errors and to determine the limits of agreement between the CT-ECV and CMR-ECV values. Root mean squared errors and residual values for the ECV and ECV were also assessed. Results: The correlations between ECV and ECV for both septal and global measurement were r = 0.95 (p < 0.01) and 0.91 (p < 0.01), respectively, while those between the mean ECV and CMR-ECV were r = 0.90 (septal, p < 0.01) and 0.84 (global, p < 0.01), and those between ECV and CMR-ECV were r = 0.94 (septal, p < 0.01) and 0.95 (global, p < 0.01). Bland-Altman plots showed lower 95% limits of agreement between ECV and CMR-ECV compared with that between ECV and CMR-ECV in both septal and global measurement. The root mean squared error of ECV was higher than that of ECV . The mean residual value of ECV was significantly higher than that of ECV . Conclusion: ECV yielded more accurate myocardial ECV quantification than ECV , and provided a comparable ECV value to that obtained by CMR. sub iodine sub iodine sub iodine sub iodine sub iodine iodine sub sub iodine sub iodine iodine sub
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Significance of Blood Test During Antithrombotic Therapy Reviewed
45 ( 5 ) 273 - 279 2021.5
Authorship：Lead author Language：Japanese Publishing type：Research paper (scientific journal)
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抗血栓療法時の検査法の意義.
海北幸一, 辻田賢一.
ICUとCCU 集中治療医学 45 ( 5 ) 273 - 279 2021.5
Authorship：Lead author Publishing type：Research paper (scientific journal)
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JCS 2018 Guideline on Diagnosis of Chronic Coronary Heart Diseases. Reviewed
Yamagishi M, Tamaki N, Akasaka T, Ikeda T, Ueshima K, Uemura S, Otsuji Y, Kihara Y, Kimura K, Kimura T, Kusama Y, Kumita S, Sakuma H, Jinzaki M, Daida H, Takeishi Y, Tada H, Chikamori T, Tsujita K, Teraoka K, Nakajima K, Nakata T, Nakatani S, Nogami A, Node K, Nohara A, Hirayama A, Funabashi N, Miura M, Mochizuki T, Yokoi H, Yoshioka K, Watanabe M, Asanuma T, Ishikawa Y, Ohara T, Kaikita K, Kasai T, Kato E, Kamiyama H, Kawashiri M, Kiso K, Kitagawa K, Kido T, Kinoshita T, Kiriyama T, Kume T, Kurata A, Kurisu S, Kosuge M, Kodani E, Sato A, Shiono Y, Shiomi H, Taki J, Takeuchi M, Tanaka A, Tanaka N, Tanaka R, Nakahashi T, Nakahara T, Nomura A, Hashimoto A, Hayashi K, Higashi M, Hiro T, Fukamachi D, Matsuo H, Matsumoto N, Miyauchi K, Miyagawa M, Yamada Y, Yoshinaga K, Wada H, Watanabe T, Ozaki Y, Kohsaka S, Shimizu W, Yasuda S, Yoshino H, Japanese Circulation Society Working Group.
Circulation journal : official journal of the Japanese Circulation Society 85 ( 4 ) 402 - 572 2021.3
Language：English Publishing type：Research paper (scientific journal)
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Nakanishi N., Kaikita K., Ishii M., Kuyama N., Tabata N., Ito M., Yamanaga K., Fujisue K., Hoshiyama T., Kanazawa H., Hanatani S., Sueta D., Takashio S., Arima Y., Araki S., Usuku H., Nakamura T., Suzuki S., Yamamoto E., Soejima H., Matsushita K., Tsujita K.
International Journal of Cardiology 325 121 - 126 2021.2
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background: Antithrombotic therapy is established for the treatment of various cardiovascular events. However, it has been shown to increase the bleeding risk. Total Thrombus-formation Analysis System (T-TAS) is reported to be useful for evaluating thrombogenicity. Here, we estimated whether T-TAS is useful for predicting bleeding events risk in patients undergoing percutaneous coronary intervention (PCI). Methods: This was a retrospective, observational study at Kumamoto University Hospital between April 2017 and March 2019. Blood samples obtained on the day of PCI were used in T-TAS to compute the thrombus formation area under the curve (AUC) (AR -AUC , AUC for AR chip). We divided the study population into 2 groups according to the Academic Research Consortium for High Bleeding Risk (ARC-HBR) (182 patients in ARC-HBR positive, 118 in ARC-HBR negative). The primary endpoint was 1-year bleeding events that were defined by Bleeding Academic Research Consortium type2, 3, or 5. Results: The AR -AUC levels were significantly lower in the ARC-HBR positive group than in the ARC-HBR negative group (median [interquartile range] 1571.4 [1277.0–1745.3] vs. 1726.2 [1567.7–1799.6], p < 0.001). The combination of ARC-HBR and AR -AUC could discriminate the bleeding risk, and improved predictive capacity compared with ARC-HBR by c-statistics. Decision-curve analysis also revealed that combining AR -AUC with ARC-HBR ameliorated bleeding risk-prediction. In multivariate Cox hazards analyses, combining ARC-HBR with lower AR -AUC levels was significantly associated with 1-year bleeding events. Conclusions: The results highlight that AR -AUC evaluated by T-TAS could be a potentially useful marker for predicting high bleeding risk in patients undergoing PCI. 10 30 10 30 10 30 10 30 10 30 10 30
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Fujisue K., Yamanaga K., Nagamatsu S., Shimomura H., Yamashita T., Nakao K., Nakamura S., Ishihara M., Matsui K., Sakaino N., Miyazaki T., Yamamoto N., Koide S., Matsumura T., Fujimoto K., Tsunoda R., Morikami Y., Matsuyama K., Oshima S., Sakamoto K., Izumiya Y., Kaikita K., Hokimoto S., Ogawa H., Tsujita K.
Journal of Atherosclerosis and Thrombosis 28 ( 2 ) 181 - 193 2021.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Atherosclerosis and Thrombosis
Aim: Coronary plaque regression is weak in acute coronary syndrome (ACS) patients with diabetes mellitus (DM). We evaluated whether dual lipid-lowering therapy (DLLT) with ezetimibe and atorvastatin attenuates coronary plaques in ACS patients with DM. Methods: The prospective, randomized controlled, multicenter PRECISE-IVUS (Plaque Regression with Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound) trial assigned 246 patients undergoing percutaneous coronary intervention to DLLT or atorvastatin monotherapy and evaluated IVUS-derived changes in percent atheroma volume (ΔPAV), at baseline and 9–12-month follow-up, in 126 ACS cases, including 25 DM patients. The atorvastatin dose was up-titrated to achieve low-density lipoprotein cholesterol (LDL-C) ＜70 mg/dL. Results: In DM patients, the monotherapy group (n=13) and the DLLT group (n=12) showed a similar preva-lence of coronary risks and baseline lipid profiles. During the study, the change in LDL-C level was similar between DM and non-DM patients. Compared with non-DM patients, DM patients showed weaker regression of ΔPAV by DLLT than those who underwent monotherapy (DM: −2.77±3.47% vs. −0.77±2.51%, P=0.11; non-DM: −2.01±3.36% vs. −0.08±2.66%, P=0.008). The change in LDL-C level was not correlated with Δ PAV in non-DM patients, but there was significant correlation between the change in LDL-C level and ΔPAV in DM patients (r=0.52, P=0.008). Conclusions: ACS patients with DM showed weaker coronary plaque regression than their counterparts. A significant correlation between the change in LDL-C level and ΔPAV in DM patients suggested that more intensive lipid-lowering therapy is required in ACS patients with DM.
DOI： 10.5551/jat.54726
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Temporal trends in coronary intervention strategies and the impact on one-year clinical events: data from a Japanese multi-center real-world cohort study. Reviewed
Sakamoto K, Sato R, Tabata N, Ishii M, Yamashita T, Nagamatsu S, Motozato K, Yamanaga K, Hokimoto S, Sueta D, Araki S, Fujisue K, Arima Y, Takashio S, Fujimoto K, Shimomura H, Tsunoda R, Hirose T, Sato K, Kikuta K, Sakaino N, Nakamura S, Yamamoto N, Matsumura T, Kajiwara I, Tayama S, Sakamoto T, Nakao K, Oshima S, Yamamoto E, Kaikita K, Tsujita K, Kumamoto Intervention Conference Study (KICS) Investigators.
Cardiovascular intervention and therapeutics 37 ( 1 ) 66 - 77 2021.1
Language：English Publishing type：Research paper (scientific journal)
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特集 抗血小板･抗凝固薬投与の問題は解決した? 診る4 抗血栓療法の効果はどこまで評価できるか?
海北幸一, 辻田賢一.
Heart View 25 ( 1 ) 26 - 31 2021.1
Authorship：Lead author Publishing type：Research paper (scientific journal)
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Nishihara T., Tokitsu T., Sueta D., Oike F., Takae M., Fujisue K., Usuku H., Ito M., Kanazawa H., Araki S., Arima Y., Takashio S., Nakamura T., Sakamoto K., Suzuki S., Kaikita K., Yamamoto E., Tsujita K.
Journal of Cardiac Failure 27 ( 1 ) 57 - 66 2021.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiac Failure
Background: We investigated the clinical significance of the derivative of reactive oxygen metabolites (DROM), a new marker of reactive oxygen species (ROS), in patients with heart failure (HF) with reduced left ventricular ejection fraction (LVEF) (HFrEF). Methods and Results: Serum DROM concentrations were measured in 201 consecutive patients with HFrEF (EF < 50%) in stable condition. DROM values were significantly higher in patients with HFrEF than in risk-matched patients without HF (P < 0.01). They also correlated significantly with high-sensitivity C-reactive protein and B-type natriuretic peptide. Kaplan-Meier analysis demonstrated significantly higher probabilities of HF-related events in the high-DROM group than in the low-DROM group (log-rank test, P < 0.01). Multivariable Cox hazard analysis revealed that DROM were independent and significant predictors of cardiovascular events. In a subgroup analysis, DROM levels were also measured at the aortic root and coronary sinus in 49 patients. The transcardiac gradient of DROM values was significantly higher in patients with HFrEF than in patients without HF (P = 0.04), indicating an association between DROM production in the coronary circulation and HFrEF development. Changes in DROM following optimal therapy were significantly associated with LVEF improvement (r = 0.34, P = 0.04). Conclusions: The higher levels of DROM and their association with cardiovascular events suggest the clinical benefit of DROM measurements in the risk stratification of patients with HFrEF.
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To what extent can the effect of antithrombotic therapy be evaluated? Reviewed
Heart view 25 ( 1 ) 26 - 31 2021.1
Authorship：Lead author, Corresponding author Language：Japanese Publishing type：Research paper (scientific journal)
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Misumi I., Sato K., Nagano M., Yamada Y., Urata J., Kaikita K., Tsujita K.
Journal of Echocardiography 19 266 - 268 2021
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Echocardiography
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Left ventricular apical thrombus mimicking hypertrabeculation.
Misumi I, Sato K, Nagano M, Obata M, Urata J, Usuku H, Kaikita K, Tsujita K.
Intern Med 60 2245 - 2250 2021
Language：English Publishing type：Research paper (scientific journal)
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Morikawa K., Takashio S., Sato R., Yamamoto E., Kaikita K., Tsujita K., Komohara Y.
Internal Medicine 59 ( 24 ) 3171 - 3175 2020.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Internal Medicine
We herein report the histological findings of a patient who had progressed to persistent cardiac arrest for 25 days due to lymphocytic fulminant myocarditis despite mechanical circulatory support (MCS). There were few residual cardiomyocytes, and extensive replacement fibrosis was present. Therefore, improvement of the cardiac function for this patient was considered improbable. Further research is warranted to improve predictions for the recovery of the cardiac function and optimize MCS strategies for patients with fulminant myocarditis.
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Association of short term exposure to Asian dust with increased blood pressure Reviewed
Ishii M., Seki T., Sakamoto K., Kaikita K., Miyamoto Y., Tsujita K., Masuda I., Kawakami K.
Scientific Reports 10 ( 1 ) 17630 2020.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports
Air pollution causes hypertension, cardiovascular disease, and mortality. Asian dust (AD) reportedly induces asthma or acute myocardial infarction along with air pollution, but its impact on blood pressure (BP) is unknown. We investigated the association between short-term AD exposure and BP fluctuations in 300,952 individuals whose BP was measured during April 2005–March 2015 and divided them into AD and non-AD groups based on visitation for AD-related events. AD’s occurrence, air pollutants’ concentration (suspended particulate matter, SO , NO , photochemical oxidants), and meteorological variables (mean ambient temperature, relative humidity) were obtained from a monitoring station; AD events correlated with decreased visibility (< 10 km). We observed 61 AD days, with 3897 participants undergoing medical check-ups. Short-term AD exposure at lag day-0 was significantly associated with higher systolic BP (SBP), diastolic BP (DBP), and pulse rate (PR) risk (β = 1.85, 95% confidence interval (CI) 1.35–2.35 for SBP, β = 2.24, 95% CI 1.88–2.61 for DBP, β = 0.52, 95% CI 0.14–0.91 for PR) using multi-pollutant model. Population-attributable fractions exposed to AD were 11.5% for those with elevated SBP (SBP ≥ 120 mmHg) and 23.7% for those with hypertension (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg). This study showed a strong association between short-term AD exposure and increased SBP and DBP. 2 2
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Questionnaire in patients with aborted sudden cardiac death due to coronary spasm in Japan Reviewed
Sueda S., Shinohara T., Takahashi N., Shite J., Shoji T., Akao M., Kijima Y., Masuyama T., Miyaji T., Yamamoto K., Iwasaki Y., Yoshida R., Nakamura S., Ogino Y., Kimura K., Sasai M., Suzuki H., Wakatsuki T., Asajima H., Teragawa H., Ishikawa T., Kitamura K., Oda T., Nakayama T., Kobayashi Y., Sunada D., Yamaki M., Nishizaki F., Tomita Y., Usuda K., Fujinaga H., Kuramitsu S., Andou K., Kiyooka T., Kadota K., Ishii Y., Ohtani H., Maekawa Y., Taguchi E., Nakao K., Kobayashi N., Seino Y., Nakagawa H., Saito Y., Komuro I., Sasaki Y., Ikeda S., Yamaguchi O., Kakutani A., Imanaka T., Ishihara M., Ishii M., Kaikita K., Tsujita K.
Heart and Vessels 35 ( 12 ) 1640 - 1649 2020.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Heart and Vessels
Objectives: We investigated the medical or mechanical therapy, and the present knowledge of Japanese cardiologists about aborted sudden cardiac death (ASCD) due to coronary spasm. Methods: A questionnaire was developed regarding the number of cases of ASCD, implantable cardioverter–defibrillator (ICD), and medical therapy in ASCD patients due to coronary spasm. The questionnaire was sent to the Japanese general institutions at random in 204 cardiology hospitals. Results: The completed surveys were returned from 34 hospitals, giving a response rate of 16.7%. All SCD during the 5 years was observed in 5726 patients. SCD possibly due to coronary spasm was found in 808 patients (14.0%) and ASCD due to coronary spasm was observed in 169 patients (20.9%). In 169 patients with ASCD due to coronary spasm, one or two coronary vasodilators was administered in two-thirds of patients [113 patients (66.9%)], while more than 3 coronary vasodilators were found in 56 patients (33.1%). ICD was implanted in 117 patients with ASCD due to coronary spasm among these periods including 35 cases with subcutaneous ICD. Majority of cause of ASCD was ventricular fibrillation, whereas pulseless electrical activity was observed in 18 patients and complete atrioventricular block was recognized in 7 patients. Mean coronary vasodilator number in ASCD patients with ICD was significantly lower than that in those without ICD (2.1 ± 0.9 vs. 2.6 ± 1.0, p < 0.001). Although 16 institutions thought that the spasm provocation tests under the medications had some clinical usefulness of suppressing the next fatal arrhythmias, spasm provocation tests under the medication were performed in just 4 institutions. Conclusions: In the real world, there was no fundamental strategy for patients with ASCD due to coronary spasm. Each institution has each strategy for these patients. Cardiologists should have the same strategy and the same knowledge about ASCD patients due to coronary spasm in the future.
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アスピリンの適応と動向
海北幸一, 辻田賢一.
循環器内科 88 ( 6 ) 594 - 598 2020.12
Authorship：Lead author Publishing type：Research paper (scientific journal)
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Usuku H, Yamamoto E, Nishi M, Komorita T, Takae M, Nishihara T, Oike F, Ishii M, Fujisue K, Sueta D, Araki S, Takashio S, Oda S, Misumi Y, Ueda M, Nakamura T, Kawano H, Soejima H, Sakamoto K, Kaikita K, Ando Y, Matsui H, Tsujita K
Circulation reports 2 ( 12 ) 730 - 738 2020.11
Language：English Publishing type：Research paper (scientific journal) Publisher：一般社団法人 日本循環器学会
<b><i>Background:</i></b>Using transthoracic echocardiography, including 2D speckle tracking imaging (STI), this study examined cardiac function after domino liver transplantation (DLT) with liver grafts explanted from patients with hereditary amyloidogenic transthyretin amyloidosis.<b><i>Methods and Results:</i></b>In all, 14 patients who underwent DLT at Kumamoto University Hospital and for whom 2D STI information was available were enrolled in the study; time-dependent echocardiographic changes were evaluated in 7. Although left ventricular (LV) systolic and diastolic function did not differ between the pre- and post-DLT periods (mean [±SD] 5.4±1.0 years after DLT), there were significant (P<0.05 for all) increases in the post- vs. pre-DLT period in basal longitudinal strain (LS; −13.4±2.3 vs. −19.3±4.4), relative apical LS index (=apical LS/[basal LS+mid LS]; 0.75±0.20 vs. 0.58±0.08), and LV ejection fraction/global LS (3.91±0.58 vs. 3.06±0.44). Age at the time of DLT was significantly higher in the group with impaired (>−14%) than preserved basal LS (57.2±3.5 vs. 39.6±16.0 years; P<0.05). When control subjects (n=14) were added to the enrolled DLT recipients, multivariable logistic regression analysis revealed that a history of DLT was significantly associated with impaired basal LS (>−14%; odds ratio 28.39, 95% confidence interval 1.89–427.45, P<0.05).<b><i>Conclusions:</i></b>LV systolic and diastolic function was preserved in the long term after DLT. However, 2D STI revealed subtle cardiac dysfunction in DLT recipients, which may be an early manifestation of cardiac amyloidosis.
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Usuku H., Takashio S., Yamamoto E., Kinoshita Y., Nishi M., Oike F., Marume K., Hirakawa K., Tabata N., Oda S., Misumi Y., Ueda M., Kawano H., Kaikita K., Matsushita K., Ando Y., Matsui H., Tsujita K.
Echocardiography 37 ( 11 ) 1774 - 1783 2020.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Echocardiography
Background: We previously reported that a high score (2 or 3 points) according to the Kumamoto criteria, a combination of high-sensitivity cardiac troponin T (hs-cTnT) ≥0.308 ng/mL, the length of QRS ≥ 120 ms in electrocardiogram, and left ventricular (LV) posterior wall thickness ≥ 13.6 mm, increases the pretest probability of Tc-labeled pyrophosphate ( Tc-PYP) scintigraphy in patients with suspected transthyretin amyloid cardiomyopathy (ATTR-CM). However, some patients with a low score (0 or 1 point) show positive findings on Tc-PYP scintigraphy. Therefore, we evaluated the usefulness of additional examinations, including echocardiographic assessment of myocardial strain, to raise the pretest probability of Tc-PYP scintigraphy for these patients. Methods and Results: We examined 109 consecutive patients aged ≥70 years with low scores according to the Kumamoto criteria who underwent Tc-PYP scintigraphy. Nineteen patients (17%) had positive Tc-PYP scintigraphy findings. The relative apical longitudinal strain (LS) index (apical LS/ basal LS + mid LS) (RapLSI) was significantly higher in patients with positive than negative Tc-PYP scintigraphy findings (1.04 ± 0.37 vs 0.70 ± 0.28, P <.01). Multivariable logistic regression analysis revealed that a high RapLSI (≥1.04) was significantly associated with Tc-PYP positivity (odds ratio, 14.14; 95% confidence interval, 3.36-59.47; P <.01). The sensitivity, specificity, and accuracy of the diagnostic model using the RapLSI for identification of Tc-PYP positivity were 53%, 94%, and 87%, respectively. Conclusions: A high RapLSI can raise the pretest probability of Tc-PYP scintigraphy in patients with a low score according to the Kumamoto criteria. The RapLSI can assist clinicians in determining strategies for these patients. 99m 99m 99m 99m 99m 99m 99m 99m 99m 99m
DOI： 10.1111/echo.14892
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Late-gadolinium enhancement in a subject with normal left ventricular function Reviewed
Misumi I., Sato K., Nagano M., Urata J., Usuku H., Kaikita K., Tsujita K.
Radiology Case Reports 15 ( 11 ) 2464 - 2470 2020.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Radiology Case Reports
A 27-year-old man visited our hospital after experiencing palpitations. His 12-lead electrocardiogram and chest radiograph were unremarkable. Blood test results showed normal plasma brain natriuretic peptide level (<5.8 pg/mL). Transthoracic echocardiography revealed normal left ventricular structure and function by demonstrating left ventricular wall thickness of 10 mm, end-diastolic dimension of 46 mm, end-systolic dimension of 31 mm, and ejection fraction of 64%. Pulsed-wave Doppler echocardiography demonstrated normal E/e’ ratio of 7.5. Cardiac magnetic resonance imaging showed normal coronary artery. However, there was massive late-gadolinium enhancement at the mid-layer wall, suggesting massive left ventricular fibrosis. This case reveals that left ventricular function may be normal even in massive late-gadolinium enhancement. Pathophysiology other than fibrosis might have contributed to this specific finding in late-gadolinium enhancement.
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Assessment of diffuse ventricular fibrosis in atrial fibrillation using cardiac CT-derived myocardial extracellular volume fraction Reviewed
Kidoh M, Oda S, Takashio S, Kanazawa H, Ikebe S, Emoto T, Nakaura T, Nagayama Y, Sasao A, Inoue T, Funama Y, Araki S, Yamamoto E, Kaikita K, Tsujita K, Ikeda O
JACC Clin Electrophysiol 6 ( 12 ) 1573 - 1575 2020.11
Language：English Publishing type：Research paper (scientific journal)
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Yamada T., Takashio S., Arima Y., Nishi M., Morioka M., Hirakawa K., Hanatani S., Fujisue K., Yamanaga K., Kanazawa H., Sueta D., Araki S., Usuku H., Nakamura T., Suzuki S., Yamamoto E., Ueda M., Kaikita K., Tsujita K.
ESC Heart Failure 7 ( 5 ) 2829 - 2837 2020.10
Language：English Publishing type：Research paper (scientific journal) Publisher：ESC Heart Failure
Aims: The focus on wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is increasing because of novel treatment options. There is currently no report on a large number of Japanese patients with ATTRwt-CM. The study aimed to examine the characteristics and prognosis of ATTRwt-CM in Japan. Methods and results: Consecutive patients (78.5 ± 6.4 years old at diagnosis) with ATTRwt-CM diagnosed at Kumamoto University Hospital between December 2002 and December 2019 were retrospectively reviewed. Data, including demographic characteristics, co-morbidities, clinical manifestations at diagnosis, laboratory results, electrocardiographic and echocardiographic data, imaging and pathological findings, and treatment were obtained. Of 129 patients included in this study, 110 patients (85%) were male. The median period from initial symptom onset to diagnosis was 15.5 (2–75) months. Heart failure was the most common clinical manifestation leading to diagnosis (61%) and initial manifestations (49%). Of 106 patients, carpal tunnel syndrome was observed in 57 patients (54%), and the median period from initial symptom onset to diagnosis was 96 (48–120) months. Histopathological confirmation of transthyretin amyloid was achieved in 94 patients (73%), including 66 (51%) and 28 cases (22%) with endomyocardial and extracardiac biopsies. During the observation period (median 15.0 [inter-quartile range, 5.4–33.2] months after diagnosis), 34 patients (26%) died. Of these, 27 patients (79%) had cardiovascular deaths (heart failure, 25; sudden death, two). The median survival duration was 58.9 months and the 5 years' survival rate was 48%. According to a multivariate Cox hazard analysis, age [hazard ratio (HR), 1.14; 95% confidence interval (CI), 1.05–1.23, P = 0.002] and low serum sodium levels (HR, 0.89; 95% CI, 0.79–0.996; P = 0.04) contributed to all-cause mortality, and low serum sodium levels contributed to hospitalization for heart failure (HR, 0.86; 95% CI, 0.77–0.96; P = 0.005). Conclusions: Clinical characteristics and prognosis of ATTRwt-CM patients in Japan were examined. Carpal tunnel syndrome can be considered an indication for diagnosis of ATTRwt-CM. Age and low serum sodium level were significant predictive factors of all survival outcomes. The clinical features of ATTRwt-CM should be recognized to provide appropriate treatment.
DOI： 10.1002/ehf2.12884
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Takashio S., Kaikita K., Nishi M., Morioka M., Higo T., Shiose A., Doman T., Horiuchi H., Fukui T., Tsujita K.
ESC Heart Failure 7 ( 5 ) 3235 - 3239 2020.10
Language：English Publishing type：Research paper (scientific journal) Publisher：ESC Heart Failure
Aims: Bleeding is a serious complication in patients with continuous-flow left ventricular assist device (CF-LVAD). Acquired von Willebrand syndrome (AVWS; type 2A) develops because of high shear stress inside the pumps and is a cause of bleeding complication. Although von Willebrand factor (vWF) multimer analysis is useful for diagnosing AVWS, it is only performed in specialized research institutes. A novel microchip flow chamber system, the total thrombus-formation analysis system (T-TAS), is a point-of-care system to evaluate the thrombus-formation process and useful for monitoring platelet thrombus-formation capacity in patients receiving antiplatelet therapy and the diagnosis and evaluation of the clinical severity of von Willebrand disease type 1. However, little is known about the association between AVWS and platelet thrombus-formation capacity evaluated by T-TAS in patients with CF-LVAD. We aimed to evaluate the utility of T-TAS for easy detection of AVWS in patients with CF-LVAD. Methods and results: We simultaneously evaluated the vWF large multimers and T-TAS parameters in four consecutive patients with axial-type CF-LVAD and eight control patients treated with aspirin and warfarin. vWF large multimer index was defined as the proportion of large multimers in total vWF derived from a normal control plasma. T-TAS analyses different thrombus-formation processes using two microchips with different thrombogenic surfaces. PL -AUC levels in the platelet (PL) chip are highly sensitive for platelet functions, while AR -AUC levels in the atheroma (AR) chip allow the assessment of the overall haemostatic ability. vWF large multimer index and T-TAS parameters were decreased in all patients with CF-LVAD. The mean PL -AUC level (5.4 ± 2.9 vs. 219 ± 67; P < 0.01), AR -AUC level (338 ± 460 vs. 1604 ± 160; P < 0.01) and vWF large multimer index (49 ± 11% vs. 112 ± 27%; P < 0.01) were significantly lower in the patients with CF-LVAD than in control patients. One patient showed changes in T-TAS levels before and after implantation of CF-LVAD. PL -AUC and AR -AUC levels decreased from 438.1 to 5.0 and from 1667.9 to 1134.3, respectively. Conclusions: In patients with CF-LVAD, the platelet thrombus-formation capacity was extremely impaired because of AVWS, and T-TAS parameters could detect the presence of AVWS. T-TAS can be used for easy detection of AVWS as a point-of-care testing. Further studies with a large sample size are needed to validate our results in several LVAD models and evaluate the prognostic value of bleeding complications and thromboembolism in patients with LVAD. 24 10 10 30 24 10 10 30 24 10 10 30
DOI： 10.1002/ehf2.12824
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Oike F., Yamamoto E., Sueta D., Tokitsu T., Usuku H., Nishihara T., Takae M., Fujisue K., Arima Y., Kanazawa H., Ito M., Hanatani S., Araki S., Takashio S., Sakamoto K., Suzuki S., Kawano H., Soejima H., Kaikita K., Tsujita K.
International Journal of Cardiology 316 145 - 151 2020.10
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Objectives: Because diastolic late mitral annular velocity (a') obtained by transthoracic-echocardiography (TTE) represents left atrial (LA) function, we investigated the clinical significance of a' in heart failure (HF) with a preserved left ventricular (LV) ejection fraction (HFpEF). Methods: We enrolled 448 consecutive HFpEF patients (sinus rhythm: 66.3%, atrial fibrillation [AF] rhythm: 33.7%) and performed TTE under stable conditions after optimal therapy. In patients with sinus rhythm, a' values were measured at septal mitral annuli. Results: A' had weak but significant negative correlations with the natural-logarithm-B-type natriuretic peptide (Ln-BNP), LA diameter, LV mass index and tricuspid regurgitation pressure gradient. Receiver operating characteristic (ROC) curve analysis showed that the best cut-off value of a' and systolic mitral annular velocity (s') for the prediction of HF-related events were 7.45 cm/s and 6.5 cm/s with areas under the curve (AUC) of 0.841 and 0.682, respectively. The AUC of ROC analysis for the logistic regression model of a' plus s' was improved to 0.97. In Kaplan-Meier analysis, HFpEF patients with low-a' (<7.45 cm/s) had a significantly higher risk of total cardiovascular and HF-related events (both p < .01 by log-rank test) than those with high-a' (≥ 7.45 cm/s) and were prognostically equivalent to those with AF. Multivariate Cox proportional hazard analysis identified low-a' as an independent predictor of both total cardiovascular (hazard ratio [HR]: 0.823, 95% confidence interval [CI]: 0.714–0.949, p = .007) and HF-related events (HR: 0.551, 95% CI: 0.422–0.720, p < .001). Conclusion: A' value measurement is a non-invasive and useful method for risk stratification in HFpEF.
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Left-dominant arrhythmogenic cardiomyopathy with a nonsense mutation in DSP Reviewed
Tsuruta Y., Sueta D., Takashio S., Oda S., Sakamoto K., Kaikita K., Kato K., Ohno S., Horie M., Tsujita K.
ESC Heart Failure 7 ( 5 ) 3174 - 3178 2020.10
Language：English Publishing type：Research paper (scientific journal) Publisher：ESC Heart Failure
A 74-year-old man had abnormal left ventricular (LV) function according to a perioperative test at a local hospital and was transferred to our institution for further evaluation and treatment. His electrocardiogram demonstrated the presence of premature ventricular contraction with a QRS complex of the right bundle branch block type and superior axis. His echocardiography showed systolic dysfunction of the LV (LV ejection fraction, 44.6%). Cardiac computed tomography imaging revealed banded and patchy densities observed frequently from the middle to epicardial layer of the LV wall. Cardiac magnetic resonance imaging showed fat signals on fat-selective images and late gadolinium enhancement in the mid-wall to subepicardial layers in the LV myocardium. Endomyocardial biopsy revealed the histological presence of fibrofatty replacement. A genetic analysis revealed a nonsense mutation in the desmoplakin gene. Thus, he was diagnosed with left-dominant arrhythmogenic cardiomyopathy. To prevent fatal ventricular arrhythmias, an implantable cardioverter defibrillator was successfully implanted.
DOI： 10.1002/ehf2.12790
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A case of severe pulmonary thromboembolism in mycoplasma infection during early pregnancy Reviewed
Ohno M., Yamada T., Otsuka Y., Nakashima N., Matsubara J., Matsukawa M., Sueta D., Arima Y., Yamamoto E., Tamaya S., Kaikita K., Fujimoto K., Tsujita K.
Journal of Cardiology Cases 22 ( 3 ) 140 - 142 2020.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology Cases
Mycoplasma infection and pregnancy are both characterized by thrombogenesis. A 38-year-old pregnant woman was admitted to a general hospital for mycoplasma pneumonia treatment. She experienced sudden dyspnea and fell into cardiopulmonary arrest. Emergent pulmonary arteriography revealed contrast deficits in the bilateral pulmonary arteries, and she was diagnosed with pulmonary thromboembolism (PTE). Reperfusion treatment and hemodynamic support were initiated. This is a rare case report of PTE attributed to mycoplasma infection during pregnancy. <Learning objective: Since mycoplasma infection has been reported to be a fatal extrapulmonary finding associated with pulmonary thromboembolism (PTE), if sudden respiratory failure occurs during the clinical course, PTE should be investigated, and pregnant women should be especially careful.>
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Komorita T., Yamamoto E., Sueta D., Tokitsu T., Fujisue K., Usuku H., Nishihara T., Oike F., Takae M., Egashira K., Takashio S., Ito M., Yamanaga K., Arima Y., Sakamoto K., Suzuki S., Kaikita K., Tsujita K.
IJC Heart and Vasculature 29 100563 2020.8
Language：English Publishing type：Research paper (scientific journal) Publisher：IJC Heart and Vasculature
Backgrounds: The relationship between cardiovascular outcomes and the Controlling Nutritional Status (CONUT) score in heart failure (HF) with preserved ejection fraction (HFpEF) patients is unknown. This study aimed to evaluate the relationship between the score and cardiovascular outcomes in HFpEF patients. Methods and results: A total of 506 consecutive HFpEF patients were prospectively observed for up to 1500 days or until the occurrence of cardiovascular events. The mean age was 71.6 ± 9.4 years. Cardiovascular outcomes were compared between the CONUT score 0–1 group with a normal nutritional state (normal group), the CONUT score 2–4 group with a light degree of undernutrition (light group), and the CONUT score 5–8 group with a moderate degree of undernutrition (moderate group). In this study, there were no patients who scored 9–12, which was defined as a severe state of undernutrition. Overall, 238 cardiovascular events were observed during the follow-up period (median: 1159 days). Kaplan–Meier analysis showed that the moderate group was at higher risk of composite cardiovascular events than the normal group (P < 0.001) and the light group (P = 0.031). The analysis also showed that the light group was at higher risk of composite cardiovascular events than the normal group (P = 0.038). Multivariable Cox proportional hazards analysis with the significant factors from the univariate analysis showed that the CONUT score (hazard ratio: 1.12, 95% confidence interval: 1.03–1.21, P = 0.005) significantly predicted future cardiovascular events. Conclusion: Nutritional screening using the CONUT score may be useful for predicting cardiovascular events in HFpEF patients.
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Mori H., Takahashi J., Sato K., Miyata S., Takagi Y., Tsunoda R., Sumiyoshi T., Matsui M., Tanabe Y., Sueda S., Momomura S., Kaikita K., Yasuda S., Ogawa H., Shimokawa H., Suzuki H.
IJC Heart and Vasculature 29 100561 2020.8
Language：English Publishing type：Research paper (scientific journal) Publisher：IJC Heart and Vasculature
Background: Antiplatelet therapy (APT) is generally used in patients with coronary artery disease. However, for patients with vasospastic angina (VSA), the impact of APT is not fully understood. Methods: In a multicenter registry study of the Japanese Coronary Spasm Association (n = 1429), patients with or without APT were compared. The primary endpoint was major adverse cardiac events (MACEs), defined as cardiac death, non-fatal myocardial infarction, unstable angina, heart failure and appropriate ICD (Implantable cardioverter defibrillator) shock. Propensity score matching and a multivariable cox proportional hazard model were used to adjust for selection bias for treatment and potential confounding factors. Results: In the whole population, 669 patients received APT, while 760 patients did not receive APT. Patients with APT had a greater prevalence of comorbidities, such as hypertension, diabetes, dyslipidemia and smoking, than those without APT. The prevalences of previous myocardial infarction, spontaneous ST changes, significant organic stenosis and medications including calcium channel blocker, nitrate, statin and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker were greater in patients with APT than those without APT. After propensity matching (n = 335 for both groups), during the median follow-up period of 32 months, the incidence rate of MACE was comparable between the patients with and without APT (P = 0.24). MACEs occurred in 5.7% of patients with APT and in 3.6% of those without APT (P = 0.20). All-cause death occurred in 0.6% of patients with APT and 1.8% of those without APT (p = 0.16). Conclusion: In this multicenter registry study, anti-platelet therapy exerted no beneficial effects for VSA patients.
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Marume K., Nagatomo K., Yamamoto N., Kaichi R., Mori T., Komaki S., Ishii M., Kusaka H., Toida R., Kurogi K., Nagamine Y., Takashio S., Arima Y., Sakamoto K., Yamamoto E., Kaikita K., Tsujita K.
Journal of Cardiology 76 ( 2 ) 184 - 190 2020.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
Background: Owing to reduced staffing, patients hospitalized for acute myocardial infarction (AMI) during off-hours (nights, weekends, and holidays) have poorer outcomes than those admitted during regular hours. Whether the presence of an on-duty cardiologist in a hospital during off-hours is related to better outcomes for patients with AMI remains unclear. The Miyazaki Prefectural Nobeoka Hospital had a unique medical care system in that cardiologists were on call for half of the week and on duty for the other half during off-hours, thus providing an opportunity to assess the relationship between the presence of an on-duty cardiologist and patient outcomes. We examined clinical outcomes of patients admitted for AMI during off-hours according to the presence of an on-duty cardiologist. Methods: We recruited 225 consecutive patients with AMI hospitalized during off-hours, who underwent stent implantation at Miyazaki Prefecture Nobeoka Hospital from 2013 to 2017. The endpoints were in-hospital death or long-term major adverse cardiac events (MACE) including cardiovascular death, non-fatal MI, non-fatal stroke, stent thrombosis, ischemia-driven target-lesion revascularization, admission owing to unstable angina, or admission owing to heart failure. Results: Based on the presence of an on-call cardiologist at admission, we divided patients into the cardiologist on-call group (n = 112) or cardiologist on-duty group (n = 113). The presence of an on-duty cardiologist did not affect door-to-reperfusion time (p = 0.776), level of peak creatine kinase (p = 0.971), or in-hospital death (p = 0.776). The Kaplan–Meier curve analysis showed similar prognosis for the cardiologist on-duty and cardiologist on-call groups (p = 0.843), and multivariable Cox regression analysis showed that the presence of an on-duty cardiologist was not associated with MACE. Conclusions: The presence of an on-duty cardiologist is not a prognostic factor for patients hospitalized for AMI during off-hours in our medical system. Further prospective multicenter studies should confirm our results.
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Nagamatsu S., Sakamoto K., Yamashita T., Sato R., Tabata N., Motozato K., Yamanaga K., Ito M., Fujisue K., Kanazawa H., Sueta D., Usuku H., Araki S., Arima Y., Takashio S., Suzuki S., Yamamoto E., Izumiya Y., Soejima H., Utsunomiya D., Kaikita K., Yamashita Y., Tsujita K.
Journal of Cardiology 76 ( 1 ) 73 - 79 2020.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
Background: Although pressure equalization of the sensor-tipped guidewire and systemic pressure is mandatory in measuring fractional flow reserve (FFR), pressure in the distal artery (Pd) with wire advancement can be influenced by hydrostatic pressure related to the height difference between the catheter tip and the distal pressure sensor. We therefore analyzed the impact of hydrostatic pressure on FFR in vivo by modification of the height difference. Methods: To reveal the anatomical height difference in human coronary arteries, measurement was performed during computed tomography angiography (CTA) of five consecutive patients. Utilizing the healthy coronary arteries of female swine, height difference diversity was reproduced by body rotation and vertical inclination. FFR measurements were performed during maximum hyperemia with adenosine. The height difference was calculated fluoroscopically with a contrast medium–filled balloon for reference. Results: In human coronary CTA, height averages from the ostium in the left anterior descending artery (34.6 mm) were significantly higher than in the left circumflex (−15.5 mm, p = 0.008) and right coronary arteries (−2.3 mm, p = 0.008). In our swine model, reproduced height variation ranged from −7.2 cm to +6.5 cm. Mean FFR was significantly lower in positive sensor height and higher in negative sensor height compared to the reference height. Linear regression analyses revealed significant correlations between height difference and FFR, observed among all coronary arteries, as well as between the height difference and Pd–aortic pressure mismatch. Subtracting 0.622 mmHg/cm height difference from Pd could correct the expected hydrostatic pressure influence. Conclusion: Hydrostatic pressure variation resulting from sensor height influenced FFR values might affect interpretation during FFR assessment.
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Long-Term Prognosis of Patients with Myocardial Infarction Type 1 and Type 2 with and without Involvement of Coronary Vasospasm. Reviewed
Sato R, Sakamoto K, Kaikita K, Tsujita K, Nakao K, Ozaki Y, Kimura K, Ako J, Noguchi T, Yasuda S, Suwa S, Fujimoto K, Nakama Y, Morita T, Shimizu W, Saito Y, Hirohata A, Morita Y, Inoue T, Okamura A, Mano T, Hirata K, Tanabe K, Shibata Y, Owa M, Funayama H, Kokubu N, Kozuma K, Uemura S, Toubaru T, Saku K, Ohshima S, Nishimura K, Miyamoto Y, Ogawa H, Ishihara M
Journal of clinical medicine 9 ( 6 ) 2020.6
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Kiyama T., Kanazawa H., Yamabe H., Ito M., Kaneko S., Kanemaru Y., Kawahara Y., Yamanaga K., Fujisue K., Sueta D., Takashio S., Arima Y., Araki S., Usuku H., Nakamura T., Izumiya Y., Sakamoto K., Suzuki S., Yamamoto E., Soejima H., Kaikita K., Tsujita K.
Journal of Cardiology 75 ( 6 ) 673 - 681 2020.6
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
Background: It has been shown that most paroxysmal atrial fibrillation (AF) can be terminated by pulmonary vein (PV) isolation alone, suggesting that rapid discharges from PV drive AF. To define the driving mechanism of AF, we compared the activation sequence in the body of left atrium (LA) to that within PV. Methods: Endocardial noncontact mapping of LA body (LA group; n = 16) and selective endocardial mapping of left superior PV (LSPV) (PV group; n = 13) were performed in 29 paroxysmal AF patients. The frequency of pivoting activation, wave breakup, and wave fusion observed in LA were compared to those in LSPV to define the driving mechanism of AF. Circumferential ablation lesion around left PV was performed after right PV isolation to examine the effect of linear lesion around PV on AF termination both in LA and PV groups. Results: The frequency of pivoting activation, wave breakup, and wave fusion in PV group were significantly higher than those in LA group (36.5 ± 17.7 vs 5.0 ± 2.2 times/seconds, p < 0.001, 10.1 ± 4.3 vs 5.0 ± 2.2 times/seconds, p = 0.004, 18.1 ± 5.7 vs 11.0 ± 5.2, p = 0.002). Especially in the PV group, the frequency of pivoting activation was significantly higher than that of wave breakup and wave fusion (36.5 ± 17.7 vs 10.1 ± 4.3 times/seconds, p < 0.001, 36.5 ± 17.7 vs 18.1 ± 5.7 times/seconds, p < 0.001). These disorganized activations in LSPV were eliminated by the circumferential ablation lesion around left PV (pivoting activation; 36.5 ± 17.7 vs 9.3 ± 2.3 times/seconds, p < 0.001, wave breakup; 10.1±1.3 times/seconds, p = 0.003, wave fusion; 18.1 ± 5.7 vs 5.7 ± 1.8, p < 0.001), resulted in AF termination in all patients in both LA and PV groups. Conclusions: Activation sequence within PV was more disorganized than that in LA body. Frequent episodes of pivoting activation rather than wave breakup and fusion observed within PV acted as the driving sources of paroxysmal AF.
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Minimum-contrast percutaneous coronary intervention guided by optical coherence tomography using low-molecular weight dextran Reviewed
Kurogi K, Ishii M, Sakamoto K, Kusaka H, Yamamoto N, Takashio S, Arima Y, Yamamoto E, Kaikita K, Tsujita K
JACC: Cardiovascular Interventions 13 ( 10 ) 1270 - 1272 2020.5
Language：English Publishing type：Research paper (scientific journal)
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Quantification of myocardial extracellular volume with planning computed tomography for transcatheter aortic valve replacement to identify occult cardiac amyloidosis in patients with severe aortic stenosis Reviewed
Oda S, Kidoh M, Takashio S, Inoue T, Nagayama Y, Nakaura T, Shiraishi S, Tabata N, Usuku H, Kaikita K, Tsujita K, Ikeda O.
Circ Cardiovasc Imaging 13 ( 5 ) e010358 2020.5
Language：English Publishing type：Research paper (scientific journal)
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Ishii M., Seki T., Kaikita K., Sakamoto K., Nakai M., Sumita Y., Nishimura K., Miyamoto Y., Noguchi T., Yasuda S., Tsutsui H., Komuro I., Saito Y., Ogawa H., Tsujita K., Kawakami K.
European Journal of Epidemiology 35 ( 5 ) 455 - 464 2020.5
Language：English Publishing type：Research paper (scientific journal) Publisher：European Journal of Epidemiology
Particulate matter from natural sources such as desert dust causes harmful effects for health. Asian dust (AD) increases the risk of acute myocardial infarction (AMI). However, little is known about the risk of myocardial infarction with nonobstructive coronary arteries (MINOCA), compared to myocardial infarction with coronary artery disease (MI-CAD). Using a time-stratified case-crossover design and conditional logistic regression models, the association between short-term exposure to AD whereby decreased visibility (< 10 km) observed at each monitoring station nearest to the hospitals was used for exposure measurements and admission for AMI in the spring was investigated using a nationwide administrative database between April 2012 and March 2016. According to presence of revascularization and coronary atherosclerosis, AMI patients (n = 30,435) were divided into 2 subtypes: MI-CAD (n = 27,202) or MINOCA (n = 3233). The single lag day-2 was used in AD exposure based on the lag effect analysis. The average level of meteorological variables and co-pollutants on the 3 days prior to the case/control days were used as covariates. The occurrence of AD events 2 days before the admission was associated with admission for MINOCA after adjustment for meteorological variables [odds ratio 1.65; 95% confidence interval (CI) 1.18–2.29], while the association was not observed in MI-CAD. The absolute risk difference of MINOCA admission was 1.79 (95% CI 1.21–2.38) per 100,000 person-year. These associations between AD exposure and the admission for MINOCA remained unchanged in two-pollutant models. This study provides evidence that short-term exposure to AD is associated with a higher risk of MINOCA, but not MI-CAD.
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Sueta D., Tabata N., Tanaka M., Hanatani S., Arima Y., Sakamoto K., Yamamoto E., Izumiya Y., Kaikita K., Arizono K., Matsui K., Tsujita K.
Hemodialysis International 24 ( 2 ) 202 - 211 2020.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Hemodialysis International
Introduction: Mortality in hemodialysis patients is relatively high; thus, its risk stratification is very important. There are insufficient data describing the current status of the management of serum phosphate and calcium levels. Methods: We conducted a multicenter, prospective, registry study throughout the Kumamoto Prefecture in Japan. We enrolled 1993 patients at 58 facilities with complete explanatory data, including serum phosphate, corrected calcium, and intact parathyroid hormone levels. We categorized subjects into nine categories according to low, normal, and high levels of phosphate and corrected calcium levels. The endpoint was all-cause mortality. Results: Of the total number of subjects, 56.1% of the patients were in the normal phosphate and calcium category, and 72% and 77.1% had controlled serum phosphate and calcium levels, respectively. Two hundred twenty-six deaths occurred during the follow-up period. In the nine categories, the highest mortality rates were observed in the highest corrected calcium and lowest phosphate categories. Stepwise backward multivariate regression analyses identified the serum corrected calcium level (OR, 1.38; 95% CI, 1.06–1.79; P = 0.016) and the serum phosphate level (OR, 1.26; 95% CI, 1.08–1.48; P = 0.003) as significant and independent predictors of all-cause mortality. Conclusions: The corrected serum calcium and phosphate levels are associated with mortality in our dialysis population, with poorest survival in patients with high corrected serum calcium and low serum phosphorus.
DOI： 10.1111/hdi.12824
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Yamamoto M., Takashio S., Nakashima N., Hanatani S., Arima Y., Sakamoto K., Yamamoto E., Kaikita K., Aoki Y., Tsujita K.
ESC Heart Failure 7 ( 2 ) 721 - 726 2020.4
Language：English Publishing type：Research paper (scientific journal) Publisher：ESC Heart Failure
We present a case of double-chambered right ventricle (DCRV) complicated by hypertrophic obstructive cardiomyopathy (HOCM) in KRAS mutation-associated Noonan syndrome. The diagnosis was incidental and made during diagnostic testing for an intradural extramedullary tumour. Spinal compression, if not surgically treated, may cause paralysis of the extremities. We decided to pursue pharmacological therapy to control biventricular obstructions and reduce the perioperative complication rate. We initiated treatment with cibenzoline and bisoprolol; the doses were titrated according to the response. After 2 weeks, the peak pressure gradient of the two RV chambers decreased from 101 to 68 mmHg, and the LV peak pressure gradient decreased from 109 to 14 mmHg. Class 1A antiarrhythmic drugs and β-blockers decreased the severe pressure gradients of biventricular obstructions caused by DCRV and HOCM. The patient was able to undergo surgery to remove the intradural extramedullary tumour, which was diagnosed as schwannoma.
DOI： 10.1002/ehf2.12650
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A Mechanism for L-Wave Generation via Color M-Mode Imaging in a Patient with Mitral Regurgitation. Reviewed
Misumi I, Motozato K, Usuku H, Sakamoto K, Kaikita K, Tsujita K, Fukui T
CASE (Philadelphia, Pa.) 4 ( 2 ) 86 - 89 2020.4
Language：English Publishing type：Research paper (scientific journal)
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Tabata N., Sueta D., Arima Y., Okamoto K., Shono T., Hanatani S., Takashio S., Oniki K., Saruwatari J., Sakamoto K., Kaikita K., Sinning J.M., Werner N., Nickenig G., Sasaki Y., Fukui T., Tsujita K.
IJC Heart and Vasculature 27 100498 2020.4
Language：English Publishing type：Research paper (scientific journal) Publisher：IJC Heart and Vasculature
Aims: Although the bacterial virulent factor of cytotoxin-associated gene-A (CagA)-seropositivity and the host genetic factors of interleukin (IL)-1 polymorphisms have been suggested to influence Helicobacter pylori (HP) -related diseases, the underlying mechanisms of the association between HP infection and acute coronary syndrome (ACS) remain unknown. Methods and results: Among 341 consecutive ACS patients, the clinical outcomes after ACS included composite cardiovascular events within the 2-year follow-up period. A significantly higher probability of primary outcomes was observed in HP positive patients than in HP negative patients. There were no significant differences in the rate of cardiovascular events between HP positive and HP negative patients in the absence of an IL-polymorphism, while there were significant differences in the presence of an IL-polymorphism. There were significant differences in the rate of cardiovascular events among CagA positive, CagA negative/ HP positive and CagA negative/HP negative patients. Moreover, via immunohistochemical staining, aortic CagA positive cells were confirmed in the vasa vasorum in CagA positive patients, whereas they could not be identified in CagA negative patients. Conclusions: The bacterial virulence factor CagA and host genetic IL-1 polymorphisms influence the incidence of adverse cardiovascular events, possibly through infection of atherosclerotic lesions. Registration: University Hospital Medical Information Network (UMIN)-CTR (http://www.umin.ac.jp/ctr/). Identifier: UMIN000035696.
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Utility of Kumamoto Criteria in Diagnosing Transthyretin Cardiac Amyloidosis in Real-World Practice - Reply. Reviewed
Takashio S, Marume K, Nishi M, Kaikita K, Tsujita K
Circulation journal : official journal of the Japanese Circulation Society 84 ( 4 ) 681 - 682 2020.3
Language：English Publishing type：Research paper (scientific journal)
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Nakanishi N, Kaikita K, Ishii M, Oimatsu Y, Mitsuse T, Ito M, Yamanaga K, Fujisue K, Kanazawa H, Sueta D, Takashio S, Arima Y, Araki S, Nakamura T, Sakamoto K, Suzuki S, Yamamoto E, Soejima H, Tsujita K
Circulation reports 2 ( 3 ) 158 - 166 2020.3
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：一般社団法人 日本循環器学会
<b><i>Background:</i></b>Direct-activated factor X (FXa) plays an important role in thrombosis and is also involved in inflammation via the protease-activated receptor (PAR)-1 and PAR-2 pathway. We hypothesized that rivaroxaban protects against cardiac remodeling after myocardial infarction (MI).<b><i>Methods and Results:</i></b>MI was induced in wild-type mice by permanent ligation of the left anterior descending coronary artery. At day 1 after MI, mice were randomly assigned to the rivaroxaban and vehicle groups. Mice in the rivaroxaban group were provided with a regular chow diet plus rivaroxaban. We evaluated cardiac function by echocardiography, pathology, expression of mRNA and protein at day 7 after MI. Rivaroxaban significantly improved cardiac systolic function, decreased infarct size and cardiac mass compared with the vehicle. Rivaroxaban also downregulated the mRNA expression levels of tumor necrosis factor-α, transforming growth factor-β, PAR-1 and PAR-2 in the infarcted area, and both A-type and B-type natriuretic peptides in the non-infarcted area compared with the vehicle. Furthermore, rivaroxaban attenuated cardiomyocyte hypertrophy and the phosphorylation of extracellular signal-regulated kinase in the non-infarcted area compared with the vehicle.<b><i>Conclusions:</i></b>Rivaroxaban protected against cardiac dysfunction in MI model mice. Reduction of PAR-1, PAR-2 and proinflammatory cytokines in the infarcted area may be involved in its cardioprotective effects.
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Sueta D., Yamamoto E., Sato M., Sato T., Fujisue K., Arima Y., Takashio S., Sakamoto K., Soejima H., Kaikita K., Shigaki N., Takasu Y., Tsujita K.
Circulation journal : official journal of the Japanese Circulation Society 84 ( 3 ) 524 - 528 2020.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation journal : official journal of the Japanese Circulation Society
BACKGROUND: Although it has been discussed which measures against atherosclerotic diseases should be started in childhood, the current situation in Japan is unclear.Methods and Results:We conducted a health management survey of all 12-year-old children in a local town for 20 years. The body mass index tended to decrease over time. Although the serum low-density lipoprotein cholesterol level did not change, the levels of serum high-density lipoprotein cholesterol and serum triglycerides significantly increased over time. CONCLUSIONS: The serum triglyceride levels in school children increased significantly, probably through lifestyle changes, and the health management system should be reviewed.
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Ishii M., Kaikita K., Sakamoto K., Seki T., Kawakami K., Nakai M., Sumita Y., Nishimura K., Miyamoto Y., Noguchi T., Yasuda S., Tsutsui H., Komuro I., Saito Y., Ogawa H., Tsujita K.
International Journal of Cardiology 301 108 - 113 2020.2
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background: Myocardial infarction with nonobstructive coronary arteries (MINOCA) is a common presentation of acute myocardial infarction (AMI) and has a better prognosis. However, there were few reports on large-scale, high aged population. The aim of this study was to determine the differences in the clinical characteristics and short-term prognosis between MINOCA and myocardial infarction with obstructive coronary artery disease (MI-CAD) using a nationwide administrative database in the super-aging society, Japan. Methods: This was an observational study using data of 137,678 AMI patients who underwent angiography between April 2012 through March 2016. Using the international classification of diseases 10th revision, AMI patients were divided into two groups based on the presence or absence of revascularization and coronary atherosclerosis, identifying 123,633 MI-CAD and 14,045 working diagnosis of MINOCA patients. The true MINOCA (n = 13,022) was defined as the MINOCA excluding non-ischemic causes. We assessed in-hospital mortality within 30 days. Results: Both MINOCA groups were typically found in non-obese, non-smoker young females, with a low grade on Killip classification, and non-low ADL status. Compared to MI-CAD, chronic pulmonary diseases, peripheral vascular diseases, liver diseases, renal diseases, and cerebrovascular diseases were more common, whereas diabetes was less common in the MINOCA groups. In-hospital mortality within 30 days was higher in both MINOCA groups than in MI-CAD. Multivariate frailty model identified both MINOCA groups as an independent risk factor for in-hospital mortality. Conclusions: Our large-population study demonstrated that MINOCA was associated with a high risk of in-hospital mortality compared with MI-CAD in the super-aging society.
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Kanemaru Y., Arima Y., Kaikita K., Kiyama T., Kaneko S., Ito M., Yamabe H., Motozato K., Yamanaga K., Fujisue K., Sueta D., Takashio S., Araki S., Usuku H., Nakamura T., Fukunaga T., Suzuki S., Izumiya Y., Sakamoto K., Soejima H., Yamamoto E., Kawano H., Kanazawa H., Tsujita K.
International Journal of Cardiology 300 147 - 153 2020.2
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background: The impact of intra-atrial conduction delay on the recurrence of atrial tachyarrhythmia after radio frequency catheter ablation (RFCA) has not been fully elucidated. Methods: We retrospectively analyzed 155 AF patients who were sinus rhythm at the start of RFCA. The conduction time from the onset of the earliest atrial electrogram at the high right atrium (HRA) to the end of the latest electrogram at the coronary sinus (CS) during sinus rhythm was defined as HRA-CS conduction time. Pulmonary vein isolation (PVI) was performed followed by linear roof lesion and complex fractionated atrial electrogram (CFAE) ablation until AF termination. We evaluated atrial tachyarrhythmia recurrence 12 months after RFCA. Results: The follow-up data were available for 148 patients. The recurrence of atrial tachyarrhythmia was noted in 28 (18.9%) patients. Atrial tachyarrhythmia recurrence patients had longer HRA-CS conduction times (151.3 ± 22.1 ms vs 160.1 ± 32.6 ms, p =.017). The patients were divided into the long or short HRA-CS conduction time group. The Kaplan–Meier analysis revealed that the long HRA-CS conduction time group held a higher risk of atrial tachyarrhythmia recurrence (log-rank test, p =.019). The multivariable Cox hazard analysis revealed that a long HRA-CS conduction time was a significant risk factor for the recurrence of atrial tachyarrhythmia, despite a long AF duration, persistent AF, and larger left atrial diameter (LAD) were not statistically significant. Conclusions: The HRA-CS conduction time was the primary influencing factor that predicted the recurrence of atrial tachyarrhythmia after catheter ablation.
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Suzuki S., Kaikita K., Yamamoto E., Sueta D., Yamamoto M., Ishii M., Ito M., Fujisue K., Kanazawa H., Araki S., Arima Y., Takashio S., Usuku H., Nakamura T., Sakamoto K., Izumiya Y., Soejima H., Kawano H., Jinnouchi H., Matsui K., Tsujita K.
ESC Heart Failure 7 ( 1 ) 65 - 74 2020.2
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ESC Heart Failure
Aims: The prediction of future heart failure (HF) in stable outpatients is often difficult for general practitioners and cardiologists. Recently, the H FPEF score (0–9 points) has been proposed for the discrimination of HF with preserved ejection fraction from non-cardiac causes of dyspnoea. The six clinical and echocardiographic variables that constitute the H FPEF score include the following: (i) obesity (H); (ii) the use of ≥2 antihypertensive drugs (H); (iii) atrial fibrillation (F); (iv) pulmonary hypertension (P); (v) an age > 60 years (E); and (vi) E/e' > 9 (F). We performed an external validation study that investigated whether the H FPEF score could predict future HF-related events in stable outpatients with cardiovascular risk factor(s) in Japan. Methods and results: In this prospective cohort study, after exclusion of 195 from 551 consecutive, stable Japanese outpatients with at least one cardiovascular risk factor who were enrolled between September 2010 and July 2013, the remaining 356 outpatients (171 men, 185 women, mean age 73.2 years) were eligible for the analysis. We calculated the H FPEF score (0–9 points), and followed up the patients for an average of 517 days. In all of the 356 patients, the mean H FPEF score was 3.1 ± 1.8, and 15 developed HF-related events during the follow-up period, including cardiovascular death (n = 2) and hospitalization for HF decompensation (n = 13). Multivariate Cox proportional hazards analysis showed that the H FPEF score was an independent predictor of future HF-related events (P < 0.001 for all three models). Kaplan–Meier survival curves showed a significantly higher probability of HF-related events in the outpatients with a high H FPEF score (P < 0.001). In receiver operating characteristic (ROC) curve analysis, the H FPEF score was significantly associated with the occurrence of future HF-related events (P < 0.001). In ROC curve analysis, the sensitivity, specificity, and positive likelihood ratio of a H FPEF score of 7 points to predict HF-related events were 47%, 96%, and 11.4%, respectively. Conclusions: The H FPEF score could provide useful information for future HF-related events in stable outpatients with cardiovascular risk factor(s) in Japan. 2 2 2 2 2 2 2 2 2 2
DOI： 10.1002/ehf2.12570
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Emoto T., Kidoh M., Oda S., Nakaura T., Nagayama Y., Sasao A., Funama Y., Araki S., Takashio S., Sakamoto K., Yamamoto E., Kaikita K., Tsujita K., Yamashita Y.
European Radiology 30 ( 2 ) 691 - 701 2020.2
Language：English Publishing type：Research paper (scientific journal) Publisher：European Radiology
Objectives: To compare the effects of hybrid iterative reconstruction (HIR) and model-based iterative reconstruction (MBIR) that incorporates a beam-hardening model for myocardial extracellular volume (ECV) quantification by cardiac CT using MRI as a reference standard. Methods: In this retrospective study, a total of 34 patients were evaluated using cardiac CT and MRI. Paired CT image sets were created using HIR and MBIR with a beam-hardening model. We calculated mean absolute differences and correlations between the global mid-ventricular ECV derived from CT and MRI via Pearson correlation analysis. In addition, we performed qualitative analysis of image noise and beam-hardening artifacts on postcontrast images using a four-point scale: 1 = extensive, 2 = strong, 3 = mild, and 4 = minimal. Results: The mean absolute difference between the ECV derived from CT and MRI for MBIR was significantly smaller than that for HIR (MBIR 3.74 ± 3.59%; HIR 4.95 ± 3.48%, p = 0.034). MBIR improved the correlation between the ECV derived from CT and MRI when compared with HIR (MBIR, r = 0.60, p < 0.001; HIR, r = 0.47, p = 0.006). In qualitative analysis, MBIR significantly reduced image noise and beam-hardening artifacts when compared with HIR ([image noise, MBIR 3.4 ± 0.7; HIR 2.1 ± 0.8, p < 0.001], [beam-hardening artifacts, MBIR 3.8 ± 0.4; HIR 2.6 ± 1.0, p < 0.001]). Conclusions: MBIR with a beam-hardening model effectively reduced image noise and beam-hardening artifacts and improved myocardial ECV quantification when compared with HIR using MRI as a reference standard. Key Points: • MBIR with a beam-hardening model effectively reduced image noise and beam-hardening artifacts. • The mean absolute difference between the global mid-ventricular ECV derived from CT and MRI for MBIR was significantly smaller than that for conventional HIR. • MBIR provided more accurate myocardial CT number and improved ECV quantification when compared with HIR.
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Yamamura S., Izumiya Y., Araki S., Nakamura T., Kimura Y., Hanatani S., Yamada T., Ishida T., Yamamoto M., Onoue Y., Arima Y., Yamamoto E., Sunagawa Y., Yoshizawa T., Nakagata N., Bober E., Braun T., Sakamoto K., Kaikita K., Morimoto T., Yamagata K., Tsujita K.
Hypertension (Dallas, Tex. : 1979) 75 ( 1 ) 98 - 108 2020.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Hypertension (Dallas, Tex. : 1979)
Sirt (Sirtuin) 7, the most recently identified mammalian sirtuin, has been shown to contribute to appropriate wound healing processes after acute cardiovascular insult. However, its role in the development of cardiac remodeling after pressure overload is unclear. Cardiomyocyte-specific Sirt7-knockout and control mice were subjected to pressure overload induced by transverse aortic constriction. Cardiac hypertrophy and functions were then examined in these mice. Sirt7 protein expression was increased in myocardial tissue after pressure overload. Transverse aortic constriction-induced increases in heart weight/tibial length were significantly augmented in cardiomyocyte-specific Sirt7-knockout mice compared with those of control mice. Histological analysis showed that the cardiomyocyte cross-sectional area and fibrosis area were significantly larger in cardiomyocyte-specific Sirt7-deficient mice. Cardiac contractile functions were markedly decreased in cardiomyocyte-specific Sirt7-deficient mice. Mechanistically, we found that Sirt7 interacted directly with GATA4 and that the exacerbation of phenylephrine-induced cardiac hypertrophy by Sirt7 knockdown was decreased by GATA4 knockdown. Sirt7 deacetylated GATA4 in cardiomyocytes and regulated its transcriptional activity. Interestingly, we demonstrated that treatment with nicotinamide mononucleotide, a known key NAD+ intermediate, ameliorated agonist-induced cardiac hypertrophies in a Sirt7-dependent manner in vitro. Sirt7 deficiency in cardiomyocytes promotes cardiomyocyte hypertrophy in response to pressure overload. Sirt7 exerts its antihypertrophic effect by interacting with and promoting deacetylation of GATA4.
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Saku T., Takashio S., Tsuruta Y., Otsuka Y., Takae M., Kiyama T., Yamamoto E., Kaikita K., Hotta T., Matsumoto S., Kang D., Tsujita K., Komohara Y.
Medical Molecular Morphology 54 ( 2 ) 181 - 186 2020
Language：English Publishing type：Research paper (scientific journal) Publisher：Medical Molecular Morphology
Mitochondrial cardiomyopathy can be described as a condition characterized by abnormal heart-muscle structure and/or function, secondary to mutations in nuclear or mitochondrial DNA. Its severity can range from subclinical to critical conditions. We presented three cases of mitochondrial cardiomyopathy with m.3243A > G mutation and compared the clinical manifestations with the histological findings for each of these cases. All cases showed cardiac hypertrophy, juvenile-onset diabetes mellitus, and hearing loss. Case 1 (43-year-old male) showed less cardiac involvement and shorter duration of mitochondrial disease-related symptoms than case 2 (67-year-old female) and case 3 (51-year-old male), who showed the most advanced cardiac condition and longest duration from the manifestation of heart failure. The histological findings revealed that cardiomyocytes from case 1 showed no hypertrophy and mitochondrial degeneration in electron microscopy. Alternatively, cases 2 and 3 showed hypertrophy in their cardiomyocytes, and mitochondrial degeneration (e.g. onion-like lesions, swollen cristae, and lamellar bodies) was most apparent in case 3. These results suggested that mitochondrial degeneration, as evaluated by electron microscopy, might be correlated with impaired heart function in patients with mitochondrial cardiomyopathy.
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Kurogi K., Ishii M., Sakamoto K., Komaki S., Kusaka H., Yamamoto N., Takashio S., Arima Y., Yamamoto E., Kaikita K., Tsujita K.
Circulation Journal 84 ( 6 ) 917 - 925 2020
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: The excessive volume of contrast needed is a significant limitation of optical coherence tomography (OCT)-guided percutaneous coronary intervention (PCI). Low-molecular-weight dextran (LMWD) has been used for OCT image acquisition instead of contrast media. This study compared the effects of OCT-guided PCI using LMWD on renal function and clinical outcomes to those of intravascular ultrasound (IVUS)-guided PCI. Methods and Results: In all, 1,183 consecutive patients who underwent intracoronary imaging-guided PCI were enrolled in this single-center, retrospective, observational study. After propensity score matching, 133 pairs of patients were assigned to undergo either OCT-guided PCI using LMWD or IVUS-guided PCI. There was no significant change from baseline in the primary endpoint, serum creatinine concentrations, after the procedure in either group. There were no significant differences between the OCT and IVUS groups in the volume of contrast medium, the incidence of contrast-induced nephropathy (1.5% vs. 2.3%; P=0.65), and major adverse cardiovascular events (MACE) at 30 days (2.3% vs. 6.0%; P=0.12) and 12 months (2.3% vs. 3.0%; P=0.70) after the procedure. Kaplan-Meier analysis at the 12-month follow-up revealed no significant difference in the incidence of MACE between the 2 groups (P=0.75). Conclusions: OCT-guided PCI using LMWD did not negatively affect renal function and achieved similar short- and long-term clinical outcomes to IVUS-guided PCI.
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Mitsuse T., Kaikita K., Ishii M., Oimatsu Y., Nakanishi N., Ito M., Arima Y., Sueta D., Iwashita S., Fujisue K., Kanazawa H., Takashio S., Araki S., Usuku H., Suzuki S., Sakamoto K., Yamamoto E., Soejima H., Tsujita K.
Journal of Atherosclerosis and Thrombosis 27 ( 3 ) 215 - 225 2020
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Atherosclerosis and Thrombosis
Aims: The assessment of bleeding risk in patients with coronary artery disease (CAD) is clinically important. We recently developed the Total Thrombus-Formation Analysis System (T-TAS) for the quantitative analysis of thrombus formation using microchips with thrombogenic surfaces. Here, we assessed the utility of T-TAS parameters in predicting 1-year bleeding events in patients with CAD. Methods: The study subjects were 561 consecutive patients who underwent coronary angiography (CAG) between August 2013 and September 2016 for suspected CAD. Blood samples collected at the time of CAG were used for T-TAS to compute the area under the curve (AUC) (AR10-AUC30) in the AR chip. Patients were divided into three groups according to AR10-AUC30 (low: ≤ 1603, intermediate, and high: ＞1765, n =187 each). One-year bleeding events were defined by the Platelet Inhibition and Patient Outcomes criteria. Results: Bleeding occurred in 21 (3.7%) patients and was classified as major (8 [1.4%]) and minor (13 [2.3%]). The AR10-AUC30 levels were significantly lower in the bleeding group than the non-bleeding group (median [interquartile range] 1590 [1442–1734] vs. 1687 [1546–1797], p=0.04). Univariate Cox regression analysis demonstrated that low AR10-AUC30, high prothrombin time-international normalized ratio levels, and diabetes correlated with bleeding events. Multivariate Cox regression analysis identified low AR10-AUC30 levels as a significant determinant of bleeding events. Kaplan-Meier survival curves showed a higher rate of bleeding events in the low than the high AR10-AUC30 group (p =0.007). Conclusions: The results highlight the potential usefulness of the AR10-AUC30 levels in the prediction of 1-year bleeding events in patients with CAD treated with various antithrombotic therapies.
DOI： 10.5551/jat.49700
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Kurogi K., Ishii M., Sakamoto K., Komaki S., Marume K., Kusaka H., Yamamoto N., Arima Y., Yamamoto E., Kaikita K., Tsujita K.
Journal of the American Heart Association 8 ( 23 ) e014096 2019.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American Heart Association
Background: The long-term prognosis of patients with acute myocardial infarction who develop persistent renal dysfunction (RD) remains unclear. We investigated risk factors and prognostic implications of persistent RD after contrast-induced nephropathy (CIN) in patients with acute myocardial infarction after primary percutaneous coronary intervention. Methods and Results: We enrolled 952 consecutive patients who underwent primary percutaneous coronary intervention for acute myocardial infarction. CIN was defined as an increase in serum creatinine levels ≥0.5 mg/dL or ≥25% from baseline within 72 hours after percutaneous coronary intervention. Persistent RD was defined as residual impairment of renal function over 2 weeks, and transient RD was defined as recovery of renal function within 2 weeks, after CIN. The overall incidence of CIN was 8.8% and that of persistent CIN was 3.1%. A receiver-operator characteristic curve showed that the optimal cutoff value of the contrast volume/baseline estimated glomerular filtration rate ratio for persistent CIN was 3.45. In multivariable logistic analysis, a contrast volume/baseline estimated glomerular filtration rate >3.45 was an independent correlate of persistent RD. At 3 years, the incidence of death was significantly higher in patients with persistent RD than in those with transient RD (P=0.001) and in those without CIN (P<0.001). Cox regression analysis showed that persistent RD (hazard ratio, 4.99; 95% CI, 2.30–10.8; P<0.001) was a significant risk factor for mortality. A similar trend was observed for the combined end points, which included mortality, hemodialysis, stroke, and acute myocardial infarction. Conclusions: Persistent RD, but not transient RD, is independently associated with long-term mortality. A contrast volume/baseline estimated glomerular filtration rate >3.45 is an independent predictor of persistent RD.
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A case of repetitive acute coronary syndrome in a patient with familial hypercholesterolemia Reviewed
Motozato K., Sueta D., Sakamoto K., Nagamatsu S., Yamashita T., Sato R., Mitsuse T., Kanemaru Y., Takaoka K., Fujisue K., Takashio S., Arima Y., Yamamoto E., Kaikita K., Tsujita K.
Journal of Cardiology Cases 20 ( 6 ) 200 - 204 2019.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology Cases
The low-density lipoprotein-cholesterol (LDL-C) level of a 60-year-old woman diagnosed with acute coronary syndrome (ACS) was 212 mg/dL. She was suspected of having familial hypercholesterolemia, therefore, administration of a proprotein convertase subtilisin-kexin type 9 (PCSK9) antibody in addition to atorvastatin plus ezetimibe was initiated, reducing her LDL-C level to 42 mg/dL. Nine months after initial ACS, the PCSK9 antibody was discontinued. Six months after the iturruption, she relapsed with ACS, and neoatherosclerosis progression was confirmed via intravascular ultrasound. Then, the PCSK9 antibody was reintroduced. Disruption of a PCSK9 may be associated with the progression and destabilization of neoatherosclerosis. <Learning objective: Administration of a proprotein convertase subtilisin-kexin type 9 (PCSK9) antibody in addition to statin decreases low-density lipoprotein-cholesterol level and is effective in suppressing cardiovascular events, the effect on neoatherosclerosis after coronary artery stent deployment is not clear. We experienced an interesting reccurent ACS case with familial hypercholesterolemia, and reported the possibility that PCSK9 antibody disruption might contribute to destabilization of neoatherosclerosis after coronary stenting utilizing intravascular ultrasound.>
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Sakuma I., Uchiyama S., Atarashi H., Inoue H., Kitazono T., Yamashita T., Shimizu W., Ikeda T., Kamouchi M., Kaikita K., Fukuda K., Origasa H., Shimokawa H.
Heart and Vessels 34 ( 11 ) 1839 - 1851 2019.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Heart and Vessels
For Japanese patients with non-valvular atrial fibrillation (NVAF), the risk of stroke and major bleeding events was assessed by using the CHADS CHA DS -VASc, and HAS-BLED scores. The risk factors for embolism and major bleeding under DOAC may be different from current reports. We analyzed the data set of the EXPAND Study to determine the risk factors for events among Japanese NVAF patients in the era of direct oral anticoagulant. Using the data of EXPAND Study, the validity for predictability of the CHADS , CHA DS -VASc, and HAS-BLED scores was identified using the receiver operating characteristic curve analysis. Multivariate analysis was performed with the Cox proportional hazard model to determine the independent risk factors for stroke/systemic embolism and major bleeding among NVAF patients receiving rivaroxaban. Explanatory variables were selected based on the univariate analysis. A total of 7141 patients (mean age 71.6 ± 9.4 years, women 32.3%, and rivaroxaban 15 mg per day 56.5%) were included. Incidence rates of stroke/systemic embolism and major bleeding were 1.0%/year and 1.2%/year, respectively. The multivariate analysis revealed that only history of stroke was associated with stroke/systemic embolism (hazard ratio 3.4, 95% confidence interval 2.5-4.7, p < 0.0001). By contrast, age (1.7, 1.1–2.6, p = 0.0263), creatinine clearance (CrCl) 30–49 mL/min (1.6, 1.2-2.2, p = 0.0011), liver dysfunction (1.7, 1.1–2.8, p = 0.0320), history/disposition of bleeding (1.8, 1.0–3.0, p = 0.0348), and concomitant use of antiplatelet agents (1.6, 1.2–2.3, p = 0.0030) were associated with major bleeding. This sub-analysis showed that some components of the HAS-BLED score were independently associated with major bleeding in Japanese NVAF patients receiving anticoagulation therapy by rivaroxaban. Additionally, CrCl value of 30–49 mL/min was an independent predictor of major bleeding in patients receiving rivaroxaban. 2, 2 2 2 2 2
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Sueta D, Sakamoto K, Usuku H, Fujisue K, Yamanaga K, Arima Y, Takashio S, Suzuki S, Yamamoto E, Kaikita K, Tsujita K
Circulation reports 1 ( 11 ) 531 - 533 2019.10
Language：English Publishing type：Research paper (scientific journal) Publisher：一般社団法人 日本循環器学会
<b><i>Background:</i></b>Although "disaster-related death" as a category awarded disaster-related compensation includes death not caused by the tragedy itself, the actual definition remains unclear.<b><i>Methods and Results:</i></b>In the Kumamoto earthquake 2016, compared with the Great East Japan Earthquake 2011, excessive mental and physical stress and suicide were observed significantly more as causes of disaster-related death.<b><i>Conclusions:</i></b>It is essential to give maximum consideration to refugees to support them while in shelters.
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H<inf>2</inf>FPEF Score as a Prognostic Value in HFpEF Patients Reviewed
Sueta D., Yamamoto E., Nishihara T., Tokitsu T., Fujisue K., Oike F., Takae M., Usuku H., Takashio S., Arima Y., Suzuki S., Nakamura T., Ito M., Kanazawa H., Sakamoto K., Kaikita K., Tsujita K.
American Journal of Hypertension 32 ( 11 ) 1082 - 1090 2019.10
Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Hypertension
Background: The H FPEF score is recognized as a simple method to diagnose heart failure (HF) with preserved left ventricular ejection fraction (HFpEF). We investigated the value of the H FPEF score in predicting subsequent cardiovascular events in HFpEF patients. Methods: This study was a retrospective, single-center, observational study. We calculated the H FPEF scores for 404 consecutive HFpEF patients. Subjects were subdivided into low- (0-3), intermediate- (4-6), and high-score (7-9) groups and followed for 50 months. The primary and secondary endpoints were composite cardiovascular/cerebrovascular events (cardiovascular death, nonfatal myocardial infarction, unstable angina pectoris, hospitalization for HF decompensation, and nonfatal stroke) occurrence and HF-related events (hospitalization for HF decompensation) occurrence at 50 months, respectively. Results: Kaplan-Meier analyses demonstrated a significantly higher incidence of cardiovascular/cerebrovascular events among those with a higher H FPEF score (log-rank test, P = 0.005). The HF-related event rate was higher in proportion to the H FPEF score (log-rank test, P < 0.001). Multivariate Cox hazard analyses identified the H FPEF score (per 1 point) as an independent predictor of cardiovascular and HF-related events (hazard ratio [HR], 1.179; 95% confidence interval [CI], 1.066-1.305; P = 0.001 and HR, 1.288; 95% CI, 1.134-1.463; P = 0.001, respectively). Receiver operating characteristic analysis showed that the H FPEF significantly predicted cardiovascular events (area under the curve [AUC], 0.626; 95% CI, 0.557-0.693; P < 0.001) and HF-related events (AUC, 0.680; 95% CI, 0.600-0.759; P < 0.001). The cutoff H FPEF score was 5.5 for the identification of cardiovascular and HF-related events. Conclusion: The H FPEF score might be a potentially useful marker for the prediction of cardiovascular and HF-related events in HFpEF patients. Clinical Trails Registration: Trail Number UMIN000029600. 2 2 2 2 2 2 2 2 2
DOI： 10.1093/ajh/hpz108
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Usuku H., Yamamoto E., Arima Y., Takashio S., Araki S., Sueta D., Kanazawa H., Suzuki S., Yoshimura H., Tsunoda R., Nishigami K., Uekihara S., Sakamoto K., Kawano H., Kaikita K., Matsui H., Tsujita K.
International Journal of Cardiology 293 248 - 253 2019.10
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background: In patients undergoing dialysis therapy, mitral annular calcification (MAC) is a powerful predictor of cardiovascular events and all-cause mortality. However, there is little data on predictors for MAC progression in patients undergoing dialysis therapy. Methods and results: We retrospectively analyzed 98 hemodialysis-dependent patients in Japanese Red Cross Kumamoto Hospital who underwent routine transthoracic echocardiography (TTE) in 2017. Three patients with history of surgical valve replacement or severe valvular heart diseases were excluded. In the 95 enrolled patients, MAC was detected by TTE in 28 patients (29%). A multivariate logistic regression analysis revealed that duration of hemodialysis therapy was independently associated with presence of MAC (odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.02–1.16; p < 0.01). Among the 95 patients, 72 patients also underwent routine TTE 5 years previously in 2012. In these patients, progression of MAC from 2012 to 2017 was observed in 11 patients (15%). A multivariate logistic regression analysis revealed that number of coronary risk factors (OR: 2.67; 95% CI: 1.24–5.76; p = 0.01), baseline MAC diameter (OR: 1.23; 95% CI: 1.05–1.45; p = 0.01), and left atrial diameter (OR: 0.81; 95% CI: 0.68–0.95; p = 0.01) were significantly associated with progression of MAC. Conclusions: Accumulation of coronary risk factors was associated with progression of MAC in patients undergoing dialysis. Management of coronary risk factors may be important for inhibition of MAC progression.
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Antithrombotic therapy for atrial fibrillation with stable coronary disease Reviewed
Yasuda S., Kaikita K., Akao M., Ako J., Matoba T., Nakamura M., Miyauchi K., Hagiwara N., Kimura K., Hirayama A., Matsui K., Ogawa H.
New England Journal of Medicine 381 ( 12 ) 1103 - 1113 2019.9
Language：English Publishing type：Research paper (scientific journal) Publisher：New England Journal of Medicine
BACKGROUND There are limited data from randomized trials evaluating the use of antithrombotic therapy in patients with atrial fibrillation and stable coronary artery disease. METHODS In a multicenter, open-label trial conducted in Japan, we randomly assigned 2236 patients with atrial fibrillation who had undergone percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) more than 1 year earlier or who had angiographically confirmed coronary artery disease not requiring revascularization to receive monotherapy with rivaroxaban (a non-vitamin K antagonist oral anticoagulant) or combination therapy with rivaroxaban plus a single antiplatelet agent. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause; this end point was analyzed for noninferiority with a noninferiority margin of 1.46. The primary safety end point was major bleeding, according to the criteria of the International Society on Thrombosis and Hemostasis; this end point was analyzed for superiority. RESULTS The trial was stopped early because of increased mortality in the combination-therapy group. Rivaroxaban monotherapy was noninferior to combination therapy for the primary efficacy end point, with event rates of 4.14% and 5.75% per patient-year, respectively (hazard ratio, 0.72; 95% confidence interval [CI], 0.55 to 0.95; P<0.001 for noninferiority). Rivaroxaban monotherapy was superior to combination therapy for the primary safety end point, with event rates of 1.62% and 2.76% per patient-year, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P=0.01 for superiority). CONCLUSIONS As antithrombotic therapy, rivaroxaban monotherapy was noninferior to combination therapy for efficacy and superior for safety in patients with atrial fibrillation and stable coronary artery disease.
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Sato K., Takahashi J., Odaka Y., Suda A., Sueda S., Teragawa H., Ishii K., Kiyooka T., Hirayama A., Sumiyoshi T., Tanabe Y., Kimura K., Kaikita K., Ong P., Sechtem U., Camici P.G., Kaski J.C., Crea F., Beltrame J.F., Shimokawa H.
International Journal of Cardiology 291 13 - 18 2019.9
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background: Possible ethnic differences in clinical characteristics and long-term prognosis of contemporary patients with vasospastic angina (VSA) remain to be elucidated. Methods and results: The Japanese Coronary Spasm Association (JCSA) conducted an international, prospective, and multicenter registry study for VSA patients. A total of 1457 VSA patients (Japanese/Caucasians, 1339/118) were enrolled based on the same diagnostic criteria. Compared with Caucasian patients, Japanese patients were characterized by higher proportions of males (68 vs. 51%) and smoking history (60 vs. 49%). Japanese patients more often had angina especially during the night and early morning hours, compared with Caucasians. Ninety-five percent of Japanese and 84% of Caucasian patients underwent pharmacological provocation test. Importantly, no significant differences in the patterns of coronary spasm were apparent, with diffuse spasm most frequently noted in both ethnicities. The prescription rate of calcium-channel blockers was higher in Japanese (96 vs. 86%), whereas the uses of nitrates (46 vs. 59%), statins (43 vs. 65%), renin-angiotensin-system inhibitors (27 vs. 51%), and β-blockers (10 vs. 24%) were more common in Caucasian patients. Survival rate free from major adverse cardiac events (MACE) was slightly but significantly higher in Japanese than in Caucasians (86.7 vs. 76.6% at 5 years, P < 0.001). Notably, multivariable analysis revealed that the JCSA risk score correlated with MACE rates not only in Japanese but also in Caucasian patients. Conclusion: These results indicate that there are ethnic differences in clinical profiles and long-term prognosis of contemporary VSA patients.
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Nishihara T., Yamamoto E., Sueta D., Fujisue K., Usuku H., Oike F., Takae M., Arima Y., Araki S., Takashio S., Nakamura T., Suzuki S., Sakamoto K., Soejima H., Kawano H., Kaikita K., Tsujita K., Roever L.
Medicine (United States) 98 ( 38 ) e17069 2019.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Medicine (United States)
Although serum magnesium (Mg) levels are closely associated with the prognosis of heart failure (HF) patients, the clinical significance of sMg levels on the cardiovascular outcomes of HF with preserved ejection fraction (HFpEF) patients is not fully understood. This study was a retrospective, single-center, observational study. We enrolled 452 consecutive HFpEF patients admitted to Kumamoto University Hospital. We defined lower sMg as <2.0mg/dl (=0.8mmol/L) based on recent clinical evidence and compared their clinical characteristics and prognosis. There were no significant differences between groups in the use of all medications (loop diuretics, mineralocorticoid receptor antagonists, renin-angiotensin-aldosterone system inhibitors, calcium channel blockers, beta blockers, statins, and Mg preparations). The lower sMg group showed a significantly higher prevalence of diabetes mellitus (DM), uric acid levels, and BNP levels compared with the higher sMg group. Kaplan-Meier curve revealed a significantly higher probability of HF-related events in the lower sMg group compared with the higher sMg group (log-rank test, P=.012). Multivariate Cox-proportional-hazard analysis revealed that the lower sMg group had significantly and independently higher probabilities of HF-related events compared with the higher sMg group (hazard ratio=2.37, 95% confidence intervals = 1.27-4.41, P=.007). We reclassified the risk of HF-related events after adding the lower sMg to the other prognostic factors (age, previous hospitalization for HF, DM, Ln-BNP); the continuous net reclassification improvement was 29.0% (P=.041). sMg levels might provide important prognostic information in regard to HFpEF.
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New definition of pulmonary hypertension in patients with heart failure with preserved ejection fraction Reviewed
Nishihara T, Yamamoto E＊, Tokitsu T, Sueta D, Fujisue K, Usuku H, Takashio S, Sakamoto K, Kaikita K, Tsujita K
American Journal of Respiratory and Critical Care Medicine 200 ( 3 ) 386 - 388 2019.8
Language：English Publishing type：Research paper (scientific journal)
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Fujisue K., Tokitsu T., Yamamoto E., Sueta D., Takae M., Nishihara T., Oike F., Usuku H., Ito M., Motozato K., Kanazawa H., Araki S., Arima Y., Takashio S., Izumiya Y., Suzuki S., Sakamoto K., Kaikita K., Tsujita K.
Medicine (United States) 98 ( 28 ) e15959 2019.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Medicine (United States)
The prognostic significance of systemic atherothrombosis in heart failure (HF) with preserved ejection fraction (HFpEF) remains unclear. This study aimed to investigate the relation between the presence of polyvascular disease (PVD) and cardiovascular outcomes in HFpEF patients.A total of 510 consecutive HFpEF patients were prospectively observed for up to 1500 days or until occurrence of cardiovascular events. PVD was defined as ≥2 coexistence of coronary artery disease, peripheral arterial disease, and cerebrovascular disease.Overall, 124 cardiovascular events were observed during follow-up (median: 1430 days). Kaplan-Meier curve showed HFpEF with PVD (n=84) experienced more cardiovascular events than did those without PVD patients (44.0% vs 20.4%, log-rank: P<.001). Multivariable Cox proportional hazards analysis with significant factors from univariate analysis showed the presence of PVD (hazard ratio [HR]: 2.875, 95% [CI]: 1.894-4.365, P<.001), previous HF hospitalization (HR: 1.578, 95% CI: 1.031-2.414, P=.036), hemoglobin (HR: 0.889, 95% CI: 0.805-0.983, P=.021), serum sodium (HR: 0.946, 95% CI 0.896-1.000, P=.048), ln-BNP (per 1.0, HR: 1.255, 95% CI: 1.055-1.494, P=.010), and E/e' (HR: 1.047, 95% CI: 1.020-1.075, P<.001) significantly predicted future cardiovascular events. Multivariable Cox hazard analysis with 4 established factors (age, BNP, diabetes mellitus, and previous HF hospitalization) from the I-PRESERVE (Irbesartan in HFpEF) study showed PVD was independently associated with cardiovascular events in HFpEF patients (HR: 2.562, 95% CI: 1.715-3.827, P<.001).The presence of PVD is significantly associated with cardiovascular events in HFpEF, suggesting the importance of screening PVD in HFpEF.
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Takae M., Yamamoto E., Tokitsu T., Oike F., Nishihara T., Fujisue K., Sueta D., Usuku H., Motozato K., Ito M., Kanazawa H., Araki S., Nakamura T., Arima Y., Takashio S., Suzuki S., Sakamoto K., Soejima H., Yamabe H., Kaikita K., Tsujita K.
American Journal of Hypertension 32 ( 7 ) 657 - 667 2019.6
Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Hypertension
BACKGROUND: Although pulse wave velocity (PWV) is recognized to be a risk predictor for various cardiovascular diseases, the association of brachial-ankle PWV (baPWV) with cardiovascular outcomes in heart failure (HF) with reduced ejection fraction (HFrEF) patients remains uncertain. METHODS: We measured ankle-brachial pressure index (ABI) and baPWV values at stable condition after optimal therapy for HF in 201 consecutive HFrEF patients admitted to Kumamoto University Hospital from 2007 to 2015 who were enrolled and followed until the occurrence of cardiovascular events. We defined peripheral artery disease (PAD) as ABI value ≤ 0.9. RESULTS: Kaplan-Meier analysis revealed that HFrEF patients with peripheral artery disease PAD had a significant higher risk of total cardiovascular and HF-related events than those without PAD (P = 0.03 and P = 0.01, respectively). Next, we divided HFrEF patients without PAD into 3 groups according to baPWV values. In the Kaplan-Meier analysis, total cardiovascular and HF-related events in the highest baPWV group (1,800 cm/second ≤ baPWV) had a significantly higher frequency than those in the mid-level baPWV group (1,400 cm/second ≤ baPWV < 1,800 cm/second) (P = 0.007 and P = 0.004, respectively). The hazard ratio between HFrEF patients in the mid-level baPWV group and those with other baPWV groups was compared after adjustment for other cofounders. The probabilities of HF-related events were significantly higher in the lowest and highest baPWV group. CONCLUSION: Identifying complications of PAD and measuring baPWV values in HFrEF patients were useful for predicting their prognosis. Trial Registration: UMIN000034358.
DOI： 10.1093/ajh/hpz048
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Ishii M., Kaikita K., Mitsuse T., Nakanishi N., Oimatsu Y., Yamashita T., Nagamatsu S., Tabata N., Fujisue K., Sueta D., Takashio S., Arima Y., Sakamoto K., Yamamoto E., Tsujita K.
IJC Heart and Vasculature 23 100346 2019.6
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：IJC Heart and Vasculature
Introduction: Bleeding complications after transcatheter aortic valve implantation (TAVI) is a major problem in clinical practice. However, there is few information on thrombogenicity after TAVI. The aim of this study was to establish a monitoring of total thrombogenicity in perioperative TAVI using the Total Thrombus-formation Analysis System (T-TAS), a microchip-based flow chamber system for analysis of thrombus formation under flow condition. Methods: Twenty-three patients with severe aortic stenosis who underwent TAVI between August 2017 and March 2018 at Kumamoto university hospital were enrolled. After exclusion, data of 21 patients were analyzed. Blood samples were obtained before, 2, 7, and 30 days after TAVI. Thrombogenicity were assessed by the T-TAS to compute the area under the curve (AUC) (AR -AUC ) in the AR chip. We also measured platelet count, high-molecular-weight von Willebrand factor (HMW-vWF) multimers, and plasma thrombopoietin. Computational fluid dynamics (CFD) analysis was performed to calculate the wall shear stress (WSS). Results: The AR -AUC levels and platelet counts were significantly lower at 2 days post-TAVI, and then increased gradually. HMW-vWF multimers, and plasma thrombopoietin, were significantly higher at 2 days post-TAVI, compared with before TAVI. CFD analysis showed that WSS of the aortic valve and posterior ascending aortic wall were significantly lower after TAVI than before-TAVI. Multivariate analysis identified max velocity measured by echocardiography, platelet count, and D-dimer as significant determinants of AR -AUC , representing total thrombogenicity. Conclusions: Although HMW-vWF multimers improved earlier after TAVI, total thrombogenic activity evaluated by T-TAS remained relatively low followed by improvement in thrombogenic activity at 30 days after TAVI. Clinical Trial Registration: https://clinicaltrials.gov. Unique identifiers: NCT03248232. 10 30 10 30 10 30
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Basal septal perforator vein mimicking the “late iodine enhancement” in delayed phase cardiac CT for myocardial scar assessment Reviewed
Kidoh M＊, Oda S, Utsunomiya D, Emoto R.T, Nakaura T, Nagayama Y, Yamamoto M, Sakamoto K, Yamamoto E, Kaikita K, Tsujita K, Yamashita Y
Radiology Case Reports 14 ( 5 ) 588 - 590 2019.5
Language：English Publishing type：Research paper (scientific journal)
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A retrospective study of arterial stiffness and subsequent clinical outcomes in cancer patients undergoing percutaneous coronary intervention. Reviewed
Tabata N, Sueta D, Yamamoto E, Takashio S, Arima Y, Araki S, Yamanaga K, Ishii M, Sakamoto K, Kanazawa H, Fujisue K, Hanatani S, Soejima H, Hokimoto S, Izumiya Y, Kojima S, Yamabe H, Kaikita K, Matsui K, Tsujita K
Journal of hypertension 37 ( 4 ) 754 - 764 2019.4
Language：English Publishing type：Research paper (scientific journal)
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Misumi I., Motozato K., Yamabe H., Ohmori K., Usuku H., Kaikita K., Tsujita K.
Echocardiography 36 ( 3 ) 605 - 608 2019.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Echocardiography
A 16-year-old healthy boy visited our department because of a heart murmur. A 12-lead electrocardiogram showed left QRS axis deviation and repolarization abnormalities. Transthoracic echocardiography and a computed tomographic scan revealed a hypertrophied papillary muscle and a discrete ridge arising from the septal wall, causing mid-ventricular obstruction. Doppler echocardiography revealed that the pressure gradient at the obstruction was mild. The patient will be followed up annually, without medication or physical restriction.
DOI： 10.1111/echo.14259
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Takae M., Yamamoto E., Fujisue K., Oike F., Nishihara T., Sueta D., Usuku H., Motozato K., Ito M., Hanatani S., Kanazawa H., Arima Y., Takashio S., Nakamura T., Suzuki S., Sakamoto K., Izumiya Y., Soejima H., Kojima S., Yamabe H., Kaikita K., Tsujita K.
International Journal of Cardiology 277 3 - 7 2019.2
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background: Thrombus formation is one of the main pathogeneses of acute coronary syndrome with atherosclerotic rupture. Previous studies have reported that atherosclerosis increases platelet aggregability and that vascular endothelial dysfunction reflects early change of atherosclerosis. However, the relationship between coronary endothelial dysfunction and platelet reactivity remains unclear. Therefore, in this study, we investigated the relationship between them in non-obstructive ischemic heart disease (IHD) patients. Methods: Three hundred sixty-eight consecutive stable patients with suspected angina presenting non-obstructive coronary arteries (<50% diameter) in coronary angiography were investigated with the intracoronary acetylcholine provocation test and measured adenosine triphosphate-induced coronary flow reserve. Finally, 25 non-obstructive IHD patients who had no anti-platelet agents were assessed for the relationship between coronary blood flow volume (CBFV) change and platelet aggregability as P2Y12 reaction unit (PRU) by VerifyNow P2Y12 assay system. Results: CBFV change by intracoronary 20 μg/kg per minute acetylcholine provocation showed a significant negative correlation with platelet aggregability as PRU (r = 0.44, P = 0.03). Conversely, there was no significant correlation between PRU and endothelial function as coronary flow reserve. Furthermore, multivariable linear regression analysis indicated that an incremental CBFV change was independently associated with PRU (β = 0.63, P < 0.001) in non-obstructive IHD patients. Conclusions: In patients with non-obstructive IHD, CBFV change was significantly associated with platelet aggregability, indicating that coronary endothelial dysfunction might mediate higher platelet aggregability.
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Comprehensive assessment of takotsubo cardiomyopathy by cardiac computed tomography Reviewed
Sueta D., Oda S., Izumiya Y., Kaikita K., Kidoh M., Utsunomiya D., Yamashita Y., Tsujita K.
Emergency Radiology 26 ( 1 ) 109 - 112 2019.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Emergency Radiology
Cardiac computed tomography (CT) now plays an important role in emergency settings because of its accessibility and fast acquisition time, which cardiac magnetic resonance imaging (CMR) cannot match. Although cardiac CT was originally conceived for the assessment of the coronary artery tree, it has evolved to embrace several non-coronary applications. These include myocardial assessment, resulting in myocardial characterization comparable with that of CMR and cardiac CT for late enhancement imaging. In this report, we describe a patient with takotsubo cardiomyopathy who underwent a comprehensive assessment using cardiac CT. This technique enabled to identify the condition of the coronary arteries and to evaluate the four-dimensional left ventricular function and myocardial late iodine enhancement immediately. The information obtained was similar to that provided by CMR; however, cardiac CT is more practical than CMR in emergency settings. Comprehensive assessment by cardiac CT can be beneficial for a noninvasive evaluation of patients with suspected takotsubo cardiomyopathy.
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Hirakawa K., Takashio S., Marume K., Yamamoto M., Hanatani S., Yamamoto E., Sakamoto K., Izumiya Y., Kaikita K., Oda S., Utsunomiya D., Shiraishi S., Ueda M., Yamashita T., Yamashita Y., Ando Y., Tsujita K.
ESC Heart Failure 6 ( 1 ) 122 - 130 2019.2
Language：English Publishing type：Research paper (scientific journal) Publisher：ESC Heart Failure
Aims: Mutant transthyretin (ATTRm) amyloidosis is a systemic disease caused by the deposition of amyloid fibrils derived from mutated transthyretin. Although cardiac involvement impacts the prognosis of patients with ATTRm amyloidosis, the incidence of cardiac events, such as bradyarrhythmia, ventricular tachycardia, and heart failure, has not been fully elucidated. The aim of this study was to evaluate the prognosis and predictors of clinical outcomes, including cardiac events, in patients with ATTRm amyloidosis in Japan. Methods and results: We evaluated 90 consecutive patients with ATTRm amyloidosis at Kumamoto University. ATTRm amyloidosis was diagnosed by the observation of both amyloid fibril deposition on tissue biopsy and a transthyretin mutation on sequential analysis. Sympathetic nerve activity was evaluated in 59 patients using 123-iodine metaiodobenzylguanidine ( I-MIBG) imaging. The endpoint was a composite of all-cause death, hospitalization for heart failure, and implantation of a pacemaker, implantable cardioverter defibrillator, or cardiac resynchronization therapy defibrillator. Sixty-seven patients had the Val30Met mutation (74%). The composite endpoint occurred in 23 patients (26%): all-cause death (n = 6), hospitalization for worsening heart failure (n = 1), and implantation of an implantable cardioverter defibrillator (n = 6), cardiac resynchronization therapy defibrillator (n = 3), or pacemaker (n = 7). The 5-year incident rate for clinical outcomes was 19%. In a multivariate Cox hazard analysis, age [hazard ratio (HR): 1.07, 95% confidence interval (95% CI): 1.01–1.12, P = 0.015], PQ interval (HR: 1.01, 95% CI: 1.00–1.02, P = 0.042), interventricular septum thickness in diastole (HR: 1.25, 95% CI: 1.09–1.42, P = 0.001), and non-Val30Met mutation (HR: 4.31, 95% CI: 1.53–12.16, P = 0.006) were independent predictive factors of clinical outcomes. Kaplan–Meier analysis demonstrated a significantly higher probability of the composite endpoint in the non-Val30Met group than in the Val30Met group (log-rank test: P = 0.002) and in patients with left ventricular hypertrophy than in patients without left ventricular hypertrophy (log-rank test: P < 0.001). In patients who underwent I-MIBG imaging, a delayed heart-to-mediastinum (HM) ratio <1.6 was a significant predictive factor of the composite endpoint (HR: 4.98, 95% CI: 1.73–14.37, P = 0.003) in the univariate Cox hazard analyses. Kaplan–Meier curve analysis showed that a delayed HM ratio <1.6 was associated with a poor prognosis (log-rank test: P = 0.001). Conclusions: Non-Val30Met mutation, septal hypertrophy, and a delayed HM ratio are useful predictors of clinical outcomes in patients with ATTRm amyloidosis in Japan. These results suggest that it is important to evaluate cardiac involvement in terms of morphological (left ventricular hypertrophy) and functional (cardiac denervation) perspectives using echocardiography and I-MIBG imaging, respectively. 123 123 123
DOI： 10.1002/ehf2.12361
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Uchiyama S., Atarashi H., Inoue H., Kitazono T., Yamashita T., Shimizu W., Ikeda T., Kamouchi M., Kaikita K., Fukuda K., Origasa H., Shimokawa H.
Heart and Vessels 34 ( 1 ) 141 - 150 2019.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Heart and Vessels
The EXPAND Study examined the real-world efficacy and safety of rivaroxaban for the prevention of stroke and systemic embolism (SE) in Japanese patients with non-valvular atrial fibrillation (NVAF). In this sub-analysis, we compared the differences in efficacy and safety between patients with and those without history of stroke or transient ischemic attack (TIA). This multicenter, prospective, non-interventional, observational, cohort study was conducted at 684 medical centers in Japan. A total of 7141 NVAF patients aged ≥ 20 years [mean age 71.6 ± 9.4 (SD) years] who were being or planned to be treated with rivaroxaban (10 mg/day, 43.5%; 15 mg/day, 56.5%) were followed for a mean period of 897.1 ± 206.8 days with a high follow-up rate (99.7%). The primary prevention group comprised patients without history of ischemic stroke or TIA (n = 5546, 77.7%), and the secondary prevention group comprised those with history of ischemic stroke or TIA (n = 1595, 22.3%). In the primary and secondary prevention groups, the incidence rate of stroke or SE (primary efficacy endpoint) was 0.7 and 2.2%/year, respectively (P < 0.001), and the incidence rate of major bleeding (primary safety endpoint) was 1.2 and 1.5%/year, respectively (P = 0.132). For major bleeding events, the incidence rate of intracranial bleeding was 0.4 and 0.8%/year (P = 0.002) in the primary and secondary prevention groups, respectively. This sub-analysis of the EXPAND Study showed that the Japan-specific dosages of rivaroxaban were effective and safe in Japanese NVAF patients with and those without ischemic stroke or TIA in routine clinical practice.
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Myocardial ischemia suppresses ketone body utilization Reviewed
Arima Y＊, Izumiya Y, Ishida T, Takashio S, Ishii M, Sueta D, Sakamoto K, Fujisue K, Kaikita K, Tsujita K
J Am Coll Cardiol 73 ( 2 ) 246 - 247 2019.1
Language：English Publishing type：Research paper (scientific journal)
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Marume K., Takashio S., Nishi M., Hirakawa K., Yamamoto M., Hanatani S., Oda S., Utsunomiya D., Shiraishi S., Ueda M., Yamashita T., Sakamoto K., Yamamoto E., Kaikita K., Izumiya Y., Yamashita Y., Ando Y., Tsujita K.
Circulation Journal 83 ( 8 ) 1698 - 1708 2019
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: A recent study revealed a high prevalence of transthyretin (TTR) cardiac amyloidosis (CA) in elderly patients. 99 Tc-labeled pyrophosphate ( Tc-PYP) scintigraphy is a remarkably sensitive and specific modality for TTR-CA, but is only available in specialist centres; thus, it is important to raise the pretest probability. The aim of this study was to evaluate the characteristics of patients with Tc-PYP positivity and make recommendations about patient selection for Tc-PYP scintigraphy. Methods and Results: We examined 181 consecutive patients aged ≥70 years who underwent Tc-PYP scintigraphy at Kumamoto University Hospital between January 2012 and December 2018. Logistic regression analyses showed that high-sensitivity cardiac troponin T (hs-cTnT) ≥0.0308 ng/mL, left ventricular posterior wall thickness ≥13.6 mm, and wide QRS (QRS ≥120 ms) were strongly associated with Tc-PYP positivity. We developed a new index for predicting Tc-PYP positivity by adding 1 point for each of the 3 factors. The Tc-PYP positive rate increased by a factor of 4.57 for each 1-point increase (P<0.001). Zero points corresponded to a negative predictive value of 87% and 3 points corresponded to a positive predictive value of 96% for Tc-PYP positivity. Conclusions: The combination of biochemical (hs-cTnT), physiological (wide QRS), and structural (left ventricular posterior wall thickness) findings can raise the pretest probability for Tc-PYP scintigraphy. It can assist clinicians in determining management strategies for elderly patients with suspected CA. m 99 m 99 m 99 m 99 m 99 m 99 m 99 m 99 m 99 m
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Takotsubo Cardiomyopathy mimicking acute coronary syndrome - extracellular volume quantification using cardiac computed tomography Reviewed
Sueta D＊, Oda S, Yamamoto E, Nishi M, Kaikita K, Kidoh M, Utunomiya D, Nakaura T, Yamashita Y, Tsujita K
Circulation Journal 83 ( 7 ) 1613 2019
Language：English Publishing type：Research paper (scientific journal)
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Isolated right ventricular apical hypoplasia without atrial septal defect Reviewed
Otsuka Y, Sato K, Sueta D＊, Suzuki S, Matsuo O, Usuku H, Imamura K, Takashio S, Oda S, Arima Y, Sakamoto K, Yamamoto E, Nakamura S, Kawano H, Kaikita K, Tsujita K
Circulation Journal 83 ( 7 ) 1615 2019
Language：English Publishing type：Research paper (scientific journal)
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Ito M., Yamabe H., Koyama J., Kanazawa H., Kaneko S., Kanemaru Y., Kiyama T., Arima Y., Takashio S., Yamamoto E., Izumiya Y., Kojima S., Kaikita K., Shono T., Utsunomiya D., Sasaki Y., Yamashita Y., Tsujita K.
Journal of Cardiology 72 ( 6 ) 480 - 487 2018.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
Background: Esophageal injury (EI) is a serious complication that occurs after catheter ablation of atrial fibrillation (AF), however predictable factor of EI is unclear. Methods: Among 308 patients who underwent AF ablation, upper gastrointestinal tract endoscopy was performed the next day after ablation to examine for EI. To define the primary factor that predicts EI, patients’ characteristics, number and amount of radiofrequency energy applied to the posterior wall, ablation procedure, and the shortest distance between esophagus and posterior left atrium measured on contrast computed tomography (SD-CT) were analyzed. Results: EI was found in 27 patients (8.8%). There were no significant differences in the patient characteristics, number and amount of radiofrequency energy applied to posterior wall or ablation procedure between patients with (Injury Group) and without EI (Non-Injury Group). However, SD-CT in the Injury Group was significantly shorter than that in Non-Injury Group (2.3 ± 0.6 mm vs 4.1 ± 0.9 mm, p < 0.001). The area under a receiver operating characteristic curve using SD-CT as a predictive marker in EI patients was 0.988 (p < 0.001). When the cut-off value of SD-CT was set at 2.9 mm, the sensitivity and specificity for EI diagnosis were 92.3% and 96.8%, and the positive predictive value and negative predictive value were 0.75 and 0.99, respectively. Conclusions: EI observed after catheter ablation of AF was closely associated with the SD-CT. Patients with SD-CT below 2.9 mm have a potential risk of EI and thus must be strictly followed.
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冠攣縮と急性冠症候群
海北幸一, 辻田賢一.
日本臨牀 76 ( 12 ) 2109 - 2114 2018.12
Authorship：Lead author Publishing type：Research paper (scientific journal)
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Fujisue K., Nagamatsu S., Shimomura H., Yamashita T., Nakao K., Nakamura S., Ishihara M., Matsui K., Yamamoto N., Koide S., Matsumura T., Fujimoto K., Tsunoda R., Morikami Y., Matsuyama K., Oshima S., Sakamoto K., Izumiya Y., Kaikita K., Hokimoto S., Ogawa H., Tsujita K.
International Journal of Cardiology 268 23 - 26 2018.10
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background: Chronic kidney disease (CKD) deteriorates the prognosis of patients undergoing percutaneous coronary intervention (PCI). Because coronary artery disease (CAD) is the major cause of death in CKD patients, cardiovascular risk reduction has been clinically important in CKD. We hypothesized intensive lipid-lowering with statin/ezetimibe attenuated coronary atherosclerotic development even in patients with CKD. Methods: In the prospective, randomized, controlled, multicenter PRECISE-IVUS trial, 246 patients undergoing intravascular ultrasound (IVUS)-guided PCI were randomly assigned to receive atorvastatin/ezetimibe combination or atorvastatin alone (the dosage of atorvastatin was up-titrated to achieve the level of low-density lipoprotein cholesterol < 70 mg/dL). Serial volumetric IVUS findings obtained at baseline and 9–12 month follow-up to quantify the coronary plaque response in 202 patients were compared stratified by the presence or absence of CKD. Results: CKD was observed in 52 patients (26%) among 202 enrolled patients. Compared with the non-CKD group, the CKD group was significantly older (71.5 ± 8.6 years vs. 64.4 ± 9.6 years, P < 0.001) with similar prevalence of comorbid coronary risk factors and lipid profiles. Similar to the non-CKD group (−1.4 [−2.8 to −0.1]% vs. −0.2 [−1.7 to 1.0]%, P = 0.002), the atorvastatin/ezetimibe combination significantly reduced ∆PAV compared with atorvastatin alone even in the CKD group (−2.6 [−5.6 to −0.4]% vs. −0.9 [−2.4 to 0.2]%, P = 0.04). Conclusions: As with non-CKD, intensive lipid-lowering therapy with atorvastatin/ezetimibe demonstrated stronger coronary plaque regression effect even in patients with CKD compared with atorvastatin monotherapy. Trial registration: NCT01043380 (ClinicalTrials.gov).
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Hanatani S., Izumiya Y., Onoue Y., Tanaka T., Yamamoto M., Ishida T., Yamamura S., Kimura Y., Araki S., Arima Y., Nakamura T., Fujisue K., Takashio S., Sueta D., Sakamoto K., Yamamoto E., Kojima S., Kaikita K., Tsujita K.
International Journal of Cardiology 268 216 - 221 2018.10
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background: Sarcopenia is frequently observed and associated with poor outcomes in patients with chronic kidney disease (CKD). A simple screening test for sarcopenia using age, grip strength, and calf circumference was recently developed. However, the clinical utility of this sarcopenia score in patients with CKD remains unclear. Methods and results: We calculated the sarcopenia score of 265 patients with CKD and followed the patients for cardiovascular events. The endpoint of this study was the composite of cardiovascular hospitalization and total mortality. We divided all participants into high (n = 166) and low (n = 99) sarcopenia score groups using a simple scoring system. Patients in the high sarcopenia score group showed significantly higher plasma B-type natriuretic peptide (BNP) levels than those in the low sarcopenia score group (median: 103.1, interquartile range: 46.3–310.0 vs. 46.7, 18.0–91.8 pg/mL; p < 0.0001). The Kaplan–Meier curve revealed that the risk of cardiovascular events was significantly greater in the high sarcopenia score group (log-rank test: p < 0.0001), even after potential confounding factors were corrected using propensity score matching. Multivariate Cox hazard analysis identified a high sarcopenia score (hazard ratio: 3.04, 95% confidence interval: 1.45–6.38, p = 0.003) as an independent predictor of the primary endpoints. Furthermore, the combination of a high sarcopenia score and high BNP level identified patients with a significantly higher probability of future events (p < 0.0001). Conclusions: This study demonstrates that this simple screening score for sarcopenia could be a useful tool for estimating the future adverse event risk in patients with CKD.
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Fujisue K., Shirakawa T., Nakamura S., Yamamoto N., Oshima S., Matsumura T., Tsunoda R., Hirai N., Tayama S., Nakamura N., Hirose T., Maruyama H., Fujimoto K., Kajiwara I., Sakamoto T., Nakao K., Sakaino N., Hokimoto S., Nagayoshi Y., Hokamaki J., Shimomura H., Sakamoto K., Yamamoto E., Izumiya Y., Kaikita K., Ogawa H., Tsujita K.
Journal of Cardiology 72 ( 4 ) 350 - 355 2018.10
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
Background: Acute myocardial infarction (AMI) is mainly characterized by the rupture of lipid-rich vulnerable atherosclerotic plaque. The matrix metalloproteinases (MMPs) have been shown to play a critical role in inflammatory processes underlying plaque rupture. Some reports suggested statins inhibit the increased MMP levels after AMI. However, there are a few comparison studies between the different dosages of the same statin and circulating levels of MMPs. Purpose: This study will preliminarily investigate the potential effects of appropriate or low dose of rosuvastatin on circulating MMPs levels in AMI patients. Moreover, we will also obtain plasma from patients while undergoing diagnostic angiography to determine differences in various cardiac sites and peripheral vessels. Methods: This study is a multicenter, open-label, randomized, parallel-group study to be conducted to compare the appropriate or low dose of rosuvastatin in the effect on serum levels of inflammatory markers in AMI patients. The eligible patients undergoing percutaneous coronary intervention (PCI) will be randomly assigned to receive either appropriate or low-dose rosuvastatin daily using a web-based randomization software within 24 h after PCI. The low-dose group will be treated with rosuvastatin 2.5 mg once daily with a follow-up. The appropriate-dose group will begin treatment with rosuvastatin 5 mg once daily, and the dose of rosuvastatin will be titrated to 10 mg within 4 weeks. During administration of the study treatment, subjects will undergo laboratory testing including MMPs and be monitored for the occurrence of adverse events up to 24 weeks. The primary endpoint will be the change rate of MMPs at 24 weeks after administration. Conclusions: INVITATION will compare the appropriate or low dose of rosuvastatin in the effects on serum levels of inflammatory markers including MMPs in AMI patients. This study will provide significant information on rosuvastatin as an anti-inflammatory agent for AMI.
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Impact of current and past cancer history on the risk of cardiovascular events following percutaneous coronary intervention: a Kumamoto University Malignancy and Atherosclerosis (KUMA) study Reviewed
Tabata N, Sueta D＊, Yamamoto E, Takashio S, Arima Y, Araki S, Yamanaga K, Ishii M, Sakamoto K, Kanazawa H, Fujisue K, Hanatani S, Soejima H, Hokimoto S, Izumiya Y, Kojima S, Yamabe H, Kaikita K, Tsujita K
Eur Heart J - Qual Care Clin Outcomes 4 ( 4 ) 290 - 300 2018.10
Language：English Publishing type：Research paper (scientific journal)
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Nishihara T., Tokitsu T., Sueta D., Takae M., Oike F., Fujisue K., Usuku H., Takashio S., Hanatani S., Kanazawa H., Arima Y., Sakamoto K., Izumiya Y., Yamabe H., Kaikita K., Yamamoto E., Tsujita K.
American Journal of Hypertension 31 ( 10 ) 1098 - 1105 2018.9
Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Hypertension
BACKGROUND Although serum potassium (sK) levels are closely associated with the prognosis of chronic heart failure patients, the clinical significance of sK levels in cardiovascular outcomes of heart failure with preserved ejection fraction (HFpEF) patients is not fully understood. METHODS This study was a retrospective, single-center, observational study. We enrolled 506 consecutive HFpEF patients admitted to Kumamoto University Hospital and divided them into four groups according to the quartiles of the sK levels at discharge (Q1: sK < 4.1 mEq/l, Q2: 4.1 ≤ sK < 4.4 mEq/l, Q3: 4.4 ≤ sK < 4.7 mEq/l, and Q4: sK ≥ 4.7 mEq/l). RESULTS No significant differences were observed in the use of all drugs (loop diuretics, mineralocorticoid receptor antagonists, renin-angiotensin-aldosterone system inhibitors, calcium channel blockers, β-blockers, and statins) among the four groups. Hemoglobin, the estimated glomerular filtration rate, and pulse wave velocity levels were lower, and the serum sodium levels were higher in the Q4 group compared with those in the Q2 group. Kaplan-Meier analysis revealed significantly higher probabilities of both cardiovascular and HF-related events in the Q1, Q3, and Q4 groups than those in the Q2 group. Multivariate Cox proportional hazard analysis revealed that the Q1, Q3, and Q4 groups had significantly and independently higher probabilities of cardiovascular events compared with those in the Q2 group, indicating a J-shaped association between sK levels and cardiovascular events. CONCLUSIONS sK levels at discharge could provide important prognostic information in regard to HFpEF. Further evaluation in a larger number of patients might be needed. Clinical Trials Registration UMIN-CTR (http://www.umin.ac.jp/ctr/). Identifier UMIN000029600. Public Access Information Opt-out materials are available at the website: http://www.kumadai-junnai.com/home/wp-content/uploads/houkatsu.pdf.
DOI： 10.1093/ajh/hpy101
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Sueta D., Utsunomiya D., Izumiya Y., Nakaura T., Oda S., Kaikita K., Yamashita Y., Tsujita K.
Journal of Cardiology Cases 18 ( 3 ) 88 - 91 2018.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology Cases
Because the prognosis of pulmonary thromboembolism (PTE) will be often poor, early diagnosis and assessing severity at the first visit is important. A 76-year-old man with suspected venous thromboembolism and a contrast deficit in the pulmonary artery (PA) was revealed by contrast-enhanced computed tomography (CT) imaging by dual-layer spectral-detector CT (IQon Spectral CT , Philips Healthcare, Best, The Netherlands). The lung perfusion image showed decreased perfusion in the culprit lesion. The dual-energy analysis of the virtual monoenergetic imaging showed clear visualization of deep vein thrombosis (DVT). In a 64-year-old man, an IQon Spectral CT revealed a small contrast deficit in the PA. However, no perfusion abnormality was detected in the lung perfusion analysis. The IQon Spectral CT enables the detection of lung perfusion abnormalities in addition to PTE. The IQon Spectral CT imaging may be useful for the “one-stop shop” evaluation of PTE and DVT. <Learning objective: The prognosis of pulmonary thromboembolism (PTE) will be often poor, so early diagnosis and assessing severity at the first visit is important. The dual-layer spectral-detector computed tomography imaging for PTE, whereby the iodine map provided information regarding lung perfusion, whereas virtual monoenergetic images enabled clear visualization of deep vein thrombosis.> ® ® ® ®
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Yasuda S., Kaikita K., Ogawa H., Akao M., Ako J., Matoba T., Nakamura M., Miyauchi K., Hagiwara N., Kimura K., Hirayama A., Matsui K.
International Journal of Cardiology 265 108 - 112 2018.8
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background: In atrial fibrillation (AF) patients with coronary artery disease (CAD), anticoagulants are commonly used in combination with antiplatelet drugs. However, dual therapy can increase the risk of bleeding, and the potential therapeutic benefits must be weighed against this. Therefore, it is recommended that dual therapy is only used for a limited time, and that monotherapy with anticoagulants should start from 1 year after percutaneous coronary intervention (PCI). However, there is a lack of evidence on the use of monotherapy, in particular with direct oral anticoagulants, in this group of patients. Methods: The AFIRE Study is a multicenter, prospective, randomized, open-label, parallel group study conducted in patients aged ≥20 years with non-valvular AF (NVAF) and CAD. Patients who have undergone PCI or coronary artery bypass graft at least 1 year prior to enrollment, or those without significant coronary lesions requiring PCI (≥50% stenosis), will be included. Approximately 2200 participants will be randomized to receive either rivaroxaban monotherapy or rivaroxaban plus an antiplatelet drug (aspirin, clopidogrel, or prasugrel). The primary efficacy endpoints are the composite of cardiovascular events (stroke, non-central nervous system embolism, myocardial infarction, and unstable angina pectoris requiring revascularizations) and all-cause mortality. The primary safety endpoint is major bleeding as defined by the International Society on Thrombosis and Haemostasis criteria. Conclusions: This study will be the first to assess the efficacy and safety of rivaroxaban monotherapy in NVAF patients with stable CAD.
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Shimokawa H., Yamashita T., Uchiyama S., Kitazono T., Shimizu W., Ikeda T., Kamouchi M., Kaikita K., Fukuda K., Origasa H., Sakuma I., Saku K., Okumura Y., Nakamura Y., Morimoto H., Matsumoto N., Tsuchida A., Ako J., Sugishita N., Shimizu S., Atarashi H., Inoue H.
International Journal of Cardiology 258 126 - 132 2018.5
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Aims: The EXPAND study examined the real-world efficacy and safety of rivaroxaban for the prevention of stroke and systemic embolism (SE) in Japanese patients with non-valvular atrial fibrillation (NVAF). Methods and results: This multicenter, prospective, non-interventional, observational, cohort study was conducted at 684 medical centers in Japan. A total of 7141 NVAF patients ≥20 years of age (mean, 71.6 ± 9.4 years) who were being or about to be treated with rivaroxaban (10 mg/day, 43.5%; 15 mg/day, 56.5%) were followed for an average of 897.1 (±206.8) days with a high follow-up rate (99.65%). The mean CHADS score at baseline was 2.1 (1.3) (0–1, 37%; 2, 29%; ≥3, 34%). The total incidence rate of symptomatic stroke and SE (primary efficacy endpoint) was 1.0%/year, and 0.5%, 0.9%, and 1.7%/year for those with CHADS scores of 0–1, 2, and ≥3, respectively. Cumulative incidence rates for major bleeding (primary safety endpoint) and non-major bleeding (secondary safety endpoint) were 1.2%/year and 4.9%/year, respectively. Differences were noted between new and current users only for major bleeding event rate (1.7% vs. 1.1%/year, P = 0.0024). Comparisons with previous studies suggested that rivaroxaban is effective and safe for low-risk patients (0–1 CHADS ), as shown for warfarin in the XANTUS international prospective post-marketing study. Conclusions: The EXPAND study demonstrated that low dosages of rivaroxaban for Japanese NVAF patients in real-world clinical practice, including those with CHADS scores 0–1, resulted in low rates of stroke and SE, and major and non-major bleeding. 2 2 2 2
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Nakayama M., Yamamuro M., Takashio S., Uemura T., Nakayama N., Hirakawa K., Oda S., Utsunomiya D., Kaikita K., Hokimoto S., Yamashita Y., Morita Y., Kimura K., Tamura K., Tsujita K.
Heart and Vessels 33 ( 4 ) 393 - 402 2018.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Heart and Vessels
Myocardial fibrosis and coronary endothelial dysfunction are important determinants of outcome in patients with heart failure. However, the relationship of these factors in patients with dilated cardiomyopathy (DCM) is not fully understood. This study aimed to investigate the relationship between endothelium-dependent coronary vasomotor abnormality and late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) in patients with DCM. We examined 38 consecutive patients with DCM. All patients underwent CMR and the acetylcholine (ACh) provocation test using cardiac catheterization. During the ACh provocation test, we sampled blood simultaneously from the coronary sinus and aortic root to compare lactate concentrations, and quantified coronary blood flow volume using an intracoronary Doppler-tipped guidewire. LGE was detected in 17 (44.7%) patients. The lactate extraction ratio (LER) in the ACh provocation test was significantly decreased in the LGE-positive group (before vs after ACh, 18.6 ± 13.6 vs − 13.3 ± 24.8%; p < 0.001) and in the LGE-negative group (before vs after ACh, 14.2 ± 19.5 vs 3.3 ± 16.2%; p = 0.02). The rate of patients with an LER < 0% (indicating myocardial lactate production due to myocardial ischemia) was significantly higher in the LGE-positive group than in the LGE-negative group [12 (70.6%) vs 7 (33.3%); p = 0.02]. Multivariable logistic regression analysis showed that a post-ACh LER < 0% was a significant predictor of LGE positivity (odds ratio 7.75; 95% confidence interval 1.37–43.68; p = 0.02). In conclusion, ACh-provoked coronary vasomotor abnormality is associated with myocardial fibrosis in patients with DCM. These results suggest that coronary endothelial dysfunction is involved in myocardial fibrosis and worsening heart failure concomitant with DCM.
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Arima Y., Hokimoto S., Tabata N., Nakagawa O., Oshima A., Matsumoto Y., Sato T., Mukunoki T., Otani J., Ishii M., Uchikawa M., Yamamoto E., Izumiya Y., Kaikita K., Ogawa H., Nishiyama K., Tsujita K.
Journal of the American Heart Association 7 ( 6 ) 2018.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American Heart Association
BACKGROUND: Collateral arteries provide an alternative blood supply and protect tissues from ischemic damage in patients with peripheral artery disease. However, the mechanism of collateral artery development is difficult to validate. METHODS AND RESULTS: Collateral arteries were visualized using micro-x-ray computed tomography. Developmental characteristics were assessed using confocal microscopy. We conducted a single-center, retrospective, observational study and assessed the dilatation of collateral arteries on ischemic sides. We quantified the vascular volume in both ischemic and nonischemic legs. A prominent increase in vascular volume was observed in the ischemic leg using a murine hind-limb ischemia model. We also performed qualitative assessment and confirmed that the inferior gluteal artery functioned as a major collateral source. Serial analysis of murine hind-limb vessel development revealed that the inferior gluteal artery was a remnant of the ischial artery, which emerged as a representative vessel on the dorsal side during hind-limb organogenesis. We retrospectively analyzed consecutive patients who were admitted for the diagnosis or treatment of peripheral artery disease. The diameter of the inferior gluteal artery on the ischemic side showed significant dilatation compared with that on the nonischemic side. CONCLUSIONS: Our findings indicate that an embryonic remnant artery can become a collateral source under ischemic conditions. Flow enhancement in the inferior gluteal artery might become a novel therapeutic approach for patients with peripheral artery disease.
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Tokitsu T., Yamamoto E., Oike F., Hirata Y., Tsujita K., Yamamuro M., Kaikita K., Hokimoto S.
Journal of Hypertension 36 ( 3 ) 560 - 568 2018.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Hypertension
Background: Although pulse-wave velocity (PWV) is a recognized risk predictor for cardiovascular diseases, its association with cardiovascular outcomes in heart failure with preserved left ventricular ejection fraction (HFpEF) is unclear. Methods and results: The 502 patients with HFpEF finally enrolled in this study (mean follow-up duration: 1017 days) were divided into those with or without peripheral artery disease (PAD). The latter were further grouped according to brachial-Ankle PWV (baPWV) quintiles using an ankle-brachial pressure index device. Kaplan-Meier analysis revealed a significantly higher risk of all-cause mortality and total cardiovascular events (both P = 0.01) in HFpEF patients with than without PAD. Multivariate Cox hazard analysis, including predictors identified as significant by simple Cox hazard analysis, identified PAD as a significant and independent predictor of cardiovascular events (hazard ratio: 1.85; 95% confidence interval: 1.01-3.39; P = 0.04). In an analysis of HFpEF patients without PAD grouped according to baPWV quintiles, estimated glomerular filtration rate (r = 0.21, P < 0.01) and hemoglobin (r = 0.18, P = 0.01) levels correlated negatively with baPWV. In the Kaplan-Meier analysis, patients with a baPWV more than 1900 cm/s and those with the lowest baPWV (<1300 cm/s) had a significantly higher frequency of total cardiovascular events than patients with 1300 baPWV or less which is less than 1900, indicating a J-shaped association between baPWV and total cardiovascular events as well as similarities to HFpEF patients with PAD. By contrast, the lowest baPWV group had the highest risk of heart failure-related events, accompanied by the highest brain natriuretic peptide levels. Conclusion: Identifying complications of PAD and measuring baPWV values in HFpEF patients can improve risk stratification.
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Nishihara T., Oda S., Sueta D., Izumiya Y., Kaikita K., Tsujita K., Utsunomiya D., Nakaura T., Yamashita Y.
Circulation: Cardiovascular Imaging 11 ( 2 ) e007277 2018.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation: Cardiovascular Imaging
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Yamabe H., Kaikita K., Matsumura T., Iwasa A., Koyama J., Uemura T., Morikami Y., Tsunoda R., Morihisa K., Fujimoto K., Kajiwara I., Matsui K., Tsujita K., Ogawa H.
Journal of Cardiology 71 ( 2 ) 129 - 134 2018.2
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
Background Experimental studies suggest that angiotensin II-receptor blockers can influence atrial remodeling and may prevent atrial fibrillation (AF). Therefore, we hypothesized that irbesartan may prevent the recurrence of AF following either catheter ablation or electrical cardioversion of AF. Methods Study on the Effect of Irbesartan on Atrial Fibrillation Recurrence in Kumamoto (SILK study) is a prospective, multicenter, randomized, and open-label comparative evaluation of the effects of irbesartan and amlodipine on AF recurrence in hypertensive patients with AF who are scheduled to undergo catheter ablation or electrical cardioversion of AF. The primary end point was either AF or atrial tachycardia (AT) recurrence. AF/AT recurrence was evaluated for 6 months using 24-h Holter electrocardiogram and portable electrocardiogram. The secondary endpoints included the change in blood pressure, the interval from the procedure to the first AF/AT recurrence, cardiovascular events, left atrial diameter (LAD), left ventricular ejection fraction (LVEF), and changes in the biomarkers [brain natriuretic polypeptide (BNP), high-sensitivity C-reactive protein (hs-CRP), urinary albumin/creatinine]. Results The study enrolled 98 patients (irbesartan; n = 47, amlodipine; n = 51). The recurrence of AF/AT was observed in 8 patients (17.0%) in the irbesartan group and in 10 patients (19.6%) in the amlodipine group. There was no significant difference in the AF/AT recurrence between the irbesartan and amlodipine groups. Blood pressure decreased similarly in both groups. There were no significant differences between the two groups as regards to the interval from the procedure to the first AF/AT recurrence, occurrence of cardiovascular events, changes in LAD and LVEF. BNP and urinary albumin/creatinine significantly decreased similarly in both groups, but no significant difference was found in hs-CRP between the two groups. Conclusions In hypertensive patients with AF, treatment with irbesartan did not have any advantage over amlodipine in the reduction of AF/AT recurrence after catheter ablation or electrical cardioversion.
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Onoue Y., Izumiya Y., Hanatani S., Ishida T., Arima Y., Yamamura S., Kimura Y., Araki S., Ishii M., Nakamura T., Oimatsu Y., Sakamoto K., Yamamoto E., Kojima S., Kaikita K., Tsujita K.
Circulation Journal 82 ( 11 ) 2905 - 2912 2018
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: Resistance exercise has beneficial effects for patients with peripheral arterial diseases. The hypothesis that muscle growth promotes angiogenesis by interacting with neighboring cells in ischemic lesions was assessed. Methods and Results: Skeletal muscle-specific inducible Akt1 transgenic (Akt1-TG) mice that induce growth of functional skeletal muscles as a model of resistance training were used. Proteomics analysis identified significant upregulation of heme oxigenase-1 (HO-1) in muscle tissue in Akt1-TG mice compared with control mice. Blood flow recovery after hindlimb ischemia was significantly increased in Akt1-TG mice compared with control mice. Enhanced blood flow and capillary density in Akt1-TG mice were completely abolished by the HO-1 inhibitor, Tin-mesoporphyrin. Immunohistochemistry showed that HO-1 expression was not increased in muscle cells, but it was increased in macrophages and endothelial cells. Consistent with these findings, blood flow recovery after hindlimb ischemia was similar between control mice and skeletal muscle-specific HO-1-knockout mice. Adenoviral-mediated overexpression of Akt1 did not increase HO-1 protein expression in C2C12 myotubes; however, the conditioned medium from Akt1-overexpressing C2C12 myotubes increased HO-1 expression in endothelial cells. Cytokine array demonstrated that a panel of cytokine secretion was upregulated in Akt1-overexpressing C2C12 cells, suggesting paracrine interaction between muscle cells and endothelial cells and macrophages. Conclusions: Akt1-mediated muscle growth improves blood flow recovery after hindlimb ischemia by enhancing HO-1 expression in neighboring cells.
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Shirahama R., Ono T., Nagamatsu S., Sueta D., Takashio S., Chitose T., Fujisue K., Sakamoto K., Yamamoto E., Izumiya Y., Kaikita K., Hokimoto S., Hori M., Harada-Shiba M., Kajiwara I., Ogawa H., Tsujita K.
Internal Medicine 57 ( 24 ) 3551 - 3557 2018
Language：English Publishing type：Research paper (scientific journal) Publisher：Internal Medicine
The low-density lipoprotein-cholesterol (LDL-C) level of a 38-year-old man diagnosed with acute coronary syndrome was 257 mg/dL. The administration of a proprotein convertase subtilisin-kexin type 9 (PCSK9) antibody in addition to rosuvastatin plus ezetimibe was initiated, reducing his LDL-C level to 37 mg/dL. A genetic analysis revealed both an LDL receptor (LDLR) mutation and a PCSK9 V4I mutation. Nine months after revascularization, intravascular ultrasound revealed plaque regression in the coronary arteries. LDLR/PCSK 9 mutation carriers are prone to coronary artery disease. Intensive LDL-C lowering by including PCSK9 antibody was associated with coronary plaque regression, suggesting the expectation of prognosis improvement.
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Sueta D., Kaikita K., Okamoto N., Yamabe S., Ishii M., Arima Y., Ito M., Oimatsu Y., Mitsuse T., Iwashita S., Nakamura E., Hokimoto S., Mizuta H., Ogawa H., Tsujita K.
Circulation Journal 82 ( 2 ) 524 - 531 2018
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: The pharmacological advantage of combining physiotherapy with anticoagulants for the prevention of venous thromboembolism (VTE) after total knee arthroplasty (TKA) is not fully known. Herein we investigated the potential benefit of this combination therapy in patients undergoing TKA. Methods and Results: The 38 patients were randomly assigned to a physiotherapy group (n=19) or a physiotherapy plus 30 mg/day edoxaban group (n=19). The occurrence of VTE was evaluated, as were serial changes in parameters measured by the Total Thrombus-formation Analysis System, a novel system for quantitatively analyzing thrombus formation using microchips with throm-bogenic surfaces (collagen plus tissue factor, atheroma [AR]-chip). Combination therapy significantly reduced the incidence of VTE after TKA compared with monotherapy (P=0.038). The area under the curve (AUC) of thrombus formation for the AR-chip (AR -AUC ) was significantly lower in the combination group (P=0.001) on Day 7 after TKA than before TKA, but no significant change was observed with monotherapy (P=0.809). In 13 VTE-positive patients, AR -AUC was significantly lower in the combination group (n=3) than in the monotherapy group (n=10) on Day 7 (P=0.045). Conclusions: The combination of physiotherapy and edoxaban significantly reduced the incidence of VTE after TKA compared with physiotherapy alone. However, it is possible that VTE occurrence after TKA is not only associated with thrombogenicity, but also rheological factors. 10 30 10 30
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Kaikita K., Yoshimura H., Ishii M., Kudoh T., Yamada Y., Yamamoto E., Izumiya Y., Kojima S., Shimomura H., Tsunoda R., Matsui K., Ogawa H., Tsujita K.
Circulation Journal 82 ( 6 ) 1517 - 1525 2018
Authorship：Lead author, Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: Patients with reduced-function CYP2C19 genotypes on dual antiplatelet therapy (DAPT) with aspirin and clopidogrel show higher clinical risk for acute myocardial infarction (AMI). We investigated the effect of CYP2C19 genotype-tailored adjunctive cilostazol therapy on treatment of AMI. Methods and Results: The study group of 138 patients with suspected AMI were screened for CYP2C19 genotype immediately after percutaneous coronary intervention (PCI) using a SPARTAN RX point-of-care device. Carriers of the CYP2C19 reducedfunction allele were randomized into DAPT (Carrier/DAPT) and DAPT plus 14-day cilostazol (Carrier/DAPT+Cilostazol) groups, while noncarriers were treated with DAPT (Noncarrier/DAPT). After exclusion of 10 patients, the remaining 128 patients were analyzed for P2Y12 reaction unit (PRU) using VerifyNow® P2Y12 system, and levels of biomarkers immediately after, and 1, 14, and 28 days after PCI. DAPT+Cilostazol reduced PRU levels in carriers (n=46) to those found in the Noncarrier/DAPT group (n=40), and significantly lower than those of the Carrier/DAPT group (n=42) at 14 days post-PCI. Discontinuation of cilostazol for 14 days was associated with a significant rise in PRU levels to those of the Carrier/DAPT group at 28 days post-PCI. Plasma B-type natriuretic peptide levels at 14 days post-PCI were lower in Carrier/DAPT+Cilostazol than in the other 2 groups, and the levels increased to those of the other groups at 28 days post-PCI after withdrawal of cilostazol. Conclusions: Adjunctive cilostazol therapy tailored to CYP2C19 genotype seemed useful in AMI patients with the CYP2C19 reduced-function allele.
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Disease on clinical outcomes after percutaneous coronary intervention for chronic total occlusions: A Japanese multicentre registry Reviewed
Naganuma T＊, Tsujita K, Mitomo S, Ishiguro H, Basavarajaiah S, Sato K, Kobayashi T, Obata J, Nagamatsu S, Yamanaga K, Komura N, Sakamoto K, Miyazaki T, Yamamoto E, Izumiya Y, Kojima S, Kaikita K, Hokimoto S, Ogawa H
Am J Cardiol 121 1519 - 1523 2018
Language：English Publishing type：Research paper (scientific journal)
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Direct Oral Anticoagulants Form Thrombus Different from Warfarin in a Microchip Flow Chamber System Reviewed
Ishii M., Kaikita K., Ito M., Sueta D., Arima Y., Takashio S., Izumiya Y., Yamamoto E., Yamamuro M., Kojima S., Hokimoto S., Yamabe H., Ogawa H., Tsujita K.
Scientific Reports 7 ( 1 ) 7399 2017.12
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports
Direct oral anticoagulants (DOACs) have low risk of intracranial hemorrhage compared to warfarin. We sought to clarify the different mechanisms responsible for suppression of bleeding events using the Total Thrombus-formation Analysis System (T-TAS), a flow-microchip chamber with thrombogenic surfaces. Blood samples were obtained at Off- and On-anticoagulant (trough) from 120 consecutive patients with atrial fibrillation (warfarin; n = 29, dabigatran; n = 19, rivaroxaban; n = 47, apixaban; n = 25), which were used for T-TAS to compute the area under the curve (AUC) (AR -AUC ) in the AR chip, and to measure plasma concentrations of DOACs at On-anticoagulant. In addition, the two-dimensional area covered by thrombi (%) in the capillary was analyzed every 3 minutes after sample applications. The AR -AUC correlated weakly and negatively with plasma concentrations of DOACs, and the levels at On-anticoagulant were lower in all groups than at Off-anticoagulant. AR -AUC levels at Off- and On-anticoagulant were identical among the groups. The thrombi areas in early phase were significantly larger in rivaroxaban and apixaban than warfarin and dabigatran groups. The findings suggested that visual analysis of the AR-chip can identify the differential inhibitory patterns of warfarin and DOACs on thrombus formation under flow condition. 10 30 10 30 10 30
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Ishii M., Kaikita K., Sato K., Sueta D., Fujisue K., Arima Y., Oimatsu Y., Mitsuse T., Onoue Y., Araki S., Yamamuro M., Nakamura T., Izumiya Y., Yamamoto E., Kojima S., Kim-Mitsuyama S., Ogawa H., Tsujita K.
JACC: Basic to Translational Science 2 ( 6 ) 655 - 668 2017.12
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：JACC: Basic to Translational Science
LCZ696 (sacubitril/valsartan) can lower the risk of cardiovascular events in chronic heart failure. However, it is unclear whether LCZ696 can improve prognosis in patients with acute myocardial infarction (MI). The present study shows that LCZ696 can prevent cardiac rupture after MI, probably due to the suppression of pro-inflammatory cytokines, matrix metalloproteinase-9 activity and aldosterone production, and enhancement of natriuretic peptides in mice. These findings suggest the mechanistic insight of cardioprotective effects of LCZ696 against acute MI, resulting in the belief that LCZ696 might be useful clinically to improve survival after acute MI.
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Tabata N., Yamamoto E., Hokimoto S., Yamashita T., Sueta D., Takashio S., Arima Y., Izumiya Y., Kojima S., Kaikita K., Matsui K., Fujimoto K., Sakamoto K., Shimomura H., Tsunoda R., Hirose T., Nakamura N., Sakaino N., Nakamura S., Yamamoto N., Matsumura T., Kajiwara I., Koide S., Sakamoto T., Nakao K., Oshima S., Tsujita K., Hanatani S., Fujisue K., Horio E., Morihisa K., Nishijima T., Noda K., Nagano M., Fukunaga T., Taguchi E., Miyamoto S., Katayama T., Matsubara J., Matsukawa M., Miyao Y., Ogura Y., Kudo T., Yamada Y., Usuku H., Yoshimura H., Fuchigami S., Ikemoto T., Ito T., Uemura T., Kurokawa H., Maruyama H., Sato K., Yamanaga K., Nakamura S., Chitose T., Ono T., Abe K., Doi H., Miyazaki T., Miura M., Okuyama E., Kikuta K., Kusaka H., Kuroki K., Fukushima R., Tayama S., Rokutanda T., Hanaoka Y.
Journal of the American Heart Association 6 ( 8 ) 2017.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American Heart Association
Background--The CHADS score has mainly been used to predict the likelihood of cerebrovascular accidents in patients with atrial fibrillation. However, increasing attention is being paid to this scoring system for risk stratification of patients with coronary artery disease. We investigated the value of the CHADS score in predicting cardiovascular/cerebrovascular events in coronary artery disease patients without atrial fibrillation. Methods and Results--This was a multicenter, observational cohort study. The subjects had been admitted to one of the participating institutions with coronary artery disease requiring percutaneous coronary intervention. We calculated the CHADS scores for 7082 patients (mean age, 69.7 years; males, 71.9%) without clinical evidence of atrial fibrillation. Subjects were subdivided into low- (0-1), intermediate- (2-3), and high-score (4-6) groups and followed for 1 year. The end point was a composite of cardiovascular/cerebrovascular death, nonfatal myocardial infarction, and ischemic stroke at 1-year follow-up. Rates of triple-vessel/left main trunk disease correlated positively with CHADS score categories. CHADS scores among single, double, and triple-vessel/left main trunk groups were 2 (1-2), 2 (1-3), and 2 (2-3), respectively (P < 0.001). A total of 194 patients (2.8%) had a cardiovascular/cerebrovascular event, and Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular/cerebrovascular events in proportion to a higher CHADS score (log-rank test, P < 0.001). Multivariate Cox hazard analysis identified CHADS score (per 1 point) as an independent predictor of cardiovascular/cerebrovascular events (hazard ratio, 1.31; 95% CI, 1.17-1.47; P < 0.001). Conclusions--This large cohort study indicated that the CHADS score is useful for the prediction of cardiovascular/cerebrovascular events in coronary artery disease patients without atrial fibrillation. 2 2 2 2 2 2 2 2
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CYP2C19 variants and epoxyeicosatrienoic acids in patients with microvascular angina Reviewed
Akasaka T., Sueta D., Arima Y., Tabata N., Takashio S., Izumiya Y., Yamamoto E., Tsujita K., Kojima S., Kaikita K., Kajiwara A., Morita K., Oniki K., Saruwatari J., Nakagawa K., Hokimoto S.
IJC Heart and Vasculature 15 15 - 20 2017.6
Language：English Publishing type：Research paper (scientific journal) Publisher：IJC Heart and Vasculature
Background Categorization as a cytochrome P450 (CYP) 2C19 poor metabolizer (PM) is reported to be an independent risk factor for cardiovascular disease. Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid by CYP2C19 epoxygenases and anti-inflammatory properties, especially in microvascular tissues. We examined the impact of CYP2C19 polymorphisms and EETs on the patients with microvascular angina (MVA) caused by coronary microvascular dysfunction. Methods and results We examined CYP2C19 genotypes in patients with MVA (n = 81). MVA was defined as absence of coronary artery stenosis and epicardial spasms, and the presence of inversion of lactic acid levels between intracoronary and coronary sinuses in acetylcholine-provocation test or the adenosine-triphosphate-induced coronary flow reserve ratio was below 2.5. CYP2C19 PM have two loss-of-functon alleles (*2, *3). We measured serum dihydroxyeicosatrienoic acid (DHET) as representative EET metabolite. In MVA, the patients with CYP2C19 PM were 34.6% and high sense C-reactive protein (hs-CRP) levels in CYP2C19 PM were significantly higher than that of non-PM group (0.165 ± 0.116 vs. 0.097 ± 0.113 mg/dL, P = 0.026). Moreover, DHET levels in CYP2C19 PM were significantly lower than that of non-PM (10.4 ± 4.58 vs. 15.6 ± 11.1 ng/mL, P = 0.003 (11,12-DHET); 12.1 ± 3.79 vs. 17.3 ± 6.49 ng/mL, P = 0.019 (14,15-DHET)). Conclusions The decline of EET owing to CYP2C19 variants may affects coronary microvascular dysfunction via chronic inflammation.
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Yamamura S., Izumiya Y., Ishida T., Onoue Y., Kimura Y., Hanatani S., Araki S., Fujisue K., Sueta D., Kanazawa H., Takashio S., Usuku H., Sugamura K., Sakamoto K., Yamamoto E., Yamamuro M., Yasuda H., Kojima S., Kaikita K., Hokimoto S., Ogawa H., Tsujita K.
Heart and Vessels 32 ( 6 ) 708 - 713 2017.6
Language：English Publishing type：Research paper (scientific journal) Publisher：Heart and Vessels
Wild-type transthyretin amyloidosis (ATTRwt) is often overlooked in elderly patients with left ventricular hypertrophy (LVH). Impaired atrial function, in addition to ventricular diastolic dysfunction, is one of the hallmarks of cardiac amyloidosis. Here, we assessed the hypothesis that atrial function evaluated by A-velocity in pulse Doppler echocardiography is useful to differentiate ATTRwt in elderly patients with LVH. We analyzed 133 consecutive patients who underwent tissue biopsy to rule out infiltrative cardiomyopathy in our institute. We excluded patients younger than 50 years, without LVH (LV thickness was less than 12 mm), with other types of cardiac amyloidosis and patients with chronic atrial fibrillation, and analyzed remaining 51 patients (ATTRwt: 16, non-ATTRwt: 35). ATTRwt patients were significantly older and had advanced heart failure compared with non-ATTRwt group. In echocardiography, E/A, E/e′, and relative wall thickness was significantly higher in ATTRwt group than non-ATTRwt group. A-velocity was significantly decreased in ATTRWT group compared with non-ATTRwt group (40.8 ± 20.8 vs. 78.7 ± 28.2 cm/s, p = 0.0001). Multivariate logistic analysis using eight forced inclusion models identified trans-mitral Doppler A-wave velocity was more significant factor of cardiac amyloidosis in ATTRwt. In receiver operating characteristic (ROC) analysis, the area under the curve (AUC) for A-wave velocity in discrimination between ATTRwt and non-ATTRwt were 0.86 (CI 0.76–0.96, p < 0.001). The cut-off value was 62.5 cm/s, and it yielded the best combination of sensitivity (69.7%) and specificity (87.5%) for prediction of amyloidosis. We concluded that reduced A-velocity predicts the presence of ATTRwt in elderly patients with LVH in sinus rhythm.
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Akasaka T., Sueta D., Tabata N., Takashio S., Yamamoto E., Izumiya Y., Tsujita K., Kojima S., Kaikita K., Matsui K., Hokimoto S.
Journal of the American Heart Association 6 ( 5 ) 2017.5
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American Heart Association
Background-Mean amplitude of glycemic excursion (MAGE) is commonly used to gauge the degree of glucose level fluctuations. MAGE plays a significant role in vascular endothelial dysfunction and cardiovascular events in patients with diabetes mellitus (DM), but its significance is not clear in non-DM patients. Thus, we examined the impact of MAGE and vascular endothelial dysfunction on clinical outcomes in non-DM patients with coronary artery disease. Methods and Results-We followed non-DM patients (n = 65) for 12 months who underwent percutaneous coronary intervention and assessed the relationship among MAGE, reactive hyperemia index (RHI) measured by reactive hyperemia peripheral arterial tonometry as endothelial function, and cardiovascular events. Cardiovascular events analyzed were cardiovascular death, myocardial infarction, unstable angina, and revascularizations. Compared with patients with MAGE < 65 mg/dL (normal glycemic excursions), the group with MAGE ≥ 65 mg/dL (high glycemic excursions) had significantly higher high-sensitivity C-reactive protein (0.10±0.11 mg/dL versus 0.18±0.13 mg/dL, P = 0.006) and lower RHI (0.64±0.21 versus 0.51±0.22, P = 0.035). The multivariable analysis identified high MAGE and low RHI ( ≤ 0.56) as risk factors associated with cardiovascular events (hazard ratio, 5.6; 95% RI, 1.72-18.4 [P = 0.004] versus hazard ratio, 4.5; 95% RI, 1.37-14.9 [P = 0.013]). When the prognosis was classified by combination with MAGE and RHI, the incidence of cardiovascular events was 46.7% (high MAGE+low RHI), 26.7% (high MAGE+high RHI), 20.0% (low MAGE+low RHI), and 6.6% (low MAGE+high RHI) in descending order (P = 0.014). Receiver operating characteristic curve analysis revealed that MAGE, RHI, and MAGE+RHI were each associated with cardiovascular events (area under the curve 0.780, 0.727, and 0.796, respectively). Conclusions-MAGE was associated with cardiovascular events in non-DM patients with coronary artery disease. Furthermore, the combination with MAGE and RHI was useful for further subdivision of the risk of cardiovascular events.
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Sueta D., Suyama K., Sueta A., Tabata N., Yamashita T., Tomiguchi M., Takeshita T., Yamamoto-Ibusuki M., Yamamoto E., Izumiya Y., Kaikita K., Yamamoto Y., Hokimoto S., Iwase H., Tsujita K.
Atherosclerosis 260 116 - 120 2017.5
Language：English Publishing type：Research paper (scientific journal) Publisher：Atherosclerosis
Background and aims Lenvatinib (Lenvima ), an oral multi-kinase inhibitor, is effective in the treatment of differentiated thyroid carcinomas (DTCs). A severe adverse effect of lenvatinib is hypertension, thus limiting its use as an anti-cancer treatment. Although the pathogenesis of hypertension is generally assumed to involve microvascular bed reduction and an increase in peripheral vascular resistance due to a decrease in nitrogen oxide (NOx) production after vascular endothelial growth factor (VEGF) inhibition, the effects of hypertension on vascular endothelial function in actual patients remain unclear. Here, we examined how lenvatinib affects vascular endothelial function. Methods Ten consecutive DTC patients who did not take any cardiovascular agents were orally administered 24 mg of lenvatinib once daily. Using an EndoPAT2000 system, we used reactive hyperemia-peripheral arterial tonometry (RH-PAT) and evaluated vascular endothelial function on the basis of the RH-PAT index (RHI). We expressed the results as %RHI, which indicates the change compared with pretreatment levels. Additionally, we measured serum NOx and plasma VEGF concentrations pre- and post-treatment. Results All of the patients treated with lenvatinib exhibited significant hypertension; the %RHI levels were significantly decreased the day after treatment with lenvatinib. Furthermore, serum NOx and plasma VEGF concentrations were significantly decreased and increased, respectively, compared with pretreatment levels. These results indicate that hypertension induced by lenvatinib may be caused by a decrease in nitric oxide production, as a result of VEGF inhibition and impaired vascular endothelial function. Conclusions We provide the first demonstration that lenvatinib causes hypertension via vascular endothelial dysfunction in human subjects. ® ®
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Oimatsu Y., Kaikita K., Ishii M., Mitsuse T., Ito M., Arima Y., Sueta D., Takahashi A., Iwashita S., Yamamoto E., Kojima S., Hokimoto S., Tsujita K.
Journal of the American Heart Association 6 ( 4 ) 2017.4
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American Heart Association
BACKGROUND: Periprocedural bleeding events are common after percutaneous coronary intervention. We evaluated the association of periprocedural bleeding events with thrombogenicity, which was measured quantitatively by the Total Thrombus-formation Analysis System equipped with microchips and thrombogenic surfaces (collagen, platelet chip [PL]; collagen plus tissue factor, atheroma chip [AR]).
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Tabata N., Sueta D., Yamashita T., Utsunomiya D., Arima Y., Yamamoto E., Tsujita K., Kojima S., Kaikita K., Hokimoto S.
Hypertension Research 40 ( 4 ) 392 - 398 2017.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Hypertension Research
Little is known about the significance of asymptomatic intra-cranial lesions (ICL) identified by brain MRI in coronary artery disease (CAD) patients. Silent cerebral lesions are suggested to be associated with arterial stiffness in healthy subjects. We investigated whether subclinical ICL are associated with arterial stiffness and the prognosis in CAD patients without medical history of cerebrovascular diseases. We recruited CAD patients who required percutaneous coronary intervention (PCI), did not meet exclusion criteria, and agreed with MRI before PCI. Subjects were divided into two groups according to the presence of ICL of cerebral microbleeds or lacunar infarction. Arterial stiffness was evaluated by brachial-ankle pulse wave velocity (baPWV). Clinical outcome was defined as a composite of cardiovascular death, non-fatal myocardial infarction, stroke, unstable angina and heart failure. In total, 149 patients underwent brain MRI. Patients with ICL (n=55) had significantly higher baPWV than those without ICL (1591-2204 vs. 1450-1956 cm per sec; P=0.009). A multivariate analysis showed that male sex (odds ratio (OR), 3.15; 95% confidence interval (CI), 1.38-7.20; P=0.006) and baPWV (OR, 1.001; 95% CI, 1.000-1.002; P=0.023) were predictors of ICL. In total, 12 patients experienced a cardiovascular event. The Kaplan-Meier analysis indicated a significantly higher incidence of cardiovascular events in patients with ICL (log-rank test: P=0.018). Multivariate Cox proportional hazards analyses indicated that ICL finding was a significant predictor of clinical outcome (hazard ratio, 3.41; 95% CI, 1.02-11.5; P=0.047). Patients with subclinical ICL had a higher baPWV and worse prognoses than those without ICL.
DOI： 10.1038/hr.2016.159
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Sueta D., Ito M., Uchiba M., Sakamoto K., Yamamoto E., Izumiya Y., Kojima S., Kaikita K., Shinriki S., Hokimoto S., Matsui H., Tsujita K.
Thrombosis Journal 15 ( 1 ) 8 2017.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Thrombosis Journal
Background: Because the venous thromboembolisms (VTEs) due to the coagulation factor V R506Q (FV Leiden) mutation is often seen in Caucasians, the VTE onset in Japan has not been reported. Case presentation: A 34-year-old man from north Africa experiencing sudden dyspnea went to a hospital for advice. The patient had pain in his right leg and a high plasma D-dimer level. A contrast-enhanced computed tomography scan revealed a contrast deficit in the bilateral pulmonary artery and in the right lower extremity. The patient was diagnosed with VTE, and anticoagulation therapy was initiated. Our targeted gene panel sequencing revealed that the occurrence of VTE was attributed to a presence of the FV Leiden mutation. Conclusions: This is the first report demonstrating VTE caused by the FV Leiden mutation in Japan.
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Sueta D., Hokimoto S., Sakamoto K., Akasaka T., Tabata N., Kaikita K., Honda O., Naruse M., Ogawa H.
International Journal of Cardiology 230 97 - 102 2017.3
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background Malnutrition-Inflammation-Atherosclerosis (MIA) factors significantly and independently affect life prognosis of hemodialysis (HD) patients. We re-evaluated Japanese data, which have progressed ahead from a community-based observational study. The present study was designed to assess the contribution of these MIA factors to the mortality rate of Japanese HD patients in a community of 1.8 million people over a 36-month follow-up period. Methods and results A total of 5813 patients at 76 facilities were on maintenance HD in the Kumamoto Prefecture. Specifically, 4807 of these patients at 58 institutions were enrolled. Patients who exhibited lower serum albumin and higher serum C-reactive protein levels were defined as “malnourished” and “inflamed”, respectively, compared with the median values. Patients who underwent invasive procedures for atherosclerotic diseases were defined as “atherosclerotic”. The 36-month all-cause mortality rate in Japanese HD patients was 12.4%. This rate directly correlated with the number of MIA factors. The odds ratio of the all-cause mortality rate markedly and significantly increased as the number of factors increased. The presence of 3 MIA factors in HD patients was a significant predictor of mortality, as evidenced by a multivariate logistic regression analysis. Conclusions This study clearly demonstrated the close association between MIA syndrome and high mortality in Japanese HD patients. Early detection and the adjustment of MIA factors are mandatory.
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Hirakawa K., Yamamuro M., Uemura T., Takashio S., Kaikita K., Utsunomiya D., Nakayama M., Yamamoto E., Yamashita Y., Hokimoto S., Tsujita K.
International Journal of Cardiology 228 881 - 885 2017.2
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Backgrounds The relationship between microvascular dysfunction and plasma B-type natriuretic peptide (BNP) levels remains unclear in heart failure (HF) patients with cardiac fibrosis. Methods This study evaluated 55 consecutive non-ischemic HF patients in an effort to determine the relationship between endothelial independent coronary microvascular dysfunction and plasma BNP levels, as well as whether each measure is correlated with myocardial fibrosis. We evaluated plasma BNP levels in patients with stable HF. We used cardiac catheterization to measure trans-cardiac BNP release levels, measuring from the coronary sinus and the aortic root, and coronary flow reserve (CFR). Patients also underwent cardiac magnetic resonance imaging to evaluate for the presence of late gadolinium enhancement (LGE), as an indicator of cardiac fibrosis. Results CFR in cardiac catheterization was significantly and inversely correlated with plasma BNP levels (r = 0.336, p = 0.012) and trans-cardiac BNP release levels (r = 0.347, p = 0.041). Thirty-three patients were LGE-positive. CFR was significantly correlated with plasma BNP levels in the LGE-positive group (r = 0.349, p = 0.046), but this correlation was not significant in the LGE-negative group. (r = 0.338, p = 0.125). Multivariate logistic regression analysis revealed that a plasma BNP levels > 180 pg/ml at stable HF condition was significant and independent predictor of CFR < 2.5 in all patients (p = 0.035, odds ratio: 5.2, 95% confidence interval: 1.1–29.0), and in the LGE-positive group (p = 0.040, odds ratio: 5.4, 95% confidence interval: 1.1–27.2). Conclusions In non-ischemic HF patients especially those with cardiac fibrosis, endothelial independent microvascular dysfunction is closely correlated with plasma BNP levels, and ventricular wall tension.
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Nakashima N., Sueta D., Kanemaru Y., Takashio S., Yamamoto E., Hanatani S., Kanazawa H., Izumiya Y., Kojima S., Kaikita K., Hokimoto S., Tsujita K.
Thrombosis Journal 15 ( 1 ) 4 2017.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Thrombosis Journal
Background: Although vein stenting is popular for treatment for venous thromboembolism due to mechanical compression, some cases are forced to avoid inserting align agents because of immunodeficiency. Case presentation: An 82-year-old man with left extremity redness and swelling presented to a hospital for a medical evaluation. The patient was immunodeficient because of the adverse effects of his treatment for Castleman's disease. A contrast-enhanced computed tomography scan revealed a venous thromboembolism in inferior vena cava and the left lower extremity. Magnetic resonance venography showed that the iliac artery was compressing the iliac vein. We were reluctant to place a stent in the iliac vein has because of the patient's immunodeficient status. Three months of treatment using single-dose edoxaban (30 mg daily) resulted in complete resolution of the thrombus. This is the first report demonstrating that single-dose edoxaban without acute-phase parenteral anticoagulation is effective in the treatment of iliac vein compression. Conclusions: A single-dose direct oral anti-coagulant without acute-phase parenteral anticoagulation is effective for mechanical compression
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Akasaka T., Hokimoto S., Sueta D., Tabata N., Oshima S., Nakao K., Fujimoto K., Miyao Y., Shimomura H., Tsunoda R., Hirose T., Kajiwara I., Matsumura T., Nakamura N., Yamamoto N., Koide S., Nakamura S., Morikami Y., Sakaino N., Kaikita K., Nakamura S., Matsui K., Ogawa H.
Journal of Cardiology 69 ( 1 ) 103 - 109 2017.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
Background Based on the 2011 American College of Cardiology/American Heart Association percutaneous coronary intervention (PCI) guideline, it is recommended that PCI should be performed at hospital with onsite cardiac surgery. But, data suggest that there is no significant difference in clinical outcomes following primary or elective PCI between the two groups. We examined the impact of with or without onsite cardiac surgery on clinical outcomes following PCI for acute coronary syndrome (ACS). Methods and results From August 2008 to March 2011, subjects (n = 3241) were enrolled from the Kumamoto Intervention Conference Study (KICS). Patients were assigned to two groups treated in hospitals with (n = 2764) or without (n = 477) onsite cardiac surgery. Clinical events were followed up for 12 months. Primary endpoint was in-hospital death, cardiovascular death, myocardial infarction, and stroke. And we monitored in-hospital events, non-cardiovascular deaths, bleeding complications, revascularizations, and emergent coronary artery bypass grafting (CABG). There was no overall significant difference in primary endpoint between hospitals with and without onsite cardiac surgery [ACS, 7.6% vs. 8.0%, p = 0.737; ST-segment elevation myocardial infarction (STEMI), 10.4% vs. 7.5%, p = 0.200]. There was also no significant difference when events in primary endpoint were considered separately. In other events, revascularization was more frequently seen in hospitals with onsite surgery (ACS, 20.0% vs. 13.0%, p < 0.001; STEMI, 21.9% vs. 14.5%, p = 0.009). We performed propensity score matching analysis to correct for the disparate patient numbers between the two groups, and there was also no significant difference for primary endpoint (ACS, 8.6% vs. 7.5%, p = 0.547; STEMI, 11.2% vs. 7.5%, p = 0.210). Conclusions There is no significant difference in clinical outcomes following PCI for ACS between hospitals with and without onsite cardiac surgery backup in Japan.
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Fujisue K., Sugamura K., Kurokawa H., Matsubara J., Ishii M., Izumiya Y., Kaikita K., Sugiyama S.
Circulation Journal 81 ( 8 ) 1174 - 1182 2017
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: Several studies have reported that colchicine attenuated the infarct size and inflammation in acute myocardial infarction (MI). However, the sustained benefit of colchicine administration on survival and cardiac function after MI is unknown. It was hypothesized that the short-term treatment with colchicine could improve survival and cardiac function during the recovery phase of MI. Methods and Results: MI was induced in mice by permanent ligation of the left anterior descending coronary artery. Mice were then orally administered colchicine 0.1 mg/kg/day or vehicle from 1 h to day 7 after MI. Colchicine significantly improved survival rate (colchicine, n=48: 89.6% vs. vehicle, n=51: 70.6%, P<0.01), left ventricular end-diastolic diameter (5.0±0.2 vs. 5.6±0.2 mm, P<0.05) and ejection fraction (41.5±2.1 vs. 23.8±3.1%, P<0.001), as assessed by echocardiogram compared with vehicle at 4 weeks after MI. Heart failure development as pulmonary edema assessed by wet/dry lung weight ratio (5.0±0.1 vs. 5.5±0.2, P<0.01) and B-type natriuretic peptide expression in the heart was attenuated in the colchicine group at 4 weeks after MI. Histological and gene expression analysis revealed colchicine significantly inhibited the infiltration of neutrophils and macrophages, and attenuated the mRNA expression of pro-inflammatory cytokines and NLRP3 inflammasome components in the infarcted myocardium at 24 h after MI. Conclusions: Short-term treatment with colchicine successfully attenuated pro-inflammatory cytokines and NLRP3 inflammasome, and improved cardiac function, heart failure, and survival after MI.
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Sueta D., Akahoshi R., Okamura Y., Kojima S., Ikemoto T., Yamamoto E., Izumiya Y., Tsujita K., Kaikita K., Katabuchi H., Hokimoto S.
Internal Medicine 56 ( 4 ) 409 - 412 2017
Language：English Publishing type：Research paper (scientific journal) Publisher：Internal Medicine
A 40-year-old woman experiencing sudden dyspnea went to her personal doctor for advice. She was previously diagnosed with endometriosis and prescribed oral contraceptives for treatment. During earthquakes, she spent 7 nights sleeping in a vehicle. The patient had swelling and pain in her left leg and high D-dimer concentration levels. A contrast-enhanced computed tomography scan revealed a contrast deficit in the bilateral pulmonary artery and in the left lower extremity. She was diagnosed with pulmonary thromboembolism (PTE), and anticoagulation therapy was initiated. This present case is the first report of PTE attributed to the use of oral contraceptives after earthquakes.
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Simultaneous idiopathic dissections of the coronary and superior mesenteric arteries Reviewed
Nishi M., Sueta D., Miyazaki T., Sakamoto K., Yamamoto E., Izumiya Y., Tsujita K., Kojima S., Kaikita K., Ikeda O., Yamashita Y., Hokimoto S.
Internal Medicine 56 ( 11 ) 1363 - 1367 2017
Language：English Publishing type：Research paper (scientific journal) Publisher：Internal Medicine
A 49-year-old man complained of sudden upper abdominal pain but was not given a definitive diagnosis. The day after he was discharged, he noticed left chest pain. An in-depth electrocardiogram indicated acute myocardial infarction, and emergent coronary angiography revealed 99% stenosis of his left coronary artery. An intravascular ultrasound revealed spontaneous coronary artery dissection (SCAD), and the lesion was successfully stented. In an atherosclerosis screening, superior mesenteric artery dissection (SMAD) was confirmed, after which the lesion was successfully stented. This case suggests that SCAD and SMAD might have similar pathological backgrounds.
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When Is the Optimal Timing of Surgical Intervention for Severe Functional Tricuspid Regurgitation? Reviewed
Nakanishi N, Ishii M, Kaikita K, Okamoto K, Izumiya Y, Yamamoto E, Takashio S, Hokimoto S, Fukui T, Tsujita K
Case reports in cardiology 2017 9232658 2017
Language：English Publishing type：Research paper (scientific journal)
DOI： 10.1155/2017/9232658
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Pulmonary tumor thrombotic microangiopathy - Antemortem diagnosis with pulmonary artery wedge blood cell sampling in a recurrent breast cancer patient Reviewed
Fuchigami S, Tsunoda R＊, Shimizu H, Takae M, Usuku H, Yoshimura H, Ikemoto T, Nagamine M, Ito T, Izumiya Y, Kaikita K, Hokimoto S, Tsujita K
Circulation Journal 81 ( 12 ) 1959 - 1960 2017
Language：English Publishing type：Research paper (scientific journal)
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冠動脈疾患における抗血小板療法
海北幸一, 小川久雄.
医学のあゆみ 259 ( 14 ) 1453 - 1458 2016.12
Authorship：Lead author Publishing type：Research paper (scientific journal)
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Uemura T., Yamamuro M., Kaikita K., Takashio S., Utsunomiya D., Hirakawa K., Nakayama M., Sakamoto K., Yamamoto E., Tsujita K., Kojima S., Hokimoto S., Yamashita Y., Ogawa H.
Heart and Vessels 31 ( 12 ) 1969 - 1979 2016.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Heart and Vessels
Myocardial fibrosis and microvascular dysfunction are key determinants of outcome in heart failure (HF); we examined their relationship in patients with HF. Our study included 61 consecutive patients with HF but without coronary stenosis. All underwent gadolinium-enhanced cardiac magnetic resonance to evaluate late gadolinium enhancement (LGE) and an acetylcholine (ACh) provocation test to evaluate microvascular dysfunction. During the ACh provocation test, we sampled blood simultaneously from the coronary sinus and aortic root to compare lactate concentrations. We quantified coronary blood flow volume using an intracoronary Doppler-tipped guidewire. We detected LGE in 34 patients (LGE-positive); 27 were LGE-negative. Coronary blood flow volume increased significantly after the ACh provocation test only in LGE-negative patients (before vs. after ACh, 47.5 ± 36.8 vs. 69.2 ± 48.0 ml/min, respectively; p = 0.004). The myocardial lactate extraction ratio (LER) significantly decreased after the ACh test in both groups (LGE-negative, p = 0.001; LGE-positive, p < 0.001), significantly more so in the LGE-positive group (p = 0.017). Multivariate logistic regression analysis showed that a post-ACh LER < 0 (indicating myocardial lactate production) was a significant predictor of LGE-positivity (odds ratio 4.54; 95 % confidence interval 1.38–14.93; p = 0.013). In the LGE-positive group, an LGE volume greater than the median significantly predicted a post-ACh LER of <0 (p = 0.042; odds ratio 6.02; 95 % confidence interval 1.07–33.86). ACh-provoked coronary vasomotor abnormality is closely correlated with myocardial fibrosis in patients with HF but without organic coronary stenosis. Coronary vasomotor abnormalities in fibrotic myocardium may worsen HF.
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Yamamoto E., Sugiyama S., Hirata Y., Tokitsu T., Tabata N., Fujisue K., Sugamura K., Sakamoto K., Tsujita K., Matsumura T., Kaikita K., Hokimoto S.
Atherosclerosis 255 210 - 216 2016.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Atherosclerosis
Background and aims This study investigated the association of leukocyte subtype counts with vascular endothelial dysfunction and future cardiovascular events in patients with coronary artery disease (CAD). Methods The study included 389 consecutive CAD patients (259 male, 130 female; mean age, 70.1 ± 9.9 years). The patients underwent coronary angiography, and measurement of blood parameters, including leukocyte subtype counts. Results There were 84 cardiovascular events during a mean follow-up of 586 ± 378 days. Kaplan–Meier analysis showed a higher probability of cardiovascular events in the high-monocyte group (≥360/mm ) compared with the low-monocyte group (<360/mm ) (log-rank test, p = 0.047). Multivariate Cox hazard analysis identified a high monocyte count as an independent predictor of cardiovascular events (hazard ratio: 1.63, 95% confidence interval:1.05–2.51, p = 0.028). Peripheral endothelial function in 355 of the CAD patients was assessed by reactive hyperemia peripheral arterial tonometry index (RHI) to examine the association of ln-RHI with leukocyte subtype counts. Total leukocyte, monocyte and neutrophil counts were significantly higher in CAD patients with low ln-RHI (<0.57: the mean ln-RHI value) compared with those with high ln-RHI (≥0.57). Univariate analyses revealed that ln-RHI in CAD patients was positively correlated with ln-total leukocyte (r = −0.187, p < 0.001), ln-monocyte (r = 0.316, p < 0.001), and neutrophil (r = −0.175, p = 0.001) counts. Multiple regression analysis showed that the monocyte count was a significant and independent factor associated with ln-RHI (adjusted R = 0.126, p < 0.001). Conclusions A high monocyte count was an independent and incremental predictor of cardiovascular events in CAD patients. The monocyte count was also significantly correlated with peripheral endothelial dysfunction in CAD patients. 3 3 2
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Ikeda T., Atarashi H., Inoue H., Uchiyama S., Kitazono T., Yamashita T., Shimizu W., Kamouchi M., Kaikita K., Fukuda K., Origasa H., Sakuma I., Saku K., Okumura Y., Nakamura Y., Morimoto H., Matsumoto N., Tsuchida A., Ako J., Sugishita N., Shimizu S., Shimokawa H.
Tohoku Journal of Experimental Medicine 240 ( 4 ) 259 - 268 2016.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Tohoku Journal of Experimental Medicine
The use of rivaroxaban, a factor Xa inhibitor, has been increasing for prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF) in Japan. We conducted the nationwide multicenter study, termed as the EXPAND Study, to address its effectiveness and safety in the real-world practice of patients with non-valvular AF in Japan. The EXPAND Study is a prospective, non-interventional, observational cohort study to evaluate the effectiveness and safety of rivaroxaban in non-valvular AF patients in a real-world clinical practice. A total of 7,178 patients with non-valvular AF were enrolled in 684 medical institutes between November 20, 2012 and June 30, 2014. As for the baseline demographic and clinical characteristics of 7,164 patients, the proportion of female patients was 32.2%, and those of patients with creatinine clearance < 50 mL/min and non-paroxysmal (persistent or permanent) AF were 21.8% and 55.1%, respectively. The proportions of patients complicated with hypertension, congestive heart failure, diabetes mellitus, and a history of ischemic stroke were 70.9%, 25.9%, 24.3%, and 20.2%, respectively. The proportions of patients with a CHADS score ≤ 1 and a CHA DS -VASc score ≤ 1 were 37.3% and 13.6%, respectively. They were followed up until March 31, 2016 for a mean follow-up period of approximately 2.5 years. The findings of the EXPAND Study will help to establish an appropriate treatment with rivaroxaban for Japanese patients with non-valvular AF. 2 2 2
DOI： 10.1620/tjem.240.259
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Association of CYP2C19 variants and epoxyeicosatrienoic acids on patients with microvascular angina Reviewed
Akasaka T., Sueta D., Arima Y., Tabata N., Takashio S., Izumiya Y., Yamamoto E., Yamamuro M., Tsujita K., Kojima S., Kaikita K., Kajiwara A., Morita K., Oniki K., Saruwatari J., Nakagawa K., Ogata Y., Matsui K., Hokimoto S.
American Journal of Physiology - Heart and Circulatory Physiology 311 ( 6 ) H1409 - H1415 2016.12
Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Physiology - Heart and Circulatory Physiology
Categorization as a cytochrome P450 (CYP) 2C19 poor metabolizer (PM) is reported to be an independent risk factor for cardiovascular disease. Epoxyeicosatrienoic acids (EETs) are metabolites of arachi-donic acid by CYP2C19 epoxygenases and anti-inflammatory properties, especially in microvascular tissues. We examined the association of CYP2C19 polymorphisms and EETs on microvascular angina (MVA) caused by coronary microvascular dysfunction. We examined CYP2C19 genotypes in patients with MVA (« = 71) and healthy subjects as control (n = 71). MVA was defined as the absence of coronary artery stenosis and epicardial spasms and the presence of inversion of lactic acid levels between intracoronary and coronary sinuses in acetylcholine-provocation test or the adenosine-triphos-phate-induced coronary flow reserve ratio was below 2.5. CYP2C19 PM have two loss-of-functon alleles (*2, *3). We measured serum dihydroxyeicosatrienoic acid (DHET) as representative EET metabolite. MVA group showed significantly higher CYP2C19 PM incidence (35% vs. 16%; P = 0.007) and high sense C-reactive protein (hs-CRP) levels (0.127 ± 0.142 vs. 0.086 ± 0.097 mg/dl; P = 0.043) than those of controls. Moreover, in MVA group, hs-CRP levels in CYP2C19 PM were significantly higher than that of non-PM (0.180 ± 0.107 vs. 0.106 ± 0.149 mg/dl. P = 0.045). Multivariate analysis indicated that smoking, hypertension, high hs-CRP, and CYP2C19 PM are predictive factors for MVA. In MVA group, DHET levels for CYP2C19 PM were significantly lower than that of non-PM [10.9 ± 1.64 vs. 14.2 ± 5.39 ng/ml, P = 0.019 (11, 12-DHET); 15.2 ± 4.39 vs. 17.9 ± 4.73 ng/ml, P = 0.025 (14, 15-DHET)]. CYP2C19 variants are associated with MVA. The decline of EET-based defensive mechanisms owing to CYP2C19 variants may affect coronary microvascular dysfunction.
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Tsujita K., Kaikita K., Araki S., Yamada T., Nagamatsu S., Yamanaga K., Sakamoto K., Kojima S., Hokimoto S., Ogawa H.
BMC Cardiovascular Disorders 16 ( 1 ) 235 2016.11
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：BMC Cardiovascular Disorders
Background: Coronary plaques in patients with coronary vasospastic angina have been characterized by diffuse intima-media thickening with homogeneous fibrous tissue, without confluent necrotic tissue. However, coronary vasospasm can trigger coronary thrombosis, and may play an important role in the pathogenesis of acute coronary syndromes, though the precise morphological mechanisms underlying this process remain unclear. Case presentation: A 43-year-old man with a history of multivessel coronary vasospastic angina had been treated with long-acting diltiazem and fluvastatin since 2004. Eleven years later, following 1 month of medication nonadherence, he experienced recurrence of rest angina and myocardial infarction, with elevated high-sensitivity troponin T. An emergency coronary angiogram demonstrated no de novo lesions, and the current episode was diagnosed as intractable sustained coronary spasm-induced anterior myocardial infarction. Optical coherence tomography imaging revealed the coronary plaque with homogeneous high-intensity signal, and a clearly visualized intraplaque neovascular microchannel (NVMC) network. Conclusions: Neovascularization within a coronary atheroma is known to accelerate coronary atherosclerosis. The current case with coronary vasospastic angina highlights the role of NVMC formation in this process.
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A rare case of long-term survival with idiopathic dilatation of the pulmonary artery Reviewed
Sueta D., Sugamura K., Shimizu H., Shiota T., Yamamuro M., Hirakawa K., Sakamoto K., Tsujita K., Hanatani S., Yamamoto E., Araki S., Kanazawa H., Kojima S., Kaikita K., Hokimoto S., Komohara Y., Ogawa H.
International Journal of Cardiology 223 337 - 339 2016.11
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
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Tokitsu T., Yamamoto E., Hirata Y., Kusaka H., Fujisue K., Sueta D., Sugamura K., Sakamoto K., Tsujita K., Kaikita K., Hokimoto S., Sugiyama S., Ogawa H.
European Journal of Heart Failure 18 ( 11 ) 1353 - 1361 2016.11
Language：English Publishing type：Research paper (scientific journal) Publisher：European Journal of Heart Failure
Aims: Although pulse pressure (PP) is a recognized risk factor for various cardiovascular diseases, its association with cardiovascular outcomes in patients with heart failure with preserved ejection fraction (HFpEF) is uncertain. Methods and results: We enrolled 512 of 951 consecutive HFpEF patients admitted to the Kumamoto University Hospital between 2007 and 2013 and divided them into five groups according to PP quintiles. Blood pressure and pulse wave velocity (PWV) were measured by an ankle–brachial index device. The PP values in HFpEF were significantly and positively correlated with PWV and LV stroke volume index, and were negatively correlated with estimated glomerular filtration rate and haemoglobin levels. Furthermore, plasma B-type natriuretic peptide levels in HFpEF patients with the lowest (<45 mmHg) and highest PP (≥75 mmHg) were significantly higher than those with other PP (45–74 mmHg). The percentage of total cardiovascular and heart failure (HF)-related events by PP category resulted in U- and J-shaped curves. The higher frequency of coronary-related events was nearly linear. In the Kaplan–Meier analysis, HFpEF patients with the lowest and highest PP quintiles had a significantly higher risk of cardiovascular and HF-related events than those with other PPs (45–74 mmHg) (log-rank test, both P < 0.01). Conversely, the frequency of coronary-related events in the highest PP group, but not in the lowest PP group, was significantly higher than in other PP groups. Conclusion: Pulse pressure lower than 45 mmHg and higher than 75 mmHg was closely associated with HFpEF prognosis, indicating the clinical significance of PP for risk stratification of HFpEF.
DOI： 10.1002/ejhf.559
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Hokimoto S., Tabata N., Yamanaga K., Sueta D., Akasaka T., Tsujita K., Sakamoto K., Yamamoto E., Yamamuro M., Izumiya Y., Kaikita K., Kojima S., Matsui K., Ogawa H.
International Journal of Cardiology 222 185 - 194 2016.11
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background The aim was to examine the prevalence and characteristics of epicardial vasomotor abnormality (EVA) and coronary microvascular dysfunction (CMD) including endothelium-dependent (EDCMD) or -independent (EICMD) in patients following a second-generation drug-eluting stent (second DES) implantation without in-stent restenosis. Methods and results In 105 patients who underwent second DES implantation in the left anterior descending coronary artery (74 men; mean age, 67.9±9.6years), and in 105 suspected angina patients without stenting (65 men; mean age 66.4±9.1years), we evaluated EVA using the acetylcholine provocation test, EDCMD and EICMD by measuring the coronary flow reserve and the relationship between myocardial ischemia (intracoronary lactate production between aorta and coronary sinus and ST-T changes) or recurrent angina and vascular function. There was no difference in the incidence of EVA between DES and control (49.5% versus 55.2%; P = 0.41). Given that the prevalence of CMD was higher in DES than in control (59.0% versus 29.5%; P < 0.001), CMD may be associated with stent placement. Of the CMD patients, EDCMD alone, EICMD alone, and both CMDs were found in 40.3%, 22.6%, and 37.1%, respectively. Myocardial ischemia was detected in 42.4% of patients, and recurrent angina was more common in the presence of both EDCMD and EICMD in patients with EVA or CMD compared to patients with normal vascular function (EVA, 42.9% versus 7.7%, P = 0.015: CMD, 39.1% versus 7.7%, P = 0.007). Conclusions Myocardial ischemia and recurrent angina may be caused by the presence of both EDCMD and EICMD after a second DES implantation without ISR.
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Tabata N., Sueta D., Akasaka T., Arima Y., Sakamoto K., Yamamoto E., Izumiya Y., Yamamuro M., Tsujita K., Kojima S., Kaikita K., Morita K., Oniki K., Saruwatari J., Nakagawa K., Hokimoto S.
PLoS ONE 11 ( 11 ) e0166240 2016.11
Language：English Publishing type：Research paper (scientific journal) Publisher：PLoS ONE
Background Helicobacter pylori infection and interleukin-1 polymorphisms are associated with an increased risk of gastric cancer. We examined the prevalence of Helicobacter pylori seropositivity and interleukin-1 polymorphisms between ST-segment elevation myocardial infarction and non-ST-segment elevation acute coronary syndrome patients. Methods We recruited consecutive acute coronary syndrome patients, and 101 non-ST-segment elevation acute coronary syndrome patients and 103 ST-segment elevation myocardial infarction patients were enrolled. Interleukin-1 polymorphism analyses were performed for single nucleotide polymorphism in interleukin-1 beta-511 and the variable number of tandem repeats polymorphism in the interleukin-1 receptor antagonist by polymerase chain reaction. Immunoglobulin G antibodies against Helicobacter pylori and high sensitivity C-reactive protein were also measured. Results The rates of the simultaneous presence of interleukin-1 polymorphisms and Helicobacter pylori-seropositivity between non-ST-segment elevation acute coronary syndrome and STsegment elevation myocardial infarction groups were 25.7% and 42.7%, respectively (P = 0.012). Helicobacter pylori-seropositive subjects with interleukin-1 polymorphisms showed significantly higher levels of high sensitivity C-reactive protein (0.04-0.12 vs. 0.02-0.05; P<0.001). Multivariate logistic regression analysis revealed that the carriage of Helicobacter pylori-seropositivity and interleukin-1 polymorphisms was significantly associated with STsegment elevation myocardial infarction (odds ratio, 2.32; 95% confidence interval, 1.23-4.37; P = 0.009). The C-statistic of conventional risk factors was 0.68 (P<0.001) and that including Helicobacter pylori-seropositivity and interleukin-1 polymorphisms was 0.70 (P<0.001); continuous net reclassification improvement was 34% (P = 0.0094) and integrated discrimination improvement was 3.0% (P = 0.014). Conclusions The coincidence of Helicobacter pylori-seropositivity and interleukin-1 polymorphisms was significantly associated with higher levels of high sensitivity C-reactive protein and the increased risk of ST-segment elevation myocardial infarction.
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Tsujita K., Yamanaga K., Komura N., Sakamoto K., Miyazaki T., Oimatsu Y., Ishii M., Tabata N., Akasaka T., Sueta D., Yamamoto E., Yamamuro M., Izumiya Y., Kojima S., Nakamura S., Kaikita K., Hokimoto S., Ogawa H.
International Journal of Cardiology 220 112 - 115 2016.10
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background Although acute coronary syndrome (ACS) mainly arises from plaque ruptures (PR), precise mechanisms underlying ACS without PR are unknown. We sought to examine clinical, angiographic and intravascular ultrasound (IVUS) characteristics of ACS without PR. Methods and results Culprit lesions of 161 ACS patients were categorized by the presence or absence of PR (PR group: n = 57, Non-PR group: n = 104). Lower abdominal circumference (86 ± 10 cm vs 90 ± 9 cm, p = 0.02), lower prevalence of myocardial infarction (53% vs 82%, p = 0.0002), and higher prevalence of definite vasospasm (15% vs 2%, p = 0.006) were found in Non-PR group. Morphologically, Non-PR group was associated with simpler Ambrose classification (36% vs 14%, p = 0.004), less hypoechoic plaque (45% vs 65%, p = 0.04) and lower incidence of IVUS-detected thrombus (21% vs 54%, p < 0.0001), compared with PR group. On quantitative IVUS, although minimum lumen area (MLA) was similar between the groups, vessel (14.2 ± 5.4 mm vs 17.5 ± 5.1 mm , p = 0.0002) and plaque (11.6 ± 5.0 mm vs 14.9 ± 4.9 mm , p < 0.0001) areas were significantly smaller at MLA site in Non-PR group than in PR group. On multivariate analysis, average plaque area was only an independent IVUS-predictor of non-rupture ACS (odds ratio: 0.85, p = 0.01). Conclusion Compared to ACS with PR, non-rupture ACS arise from more hyperechoic (allegedly “stable”) plaque with smaller vessel and plaque area, leading to lower incidence of thrombotic occlusion. Coronary vasospasm might be a possible pathogenic mechanism underlying non-rupture ACS. 2 2 2 2
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Ishii M., Kaikita K., Sato K., Yamanaga K., Miyazaki T., Akasaka T., Tabata N., Arima Y., Sueta D., Sakamoto K., Yamamoto E., Tsujita K., Yamamuro M., Kojima S., Soejima H., Hokimoto S., Matsui K., Ogawa H.
International Journal of Cardiology 220 328 - 332 2016.10
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background Coronary spasm is one of the mechanisms of myocardial infarction with nonobstructive coronary arteries (MINOCA). The aim of this study was to investigate the effects of aspirin on future cardiovascular events in patients with coronary vasospastic angina (VSA) with non-significant atherosclerotic stenosis. Methods This was the retrospective analysis of the 640 VSA patients with non-significant atherosclerotic stenosis (≤ 50% stenosis) among 1,877 consecutive patients who underwent acetylcholine (ACh)-provocation testing between January 1991 and December 2010. The patients were divided into 2 groups treated with (n = 137) or without (n = 503) low-dose aspirin (81–100 mg/day). We evaluated major adverse cardiac events (MACE), defined as cardiac death, nonfatal myocardial infarction, and unstable angina. Results In the study population, 24 patients (3.8%) experienced MACE; there were 6 cases in VSA patients with aspirin and 6 in those without aspirin. Multivariate Cox hazards analysis for correlated factors of MACE indicated that use of statin (HR: 0.11; 95% CI: 0.02 to 0.84; P = 0.033), ST-segment elevation during attack (HR: 5.28; 95% CI: 2.19–12.7; P < 0.001), but not the use of aspirin as a significant predictor of MACE. After propensity score matching (n = 112, each), Kaplan–Meier survival analysis indicated almost identical rate of 5-year survival free from MACE in those with aspirin, compared to those without aspirin in the entire and matched cohort (P = 0.640 and P = 0.541, respectively). Conclusions Low-dose aspirin might not reduce future cardiovascular events in VSA patients with non-significant stenosis.
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Changes in the risk factors for coronary spasm Reviewed
Ishii M., Kaikita K., Sato K., Yamanaga K., Miyazaki T., Akasaka T., Tabata N., Arima Y., Sueta D., Sakamoto K., Yamamoto E., Tsujita K., Yamamuro M., Kojima S., Soejima H., Hokimoto S., Matsui K., Ogawa H.
IJC Heart and Vasculature 12 85 - 87 2016.9
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：IJC Heart and Vasculature
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Usuku H., Yamamoto E., Kurogi K., Izumiya Y., Tsujita K., Yamamuro M., Kojima S., Soejima H., Kaikita K., Yamamoto N., Hokimoto S., Noda K., Yamabe H., Oshima S., Ogawa H.
IJC Metabolic and Endocrine 12 52 - 54 2016.9
Language：English Publishing type：Research paper (scientific journal) Publisher：IJC Metabolic and Endocrine
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Tsujita K., Yamanaga K., Komura N., Sakamoto K., Sugiyama S., Sumida H., Shimomura H., Yamashita T., Oka H., Nakao K., Nakamura S., Ishihara M., Matsui K., Sakaino N., Nakamura N., Yamamoto N., Koide S., Matsumura T., Fujimoto K., Tsunoda R., Morikami Y., Matsuyama K., Oshima S., Kaikita K., Hokimoto S., Ogawa H.
European Journal of Preventive Cardiology 23 ( 14 ) 1524 - 1528 2016.9
Language：English Publishing type：Research paper (scientific journal) Publisher：European Journal of Preventive Cardiology
Background The IMPROVE-IT trial showed that the clinical benefit of statin/ezetimibe combination appeared to be pronounced in patients with prior statin therapy. We hypothesized that the antiatherosclerotic effect of atorvastatin/ezetimibe combination was pronounced in patients with statin pretreatment. Methods In the prospective, randomized, controlled, multicenter PRECISE-IVUS trial, 246 patients undergoing intravascular ultrasound-guided percutaneous coronary intervention were randomized to atorvastatin/ezetimibe combination or atorvastatin alone. The dosage of atorvastatin was uptitrated with a treatment goal of lowering low-density lipoprotein cholesterol to below 70 mg/dl in both groups. Serial volumetric intravascular ultrasound was performed at baseline and 9-12 month follow-up to quantify the coronary plaque response in 202 patients. We compared the intravascular ultrasound endpoints in all subjects, stratified by the presence or absence of statin pretreatment. Results The baseline low-density lipoprotein cholesterol level (100.7 ± 23.1 mg/dl vs. 116.4 ± 25.9 mg/dl, p < 0.001) and lathosterol (55 (38 to 87)) μg/100 mg total cholesterol vs. 97 (57 to 149) μg/100 mg total cholesterol, p < 0.001) was significantly lower, and campesterol/lathosterol ratio (3.9 (2.4 to 7.4) vs. 2.6 (1.5 to 4.1), p < 0.001) was significantly increased in patients with statin pretreatment. Contrary to the patients without statin pretreatment (-'1.3 (-'3.1 to -'0.1)% vs. -'0.9 (-'2.3 to 0.9)%, p = 0.12), the atorvastatin/ezetimibe combination showed a significantly stronger reduction in delta percent atheroma volume, compared with atorvastatin alone, in patients with statin pretreatment (-'1.8 (-'3.6 to -'0.3)% vs. -'0.1 (-'1.6 to 0.8)%, p = 0.002). Conclusion Compensatory increase in cholesterol absorption observed in statin-treated patients might attenuate the inhibitory effects of statins on coronary plaque progression. A low-dose statin/ezetimibe combination might be a promising option in statin-hyporesponder.
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Tsujita K., Yamanaga K., Komura N., Sakamoto K., Sugiyama S., Sumida H., Shimomura H., Yamashita T., Oka H., Nakao K., Nakamura S., Ishihara M., Matsui K., Sakaino N., Nakamura N., Yamamoto N., Koide S., Matsumura T., Fujimoto K., Tsunoda R., Morikami Y., Matsuyama K., Oshima S., Kaikita K., Hokimoto S., Ogawa H.
Atherosclerosis 251 367 - 372 2016.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Atherosclerosis
Background and aims Although dual low-density lipoprotein cholesterol (LDL-C)-lowering therapy (DLLT) with statin-ezetimibe combination showed clinical benefit in patients with acute coronary syndrome (ACS) confirming “the lower, the better,” the underlying mechanisms of DLLT are still unknown. Methods PRECISE-IVUS trial evaluated the effects of DLLT on IVUS-derived coronary atherosclerosis and lipid profile, compared with atorvastatin monotherapy, quantifying the coronary plaque response in 100 ACS patients. We explored the potential predictors of plaque regression. Results Lower total cholesterol, LDL-C, triglyceride, remnant-like particles cholesterol, and stronger reduction of small dense LDL-C and cholesterol absorption markers were observed in patients with plaque regression compared to those with progression. Multivariate analysis revealed that achieved LDL-C was the strongest predictor for coronary plaque regression (95% CI: 0.944–1.000, p = 0.05), followed by age (95% CI: 0.994–1.096, p = 0.09). Conclusions Incremental LDL-C lowering by DLLT was associated with stronger coronary plaque regression, reconfirming that lowering LDL-C to levels below previous targets provided additional clinical benefit.
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Nagatsuka K., Miyata S., Kada A., Kawamura A., Nakagawara J., Furui E., Takiuchi S., Taomoto K., Kario K., Uchiyama S., Saito K., Nagao T., Kitagawa K., Hosomi N., Tanaka K., Kaikita K., Katayama Y., Abumiya T., Nakane H., Wada H., Hattori A., Kimura K., Isshiki T., Nishikawa M., Yamawaki T., Yonemoto N., Okada H., Ogawa H., Minematsu K., Miyata T.
Thrombosis and Haemostasis 116 ( 2 ) 356 - 368 2016.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Thrombosis and Haemostasis
Several studies have indicated that approximately 25% of patients treated with aspirin exhibit high on-treatment platelet reactivity (HTPR), which is potentially associated with cardiovascular events (CVEs). However, this association is still controversial, since the mechanisms by which HTPR contributes to CVEs remain unclear and a no standardised definition of HTPR has been established. To determine whether HTPR is associated with CVE recurrence and what type of assay would best predict CVE recurrence, we conducted a multicentre prospective cohort study of 592 stable cardiovascular outpatients treated with aspirin monotherapy for secondary prevention. Their HTPR was determined by arachidonic acid- or collagen-induced aggregation assays using two different agonist concentrations. Residual cyclooxygenase (COX)-1 activity was assessed by measuring serum thromboxane (TX)B or urinary 11-dehydro TXB . Shear-induced platelet thrombus formation was also examined. We followed all patients for two years to evaluate how these seven indexes were related to the recurrence of CVEs (cerebral infarction, transient ischaemic attack, myocardial infarction, unstable angina, revascularisation, other arterial thrombosis, or cardiovascular death). Of 583 patients eligible for the analysis, CVEs occurred in 69 (11.8%>). A Cox regression model identified several classical risk factors associated with CVEs. However, neither HTPR nor high residual COX-1 activity was significantly associated with CVEs, even by applying cut-off values suggested in previous reports or a receiver-operating characteristic analysis. In conclusion, recurrence of CVEs occurred independently of HTPR and residual COX-1 activity. Thus, our findings do not support the use of platelet or COX-1 functional testing for predicting clinical outcomes in stable cardiovascular patients. 2 2
DOI： 10.1160/TH15-11-0864
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A simple sarcopenia screening test predicts future adverse events in patients with heart failure Reviewed
Onoue Y., Izumiya Y., Hanatani S., Tanaka T., Yamamura S., Kimura Y., Araki S., Sakamoto K., Tsujita K., Yamamoto E., Yamamuro M., Kojima S., Kaikita K., Hokimoto S.
International Journal of Cardiology 215 301 - 306 2016.7
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background Progressive loss of skeletal muscle termed "sarcopenia" is an independent risk factor for mortality in patients with cardiovascular diseases. A simple screening test that can identify sarcopenia using three variables (age, grip strength and calf circumference) was recently developed. We evaluated the clinical utility of this screening test in patients with heart failure (HF). Methods and results HF patients were divided into the sarcopenia (n = 82) and non-sarcopenia (n = 37) groups based on the sarcopenia score. Circulating BNP and high-sensitive cardiac troponin T levels were significantly higher, and left ventricular ejection fraction was lower in the sarcopenia group than non-sarcopenia group. Kaplan-Meier curve showed that HF event-free survival rate was significantly lower in the sarcopenia group. Multivariate Cox proportional hazards analysis identified BNP (ln[BNP]) (hazard ratio [HR]: 1.58; 95% CI: 1.09-2.29, p = 0.02), hs-CRP (ln[CRP]) (HR: 1.82; 95% CI: 1.23-2.68; p < 0.01) and sarcopenia score (HR: 1.03; 95% CI: 1.01-1.05, p < 0.01) as independent predictors of HF events. In receiver operating characteristic analysis, adding the sarcopenia score to BNP levels increased an area under the curve for future HF events (sarcopenia score alone, 0.77; BNP alone, 0.82; combination, 0.89). Conclusions The sarcopenia screening test can be used to predict future adverse events in patients with HF.
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Tabata N., Hokimoto S., Akasaka T., Arima Y., Sakamoto K., Yamamoto E., Tsujita K., Izumiya Y., Yamamuro M., Kojima S., Kaikita K., Ogawa H.
Heart and Vessels 31 ( 7 ) 1038 - 1044 2016.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Heart and Vessels
Chronic kidney disease (CKD) status might modify the predictive effect of peripheral endothelial dysfunction on cardiovascular events after percutaneous coronary intervention (PCI). The aim of this study was to examine the differential effect of peripheral endothelial dysfunction on clinical outcome after PCI between CKD and non-CKD patients. We conducted a cohort study of 435 patients following PCI. CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m . Peripheral endothelial dysfunction was examined using reactive hyperemia-peripheral arterial tonometry index (RHI), and we divided patients into low- and high-natural logarithmic RHI (Ln-RHI) group. The endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, ischemic stroke, hospitalization due to unstable angina pectoris, and coronary revascularization. A total of 56 patients had a cardiovascular event. Patients who suffered a cardiovascular event had significantly lower Ln-RHI than other patients in the non-CKD group (0.46 ± 0.18 versus 0.60 ± 0.25; P = 0.002). Kaplan–Meier analysis demonstrated a significantly higher probability of cardiovascular events in low Ln-RHI patients in the non-CKD group (log-rank test: P = 0.003). Multivariate Cox proportional hazards analysis identified Ln-RHI as an independent and significant predictor of future cardiovascular events in the non-CKD group (HR: 0.096; 95 % CI 0.02–0.47; P = 0.004) but not in the CKD group. There was a differential effect of peripheral endothelial dysfunction on clinical outcome after PCI between CKD and non-CKD patients, and peripheral endothelial dysfunction significantly correlates with subsequent cardiovascular events after PCI in non-CKD patients. 2
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Sueta D., Kaikita K., Okamoto N., Yamabe S., Ishii M., Arima Y., Ito M., Oimatsu Y., Iwashita S., Takahashi A., Sakamoto K., Tsujita K., Nakamura E., Hokimoto S., Mizuta H., Ogawa H.
Clinical Trials and Regulatory Science in Cardiology 19 1 - 4 2016.7
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Clinical Trials and Regulatory Science in Cardiology
Background Deep vein thrombosis (DVT) after total knee arthroplasty (TKA) often results in a fatal pulmonary thromboembolism (PTE). Edoxaban is an activated factor X inhibitor, which has been shown to prevent thromboembolic events in venous thromboembolism (VTE). Recently, the Total-Thrombus-formation Analysis System (T-TAS™), a microchip-based flow chamber system capable of evaluating thrombogenicity, was developed. In this study, utilizing the T-TAS™, we will examine the incidence of VTE after TKA and evaluate how thromboses form. Methods/design This study will be a prospective, single-center, open-label, randomized, controlled clinical trial aimed at exploring the efficacy of edoxaban in reducing the incidence of VTE after TKA. A total of 80 patients who will undergo TKA will be randomly and evenly divided into groups receiving edoxaban plus physiotherapy or physiotherapy alone. The primary outcome measures will include the incidence rate of VTE as detected by ultrasonography 7 days after TKA and the changes in T-TAS™ parameters. The secondary outcome measures will include the changes in prothrombin time and activated partial thromboplastin time, incidence of major/minor bleeding events and adverse effects of edoxaban. Discussion This study will provide clinical evidence on the combined efficacy and safety of edoxaban and physiotherapy compared with that of physiotherapy alone. This is will be the first prospective trial designed to explore how thrombus formation after TKA can be predicted by the T-TAS™.
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Hokimoto S., Tabata N., Sueta D., Akasaka T., Tsujita K., Sakamoto K., Kaikita K., Kojima S., Ogawa H.
Journal of Cardiology 68 ( 1 ) 20 - 28 2016.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
Background: It is unknown to what extent coronary spasm affects cardiovascular events after percutaneous coronary intervention (PCI) in clinical practice. The aim was to examine the prevalence of cardiovascular events related to coronary spasm following PCI according to stent type. Methods: We enrolled 933 consecutive patients treated with coronary stent implantation, including bare metal stents (BMS; n = 238), first-generation drug-eluting stents (1st DES; n = 185), and second-generation DES (2nd DES; n = 510). We compared stent-oriented endpoints (SOEs; stent thrombosis, target vessel myocardial infarction or unstable angina, target lesion revascularization, and cardiac death) and the differences in SOE related to coronary spasm across stent types. Among the SOEs, spasm-related cardiac event was defined based on JCS guideline. Results: The prevalence of SOE for each stent type was 16.8% (BMS), 16.8% (1st DES), and 7.8% (2nd DES) (p < 0.001) and the rates of cardiovascular events related to coronary spasm were 2.9%, 3.2%, and 0.4%, respectively (p = 0.005). Multivariate analysis identified the non-use of statin (HR, 0.275, 95% CI, 0.087-0.871, p = 0.028) and non-use of 2nd DES (hazard ratio, 0.196, 95% confidence interval, 0.043-0.887, p = 0.034) as independent predictors of cardiac events related to coronary spasm. Conclusion: The prevalence of cardiovascular events related to coronary spasm was the lowest in patients with 2nd DES. The 2nd DES may be more efficacious and safer from the point of view of the reduction of cardiac events due to coronary spasm during statin therapy.
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Tabata N., Hokimoto S., Akasaka T., Sueta D., Arima Y., Sakamoto K., Yamamoto E., Izumiya Y., Yamamuro M., Tsujita K., Kojima S., Kaikita K., Morita K., Oniki K., Saruwatari J., Nakagawa K., Ogawa H.
International Journal of Cardiology 212 54 - 56 2016.6
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
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Komura N., Tsujita K., Yamanaga K., Sakamoto K., Kaikita K., Hokimoto S., Iwashita S., Miyazaki T., Akasaka T., Arima Y., Yamamoto E., Izumiya Y., Yamamuro M., Kojima S., Tayama S., Sugiyama S., Matsui K., Nakamura S., Hibi K., Kimura K., Umemura S., Ogawa H.
Journal of the American Heart Association 5 ( 6 ) 2016.6
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American Heart Association
Background--Drug-eluting stents are replacing bare-metal stents, but in-stent restenosis (ISR) remains a problem. Reactive hyperemia index (RHI) assessed by peripheral arterial tonometry evaluates endothelial function noninvasively. We prospectively assessed the prognostic value of RHI in predicting ISR after percutaneous coronary intervention. Methods and Results--RHI was measured before percutaneous coronary intervention and at follow-up (F/U) angiography (F/U RHI; 6 and 9 months post bare-metal stents- and drug-eluting stents- percutaneous coronary intervention, respectively) in 249 consecutive patients. At F/U, ISR (stenosis > 50% of diameter) was seen in 68 patients (27.3%). F/U natural logarithm (RHI) was significantly lower in patients with ISR than in those without (0.52±0.23 versus 0.65±0.27, P < 0.01); no between-group difference in initial natural logarithm (RHI) (0.60±0.26 versus 0.62±0.25, P=0.56) was seen. By multivariate logistic regression analysis, even after adjusting for other significant parameters in univariate analysis, F/U natural logarithm (RHI) independently predicted ISR (odds ratio: 0.13; 95% CI: 0.04-0.48; P=0.002). In receiver operating-characteristic analysis, F/U RHI was the strongest predictor of ISR (area under the curve: 0.67; 95% CI: 0.60-0.75; P < 0.01; RHI < 1.73 had 67.6% sensitivity, 64.1% specificity); area under the curve significantly improved from 0.62 to 0.70 when RHI was added to traditional ISR risk factors (P=0.02). Net reclassification index was significant after addition of RHI (26.5%, P=0.002). Conclusions--Impaired RHI at F/U angiography independently correlated with ISR, adding incremental prognostic value to the ISRrisk stratification following percutaneous coronary intervention.
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More haste, less speed: Cardiac perforation by a thoracentesis catheter Reviewed
Sueta D., Hokimoto S., Okamoto K., Yasuda H., Usuku H., Tazume H., Yamamoto E., Sakamoto K., Izumiya Y., Tsujita K., Kaikita K., Sakaguchi H., Fukui T., Ogawa H.
IJC Heart and Vasculature 11 17 - 18 2016.6
Language：English Publishing type：Research paper (scientific journal) Publisher：IJC Heart and Vasculature
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Akasaka T., Hokimoto S., Sueta D., Tabata N., Sakamoto K., Yamamoto E., Yamamuro M., Tsujita K., Kojima S., Kaikita K., Kajiwara A., Morita K., Oniki K., Saruwatari J., Nakagawa K., Ogata Y., Ogawa H.
American Journal of Physiology - Heart and Circulatory Physiology 310 ( 11 ) H1494 - H1500 2016.6
Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Physiology - Heart and Circulatory Physiology
Categorization as a cytochrome P-450 (CYP) 2C19 poor metabolizer (PM) is reported to be an independent risk factor for cardiovascular disease. It is correlated with an increase in the circulating levels of high-sense C-reactive protein (hs-CRP) in women only, although its role in coronary microcirculation is unclear. We examined sex differences in the impact of the CYP2C19 genotype and low-grade inflammation on coronary microvascular disorder (CMVD). We examined CYP2C19 genotypes in patients with CMVD (n = 81) and in healthy subjects as control (n = 81). CMVD was defined as the absence of coronary artery stenosis and epicardial spasms, the presence of inverted lactic acid levels between the intracoronary and coronary sinuses, or an adenosine triphosphate-induced coronary flow reserve ratio < 2.5. CYP2C19 PMs have two loss-of-function (LOF) alleles (*2, *3). Extensive metabolizers have no LOF alleles, and intermediate metabolizers have one LOF allele. The ratio of CYP2C19 PM and hs-CRP levels in CMVD was significantly higher than that of controls, especially in women (40.9 vs. 13.8%, P = 0.013; 0.11 ± 0.06 vs. 0.07 ± 0.04 mg/dl, P = 0.001). Moreover, in each CYP2C19 genotype, hs-CRP levels in CMVD in CYP2C19 PMs were significantly higher than those of the controls, especially in women (0.15 ± 0.06 vs. 0.07 ± 0.03, P = 0.004). Multivariate analysis for CMVD indicated that the female sex, current smoking, and hypertension were predictive factors, and that high levels of hs-CRP and CYP2C19 PM were predictive factors in women only (odds ratio 3.5, 95% confidence interval 1.26–9.93, P = 0.033; odds ratio 4.1, 95% confidence interval 1.15–14.1, P = 0.038). CYP2C19 PM genotype may be a new candidate risk factor for CMVD via inflammation exclusively in the female population.
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Yamamura S., Fujisue K., Tsujita K., Sakamoto K., Miyazaki Y., Kaikita K., Hokimoto S., Ogawa H.
BMC Cardiovascular Disorders 16 ( 1 ) 116 2016.5
Language：English Publishing type：Research paper (scientific journal) Publisher：BMC Cardiovascular Disorders
Background: Stent malapposition, stent fracture, and deformity, and inadequate anti-thrombotic therapy are known as the risk of stent thrombosis. We report a case of stent deformation with subsequent thrombus adhesion at the site of a partial stent fracture detected by intravascular ultrasound (IVUS) and optical coherence tomography (OCT). Case presentation: A 61-year-old male patient was diagnosed as effort angina pectoris. Coronary angiography revealed obstructions in the proximal segment of the left anterior descending (LAD) and left circumflex artery (LCx). Elective percutaneous coronary intervention (PCI) was scheduled for these lesions in the prior hospital. First, an everolimus-eluting stent (EES) was implanted in the just proximal LAD slightly protruding into left main trunk. One week later, the treatment to residual obstruction at proximal LCx was attempted. During delivery of the stent to LCx, the proximal edge of the previously-implanted LAD stent got stuck with the newly-deploying stent and deformed into the intravascular lumen when retracting the stent into the guide-catheter. He was immediately transferred to our hospital to repair these procedural problems. Two days later after the index procedure to LCx, intracoronary imaging with an IVUS and OCT were performed, and the IVUS/OCT imaging revealed thrombus adhesion around the deformed struts. The three-dimensional OCT guide also helped the detection of the deformed stent and the repair of deformed struts by additional stenting and kissing balloon technique. Conclusion: The current case suggested that thrombus adhesion can occur at the site of deformed and/or fractured stent at very early phase after stent implantation.
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Tabata N., Hokimoto S., Akasaka T., Sueta D., Arima Y., Sakamoto K., Yamamoto E., Izumiya Y., Yamamuro M., Tsujita K., Kojima S., Kaikita K., Morita K., Oniki K., Saruwatari J., Nakagawa K., Yamabe H., Matsui K., Ogawa H.
Clinical Trials and Regulatory Science in Cardiology 17 9 - 14 2016.5
Language：English Publishing type：Research paper (scientific journal) Publisher：Clinical Trials and Regulatory Science in Cardiology
Background Host genetic factors of interleukin (IL)-1 polymorphisms influence Helicobacter pylori infection pathogenic activity. We examined whether H. pylori-infected patients with IL-1 polymorphisms are associated with myocardial infarction (MI). Materials and methods We recruited 594 consecutive coronary artery disease patients and excluded those who met exclusion criteria. After matching age and sex, 82 cases with MI and 82 controls were enrolled. Immunoglobulin G antibodies against H. pylori and IL-1 polymorphisms (IL-1 beta-511 base pairs and IL-1 receptor antagonist) were analyzed. We assessed high sensitivity C-reactive protein (hs-CRP) level and reactive hyperemia-peripheral arterial tonometry (RH-PAT) index (RHI) using the EndoPAT2000 system. Results The simultaneous prevalence of H. pylori-seropositivity and IL-1 polymorphisms was 45.1% and 19.5% in the cases and controls, respectively (P = 0.001). H. pylori-positive patients with IL-1 polymorphisms showed significantly higher serum levels of natural logarithm of hs-CRP in the cases and controls (- 2.8 ± 1.0 vs. - 3.4 ± 0.6, respectively; P = 0.003 and - 2.8 ± 0.9 vs. - 3.2 ± 0.6, respectively; P = 0.02) and significantly lower levels of natural logarithm of RHI in the cases and controls (0.51 ± 0.13 vs. 0.61 ± 0.23, respectively; P = 0.039 and 0.47 ± 0.13 vs. 0.69 ± 0.23, respectively; P = 0.005). H. pylori-seropositivity with IL-1 polymorphisms was significantly associated with MI by logistic regression analysis (odds ratio, 4.83; 95% confidence interval, 1.99-11.7; P < 0.001). Conclusions H. pylori-positive patients with IL-1 polymorphisms showed higher levels of hs-CRP and lower levels of RHI, and were significantly correlated with the MI.
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Impact of Statin Therapy on Clinical Outcome in Patients With Coronary Spasm Reviewed
Ishii M., Kaikita K., Sato K., Yamanaga K., Miyazaki T., Akasaka T., Tabata N., Arima Y., Sueta D., Sakamoto K., Yamamoto E., Tsujita K., Yamamuro M., Kojima S., Soejima H., Hokimoto S., Matsui K., Ogawa H.
Journal of the American Heart Association 5 ( 5 ) 2016.5
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American Heart Association
Background: Statin therapy reduces the risk of cardiovascular events in patients with obstructive coronary artery disease. The aim of the present study was to determine the effects of statins on the prognosis of patients with coronary vasospastic angina (VSA) free of significant atherosclerotic stenosis. Methods and Results: After exclusion of 475 from 1877 consecutive patients who underwent an acetylcholine-provocation test between January 1991 and December 2010, data of 640 VSA patients without significant organic stenosis of the remaining 1402 were analyzed retrospectively. Propensity score matching was performed to reduce the effect of treatment-selection bias and possible confounders. The primary endpoint was major adverse cardiac events (MACE), including cardiac death, nonfatal myocardial infarction, and unstable angina. Among the study population, dyslipidemia on admission was identified in 160 of 168 (95.2%) patients of the statin group compared with only 125 of 472 (26.5%) of the no-statin group. Of the 640 patients, 24 (3.8%) developed MACE. Multivariate Cox hazard regression analysis identified statin therapy as a significant negative predictor of MACE (hazard ratio, 0.11; 95% CI, 0.02-0.84; P=0.033). In the propensity-score matched cohorts (n=128 each), Kaplan-Meier survival curve showed a better 5-year MACE-free survival rate for patients of the statin group compared to the no-statin group (100% vs 91.7%, respectively; P=0.002). Conclusions: Statin therapy correlated with a lower rate of cardiovascular events in VSA patients free of significant organic stenosis. Statins seems to improve the prognosis of VSA patients free of significant organic stenosis.
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Arima Y., Kaikita K., Ishii M., Ito M., Sueta D., Oimatsu Y., Sakamoto K., Tsujita K., Kojima S., Nakagawa K., Hokimoto S., Ogawa H.
Journal of Thrombosis and Haemostasis 14 ( 4 ) 850 - 859 2016.4
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Thrombosis and Haemostasis
Background: Accurate evaluation of thrombogenicity helps to prevent thrombosis and excessive bleeding. The total thrombus-formation analysis system (T-TAS) was developed for quantitative analysis of platelet thrombus formation by the use of microchips with thrombogenic surfaces (collagen, platelet chip [PL-chip]; collagen plus tissue factor, atherome chip [AR-chip]). We examined the utility of the T-TAS in the assessment of the efficacy of antiplatelet therapy in patients with coronary artery disease (CAD). Methods and Results: In this cross-sectional study, 372 consecutive patients admitted to the cardiovascular department were divided into three groups: patients not receiving any antiplatelet therapy (control, n = 56), patients receiving aspirin only (n = 69), and patients receiving aspirin and clopidogrel (n = 149). Blood samples were used for the T-TAS to measure the platelet thrombus-formation area under the curve (AUC) at various shear rates (1500 s [PL -AUC ] and 2000 s [PL -AUC ] for the PL-chip; 300 s [AR -AUC ] for the AR-chip). The on-clopidogrel platelet aggregation was measured by the use of P2Y12 reaction units (PRUs) with the VerifyNow system. The mean PL -AUC levels were 358 ± 111 (± standard deviation) (95% confidence interval [CI] 328.9-387.1) in the control group, 256 ± 108 (95% CI 230.5-281.5) in the aspirin group, and 113 ± 91 (95% CI 98.4-127.6) in the aspirin/clopidogrel group. In the aspirin/clopidogrel group, the PL -AUC was higher in poor metabolizers (PMs) with cytochrome P450 2C19(CYP2C19) polymorphisms (152 ± 112, 95% CI 103.4-200.6) than in the non-PM group (87 ± 74, 95% CI 73.8-100.2). Conclusions: Our findings suggest that the PL -AUC level measured by the T-TAS is a potentially suitable index for the assessment of antiplatelet therapy in CAD patients. -1 -1 -1 18 10 24 10 10 30 24 10 24 10 24 10
DOI： 10.1111/jth.13256
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Fragmented QRS complex is a diagnostic tool in patients with left ventricular diastolic dysfunction Reviewed
Onoue Y., Izumiya Y., Hanatani S., Kimura Y., Araki S., Sakamoto K., Yamamoto E., Tsujita K., Tanaka T., Yamamuro M., Kojima S., Kaikita K., Hokimoto S., Ogawa H.
Heart and Vessels 31 ( 4 ) 563 - 567 2016.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Heart and Vessels
Fragmented QRS complex (fQRS) on 12-lead ECG is associated with myocardial fibrosis and ischemic scar. Interstitial fibrosis is one of the histological characteristics of left ventricular diastolic dysfunction (LVDD). However, the clinical importance of fQRS in patients with LVDD remains unclear. Here, we assessed the hypothesis that the presence of fQRS is associated with disease severity in patients with LVDD, and could be used as an additional parameter to differentiate patients with heart failure with preserved ejection fraction (HFpEF) from LVDD. We analyzed 12-lead ECG of 239 patients with LVDD. The patients were divided into two groups according to the presence or absence of fQRS; 88 patients had fQRS (fQRS group) and 151 patients did not have fQRS (non-fQRS group). The percentage of patients with heart failure in the fQRS group was significantly higher than that in the non-fQRS group. The levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T were significantly higher in the fQRS group than those in the non-fQRS group. In univariate logistic regression analysis, fQRS was associated with the presence of heart failure in patients with LVDD. Multivariate logistic regression analysis identified fQRS and BNP as independent indicators for HFpEF. In conclusion, the presence of fQRS on the ECG could be used as an additional tool to differentiate HFpEF from LVDD.
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Ogura Y., Tsujita K., Shimomura H., Yamanaga K., Komura N., Miyazaki T., Ishii M., Tabata N., Akasaka T., Arima Y., Sakamoto K., Kojima S., Nakamura S., Kaikita K., Hokimoto S., Ogawa H.
Heart and Vessels 31 ( 3 ) 341 - 350 2016.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Heart and Vessels
Acute coronary syndrome (ACS) is one of the main causes of cardiovascular death. According to rapid aging of society, the peak age of ACS onset has grown older globally. Despite growing recognition of the necessity to build the ACS prevention strategy in the elderly, patients background and culprit lesion morphology of these elderly ACS patients have not been well studied. We sought to assess the clinical characteristics and intravascular ultrasound (IVUS) findings of the culprit lesions in elderly ACS patients. One-hundred and fifty-eight consecutive ACS patients whose culprit lesions imaged by pre-intervention IVUS were divided into two groups based on the age of onset: elderly [E] group (≥75 years, n = 65) and non-elderly [NE] group (<75 years, n = 93). As compared with NE group, hemoglobin (12.7 ± 2.0 g/dL vs. 13.7 ± 1.6 g/dL, p = 0.001), estimated glomerular filtration rate (62.5 ± 22.5 mL/min/1.73 m vs. 75.5 ± 20.5 mL/min/1.73 m , p = 0.0001), and body mass index (22.9 ± 3.4 kg/m vs. 24.5 ± 3.4 kg/m , p = 0.003) were significantly lower, and comorbid malignancy was more common (20.0 vs 6.5 %, p = 0.01) in E group. Although whole culprit segment was not positively remodeled (mean vessel area was 15.2 ± 5.6 mm /mm vs. 16.2 ± 5.1 mm /mm, p = 0.16) in E group, at maximum external elastic membrane site of the culprit lesion, lumen area was smaller (5.5 ± 3.2 mm vs. 6.7 ± 3.5 mm , p = 0.04), and plaque burden tended to be more abundant (70 ± 13 vs. 66 ± 13 %, p = 0.08). Interestingly, echo attenuation arc of culprit attenuated plaque was significantly greater in E group than in NE group (157 ± 83° vs. 118 ± 60°, p = 0.01). In conclusion, extracardiac comorbidity was more common in elderly ACS patients, and their culprit coronary lesions were still rupture prone, and “vulnerable.” 2 2 2 2 3 3 2 2
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New aspects of onco-cardiology Reviewed
Sueta D., Hokimoto S., Utsunomiya D., Tabata N., Akasaka T., Sakamoto K., Tsujita K., Kaikita K., Yamashita Y., Ogawa H.
International Journal of Cardiology 206 68 - 70 2016.3
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
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Yamamoto E., Hirata Y., Tokitsu T., Kusaka H., Tabata N., Tsujita K., Yamamuro M., Kaikita K., Watanabe H., Hokimoto S., Maruyama T., Ogawa H.
ESC Heart Failure 3 ( 1 ) 53 - 59 2016.3
Language：English Publishing type：Research paper (scientific journal) Publisher：ESC Heart Failure
Aims: Although inflammation plays an important role in the pathogenesis of heart failure (HF), the precise pathophysiological role of inflammation in HF with preserved left ventricular ejection fraction (HFpEF) still remains unclear. Hence, we examined the clinical significance of plasma neopterin, an inflammatory biomarker, in HFpEF patients. Methods and results: In the present study, we recruited consecutive HFpEF patients hospitalized in Kumamoto University Hospital, and further measured plasma neopterin by high-performance liquid chromatography and serum derivatives of reactive oxidative metabolites (DROM), a new biomarker of reactive oxygen species. Compared with risk factors (number of patients, age, sex, and equal incidence of diabetes mellitus, hypertension, and dyslipidemia) -matched non-HF patients (n = 68), plasma neopterin levels, but not serum high-sensitivity C-reactive protein levels, were significantly increased in patients with HFpEF (n = 68) (P < 0.001 and P = 0.15, respectively), accompanied by an elevation in serum DROM levels (P < 0.001). Plasma neopterin levels in New York Heart Association (NYHA) class III/IV HFpEF patients were significantly higher than in NYHA class II patients (P < 0.004). Furthermore, plasma ln-neopterin levels had significant and positive correlation with ln-DROM values (r = 0.57) and parameters of cardiac diastolic dysfunction [the ratio of early transmitral flow velocity to tissue Doppler early diastolic mitral annular velocity (r = 0.34), left atrial volume index (r = 0.17), and B-type natriuretic peptide (r = 0.38)]. Kaplan–Meier analysis showed that the high-neopterin group (>51.5 nM: median value of neopterin in HFpEF patients) had a higher probability of cardiovascular events than the low-neopterin group (log-rank test, P = 0.003). Conclusions: Plasma neopterin levels significantly increased in HFpEF and correlated with the severity of HF. Furthermore, high neopterin were significantly correlated with future cardiovascular events, indicating that measurement of plasma neopterin might provide clinical benefits for risk stratification of HFpEF patients. © 2015 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.
DOI： 10.1002/ehf2.12070
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急性冠症候群における凝固・線溶異常と抗血栓療法
海北幸一, 石井正将, 小川久雄
ICUとCCU 集中治療医学 40 ( 3 ) 223 - 229 2016.3
Authorship：Lead author Publishing type：Research paper (scientific journal)
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Kimura Y., Izumiya Y., Hanatani S., Yamamoto E., Kusaka H., Tokitsu T., Takashio S., Sakamoto K., Tsujita K., Tanaka T., Yamamuro M., Kojima S., Tayama S., Kaikita K., Hokimoto S., Ogawa H.
Heart and Vessels 31 ( 1 ) 52 - 59 2016.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Heart and Vessels
Thrombospondin-2 (TSP-2) is highly expressed in hypertensive heart. Interstitial fibrosis is frequently observed in hypertensive heart, and it is a characteristic feature of heart failure with preserved ejection fraction (HFpEF). We tested here the hypothesis that high TSP-2 serum levels reflect disease severity and can predict poor prognosis of patients with HFpEF. Serum TSP-2 levels were measured by ELISA in 150 patients with HFpEF. HFpEF was defined as left ventricular ejection fraction ≥50 %, B-type natriuretic peptide (BNP) ≥100 pg/ml or E/e′ ≥15. The endpoints were mortality rate, HF-related hospitalization, stroke and non-fatal myocardial infarction. The median serum TSP-2 level was 19.2 (14.4–26.0) ng/ml. Serum TSP-2 levels were associated with the New York Heart Association (NYHA) functional class. Circulating levels of BNP and high-sensitivity troponin T were positively correlated with serum TSP-2 levels. Kaplan–Meier survival curve showed high risk of adverse cardiovascular events in the high TSP-2 group (>median value), and that the combination of high TSP-2 and high BNP (≥100 pg/ml) was associated with the worst event-free survival rate. Multivariate Cox proportional hazard analysis identified TSP-2 as independent predictor of risk of death and cardiovascular events. Circulating TSP-2 correlates with disease severity in patients with HFpEF. TSP-2 is a potentially useful predictor of future adverse cardiovascular events in patients with HFpEF.
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Tabata N., Hokimoto S., Akasaka T., Arima Y., Sakamoto K., Yamamoto E., Tsujita K., Izumiya Y., Yamamuro M., Kojima S., Kaikita K., Kumagae N., Morita K., Oniki K., Nakagawa K., Matsui K., Ogawa H.
Journal of Cardiology 67 ( 1 ) 104 - 109 2016.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
Background: There is some controversy regarding the effect of CYP2C19 polymorphism on clinical outcome in patients receiving dual antiplatelet therapy (DAPT). Peripheral endothelial dysfunction has recently been reported to predict adverse cardiovascular events. We hypothesized that CYP2C19 loss-of-function (LOF) allele carriers with peripheral endothelial dysfunction had worse prognosis. The aim of this study was to evaluate an additive effect of peripheral endothelial dysfunction on clinical outcome following percutaneous coronary intervention (PCI) in patients with a CYP2C19 variant. Methods: We enrolled 434 patients on DAPT following PCI. CYP2C19 genotype was examined, and we divided patients into two groups: carriers, who had at least one CYP2C19 LOF allele, and non-carriers. Peripheral endothelial dysfunction was examined using reactive hyperemia-peripheral arterial tonometry index (RHI), and we divided patients into low and high RHI. Thus, subjects were divided into four groups, and clinical events were followed up. Results: A total of 55 patients had a cardiovascular event. Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular events in carriers with low RHI (log-rank test: p = 0.007). Multivariate Cox proportional hazards analysis identified both CYP2C19 LOF allele possession (hazard ratio (HR): 1.94; 95% confidence interval (CI): 1.1-3.69; p = 0.045) and low RHI (HR: 2.15; 95% CI: 1.22-3.78; p = 0.008) as independent and significant predictors of future cardiovascular events. Conclusions: CYP2C19 LOF allele carriers with peripheral endothelial dysfunction were significantly correlated with cardiovascular events. The additional evaluation of peripheral endothelial function along with CYP2C19 polymorphism might improve risk stratification after coronary stent implantation.
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Ito M., Kaikita K., Sueta D., Ishii M., Oimatsu Y., Arima Y., Iwashita S., Takahashi A., Hoshiyama T., Kanazawa H., Sakamoto K., Yamamoto E., Tsujita K., Yamamuro M., Kojima S., Hokimoto S., Yamabe H., Ogawa H.
Journal of the American Heart Association 5 ( 1 ) 2016.1
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American Heart Association
Background-Non-vitamin K antagonist oral anticoagulants are used to prevent thromboembolism in patients with atrial fibrillation. The T-TAS "Total Thrombus-formation Analysis System" (Fujimori Kogyo Co Ltd) was developed for quantitative analysis of thrombus formation using microchips with thrombogenic surfaces (collagen, platelet chip [PL] ; collagen plus tissue factor, atheroma chip [AR]). We evaluated the utility of T-TAS in predicting periprocedural bleeding in atrial fibrillation patients undergoing catheter ablation (CA). Methods and Results-After exclusion of 20 from 148 consecutive patients undergoing CA, the remaining 128 patients were divided into 2 treatment groups: the warfarin group (n=30) and the non-vitamin K antagonist oral anticoagulants group (n=98). Blood samples obtained on the day of CA (anticoagulant-free point) and at 3 and 30 days after CA were used in T-TAS to compute the thrombus formation area under the curve (AUC; AUC for the first 10 minutes for PL tested at flow rate of 24 μL/min [PL - AUC ]; AUC for the first 30 minutes for AR tested at flow rate of 10 μL/min [AR -AUC ]). AR -AUC and PL -AUC levels were similar in the 2 groups on the day of CA. Levels of AR -AUC , but not PL -AUC , were significantly lower in the 2 groups at days 3 and 30 after CA. Multiple logistic regression analyses identified the AR -AUC level on the day of CA as a significant predictor of periprocedural bleeding events (odds ratio 5.7; 95% CI 1.54-21.1; P=0.009). Receiver operating characteristic analysis showed that the AR -AUC level on the day of CA significantly predicted periprocedural bleeding events (AUC 0.859, 95% CI 0.766-0.951; P < 0.001). The cutoff AR -AUC level was 1648 for identification of periprocedural bleeding events. Conclusions-These results suggested that the AR -AUC level determined by T-TAS is a potentially useful marker for prediction of bleeding events in atrial fibrillation patients undergoing CA. 24 10 10 30 10 30 24 10 10 30 24 10 10 30 10 30 10 30 10 30
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A destabilized case of stable effort angina pectoris induced by low-dose adenosine triphosphate Reviewed
Sueta D., Kojima S., Izumiya Y., Yamamuro M., Kaikita K., Hokimoto S., Ogawa H.
Internal Medicine 55 ( 22 ) 3291 - 3294 2016
Language：English Publishing type：Research paper (scientific journal) Publisher：Internal Medicine
A 79-year-old man was diagnosed with sudden deafness. He had previously experienced a suspected episode of angina pectoris. At a local hospital, after 500 mg of hydrocortisone and 80 mg adenosine triphosphate (ATP) were administered, he became aware of chest discomfort. An electrocardiogram revealed serious ST-segment depressions. He was diagnosed with a non-ST elevated myocardial infarction (NSTEMI). Emergency coronary angiography revealed triple vessel disease, and the lesion was successfully stented. The mechanisms whereby the stable effort angina pectoris destabilized in this case were thought to include a reduction of the local blood flow because of an ATP product and probable thrombus formation in response to the administered steroids.
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Hokimoto S, Soejima H, Kojima S, Kaikita K, Yamamuro M, Izumiya Y, Tsujita K, Yamamoto E, Tanaka T, Sugamura K, Arima Y, Sakamoto K, Akasaka T, Tabata N, Sueta D, Miyoshi I, Usami M, Ogawa H
Annals of vascular diseases 9 ( 1 ) 22 - 29 2016
Language：English Publishing type：Research paper (scientific journal) Publisher：Annals of Vascular Diseases 編集委員会
<b>Objective:</b> To describe the distribution of ankle-brachial index (ABI) among Japanese cardiovascular inpatients and to explore risk factors of peripheral arterial disease (PAD) associated with ABI ≤0.9.<b>Materials and Methods:</b> This study was a retrospective analysis using clinical record databases of patients with cardiovascular disease admitted to the Department of Cardiovascular Medicine, Kumamoto University Hospital between 2007 and 2014.<b>Results:</b> Of 3639 patients included in the analysis, male patients accounted for 62.1% and the mean age of patients was 66.1 years. Ischemic heart disease (IHD) was observed in 49.1%. ABI ≤0.9 was observed in 11.3% of all patients, 14.1% in the IHD group and 8.5% in the non-IHD group. Age of ≥65 years (odds ratio [OR]: 2.93, 95% confidence interval [CI]: 2.22–3.86), current smoking (OR: 2.28, 95%CI:1.71–3.04), diabetes (OR: 2.15, 95%CI:1.71–2.71), hypertension (OR: 1.42, 95%CI:1.12–1.81) and chronic kidney disease (OR: 2.52, 95%CI:1.82–3.48) were significantly associated factors with ABI ≤0.9.<b>Conclusions:</b> This study suggests that PAD is prevalent even in patients without IHD. Active management of risk factors, early detection of PAD based on ABI, and therapeutic intervention could be effective in preventing future cardiovascular events or death.
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Misumi I., Honda T., Usuku H., Togashi A., Kiyama T., Tsunoda R., Obayashi H., Yasuda H., Kaikita K., Hokimoto S., Ogawa H.
Internal Medicine 55 ( 13 ) 1747 - 1750 2016
Language：English Publishing type：Research paper (scientific journal) Publisher：Internal Medicine
A 63-year-old woman with atrial fibrillation visited our hospital due to decompensated heart failure. Because atrial fibrillation was considered a remarkable precipitating factor for heart failure, cardioversion was performed. After cardioversion, refractory hypotension and cardiopulmonary arrest occurred. An arterial blood gas analysis showed marked lactic acidosis. Chronic kidney disease, heart failure, sedatives, and hypoventilation might have contributed to refractory hypotension due to severe acidosis in this case.
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冠攣縮性狭心症の発症機序
海北幸一、小川久雄
日本臨牀 74 ( 増刊号6 ) 39 - 42 2016
Authorship：Lead author Publishing type：Research paper (scientific journal)
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冠攣縮性狭心症の診断と治療に関するガイドライン（2013年改訂版）
海北幸一、小川久雄
日本臨牀 74 ( 増刊号6 ) 54 - 57 2016
Authorship：Lead author Publishing type：Research paper (scientific journal)
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冠攣縮性狭心症の危険因子・臨床的特徴・予後
石井正将、海北幸一、小川久雄
日本臨牀 74 ( 増刊号6 ) 48 - 53 2016
Publishing type：Research paper (scientific journal)
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Yamamoto M., Yamamoto E., Yasuda O., Yasuda H., Sakamoto K., Tsujita K., Izumiya Y., Kaikita K., Hokimoto S., Ogawa H.
Journal of Cardiology Cases 12 ( 6 ) 195 - 198 2015.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology Cases
We herein report a case of Werner's syndrome (WS) with cardiac syndrome X (CSX) and heart failure with preserved ejection fraction (HFpEF), receiving nicorandil treatment. A 58-year-old woman with chest discomfort on exercise was suspected of having effort-angina pectoris because of broad ST-depression in electrocardiogram of exercise test and reversible defect in the posterior-wall portion of left ventricle in exercise thallium myocardial scintigraphy. This patient also exhibited HFpEF, diagnosed by increased ratio of early-transmitral-flow-velocity to tissue-Doppler early-diastolic mitral annular velocity (E/e') in echocardiography and plasma B-type natriuretic peptide (BNP) levels. However, coronary angiography revealed no organic stenosis in epicardial coronary arteries, and coronary physiological measurements by PressureWire™ (St. Jude Medical, St Paul, MN, USA) demonstrated that coronary flow reserve (CFR) was greatly decreased. Because impaired CFR represents coronary microvascular dysfunction in the absence of obstructive coronary narrowing, we diagnosed CSX, and initiated the administration of nicorandil to improve coronary microcirculation. After three-month-treatment of nicorandil, the patient's symptoms were diminished, and reversible defect in exercise myocardial scintigraphy was improved. Furthermore, both E/e' and BNP were decreased, indicating the improvement of HFpEF via the restoration of microvascular dysfunction.Thus, nicorandil administration could bring beneficial effects in WS with CSX and HFpEF, accompanied by coronary microcirculation dysfunction. <. Learning objective: Contrary to previous case reports regarding Werner's syndrome (WS) with obstructive coronary artery disease (CAD), we herein report a case of WS with cardiac syndrome X (CSX) without obstructive CAD, complicated with heart failure with preserved ejection fraction (HFpEF). Because impaired coronary microcirculation is known to be associated with left ventricular hypertrophy and HFpEF, nicorandil could improve not only CSX but HFpEF via the restoration of coronary microvascular dysfunction.>. 201
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Kaikita K., Ishii M., Sato K., Nakayama M., Arima Y., Tanaka T., Sugamura K., Sakamoto K., Izumiya Y., Yamamoto E., Tsujita K., Yamamuro M., Kojima S., Soejima H., Hokimoto S., Matsui K., Ogawa H.
Journal of the American Heart Association 4 ( 12 ) 2015.12
Authorship：Lead author, Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American Heart Association
Background-Myocardial lactate production in the coronary circulation during acetylcholine (ACh)-provocation test (abbreviated as lactate production) provides supporting evidence for coronary spasm-induced myocardial ischemia. The purpose of this study was to examine the clinical features, predictive factors, and prognosis of patients with coronary vasospastic angina (VSA) and lactate production. Methods and Results-We examined all 712 patients who underwent both myocardial lactate measurement during AChprovocation test in the left coronary artery and genetic screening test of a -786T/C polymorphism in the 50-flanking region of the endothelial nitric oxide synthase (eNOS) gene between January 1991 and December 2010. Lactate production was observed in 252 of the 712 patients and in 219 of 356 VSA patients diagnosed by ACh-provocation test. Compared with lactate production- negative VSA patients, the lactate production-positive counterparts were more likely to be nonsmoker female diabetics with - 786T/C eNOS polymorphism (61% vs 31%, P < 0.001, 62% vs 34%, P < 0.001, 24% vs 14%, P=0.016, and 25% vs 15%, P=0.018, respectively). Multivariable logistic regression analysis identified female sex, diabetes mellitus, and -786T/C eNOS polymorphism to correlate with lactate production (odds ratio 3.51, 95% CI 2.16 to 5.70, P < 0.001; odds ratio 2.53, 95% CI 1.38 to 4.65, P=0.003; and odds ratio 1.85, 95% CI 1.02 to 3.35, P=0.044, respectively). Kaplan-Meier survival curve showed no difference in 5-year survival rate free from major adverse cardiac events between lactate production-positive and -negative VSA patients (P=0.319). Conclusions-The results indicated that female sex, diabetes, and mutation in -786T/C eNOS gene correlate with ACh-provoked myocardial ischemia in patients with coronary spasm.
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Usefulness of excimer laser atherectomy for balloon uncrossable lesion in chronic total occlusion Reviewed
Sueta D, Hokimoto S＊, Miyazaki T, Sakamoto K, Tsujita K, Yamamoto E, Tabata N, Kojima S, Kaikita K, Ogawa H
IJC Heart &Vasculature 9 70 - 72 2015.12
Language：English Publishing type：Research paper (scientific journal)
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Nocturia in patients with sleep-disordered breathing and cardiovascular disease Reviewed
Miyazaki T., Kojima S., Yamamuro M., Sakamoto K., Izumiya Y., Tsujita K., Yamamoto E., Tanaka T., Kaikita K., Hokimoto S., Ogawa H.
Circulation Journal 79 ( 12 ) 2632 - 2640 2015.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background:Sleep apnea is a common condition and a cardiovascular risk factor. Continuous positive airway pressure (CPAP) reduces cardiovascular events and sleep apnea-related symptoms, especially in patients with obstructive sleep apnea (OSA), who occasionally experience nocturia, a common problem in individuals of advanced age.Methods and Results:The present study was a prospective, observational study including 1,429 consecutive patients with cardiovascular disease (CVD). A questionnaire on nocturia was administered and nocturnal pulse oximetry was performed. Patients with moderate-to-severe sleep-disordered breathing (SDB) underwent polysomnography, and patients with OSA received CPAP therapy. Nocturia was observed in 561 of 666 patients included in the analysis. A multiple logistic regression analysis revealed that nocturia was associated with oxygen desaturation defined as a 3% decrease (P=0.0335) independent of age (P<0.0001), male sex (P=0.0078), hypertension (P=0.0139), and B-type natriuretic peptide (BNP) level (P=0.0185). Nocturia was reduced in patients who continued CPAP treatment and they also showed a decrease in the apnea-hypopnea index (45.3±13.6 vs. 2.5±3.7 events/h, P<0.0001), systolic blood pressure (121.6±11.9 vs. 113.4±8.8 mmHg, P=0.0002), and BNP level (57.7 [15.0–144.4] vs. 27.4 [8.5–111.7] pg/ml, P=0.0006).Conclusions:CPAP has the potential to reduce nocturia and risk factors for SDB such as increased blood pressure and BNP level, which may be beneficial in older men with CVD and OSA.
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Fujisue K., Sugiyama S., Matsuzawa Y., Akiyama E., Sugamura K., Matsubara J., Kurokawa H., Maeda H., Hirata Y., Kusaka H., Yamamoto E., Iwashita S., Sumida H., Sakamoto K., Tsujita K., Kaikita K., Hokimoto S., Matsui K., Ogawa H.
Circulation Journal 79 ( 12 ) 2623 - 2631 2015.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background:Endothelial dysfunction plays a crucial role in heart failure (HF), but the association between peripheral microvascular endothelial function assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) and prognosis remains unknown in HF with reduced left ventricular (LV) ejection fraction (HFREF). We prospectively investigated the association between peripheral microvascular endothelial function and HF-related near-future cardiovascular outcomes in HFREF patients.Methods and Results:The 362 HFREF patients (LVEF <50%) were followed for HF-related events (composite of cardiovascular death and HF hospitalization) up to 3 years. A natural logarithmic-scaled RH-PAT index (Ln-RHI) was obtained for each patient. A total of 82 HF-related events were recorded. The lower-RHI group (Ln-RHI ≤0.49, median) experienced a higher rate of HF-related events compared with the higher-RHI group by Kaplan-Meier analysis (30.9% vs. 14.4%, log-rank test: P<0.001). Multivariable Cox hazard analysis identified Ln-RHI as an independent predictor for HF-related events (per 0.1, hazard ratio: 0.84, 95% confidence interval: 0.75–0.95, P=0.005). Adding Ln-RHI to the Meta-analysis Global Group in Chronic HF risk score (MAGGICs) and Seattle Heart Failure Model (SHFM), powerful prognostic predictors of HF, significantly improved the net reclassification index (MAGGICs: 20.11%, P=0.02, SHFM: 24.88%, P<0.001), and increased the C-statistics for prediction of HF-related events (MAGGICs+Ln-RHI: from 0.612 to 0.670, SHFM+Ln-RHI: from 0.662 to 0.695).Conclusions:Peripheral microvascular endothelial dysfunction assessed by RH-PAT was associated with future HF-related events in HFREF.
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Clinical significance of plasma galectin-3 in patients with coronary artery disease Reviewed
Kusaka H., Yamamoto E., Hirata Y., Fujisue K., Tokitsu T., Sugamura K., Sakamoto K., Tsujita K., Kaikita K., Hokimoto S., Sugiyama S., Ogawa H.
International Journal of Cardiology 201 532 - 534 2015.10
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
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Yamanaga K., Tsujita K., Komura N., Kaikita K., Sakamoto K., Miyazaki T., Saito M., Ishii M., Tabata N., Akasaka T., Arima Y., Yamamoto E., Yamamuro M., Izumiya Y., Kojima S., Tayama S., Nakamura S., Hokimoto S., Ogawa H.
International Journal of Cardiology 201 535 - 537 2015.10
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
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Tsujita K., Sugiyama S., Sumida H., Shimomura H., Yamashita T., Yamanaga K., Komura N., Sakamoto K., Ono T., Oka H., Nakao K., Nakamura S., Ishihara M., Matsui K., Sakaino N., Nakamura N., Yamamoto N., Koide S., Matsumura T., Fujimoto K., Tsunoda R., Morikami Y., Matsuyama K., Oshima S., Kaikita K., Hokimoto S., Ogawa H.
Journal of Cardiology 66 ( 4 ) 353 - 358 2015.10
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
Background: Although the positive association between achieved low-density lipoprotein cholesterol (LDL-C) level and the risk of coronary artery disease (CAD) has been confirmed by randomized studies with statins, many patients remain at high residual risk of events suggesting the necessity of novel pharmacologic strategies. The combination of ezetimibe/statin produces greater reductions in LDL-C compared to statin monotherapy. Purpose: The Plaque REgression with Cholesterol absorption Inhibitor or Synthesis inhibitor Evaluated by IntraVascular UltraSound (PRECISE-IVUS) trial was aimed at evaluating the effects of ezetimibe addition to atorvastatin, compared with atorvastatin monotherapy, on coronary plaque regression and change in lipid profile in patients with CAD. Methods: The study is a prospective, randomized, controlled, multicenter study. The eligible patients undergoing IVUS-guided percutaneous coronary intervention will be randomly assigned to receive either atorvastatin alone or atorvastatin plus ezetimibe (10. mg) daily using a web-based randomization software. The dosage of atorvastatin will be increased by titration within the usual dose range with a treatment goal of lowering LDL-C below 70. mg/dL based on consecutive measures of LDL-C at follow-up visits. IVUS will be performed at baseline and 9-12 months follow-up time point at participating cardiovascular centers. The primary endpoint will be the nominal change in percent coronary atheroma volume measured by volumetric IVUS analysis. Conclusion: PRECISE-IVUS will assess whether the efficacy of combination of ezetimibe/atorvastatin is noninferior to atorvastatin monotherapy for coronary plaque reduction, and will translate into increased clinical benefit of dual lipid-lowering strategy in a Japanese population.
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Nagano M., Hokimoto S., Nakao K., Kaikita K., Akasaka T., Ogawa H., Fujimoto K., Miyao Y., Shimomura H., Tsunoda R., Hirose T., Nakamura N., Sakaino N., Oka H., Yamamoto N., Morikami Y., Matsumura T., Kajiwara I., Koide S.
Journal of Cardiology 66 ( 4 ) 333 - 340 2015.10
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
Background: Stent thrombosis (ST) has emerged as a severe complication of percutaneous coronary intervention (PCI). Since the occurrence of ST is lower in Japan than Western countries, there are few data to predict ST after drug-eluting stent (DES) implantation in Japan. We examined the independent predictors of ST incidence after DES implantation in Japanese patients, including the use of calcium channel blockers (CCBs). Methods and results: We used data from the Kumamoto Intervention Conference Study registry. There were 6286 consecutive patients enrolled from June 2008 to March 2011. Among them, we analyzed 3493 patients who underwent DES implantation. The incidence of definite/probable ST throughout a median follow-up period of 364 days was 0.57% (20 patients). There were 8 patients with early ST (within 30 days), 8 patients with late ST (between 31 and 365 days), and 4 patients with very late ST (after 1 year). The frequency of CCB use was significantly lower in ST than non-ST patients (25.0% versus 51.4%, respectively, p = 0.016). Multiple regression analysis showed that longer stent length (p = 0.034), acute coronary syndrome (p = 0.039), and the absence of CCB use (p = 0.046) were significant and independent predictors of ST within 1 year. Conclusions: These results suggest that CCB use may be associated with a decreased risk of ST after DES implantation within 1 year in Japanese patients.
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Yoshimura H., Kaikita K., Ono T., Iwashita S., Nakayama N., Sato K., Horio E., Tsujita K., Kojima S., Tayama S., Hokimoto S., Ogawa H.
Heart and Vessels 30 ( 5 ) 572 - 579 2015.9
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Heart and Vessels
Peri-procedural myocardial damage (MD) is associated with increased risk of major in-hospital complications and adverse clinical events. The aim of this study was to evaluate the effects of on-clopidogrel platelet aggregation and CYP2C19-reduced-function gene variants on elective percutaneous coronary intervention (PCI)-related MD. We measured changes in serum high-sensitive troponin T (hs-TnT) levels, CYP2C19 genotype, and on-clopidogrel platelet aggregation (PA) using VerifyNow P2Y12 system in 91 patients who received stent implantation (stent group). The control group comprised 30 patients who did not receive PCI. Blood samples were obtained before and 24 h after PCI or coronary angiography (CAG). Patients of the stent group were divided into high and low MD groups based on the median value of hs-TnT level at 24 h after PCI. Serum hs-TnT levels were significantly higher 24 h after PCI (86.8 ± 121.5 pg/ml) compared with before PCI (9.4 ± 5.3, p < 0.001), whereas the levels were identical before and 24 h after CAG in the control group. Simple logistic regression analysis demonstrated that MD correlated with age (p = 0.014), estimated GFR (p = 0.003), hemoglobin A1c (p = 0.015), baseline serum hs-TnT (p = 0.049), and stent length (p < 0.001). Multiple logistic regression analysis identified old age, high hemoglobin A1c level, and long stent, but not CYP2C19 reduced-function allele or high on-clopidogrel PA, as independent predictors of elective PCI-related MD. The present study demonstrated no significant relation between peri-procedural MD and high on-clopidgrel PA associated with CYP2C19 reduced-function allele in patients undergoing elective PCI. ®
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Ishii M., Kaikita K., Sato K., Tanaka T., Sugamura K., Sakamoto K., Izumiya Y., Yamamoto E., Tsujita K., Yamamuro M., Kojima S., Soejima H., Hokimoto S., Matsui K., Ogawa H.
Journal of the American College of Cardiology 66 ( 10 ) 1105 - 1115 2015.9
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American College of Cardiology
Background Coronary artery spasm contributes to the pathogenesis of variant angina and ischemic heart disease and may play a role in the progression of atherosclerosis. It is unclear whether the location of spasm is related to outcome. Objectives This study compared the clinical features and prognosis of patients with coronary spasm at the site of significant atherosclerotic stenosis with patients with spasm at sites without stenosis or nonsignificant stenosis. Methods This was a retrospective, observational study of 1,877 consecutive patients with typical or atypical angina-like chest pain undergoing acetylcholine (ACh)-provocation testing. A total of 1,760 patients were eligible for analysis. ACh-provoked coronary spasm and significant organic stenosis were observed in 873 and 358 patients, respectively. Results In patients with significant atherosclerotic stenosis, ACh-positive patients (n = 233) were younger and without diabetes mellitus compared with nonspasm patients (n = 125). In patients without organic stenosis, ACh-positive patients (n = 640) were older, had dyslipidemia, and were more likely to have a family history of ischemic heart disease than nonspasm patients (n = 762). Multiple logistic regression analysis identified ST-segment elevation during anginal attacks, organic stenosis of the left anterior descending artery, and multivessel spasm as correlates of spasm at sites of significant organic stenosis (n = 192). Multivariate analysis identified ACh-provoked spasm at the site of significant stenosis and use of nitrates as the 2 prognostic factors for major adverse cardiac events. Conclusions The clinical features and prognosis of patients with ACh-provoked coronary spasm were different when it occurred at the site of significant atherosclerotic stenosis compared with patients with spasm elsewhere. Both spasm at the site of significant organic stenosis and nitrate use were significant predictors of major adverse cardiac events.
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Sueta D., Yamamoto E., Tanaka T., Hirata Y., Sakamoto K., Tsujita K., Kojima S., Nishiyama K., Kaikita K., Hokimoto S., Jinnouchi H., Ogawa H.
IJC Heart and Vasculature 8 52 - 54 2015.9
Language：English Publishing type：Research paper (scientific journal) Publisher：IJC Heart and Vasculature
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Misumi I., Nishida Y., Honda T., Kurokawa H., Yasuda H., Kaikita K., Hokimoto S., Ogawa H.
Internal Medicine 54 ( 17 ) 2197 - 2200 2015.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Internal Medicine
A boy with Duchenne muscular dystrophy was admitted to our hospital due to a transient loss of consciousness. Transthoracic echocardiography revealed left ventricular (LV) dilatation and diffuse hypokinesis of the LV wall. The LV wall was thin, and both non-compaction of the LV wall and marked thinning of the posterior LV wall resulting from a lesion were observed. The plasma B-type natriuretic peptide (BNP) level ultimately increased to 7,795 pg/mL, and the patient died of cardiac arrest following ventricular tachycardia. Severe heart failure, a critical condition, and thinning of the LV wall may have contributed to the markedly high plasma BNP level in this case.
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Novel vascular indices evaluated non-invasively in end-stage renal disease patients on hemodialysis Reviewed
Sueta D, Yamamoto E＊, Hirata Y, Tokitsu T, Sakamoto K, Tsujita K, Kaikita K, Hokimoto S, Sakanashi T
Clinical Trials and Regulatory Science in Cardiology 9 1 - 3 2015.9
Language：English Publishing type：Research paper (scientific journal)
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Sueta D., Kaikita K., Okamoto N., Arima Y., Ishii M., Ito M., Oimatsu Y., Iwashita S., Takahashi A., Nakamura E., Hokimoto S., Mizuta H., Ogawa H.
International Journal of Cardiology 197 98 - 100 2015.8
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
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Tsujita K., Sugiyama S., Sumida H., Shimomura H., Yamashita T., Yamanaga K., Komura N., Sakamoto K., Oka H., Nakao K., Nakamura S., Ishihara M., Matsui K., Sakaino N., Nakamura N., Yamamoto N., Koide S., Matsumura T., Fujimoto K., Tsunoda R., Morikami Y., Matsuyama K., Oshima S., Kaikita K., Hokimoto S., Ogawa H.
Journal of the American College of Cardiology 66 ( 5 ) 495 - 507 2015.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American College of Cardiology
Background Despite standard statin therapy, a majority of patients retain a high "residual risk" of cardiovascular events. Objectives The aim of this study was to evaluate the effects of ezetimibe plus atorvastatin versus atorvastatin monotherapy on the lipid profile and coronary atherosclerosis in Japanese patients who underwent percutaneous coronary intervention (PCI). Methods This trial was a prospective, randomized, controlled, multicenter study. Eligible patients who underwent PCI were randomly assigned to atorvastatin alone or atorvastatin plus ezetimibe (10 mg) daily. Atorvastatin was uptitrated with a treatment goal of low-density lipoprotein cholesterol (LDL-C) <70 mg/dl. Serial volumetric intravascular ultrasound was performed at baseline and again at 9 to 12 months to quantify the coronary plaque response in 202 patients. Results The combination of atorvastatin/ezetimibe resulted in lower levels of LDL-C than atorvastatin monotherapy (63.2 ± 16.3 mg/dl vs. 73.3 ± 20.3 mg/dl; p < 0.001). For the absolute change in percent atheroma volume (PAV), the mean difference between the 2 groups (-1.538%; 95% confidence interval [CI]: -3.079% to 0.003%) did not exceed the pre-defined noninferiority margin of 3%, but the absolute change in PAV did show superiority for the dual lipid-lowering strategy (-1.4%; 95% CI: -3.4% to -0.1% vs. -0.3%; 95% CI: -1.9% to 0.9% with atorvastatin alone; p = 0.001). For PAV, a significantly greater percentage of patients who received atorvastatin/ezetimibe showed coronary plaque regression (78% vs. 58%; p = 0.004). Both strategies had acceptable side effect profiles, with a low incidence of laboratory abnormalities and cardiovascular events. Conclusions Compared with standard statin monotherapy, the combination of statin plus ezetimibe showed greater coronary plaque regression, which might be attributed to cholesterol absorption inhibition-induced aggressive lipid lowering. (Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound [PRECISE-IVUS]; NCT01043380)
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Clinical significance of pulse pressure in patients with coronary artery disease Reviewed
Tokitsu T., Yamamoto E., Hirata Y., Fujisue K., Sueta D., Sugamura K., Sakamoto K., Kaikita K., Hokimoto S., Sugiyama S., Ogawa H.
International Journal of Cardiology 190 ( 1 ) 299 - 301 2015.8
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
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Yamamoto E., Hirata Y., Tokitsu T., Kusaka H., Sakamoto K., Yamamuro M., Kaikita K., Watanabe H., Hokimoto S., Sugiyama S., Maruyama T., Ogawa H.
International Journal of Cardiology 190 ( 1 ) 335 - 337 2015.8
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
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Systolic flow reversal in a case of mid-ventricular obstructive hypertrophic cardiomyopathy Reviewed
Misumi I., Honda T., Kurokawa H., Kubota Y., Ishii M., Sato R., Yamabe H., Yasuda H., Kaikita K., Hokimoto S., Ogawa H.
Internal Medicine 54 ( 14 ) 1765 - 1769 2015.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Internal Medicine
A 69-year-old man presented to our hospital with chest pain. Two-dimensional transthoracic echocardiography showed hypertrophy of the left ventricle, mid-ventricular obstruction and an apical aneurysm. Color-flow imaging at the obstruction site on the apical four-chamber view demonstrated systolic flow reversal in addition to a paradoxical jet flow. The systolic flow reversal may have been caused by a decreased apical contractility and pressure during systole.
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Sueta D., Yamamoto E., Tanaka T., Hirata Y., Sakamoto K., Tsujita K., Kojima S., Nishiyama K., Kaikita K., Hokimoto S., Jinnouchi H., Ogawa H.
International Journal of Cardiology 189 ( 1 ) 244 - 246 2015.6
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
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The pivotal role of a novel biomarker of reactive oxygen species in chronic kidney disease Reviewed
Hirata Y., Yamamoto E., Tokitsu T., Fujisue K., Kurokawa H., Sugamura K., Sakamoto K., Tsujita K., Tanaka T., Kaikita K., Hokimoto S., Sugiyama S., Ogawa H.
Medicine (United States) 94 ( 25 ) e1040 2015.6
Language：English Publishing type：Research paper (scientific journal) Publisher：Medicine (United States)
Risk stratification of chronic kidney disease (CKD) is clinically important because such patients are at high risk of cardiovascular events. Although reactive oxygen species (ROS) are reported to be closely associated with the pathophysiology of CKD, there are few useful ROS biomarkers known for CKD patients. Hence, our objectives in this study were to investigate whether serum derivatives of reactive oxygen metabolites (DROM), a novel biomarker of ROS, is involved in the pathophysiology of CKD (case-control study), and is a significant predictor of future cardiovascular events in CKD patients (follow-up study). Patients with suspected coronary artery disease (CAD) were enrolled and underwent coronary angiography. Patients with CKD (estimated glomerular filtration ratio <60mL/min/1.73m 2 and/or proteinuria, n=324) were compared with those without CKD (non-CKD). Serum DROM was measured at stable conditions. A case-control study of the 324 CKD patients and 263 non-CKD patients was conducted after matching risk factors, and a follow-up study of the 324 CKD patients was performed. CKD patients were divided into low- and high-DROM groups using their median value (348 unit; called the Carratelli unit [U.CARR]), and followed until the occurrence of cardiovascular events. DROM levels were significantly higher in risk factors-matched CKD patients than in risk factors-matched non-CKD patients (347.0 [301.8-391.8] U.CARR vs. 338.5 [299.8-384.3] U.CARR, P=0.03). During mean 23±14 months follow-up of 324 CKD patients, 83 cardiovascular events were recorded. Kaplan-Meier analysis demonstrated a higher probability of cardiovascular events in CKD patients with high DROM than in those with low DROM (P<0.001, log-rank test). Multivariate Cox hazard analysis including significant predictors in simple Cox hazard analysis demonstrated that high DROM was a significant and independent predictor of cardiovascular events in CKD patients (hazard ratio: 1.76, 95% confidence interval: 1.10-2.82, P=0.02). In conclusion, serum DROM values were significant and independent predictors of cardiovascular events in CKD patients, indicating that the measurements of DROM might provide clinical benefits for risk stratification of CKD patients.
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Resonant cardiac chamber with diastolic thrill Reviewed
Kurokawa H., Misumi I., Honda T., Usuku H., Yasuda H., Kaikita K., Hokimoto S., Ogawa H., Nakatsuka D., Tabata M.
Journal of Echocardiography 13 ( 2 ) 69 - 71 2015.6
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Echocardiography
A 70-year-old man with a diastolic Levine V/VI musical murmur came to our department. Doppler color-flow imaging showed eccentric severe aortic regurgitation. M-mode echocardiography demonstrated fluttering of the anterior mitral leaflet and fine tremors at the aortic root. The curved M-mode representation of the myocardial strain rate showed that the basal septum was encoded in a mixture of blue and red spots during diastole, showing massive basal septal vibration. In the present case, the force of the regurgitant flow might have caused vibration of the basal septum, thereby possibly leading to distinct thrill.
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Arima Y., Hokimoto S., Akasaka T., Mizobe K., Kaikita K., Oniki K., Nakagawa K., Ogawa H.
Journal of Cardiology 65 ( 6 ) 494 - 500 2015.6
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
Aim: CYP2C19 polymorphism modulates platelet reactivity in coronary artery disease patients with stent implants. However, the impact of the CYP2C19 genotype on clopidogrel response and clinical outcome has not been fully understood to date. Methods: We enrolled 518 consecutive patients with acute coronary syndrome (ACS) (n = 214) and stable angina (SA) (n = 304). All patients received stent implants followed by dual antiplatelet therapy of aspirin and clopidogrel. We determined CYP2C19 phenotype, measured platelet reactivity, and assessed the risk of cardiovascular events. Results: During a median follow-up of 894 days, the rate of cardiovascular events was higher in patients of the ACS group than the SA group (ACS: 20.1%, SA: 12.5%, p = 0.015). The mean platelet reactivity was significantly higher in the CYP2C19 loss-of-function allele carriers of the two groups (ACS, non-carriers: 3909 ± 1836 AU min, carriers: 4854 ± 1594 AU min, respectively, p < 0.01; SA, 3606 ± 1579 AU min, 4381 ± 1373 AU min, ±SD, p < 0.01). In the ACS group, cardiovascular events were higher in the loss-of-function allele carriers (24.6%) versus non-carriers (11.1%, p< 0.05), but no such difference was noted in the SA group (carriers: 14.8%; non-carriers: 7.9%, p = 0.078). Furthermore, landmark analysis from 30 days did not show differences in ACS group (carriers: 14.8%, non-carriers: 11.1%, p = 0.315). Multivariate Cox proportional hazards analysis identified the presence of loss-of-function allele as an independent predictor of cardiovascular events (hazard ratio, 2.1, 95% CI, 1.194-3.587, p = 0.010). Conclusions: The impact of CYP2C19 loss-of-function gene on clinical outcome is more powerful in early phase of ACS compared with SA.
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Hokimoto S., Akasaka T., Tabata N., Arima Y., Tsujita K., Sakamoto K., Kaikita K., Morita K., Kumagae N., Yamamoto E., Oniki K., Nakagawa K., Ogawa H.
Thrombosis Research 135 ( 6 ) 1081 - 1086 2015.6
Language：English Publishing type：Research paper (scientific journal) Publisher：Thrombosis Research
Objectives The aim of this study was to investigate the effect of CYP2C19 polymorphism and co-therapy with esomeprazole on the antiplatelet efficacy of clopidogrel. Background The antiplatelet efficacy of clopidogrel depends on CYP2C19 polymorphism or the co-administration of some kind of proton pump inhibitor (PPI). Methods CYP2C19 genotype and the residual platelet reactivity (RPR) were measured in 361 coronary heart disease patients (male, mean age 69 yrs), and the risk of cardiovascular events over a 3-month follow-up was assessed to evaluate the impact of co-administration of esomeprazole during dual antiplatelet therapy with aspirin and clopidogrel. Results The values of RPR did not differ between esomeprazole and non-esomeprazole groups (4389 ± 1112 versus 4079 ± 1355 AU · min, P = 0.103). RPR value was higher in intermediate metabolizers (IM) than in extensive metabolizers (EM) (4089 ± 1252 versus 3697 ± 1215 AU · min P = 0.012) and, similarly, higher in poor metabolizers (PM) than in IM (4884 ± 1027 versus 4089 ± 1252 AU · min, P < 0.001). There were no differences in RPR between esomeprazole and non-esomeprazole groups according to CYP2C19 genotype (EM, 3954 ± 1192 versus 3645 ± 1220 AU · min, P = 0.361; IM, 4401 ± 1063 versus 4051 ± 1271 AU · min, P = 0.293; PM, 4917 ± 669 versus 4876 ± 1099 AU · min, P = 0.907, respectively). There was also no difference in clinical outcomes between esomeprazole and non-esomeprazole groups in the three-month follow-up (0% versus 0.92%, P = 0.487). Conclusions These results suggest that concomitant use of esomeprazole with clopidogrel is not associated with reduced antiplatelet efficacy of clopidogrel or increased risk of cardiovascular events, irrespective of CYP2C19 genotype.
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Hokimoto S., Sakamoto K., Akasaka T., Kaikita K., Honda O., Naruse M., Ogawa H., Arizono K., Fujisawa S., Fukui H., Fukushima J., Hara M., Higuchi S., Honda O., Ikezaki N., Ikezaki S., Imafuji M., Ishimatsu T., Iwashita H., Iwashita Y., Kawabata Y., Kawatomi M., Kimura S., Kodama M., Kugiyama A., Kuwahara K., Mabe K., Machida J., Maehara A., Matsunaga Y., Matsuoka N., Matsushita K., Matsushita K., Migita A., Miyamoto T., Miyanaka T., Mizutari K., Miyamoto Y., Nabekura Y., Motoyama T., Nagano H., Nagayoshi M., Nakamura T., Nakano T., Nakashita K., Nojiri A., Oda T., Otsuka Y., Sakaguchi S., Sakanashi T., Seto Y., Shimada H., Shimomura T., Tajiri M., Tajiri T., Takamiya T., Takeshita M., Terasaki H., Tsuru T., Tsuruta K., Tsuzaki S., Tsukamoto M., Uekihara S., Uemura S., Uchigashima H., Uemura S., Yamada K., Yano S., Yasumoto N., Tazoe N., Nishi K., Hokimoto S., Sakamoto K., Akasaka T., Kaikita K., Ogawa H.
Circulation Journal 79 ( 6 ) 1269 - 1276 2015.5
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: Cardiovascular disease is a major cause of mortality in hemodialysis patients. The aim was to assess the relationship of various invasive cardiovascular procedures (ICP) to clinical outcome in hemodialysis patients. Methods and Results: A total of 5,813 patients at 76 facilities were on maintenance hemodialysis in Kumamoto Prefecture. Of these, 4,807 patients at 58 institutions were enrolled. Of 4,807 patients, 212 ICP (4.4%) were performed for various cardiovascular diseases in 189 patients (3.9%). ICP included PCI (n=80), endovascular treatment (n=59), radiofrequency catheter ablation (n=8), implantation of permanent pacemaker (n=15) and ICD (n=5), thoracotomy for valvular diseases (n=16), CABG (n=14), bypass surgery for peripheral artery disease (PAD; n=8), and artificial vessel replacement for aneurysm or aortic dissection (n=7). The overall mortality rate was 10.1% (19/189 patients). The mortality rate was highest in patients who underwent ICP for PAD, compared with other ICP (PAD, 18.2%; non-PAD, 6.7%, P=0.017). Infection and PAD were significant predictors of mortality (infection: OR, 8.30; 95% CI: 1.29–65.13, P=0.027; PAD: OR, 3.76; 95% CI: 1.35–10.48, P=0.012). The presence of inflammation/malnutrition factors was associated with high mortality (OR, 15.49; 95% CI: 3.22–74.12, P=0.0006). Conclusions: In this community-based registry study of 4,807 hemodialysis patients, the mortality rate of PAD patients was high despite ICP.
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Impact of left ventricular hypertrophy on impaired coronary microvascular dysfunction Reviewed
Tsujita K., Yamanaga K., Komura N., Sakamoto K., Miyazaki T., Ishii M., Tabata N., Akasaka T., Sueta D., Arima Y., Kojima S., Yamamoto E., Yamamuro M., Tanaka T., Izumiya Y., Tayama S., Nakamura S., Kaikita K., Hokimoto S., Ogawa H.
International Journal of Cardiology 187 ( 1 ) 411 - 413 2015.5
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
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Marume K., Hokimoto S., Tabata N., Akasaka T., Tsujita K., Sakamoto K., Yamamoto E., Yamamuro M., Kaikita K., Oniki K., Nakagawa K., Ogawa H.
International Journal of Cardiology 187 ( 1 ) 231 - 233 2015.5
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
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A case of repetitive and simultaneous stent thromboses Reviewed
Sueta D., Hokimoto S., Enomoto K., Ono T., Tabata T., Kajiwara I., Kaikita K., Saruwatari J., Oniki K., Nakagawa K., Ogawa H.
International Journal of Cardiology 186 210 - 212 2015.5
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
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Misumi I., Honda T., Kusuhara K., Yasuda H., Kaikita K., Hokimoto S., Ogawa H.
Journal of Medical Ultrasonics 42 ( 2 ) 239 - 241 2015.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Medical Ultrasonics
We report an increase in E/e′ ratio after treatment of heart failure (HF) in two patients. In case 1, the E/e′ ratio increased from 15 to 18 after treatment of HF. In case 2, the E/e′ ratio also increased from 24 to 35. Although a high E/e′ ratio suggests high pulmonary artery wedge pressure and worsening HF, the ratio may increase after improvement of HF. In the present cases of diastolic dysfunction, the high E wave did not change, but the e′ wave decreased relatively. This report may suggest difficulty in evaluating hemodynamic status based on the E/e′ ratio in patients with diastolic dysfunction.
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Yamamoto M., Tsujita K., Yamanaga K., Komura N., Sakamoto K., Kojima S., Yamamoto E., Tanaka T., Yamamuro M., Izumiya Y., Nakamura S., Kaikita K., Hokimoto S., Ogawa H.
Journal of Cardiology Cases 11 ( 4 ) 120 - 123 2015.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology Cases
We present a case of ST-segment elevation myocardial infarction in the territory of an anomalous left circumflex coronary artery running through the retroaortic region. In vivo coronary imaging with intravascular ultrasound visualized the usual atherosclerotic change and subsequent plaque rupture and thrombus formation at the culprit lesion. The clarification of pathologic mechanisms underlying the myocardial infarction case could provide information about pathophysiology of atherosclerotic development in anomalous left circumflex coronary artery, and could help in decision-making regarding the management strategy.<. Learning objective: Intravascular ultrasound (IVUS) imaging indicated that ordinary atherosclerosis could develop at retroaortic anomalous course of left circumflex coronary artery (LCX) despite absence of mechanical cause of ischemia. IVUS screening could provide significant information about pathophysiology of atherosclerotic development in anomalous LCX, and could help in decision-making regarding the management strategy. The images and discussion have high educational value for clinical cardiologists alike.>.
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Yamanaga K., Tsujita K., Komura N., Kaikita K., Sakamoto K., Miyazaki T., Saito M., Ishii M., Tabata N., Akasaka T., Sato K., Horio E., Arima Y., Kojima S., Tayama S., Nakamura S., Hokimoto S., Ogawa H.
American Journal of Physiology - Heart and Circulatory Physiology 308 ( 5 ) H478 - H484 2015.3
Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Physiology - Heart and Circulatory Physiology
Endothelial and vascular smooth muscle dysfunction of epicardial coronary arteries play a pivotal role in the pathogenesis of vasospastic angina (VSA). However, coronary microvascular (MV) function in patients with VSA is not fully understood. In the present study, subjects without coronary obstruction were divided into two groups according to the acetylcholine provocation test: VSA group (n = 29) and non-VSA group (n = 21). Hyperemic MV resistance (hMR) was measured using a dual-sensor (Doppler velocity and pressure)-equipped guidewire, and guidewire-derived hemodynamic parameters were compared. There were no between-group differences in clinical demographics, including potential factors affecting MV function (e.g., diabetes). Although coronary flow velocity reserve was similar between the two groups [2.4 ± 1.0 (VSA group) vs. 2.4 ± 0.9 (non-VSA group); P ± 0.8], coronary vessel resistance and hMR were significantly elevated in the VSA group compared with the non-VSA group (2.6 ± 3.1 vs. 1.2 ± 0.8, P = 0.04; 1.9 ± 0.6 vs. 1.6 ± 0.5, P = 0.03, respectively). Coronary vasospasm, older age, E/e’, and estimated glomerular filtration rate were significantly associated with MV dysfunction [defined as ≥ median value of hMR (1.6)] in univariate analysis. Coronary vasospasm most strongly predicted higher hMR in multivariate logistic regression analysis (odds ratio, 4.61; 95% confidence interval, 0.98 –21.60; P = 0.053). In conclusion, coronary MV resistance is impaired in patients with VSA compared with non-VSA patients, whereas coronary flow velocity reserve is maintained at normal levels in both groups. In vivo assessment of hMR might be a promising index of coronary MV dysfunction in patients with VSA.
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Hirata Y., Yamamoto E., Tokitsu T., Kusaka H., Fujisue K., Kurokawa H., Sugamura K., Maeda H., Tsujita K., Kaikita K., Hokimoto S., Sugiyama S., Ogawa H.
Journal of the American Heart Association 4 ( 2 ) 2015.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American Heart Association
BACKGROUND: Reactive oxygen species (ROS) are associated with development of coronary artery disease (CAD). However, there's no useful biomarker of ROS in CAD.
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Gender differences in impact of CYP2C19 polymorphism on development of coronary artery disease Reviewed
Hokimoto S., Tabata N., Akasaka T., Arima Y., Kaikita K., Morita K., Kumagae N., Oniki K., Nakagawa K., Ogawa H.
Journal of Cardiovascular Pharmacology 65 ( 2 ) 148 - 152 2015.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiovascular Pharmacology
The aim was to clarify whether CYP2C19 polymorphism is associated with the development of coronary artery disease (CAD). This study enrolled 723 patients with CAD (men 71%, 70 years) and healthy subjects undergoing a medical checkup (n = 453) as controls (men 69%, 53 years). We analyzed the incidence of CYP2C19 polymorphism and its association with the development of CAD in the absence of diabetes, dyslipidemia, and chronic kidney disease to minimize the influence of conventional coronary risk factors. In the analysis without risk factors, there was no difference in the incidence of the CYP2C19 genotype between CAD (n = 115) and control (n = 194) groups [extensive metabolizer, intermediate metabolizer, poor metabolizer (PM) in non-risk CAD: 33%, 46%, 21%, respectively; in non-risk control: 31%, 52%, 17%, respectively]. Analysis between CAD and control groups by the χ test showed that there was significant difference in distribution of CYP2C19 genotype in women alone (P = 0.025) but not in total subjects (P = 0.471) or men (P = 0.678), respectively. CYP2C19 PM was an independent predictor of CAD risk in women alone (odds ratio, 10.717; 95% confidence interval, 1.753-65.505; P = 0.010) but not in men. CYP2C19 PM status might be associated with the development of CAD as a disease susceptibility gene, especially in women.
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Hirata Y., Yamamoto E., Tokitsu T., Kusaka H., Fujisue K., Kurokawa H., Sugamura K., Maeda H., Tsujita K., Yamamuro M., Kaikita K., Hokimoto S., Sugiyama S., Ogawa H.
International Journal of Cardiology 179 305 - 308 2015.1
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
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Sueta D., Hokimoto S., Tayama S., Tsujita K., Sakamoto K., Yamamoto E., Tanaka T., Izumiya Y., Yamamuro M., Yamanaga K., Akasaka T., Tababa N., Arima Y., Kaikita K., Ogawa H.
International Journal of Cardiology 182 ( C ) 85 - 87 2015
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
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Ishii M., Hokimoto S., Akasaka T., Fujimoto K., Miyao Y., Kaikita K., Oshima S., Nakao K., Shimomura H., Tsunoda R., Hirose T., Kajiwara I., Matsumura T., Nakamura N., Yamamoto N., Koide S., Oka H., Morikami Y., Sakaino N., Matsui K., Ogawa H.
Circulation Journal 79 ( 5 ) 1115 - 1124 2015
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: The aim of this study was to examine the effects of different statins on the clinical outcomes of Japanese patients with coronary stent implants. Methods and Results: This study included 5,801 consecutive patients (males, 4,160; age, 69.7}11.1 years, mean } SD) who underwent stent implantation between April 2008 and March 2011. They were treated with a strong statin (n=3,042, 52%, atorvastatin, pitavastatin, or rosuvastatin), a regular statin (n=1,082, 19%, pravastatin, simvastatin, or fluvastatin) or no statin (n=1,677, 29%). The patients with chronic kidney disease (CKD) were divided into mildto- moderate CKD (30≤eGFR<60, n=1,956) and severe CKD (eGFR <30, n=559). Primary endpoints included cardiovascular death and nonfatal myocardial infarction, including stent thrombosis and ischemic stroke. The clinical outcome for the primary endpoint in mild-to-moderate CKD patients treated with a strong statin (hazard ratio 0.50, 95% confidence interval 0.31–0.81; P=0.005) was significantly lower than in those on no statins, but that in the patients treated with a regular statin was not (P=0.160). The clinical outcome for the primary endpoint in severe CKD patients treated with a strong or regular statin was no different than not being on statin therapy (P=0.446, P=0.194, respectively). Conclusions: In patients with mild-to-moderate CKD, only strong statins were associated with lower risk compared with no statin, but regular statins were not. It is possible that taking a strong statin from the early stage of CKD is useful for suppression of cardiovascular events.
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Hokimoto S., Mizuno Y., Sueta D., Morita S., Akasaka T., Tabata N., Harada E., Arima Y., Yamamuro M., Tanaka T., Yamamotoa E., Sakamoto K., Tsujita K., Kaikita K., Yasue H., Ogawa H.
International Journal of Cardiology 182 ( C ) 171 - 173 2015
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
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Tokitsu T., Yamamoto E., Hirata Y., Fujisue K., Sugamura K., Maeda H., Tsujita K., Kaikita K., Hokimoto S., Sugiyama S., Ogawa H.
Journal of Hypertension 33 ( 9 ) 1780 - 1790 2015
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Hypertension
Objective: Recent studies have shown that inter-arm blood pressure differences (IAD) may be a risk factor for cardiovascular events; however, none have addressed them in patients with coronary artery disease (CAD). Methods: We measured blood pressure bilaterally with the ankle brachial index (ABI) in 657 patients with suspected CAD and assessed the presence of CAD by coronary angiography, and the severity of coronary atherosclerosis with the Gensini score. Results: Mean IADs were significantly greater in risk factor matched patients with CAD than in those without it (P=0.01), whereas Gensini scores were significantly greater in those with high IAD (≥10 mmHg) than in those with low-IAD (P=0.01) according to cross-sectional analysis. Patients with high IAD had a significantly greater probability of cardiovascular events than those in whom it was low (log-rank test, P<0.01, mean follow-up range; 827.3±268.1 days). The presence of hypertension, ABI, usage of calcium channel blocker and high IAD were independent predictors of cardiovascular events according to longitudinal analysis (IAD; hazard ratio: 2.90, 95% confidence interval: 1.41-5.94, P<0.01) in these patients. Patients with high IAD and peripheral artery disease had the highest Gensini scores according to cross-sectional analysis (P<0.01) and highest probability of cardiovascular events according to longitudinal analysis (log-rank test, P<0.001). Conclusion: IADs were increased in CAD patients and correlated with its severity. Greater than 10mmHg of IAD was independently associated with future cardiovascular events. Assessing IAD by ABI measurement may facilitate risk stratification in CAD patients.
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Hokimoto S., Tabata N., Akasaka T., Arima Y., Tsujita K., Yamamoto E., Izumiya Y., Yamamuro M., Sakamoto K., Kaikita K., Sugamura K., Ogawa H.
International Journal of Cardiology 177 ( 2 ) 723 - 725 2014.12
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
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Marume K., Arima Y., Igata M., Nishikawa T., Yamamoto E., Yamamuro M., Tsujita K., Tanaka T., Kaikita K., Hokimoto S., Ogawa H.
Journal of Cardiology Cases 10 ( 6 ) 226 - 230 2014.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology Cases
A 58-year-old man was admitted for non-ST-elevation myocardial infarction. A medicated stent was used for severe coronary artery stenosis. However, consciousness level progressively deteriorated after angioplasty. Computed tomography showed no brain lesion but laboratory tests showed hyponatremia (serum sodium: 113. meq./l) and urine analysis showed syndrome of inappropriate antidiuretic hormone secretion (SIADH). SIADH was first suspected to be drug-induced by enalapril. However, hyponatremia persisted even after withdrawal of enalapril and required oral sodium intake. Hormone assays indicated secondary adrenal insufficiency, which was caused by adrenocorticotropic hormone (ACTH) deficiency. Furthermore, in addition to ACTH deficiency, adult growth hormone deficiency was diagnosed following tests. Treatment with hydrocortisone relieved hyponatremia and re-institution of enalapril did not reduce serum sodium concentration. The final diagnosis was hyponatremia caused by hypopituitarism.<. Learning objective: Secondary adrenal insufficiency with subsequent hypopituitarism should be suspected in cases with sudden-onset and prolonged hyponatremia in acute illness. Furthermore, the management of hypopituitarism should include assessment of growth hormone release to exclude growth hormone deficiency.>.
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Tabata N., Yamamuro M., Sugiyama S., Mizobe M., Takashio S., Tsujita K., Yamamoto E., Tanaka T., Kojima S., Kaikita K., Tayama S., Hokimoto S., Syudo C., Miyakawa T., Mitsuya H., Ogawa H.
Journal of Cardiology Cases 10 ( 5 ) 167 - 170 2014.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology Cases
A 34-year-old man presented with heart failure (HF). He suffered opportunistic infections and was shown to be human immunodeficiency virus (HIV)-positive (viral load: 156,013copies/mL) and have low CD4 lymphocytes (3/mm ), so he was initially treated for the opportunistic infections. Initial investigations showed high elevation of brain natriuretic peptide (BNP: 969pg/mL). Transthoracic echocardiography showed an enlarged left ventricle (LV: 70mm), a reduced LV ejection fraction (EF: 19%), but no LV hypertrophy or significant valvular diseases. After treatments for the infections, we started standard HF medications. Cardiac catheterization, after recovery from the opportunistic infections with negative inflammatory markers, showed no significant coronary stenosis, and endomyocardial biopsy did not show findings of myocarditis, without HIV structural protein on immunohistochemistry. Despite reduced EF, the cardiac output was elevated at 7.1l/min [cardiac index (CI): 4.3l/min/m ] and the systemic vascular resistance index was decreased at 1358dyness/cm m . Hematologists began anti-retroviral therapy; the viral load was gradually reduced to negative, and the CD4 count was increased to 50/mm at Day 182. EF was accordingly improved up to 54%, but the cardiac output decreased to a normal level at 3.9l/min (CI: 2.4l/min/m ), leading to normalization of plasma BNP (<5pg/mL). This case indicates that high cardiac output might be involved in the pathogenic mechanisms of HIV-related HF.<. Learning objective: The etiology of HIV-related HF remains unclarified. We report on a man with HIV-associated HF. There were no apparent causes of the HF, but the patient did demonstrate high cardiac output despite impaired systolic function. After anti-retroviral therapy, his systolic function was improved with a reduction and normalization of cardiac output. Therefore, this case indicates that high cardiac output might be involved in the pathogenic mechanisms of HIV-related HF>. 3 2 5 2 3 2
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Yamanaga K., Tsujita K., Shimomura H., Ogura Y., Matsumuro Y., Onoue Y., Chazono N., Morisaki S., Komura N., Sakamoto K., Kaikita K., Tayama S., Hokimoto S., Ogawa H.
Journal of Cardiology Cases 10 ( 5 ) 184 - 187 2014.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology Cases
Although spontaneous coronary artery dissection (SCAD) is one of the causes of acute coronary syndrome (ACS) or sudden cardiac death, its standard management, especially primary percutaneous coronary intervention (PCI) in ACS patients with ongoing ischemia, has not been established. We experienced three ACS patients with SCAD who were treated with a different strategy of primary PCI. Each PCI strategy led to different clinical and procedural results. We describe here such PCI strategies and results, and also discuss the literature regarding primary PCI strategies for SCAD-induced ACS patients with ongoing ischemia. < Learning objective: SCAD is a cause of ACS. However, the treatment strategy of primary PCI for SCAD has not been fully investigated. We used different PCI strategies for three SCAD patients with ongoing ischemia. Our case series suggested that plain old balloon angioplasty is an acceptable option to avoid coronary stenting because the majority of patients were young menstruating women. Coronary vasospasm might be associated with SCAD. Treatment with vasodilators could be a potential pharmacological option for avoiding recurrence of SCAD>.
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Akasaka T., Hokimoto S., Oshima S., Nakao K., Fujimoto K., Miyao Y., Shimomura H., Tsunoda R., Hirose T., Kajiwara I., Matsumura T., Nakamura N., Yamamoto N., Koide S., Oka H., Morikami Y., Sakaino N., Kaikita K., Nakamura S., Matsui K., Ogawa H.
International Journal of Cardiology 176 ( 3 ) 1385 - 1387 2014.10
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
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Takaoka N., Tsujita K., Kaikita K., Hokimoto S., Yamanaga K., Komura N., Chitose T., Ono T., Mizobe M., Horio E., Sato K., Nakayama N., Saito M., Iwashita S., Kojima S., Tayama S., Sugiyama S., Nakamura S., Ogawa H.
Heart and Vessels 29 ( 5 ) 584 - 595 2014.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Heart and Vessels
Despite current standards of care aimed at achieving targets for low-density lipoprotein cholesterol (LDL-C), many patients remain at high residual risk of cardiovascular events. We sought to assess the LDL-C-dependent differences in culprit intravascular ultrasound (IVUS) morphologies and clinical characteristics in patients with acute coronary syndrome (ACS). Eighty-six consecutive ACS patients whose culprit lesions imaged by preintervention IVUS were divided into two groups based on the fasting LDL-C level on admission: a low-LDL-C group (LDL-C <2.6 mmol/l, n = 45) and a high-LDL-C group (LDL-C ≥2.6 mmol/l, n = 41). Patients with stable angina with LDL-C <2.6 mmol/l (n = 30) were also enrolled as an age- and gender-matched control. The low-LDL-C ACS group was significantly older (72 ± 12 vs 64 ± 14 years, P = 0.007) and more diabetic (47 % vs 15 %, P = 0.001). Importantly, IVUS morphologies were comparable between low- and high-LDL-C ACS groups (all P not significant), whereas culprit plaque was more hypoechoic and less calcified in the low-LDL-C ACS group than in the low-LDL-C stable angina group. Furthermore, compared with the low-LDL-C ACS nondiabetic group, the low-LDL-C ACS diabetic group was more obese, more triglyceride rich (1.3 ± 0.6 vs 0.9 ± 0.4 mmol/l, P = 0.003), and more endothelially injured, but no different for the culprit IVUS morphologies. In multivariate analysis, diabetes was independently associated with a low LDL-C level on admission in patients with ACS. There was no relationship between the LDL-C level at onset and culprit-plaque IVUS morphologies in ACS patients, although culprit plaque in the low-LDL-C ACS group was more vulnerable than in the low-LDL-C stable angina group. In patients with low-LDL-C levels, diabetes with atherogenic dyslipidemia might be the key residual risk.
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Mizobe M., Hokimoto S., Akasaka T., Arima Y., Kaikita K., Morita K., Miyazaki H., Oniki K., Nakagawa K., Ogawa H.
Thrombosis Research 134 ( 1 ) 72 - 77 2014.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Thrombosis Research
Objective The aim of this study was to examine the impact of CYP2C19 genotype on clinical outcome in coronary artery disease (CAD) patients with or without diabetes mellitus (DM). Methods CYP2C19 polymorphism and DM are associated with increased risk of cardiovascular events during antiplatelet therapy following stent implantation. Platelet reactivity during clopidogrel therapy and CYP2C19 polymorphism were measured in 519 CAD patients (males 70%, age 69 years) treated with stent placement. Patients were divided into two groups; DM (n = 249), and non-DM (n = 270), and clinical events were evaluated according to the carrier state, which included at least one CYP2C19 loss-of-function allele. Results The level of platelet reactivity and incidence of cardiovascular events were significantly different between Carriers and non-Carriers of the non-DM (platelet reactivity: 4501 +/- 1668 versus 3691 +/- 1714AUmin, P < 0.01; events, 32/178 versus 2/92, P < 0.01, respectively), however, there was no difference in clinical outcome in the DM group (events, 34/168 versus 14/81, respectively, P = 0.57). Multivariate analysis identified CYP2C19 loss-of-function allele carriage as an independent predictor of cardiovascular events in non-DM, but not in DM (non-DM, HR 7.180, 95% CI, 1.701 to 30.298, P = 0.007; DM, HR 1.374, 95% CI, 0.394 to 4.792, P = 0.618). Conclusion The impact of CYP2C19 polymorphism on clinical outcome seems to be more significant in non-DM compared with DM in patients with coronary stents. © 2014 Elsevier Ltd.
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Hokimoto S., Chitose T., Mizobe M., Akasaka T., Arima Y., Kaikita K., Iwashita S., Morita K., Miyazaki H., Oniki K., Matsui K., Nakagawa K., Ogawa H.
European Journal of Clinical Pharmacology 70 ( 6 ) 667 - 673 2014.6
Language：English Publishing type：Research paper (scientific journal) Publisher：European Journal of Clinical Pharmacology
Background: High residual platelet reactivity in patients receiving clopidogrel is associated with an increased risk of a cardiovascular event after coronary stenting. The aim of our study was to evaluate the impact of the cytochrome P450 (CYP) 3A5 and CYP2C19 polymorphisms on platelet reactivity during dual antiplatelet therapy. Methods: We determined the CYP2C19 and CYP3A5 genotypes of 101 angina patients (65 male patients, mean age 64 years) receiving dual antiplatelet therapy with aspirin and clopidogrel and evaluated the effect of these polymorphism on platelet reactivity at the early and late phases of treatment using a conventional light transmission aggregometry. Early and late phases were defined as 24 h after the loading dose and after 9 months on a maintenance dose of 75 mg daily, respectively. Results: The distribution of the CYP2C19 genotype was 30 % in extensive metabolizers (EM; CYP2C19*1/ *1), 46 % in intermediate metabolizers (IM;*1/*2,*1/ *3), and 25 % in poor metabolizers (PM;*2/*2,*2/ *3,*3/*3). Platelet reactivity levels in during the early and late phases were 3,793±1,476 and 2,960±1,410, respectively, in EM, 4,706±1,417 and 3,239±1,479, respectively, in IM, and 5,402±776 and 4,736±1,356 aggregation units (AU)•min, respectively in EM. The distribution of the CYP3A5 genotype was 33 % in patients carrying the wild-type or one loss-of-function allele (Expressor phenotype; *1/*1 and *1/*3, respectively) and 67 % in those carrying two loss-of-function alleles (Non-expressor; *3/*3). In total, eight patients were EM+Expressor, 22 were EM+Non-expressor, 18 were IM+Expressor, 28 were IM+Non-expressor, eight were PM+Expressor, and 17 were PM+Non-expressor. In the late phase of PM with the CYP2C19 polymorphism, the levels of platelet reactivity according to CYP3A5 genotype were 3,963±1,436 and 5,100±1,190 AU•min in Expressor and Non-expressor, respectively (P<0.05), however, there was no difference in platelet reactivity between Expressor and Non-expressor in EM and IM. Conclusions: Our results suggest that antiplatelet response to clopidogrel in the late phase depends on the CYP3A5 polymorphism in PM with CYP2C19. © 2014 Springer-Verlag.
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Mid-systolic flow reversal in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy Reviewed
Ito M., Misumi I., Rokutanda T., Kusuhara K., Akahoshi R., Matsumoto M., Shojima T., Yasuda H., Kaikita K., Hokimoto S., Ogawa H.
Journal of Echocardiography 12 ( 2 ) 78 - 80 2014.6
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Echocardiography
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Takashio S., Yamamuro M., Uemura T., Utsunomiya D., Morita K., Izumiya Y., Sugiyama S., Kojima S., Yamamoto E., Tsujita K., Tanaka T., Tayama S., Kaikita K., Hokimoto S., Yasuda O., Yamashita Y., Ogawa H.
American Journal of Cardiology 113 ( 10 ) 1697 - 1704 2014.5
Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Cardiology
Persistently high cardiac troponin T (cTnT) levels reflect myocardial damage in heart failure (HF). The presence and extent of myocardial fibrosis assessed by cardiac magnetic resonance (CMR) and high levels of cTnT predict poor prognosis in various cardiomyopathies. However, the association between myocardial fibrosis and transcardiac cTnT release has not been evaluated. This study investigated the correlation between myocardial fibrosis and transcardiac cTnT release from nonischemic failing myocardium. Serum cTnT levels were measured in aortic root (Ao) and coronary sinus (CS) using highly sensitive assay (detection limit >5 ng/L) in 74 nonischemic patients with HF who underwent CMR. Transcardiac cTnT release (ΔcTnT [CS-Ao]) represented the difference between CS and Ao-cTnT levels. Myocardial fibrosis was quantified by late gadolinium enhancement (LGE) volume and %LGE on CMR. cTnT was detectable in 65 patients (88%), and ΔcTnT (CS-Ao) levels were available (ΔcTnT [CS-Ao] >0 ng/L) in 60 patients (81%). LGE was observed in 42 patients (57%), and ΔcTnT (CS-Ao) levels were available in 41 LGE-positive patients (98%). In patients with available cTnT release, ΔcTnT (CS-Ao) levels were significantly higher in LGE-positive patients than those in LGE-negative patients (4.3 [2.2-5.5] vs 1.5 [0.9-2.6] ng/L; p = 0.001). Log (ΔcTnT [CS-Ao]) levels were correlated with LGE volume (r = 0.460, p = 0.003) and %LGE (r = 0.356, p = 0.03). In conclusion, the amount of transcardiac cTnT release was higher in LGE-positive patients than LGE-negative patients and correlated with the extent of LGE in nonischemic patients with HF. These results suggested that ongoing myocardial damage correlates with the presence and extent of myocardial fibrosis. © 2014 Elsevier Inc. All rights reserved.
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Hokimoto S., Mizobe M., Akasaka T., Arima Y., Kaikita K., Nakagawa K., Ogawa H.
Thrombosis Research 133 ( 4 ) 599 - 605 2014.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Thrombosis Research
Background The response to clopidogrel, and some kind of the drug interaction are multifactorial. Methods and Results We enrolled 174 consecutive patients and determined CYP2C19 genotypes, measured platelet aggregation, and assessed the relationship between CYP2C19 genotype and platelet reactivity 24 hours after clopidogrel administration, and the risk of cardiovascular events over 18 months follow-up. A sub analysis examined the impact of rabeprazole, a proton pump inhibitor (PPI) less affected by CYP2C19. The CYP2C19 genotype was extensive metabolizer (EM) in 36%, intermediate metabolizer (IM) in 45%, and poor metabolizer (PM) in 19%. Platelet reactivity was significantly lower in the EM group than in the IM and PM groups (EM, IM, PM: 3560 ± 1404, 4203 ± 1302, 5084 ± 1007 AU•min, P < 0.05). The cardiovascular event rate was higher in the IM and PM groups than in the EM group (12.7% and 12.5% vs 1.6%; Hazard ratio for IM 10.6, P = 0.029; for PM 11.3, P = 0.040). No differences were seen between patients taking (N = 50) and not taking (N = 124) rabeprazole in residual platelet aggregation (4407 ± 1360 vs 4048 ± 1394, AU•min, P = 0.2782), or in cardiovascular events (10.0% vs 8.1%, HR 0.97, P = 0.97). Conclusions CYP2C19 genotype is associated with an increased risk of cardiovascular events following stent implantation in Japanese patients. © 2013 Elsevier Ltd.
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Horio E., Kadomatsu T., Miyata K., Arai Y., Hosokawa K., Doi Y., Ninomiya T., Horiguchi H., Endo M., Tabata M., Tazume H., Tian Z., Takahashi O., Terada K., Takeya M., Hao H., Hirose N., Minami T., Suda T., Kiyohara Y., Ogawa H., Kaikita K., Oike Y.
Arteriosclerosis, Thrombosis, and Vascular Biology 34 ( 4 ) 790 - 800 2014.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Arteriosclerosis, Thrombosis, and Vascular Biology
Objective-cardiovascular disease (CVD), the most common morbidity resulting from atherosclerosis, remains a frequent cause of death. Efforts to develop effective therapeutic strategies have focused on vascular inflammation as a critical pathology driving atherosclerosis progression. Nonetheless, molecular mechanisms underlying this activity remain unclear. Here, we ask whether angiopoietin-like protein 2 (Angptl2), a proinflammatory protein, contributes to vascular inflammation that promotes atherosclerosis progression. Approach and results-Histological analysis revealed abundant Angptl2 expression in endothelial cells and macrophages infiltrating atheromatous plaques in patients with cardiovascular disease. Angptl2 knockout in apolipoprotein E-deficient mice (ApoE /Angptl2 ) attenuated atherosclerosis progression by decreasing the number of macrophages infiltrating atheromatous plaques, reducing vascular inflammation. Bone marrow transplantation experiments showed that Angptl2 deficiency in endothelial cells attenuated atherosclerosis development. Conversely, ApoE mice crossed with transgenic mice expressing Angptl2 driven by the Tie2 promoter (ApoE /Tie2-Angptl2 Tg), which drives Angptl2 expression in endothelial cells but not monocytes/macrophages, showed accelerated plaque formation and vascular inflammation because of increased numbers of infiltrated macrophages in atheromatous plaques. Tie2-Angptl2 Tg mice alone did not develop plaques but exhibited endothelium-dependent vasodilatory dysfunction, likely because of decreased production of endothelial cell-derived nitric oxide. Conversely, Angptl2 mice exhibited less severe endothelial dysfunction than did wild-type mice when fed a high-fat diet. In vitro, Angptl2 activated proinflammatory nuclear factor-κB signaling in endothelial cells and increased monocyte/macrophage chemotaxis. Conclusions-Endothelial cell-derived Angptl2 accelerates vascular inflammation by activating proinflammatory signaling in endothelial cells and increasing macrophage infiltration, leading to endothelial dysfunction and atherosclerosis progression. © 2014 American Heart Association, Inc. -/- -/- -/- -/- -/-
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Hanatani S., Izumiya Y., Takashio S., Kojima S., Yamamuro M., Araki S., Rokutanda T., Tsujita K., Yamamoto E., Tanaka T., Tayama S., Kaikita K., Hokimoto S., Sugiyama S., Ogawa H.
Heart and Vessels 29 ( 2 ) 231 - 237 2014.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Heart and Vessels
To distinguish hypertrophic cardiomyopathy (HCM) from hypertensive left ventricular hypertrophy (H-LVH) based on a morphological examination is often challenging. Growth differentiation factor 15 (GDF-15) is a novel diagnostic and prognostic biomarker for several cardiovascular diseases. In patients with LVH, GDF-15 promises to be a useful biomarker to distinguish between HCM and H-LVH. We evaluated 93 patients with H-LVH, 28 with HCM, and 28 disease control individuals. Serum GDF-15 concentrations were measured with an enzyme-linked immunosorbent assay. Circulating GDF-15 levels were significantly higher in patients with H-LVH than with HCM (P = 0.003). On the other hand, values for plasma B-type natriuretic peptide (BNP) levels were significantly lower in patients with H-LVH than with HCM (P = 0.004). Serum GDF-15 and plasma BNP levels positively correlated in patients with H-LVH but not with HCM. Multivariate logistic regression analysis revealed GDF-15 (odds ratio 12.06, confidence interval 1.85-78.77, P < 0.01) as an independent predictor of H-LVH among patients with LVH. In receiver-operating characteristic analysis, GDF-15 achieved an area under the curve of 0.70 for the identification of H-LVH. We found that GDF-15 might be a useful biomarker for discriminating HCM from H-LVH. Understanding serum GDF-15 values may have clinical utility for patients with LVH because the therapeutic strategies for treating HCM and H-LVH differ. © 2013 Springer.
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Hemodynamic influence of triphasic mitral inflow velocity: A case report Reviewed
Misumi I., Ito M., Rokutanda T., Kusuhara K., Akahoshi R., Matsumoto M., Tanaka H., Yasuda H., Kaikita K., Hokimoto S., Ogawa H.
Journal of Echocardiography 12 ( 1 ) 43 - 45 2014.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Echocardiography
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Izumiya Y., Hanatani S., Kimura Y., Takashio S., Yamamoto E., Kusaka H., Tokitsu T., Rokutanda T., Araki S., Tsujita K., Tanaka T., Yamamuro M., Kojima S., Tayama S., Kaikita K., Hokimoto S., Ogawa H.
Canadian Journal of Cardiology 30 ( 3 ) 338 - 344 2014.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Canadian Journal of Cardiology
Background: Circulating growth differentiation factor 15 (GDF-15) levels correlate with heart mass and fibrosis; however, little is known about its value in predicting the prognosis of patients with heart failure with preserved ejection fraction (HFpEF). Methods: We measured serum GDF-15 levels in 149 consecutive patients with left ventricular diastolic dysfunction (LVDD) and normal LV ejection fraction (>50%) and followed them for cardiovascular events. LVDD was defined according to the European Society of Cardiology guidelines. Results: The New York Heart Association functional class and circulating B-type natriuretic peptide (BNP) levels were significantly higher in the high-GDF-15 group (n= 75; greater than or equal to the median value [3694 pg/mL]) than in the low-GDF-15 group (n= 74). Patients were divided into HFpEF and LVDD groups according to the presence or absence of HF. Serum GDF-15 levels were significantly higher in the HFpEF group (n= 73) than in the LVDD group (n= 76) (median, 4215 [interquartile range, 3382-5287] vs 3091 [interquartile range, 2487-4217 pg/mL]; P < 0.0001). Kaplan-Meier curve analysis showed a significantly higher probability of cardiovascular events in the high-GDF-15 group than in the low-GDF-15 group for data of all patients (log-rank test P= 0.006) and data of patients in the HFpEF group only (. P= 0.014). Multivariate Cox hazard analysis identified age (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.87-0.98; P= 0.008), atrial fibrillation (HR, 7.95; 95% CI, 1.98-31.85, P= 0.003), lnBNP (HR, 3.37; 95% CI, 1.73-6.55; P < 0.0001), and GDF-15 (ln[GDF-15]) (HR, 4.74; 95% CI, 1.26-17.88, P= 0.022) as independent predictors of primary end points. Conclusions: GDF-15 is a potentially useful prognostic biomarker in patients with HFpEF. © 2014 Canadian Cardiovascular Society.
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Takaoka N., Tsujita K., Kaikita K., Hokimoto S., Mizobe M., Nagano M., Horio E., Sato K., Nakayama N., Yoshimura H., Yamanaga K., Komura N., Kojima S., Tayama S., Nakamura S., Ogawa H.
International Journal of Cardiology 171 ( 3 ) 423 - 430 2014.2
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background Some plaques lead to ST-segment elevation myocardial infarction (STEMI), whereas others cause non-ST-segment elevation acute coronary syndrome (NSTEACS). We used angiography and intravascular ultrasound (IVUS) to investigate the difference of culprit lesion morphologies in ACS. Methods Consecutive 158 ACS patients whose culprit lesions were imaged by preintervention IVUS were enrolled (STEMI = 81; NSTEACS = 77). IVUS and angiographic findings of the culprit lesions, and clinical characteristics were compared between the groups. Results There were no significant differences in patients' characteristics except for lower rate of statin use in patients with STEMI (20% vs 44%, p = 0.001). Although angiographic complex culprit morphology (Ambrose classification) and thrombus were more common in STEMI than in NSTEACS (84% vs 62%, p = 0.002; 51% vs 5%, p < 0.0001, respectively), SYNTAX score was lower in STEMI (8.6 ± 5.4 vs 11.5 ± 7.1, p = 0.01). In patients with STEMI, culprit echogenicity was more hypoechoic (64% vs 40%, p = 0.01), and the incidence of plaque rupture, attenuation and " microcalcification" were significantly higher (56% vs 17%, p < 0.0001; 85% vs 69%, p = 0.01; 77% vs 61%, p = 0.04, respectively). Furthermore, the maximum area of ruptured cavity, echolucent zone and arc of microcalcification were significantly greater in STEMI compared with NSTEACS (1.80 ± 0.99 mm vs 1.13 ± 0.86 mm , p = 0.006; 1.52 ± 0.74 mm vs 1.21 ± 0.81 mm , p = 0.004; 99.9 ± 54.6 vs 77.4 ± 51.2, p = 0.01, respectively). Quantitative IVUS analysis showed that vessel and plaque area were significantly larger at minimum lumen area site (16.6 ± 5.4 mm vs 14.2 ± 5.5 mm , p = 0.003; 13.9 ± 5.1 mm vs 11.6 ± 5.2 mm , p = 0.003, respectively). Conclusion Morphological feature (outward vessel remodeling, plaque buildup and IVUS vulnerability of culprit lesions) might relate to clinical presentation in patients with ACS. © 2014 Elsevier Ireland Ltd. 2 2 2 2 2 2 2 2
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Tabata N., Hokimoto S., Akasaka T., Arima Y., Kaikita K., Kumagae N., Morita K., Miyazaki H., Oniki K., Nakagawa K., Matsui K., Ogawa H.
Thrombosis Research 134 ( 5 ) 939 - 944 2014
Language：English Publishing type：Research paper (scientific journal) Publisher：Thrombosis Research
Introduction: There is some controversy regarding the effect of CYP2C19 polymorphism on clinical outcome in patients with dual antiplatelet therapy. Chronic kidney disease (CKD) is associated with increased risk of cardiovascular event, but the association between the possession of CYP2C19 loss-of-function (LOF) alleles and clinical outcome according to the presence of CKD is poorly understood. The aim of this study was to investigate whether CKD status modifies the association of CYP2C19 polymorphism in predicting outcomes in a prospective cohort study. Material and Methods: We enrolled 331 patients following coronary stent implantation. Patients were divided into two groups: CKD (n = 154) and non-CKD (n = 177). Platelet reactivity and CYP2C19 polymorphism were examined. The subjects were further divided into two groups according to the possession of CYP2C19 LOF alleles: carriers and non-carriers. Patients were followed up and clinical events were evaluated according to CKD and carrier status. Results: The proportion of high platelet reactivity was significantly higher in carriers than in non-carriers in both CKD (42.4% versus 21.7%; P = 0.016) and non-CKD groups (34.3% versus 3.7%; P b 0.001). In the non-CKD group alone, the incidence of cardiovascular events was significantly higher in carriers than in non-carriers (13.7% versus 1.7%; P = 0.013). Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular events in carriers than in non-carriers in the non-CKD group (log-rank test: P = 0.013) and there was no significant difference in the CKD group (log-rank test: P = 0.591). Multivariate analysis identified carriers as an independent predictor of cardiovascular events only in the non-CKD group alone (hazard ratio: 8.048; 95% confidence interval: 1.066 to 60.757; P = 0.043). Conclusions: CYP2C19 polymorphism significantly correlates with clinical outcome in non-CKD patients, and CKD status modifies the association of CYP2C19 polymorphism in predicting clinical outcomes following coronary stent implantation.
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Nakayama N., Kaikita K., Fukunaga T., Matsuzawa Y., Sato K., Horio E., Yoshimura H., Mizobe M., Takashio S., Tsujita K., Kojima S., Tayama S., Hokimoto S., Sakamoto T., Nakao K., Sugiyama S., Kimura K., Ogawa H.
Journal of the American Heart Association 3 ( 3 ) e000795 2014
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American Heart Association
Background: The prevalence, clinical features, and long-term outcome of patients with non-ST-segment elevation acute coronary syndrome (NSTE ACS) associated with coronary spasm are not fully investigated. Methods and Results: This observational multicenter study enrolled 1601 consecutive patients with suspected NSTE-ACS who underwent cardiac catheterization between January 2001 and December 2010. A culprit lesion was found in 1152 (72%) patients. In patients without a culprit lesion, the acetylcholine provocation test was performed in 221 patients and was positive in 175 patients. In the other patients, coronary spasm was verified in 145 patients during spontaneous attack. Spasm-induced NSTE-ACS was diagnosed in 320 (20%) patients. Multivariable analysis identified age <70 years (odds ratio [OR] 2.19, 95% CI 1.58 to 3.04), estimated glomerular filtration rate >60 mL/min per 1.73 m (OR 1.72, 95% CI 1.16 to 2.56), and lack of hypertension (OR 2.55, 95% CI 1.90 to 3.41), dyslipidemia (OR 2.76, 95% CI 2.05 to 3.73), diabetes mellitus (OR 2.49, 95% CI 1.78 to 3.48), previous myocardial infarction (OR 5.37, 95% CI 2.89 to 10.0), and elevated cardiac biomarkers (OR 2.84, 95% CI 2.11 to 3.83) as significant correlates of spasm-induced NSTE-ACS (P<0.01 for all variables). Transient ST-segment elevation during spontaneous attack (variant angina) was observed in 119 patients with spasm-induced NSTE-ACS. Variant angina was more common in nondyslipidemic men among patients with spasm-induced NSTE-ACS. Conclusions: The study showed frequent involvement of coronary spasm in the pathogenesis of NSTE-ACS. Variant angina was observed in one third of patients with spasm-induced NSTE-ACS. Coronary spasm should be considered even in patients with less coronary risk factors and nonobstructive coronary arteries. 2
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Hanatani S., Izumiya Y., Takashio S., Kimura Y., Araki S., Rokutanda T., Tsujita K., Yamamoto E., Tanaka T., Yamamuro M., Kojima S., Tayama S., Kaikita K., Hokimoto S., Ogawa H.
Circulation Journal 78 ( 4 ) 903 - 910 2014
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: Thrombospondin-2 (TSP-2) is a matricellular protein found in human serum. Deletion of TSP-2 causes age-dependent dilated cardiomyopathy. We hypothesized that TSP-2 is a useful biomarker in patients with heart failure with reduced ejection fraction (HFrEF). Methods and Results: Serum TSP-2 was measured in 101 patients with HFrEF, and mortality and cardiovascular events were followed. Serum TSP-2 in the HFrEF group was significantly higher than in the non-HF group (n=17). Mean NYHA functional class was significantly higher in the high TSP-2 group (>median) than the low TSP-2 group (2.26 vs. 1.76, P=0.004). Circulating TSP-2 level was significantly associated with that of B-type natriuretic peptide (BNP; r=0.40, P<0.0001) on multivariate linear regression analysis. On Kaplan-Meier curve analysis the high TSP-2 group had a lower event-free rate than the low TSP-2 group (log-rank test, P=0.03). Multivariate Cox hazard analysis identified hemoglobin (hazard ratio [HR], 0.66; 95% confidence interval [CI]: 0.53-0.82, P<0.0001), and TSP-2 (ln[TSP-2]; HR, 3.34; 95% CI: 1.03-10.85, P=0.045) as independent predictors of adverse outcome. The area under the curve for 1-year events increased when TSP-2 was added to Framingham risk score (FRS; alone, 0.60) or BNP (alone, 0.69; FRS+TSP-2, 0.75; BNP+TSP-2, 0.76). Conclusions: TSP-2 is a potentially useful biomarker for assessment of disease severity and prognosis in HFrEF.
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Chronic thromboembolic pulmonary hypertension complicated with homocystinuria Reviewed
Ogawa S., Katayama T., Kaikita K., Tsukamoto M., Yamamoto E., Yamamuro M., Tanaka T., Tsujita K., Kojima S., Tayama S., Hokimoto S., Yamabe H., Indo Y., Endo F., Matsubara H., Ogawa H.
Internal Medicine 53 ( 22 ) 2605 - 2608 2014
Language：English Publishing type：Research paper (scientific journal) Publisher：Internal Medicine
A 17-year-old boy with homocystinuria was found to have a systolic murmur during a routine examination. Echocardiography demonstrated pulmonary hypertension (PH), and computer tomography angiography showed pulmonary thrombi. Although 12-month anticoagulation treatment reduced the thrombotic material within the main branch, it failed to clear thrombotic materials in the left and right lobar branches. Two years later, the patient was admitted to our hospital due to a worsening of PH. Treatment with bosentan, sildenafil and beraprost, in addition to anti-coagulant therapy, did not improve his PH. Balloon pulmonary angioplasty (BPA) was performed to remove the pulmonary thrombi. BPA markedly improved the patient’s hemodynamics and exercise capacity. Close follow-up is scheduled to prevent any potential future thrombotic complications.
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Kaikita K., Ono T., Iwashita S., Nakayama N., Sato K., Horio E., Nakamura S., Tsujita K., Tayama S., Hokimoto S., Sakamoto T., Nakao K., Oshima S., Sugiyama S., Ogawa H.
Journal of Atherosclerosis and Thrombosis 21 ( 1 ) 64 - 76 2014
Authorship：Lead author, Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Atherosclerosis and Thrombosis
Aim: Carriers of the reduced-function CYP2C19 allele receiving dual antiplatelet therapy (DAPT) with aspirin and clopidogrel exhibit diminished platelet inhibition and an increased risk of events. The purpose of this study was to investigate the effects of CYP2C19 gene variants on platelet function tests and coagulation and inflammatory biomarkers in patients undergoing elective percutaneous coronary intervention (PCI). Methods: This prospective, observational, multicenter study enrolled 104 consecutive Japanese patients undergoing elective PCI. We examined the CYP2C19 genotype, platelet function tests, the levels of coagulation and inflammatory biomarkers and the serum levels of high-sensitivity troponin T (hs- TnT) before, immediately after and one, two and 28 days after PCI. Results: A total of 68 (65%) of the 104 enrolled patients were carriers of the CYP2C19 reducedfunction allele. On-clopidogrel platelet aggregation (PA), measured using light transmittance aggregometry and the VerifyNow® P2Y12 system, and the platelet reactivity index (PRI) were significantly higher at all time points in the carriers than in the noncarriers (p<0.05), whereas there were no differences in the levels of the coagulation and inflammatory biomarkers or serum hs-TnT. Simple and multiple logistic regression analyses identified on-clopidogrel PA and PRI as being significant predictors of carriers of the CYP2C19 reduced-function allele. Conclusions: The present study suggests that platelet function tests, but not coagulation, inflammatory or cardiac biomarkers, are useful for identifying carriers of CYP2C19 reduced-function gene variants and monitoring the efficacy of DAPT in patients undergoing elective PCI.
DOI： 10.5551/jat.18952
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Yamanaga K., Tsujita K., Shimomura H., Nakamura Y., Ogura Y., Onoue Y., Chazono N., Nagata T., Morisaki S., Kudo T., Yamada Y., Komura N., Miyazaki T., Akasaka T., Horio E., Sato K., Arima Y., Kojima S., Kaikita K., Tayama S., Hokimoto S., Ogawa H.
Journal of Cardiology 64 ( 4 ) 279 - 284 2014
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
Purpose: In-stent restenosis has been decreasing through the introduction of drug-eluting stents (DES). On the other hand, adverse events such as very late stent thrombosis (VLST) and late catch-up phenomenon can occur especially with sirolimus-eluting stents (SES, first-generation DES) in long-term follow-up. However, the precise mechanisms underlying VLST have not been well investigated in vivo. Methods and results: From 2004 to 2010, 2034 SES were implanted in 1656 patients and caused eight VLST (0.48% per patient) at Fukuoka Tokushukai Medical Center. Of these, serial intravascular ultrasound (IVUS) images (post-stent implantation and at the time of VLST onset) were obtained from three patients with VLST. Comparing them with eight control patients with SES implanted, the vascular reactivity of VLST patients was analyzed. Eight VLST happened 50±15 months after stent implantation and three of the eight patients with VLST had not taken aspirin daily. There were no differences in minimum stent area, maximum external elastic membrane (EEM) area, and stent edge (distal and proximal) EEM area in post-procedural IVUS images. Compared with the control group patients, δEEM area (10.6±3.4mm<sup>2</sup> vs. 1.7±1.9mm<sup>2</sup>, p=0.01) and vessel expansion ratio (185.6±40.3% vs. 112.0±12.1%, p=0.01) were significantly greater in the VLST group based on the greater peri-stent plaque expansion (262.1±72.8% vs. 118.7±21.2%, p=0.01). Conclusion: Our serial IVUS study showed that the vascular positive remodeling after SES implantation is one of the most probable morphological mechanisms for VLST development.
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冠動脈内血栓形成における冠攣縮の関与
海北幸一, 辻田賢一, 掃本誠治, 小川久雄
日本血栓止血学会誌 25 ( 3 ) 396 - 398 2014
Authorship：Lead author Publishing type：Research paper (scientific journal)
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Tsujita K., Takaoka N., Kaikita K., Hokimoto S., Horio E., Sato K., Mizobe M., Nakayama N., Kojima S., Tayama S., Sugiyama S., Nakamura S., Ogawa H.
Catheterization and Cardiovascular Interventions 82 ( 7 ) 1068 - 1074 2013.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Catheterization and Cardiovascular Interventions
Objectives The present study used iMap IVUS system to compare neointimal tissue components between DES and bare-metal stents (BMSs). Background Drug-eluting stents (DESs) can cause impaired arterial healing, which constitutes the most important pathological substrate underlying late DES thrombosis. Intravascular ultrasound (IVUS)-based tissue characterization allows for the in vivo identification of neointimal tissue components. Methods and Results Follow-up IVUS data after coronary stenting (9.8 ± 9.4 months from index procedures) was obtained from consecutive 61 lesions (34 in DES, 27 in BMS). The iMap tissue components (fibrotic, lipidic, necrotic, and calcified) were measured in every recorded frame and expressed as percentages of mean neointimal cross-sectional area for the stented segment. Patients' characteristics were comparable between DES and BMS. When compared with BMSs, smaller (2.9 ± 0.4 mm vs. 3.2 ± 0.4 mm, P = 0.004) and longer (34 ± 18 mm vs. 26 ± 14 mm, P = 0.03) DESs were implanted. When compared with BMS group, minimum lumen area at follow-up was significantly greater in DES group (3.9 ± 1.8 mm vs. 3.1 ± 1.5 mm , P < 0.04), mainly attributable to suppression of neointimal hyperplasia (1.7 ± 0.8 mm vs. 3.1 ± 1.5 mm , P < 0.0001). The iMap analyses showed that neointima after DES placement was composed of smaller fibrotic component (67 ± 8% vs. 78 ± 7%, P < 0.0001), larger necrotic (14 ± 4% vs. 9 ± 3%, P < 0.0001) and calcified (15 ± 6% vs. 7 ± 4%, P < 0.0001) components compared with BMS. Logistic regression analysis showed that only intra-DES neointima was a significant predictor of necrotic neointima at follow-up. Conclusions DES implantation would be associated with iMap-derived necrotic and less-fibrotic neointimal formation. In vivo iMap evaluation of neointimal tissue may provide useful information in detecting impaired healing after stenting. Copyright © 2013 Wiley Periodicals, Inc. 2 2 2 2
DOI： 10.1002/ccd.24907
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Rokutanda T., Misumi I., Usuku H., Kusuhara K., Akahoshi R., Matsumoto M., Akahoshi G., Yasuda H., Kaikita K., Hokimoto S., Sugiyama S., Ogawa H.
Journal of Echocardiography 11 ( 4 ) 167 - 168 2013.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Echocardiography
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Mid-diastolic mitral flow vectors in complete atrioventricular block Reviewed
Kusuhara K., Misumi I., Itou M., Rokutanda T., Akahoshi R., Matsumoto M., Shimoda K., Yasuda H., Kaikita K., Hokimoto S., Ogawa H.
Journal of Echocardiography 11 ( 4 ) 169 - 170 2013.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Echocardiography
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Mid-diastolic mitral regurgitation in a patient with diastolic heart failure Reviewed
Usuku H., Misumi I., Kusuhara K., Rokutanda T., Akahoshi R., Matsumoto M., Omori K., Yasuda H., Kaikita K., Hokimoto S., Sugiyama S., Ogawa H.
Journal of Echocardiography 11 ( 4 ) 161 - 163 2013.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Echocardiography
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Tsujita K., Sakamoto K., Kojima S., Kojima S., Takaoka N., Nagayoshi Y., Sakamoto T., Tayama S., Kaikita K., Hokimoto S., Sumida H., Sugiyama S., Nakamura S., Ogawa H.
International Journal of Cardiology 168 ( 3 ) 2411 - 2415 2013.10
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background Coronary spasm plays an important role in the pathogenesis of ischemic heart disease. However, tissue components of coronary plaque in patients with vasospastic angina (VSA) have been unknown. This study used virtual histology (VH)-intravascular ultrasound (IVUS) to elucidate the tissue component of spastic coronary arteries and its gender differences in patients with VSA. Methods According to acetylcholine provocation tests, the study subjects (42 patients [19 men, 23 women, 61 ± 13 years]) were divided into 2 groups: the VSA group of 26 patients and the non-VSA group of 16 patients. After nitrate injection, IVUS volumetric analysis was done, and the parameters were compared between the groups. Results Although clinical demographics were almost identical between the groups, VSA group had lower plasma adiponectin level (5.9 ± 3.3 μg/ml vs. 11.2 ± 7.6 μg/ml, p = 0.007) and tended to have higher high-sensitivity C-reactive protein (0.15 ± 0.24 mg/dl vs. 0.06 ± 0.04 mg/dl, p = 0.1) than non-VSA group. VSA group had diffusely thickened intima (% plaque volume, 34 ± 11% vs. 27 ± 7%, p = 0.01) compared with non-VSA group. However, plaque components of patients with VSA were similar with that of non-VSA patients (dense calcium, 4 ± 6% vs. 3 ± 4%; necrotic core, 10 ± 9% vs. 8 ± 6%; fibrofatty, 19 ± 16% vs. 22 ± 11%; and fibrous, 67 ± 16% vs. 67 ± 9%). Although male patients with VSA had atherogenic lipid and metabolic profiles than female VSA patients, there were no significant gender differences in the volumetric IVUS parameters and plaque components. Conclusions Compared with non-VSA patients, VSA patients had diffusely thickened fibrous-dominant coronary plaque without gender difference, and that might suggest the role of vasospasm in the development of atherosclerosis. © 2013 Elsevier Ireland Ltd. All rights reserved.
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Takashio S., Yamamuro M., Izumiya Y., Sugiyama S., Kojima S., Yamamoto E., Tsujita K., Tanaka T., Tayama S., Kaikita K., Hokimoto S., Ogawa H.
Journal of the American College of Cardiology 62 ( 7 ) 632 - 640 2013.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American College of Cardiology
Objectives This study investigated factors associated with cardiac troponin T (cTnT) release from failing myocardium. Background Persistent and modest elevation of serum cTnT is frequently observed in heart failure (HF) patients free of coronary artery disease, although the mechanisms underlying this finding remain unclear. Methods We evaluated serum cTnT levels in the aortic root (Ao) and coronary sinus (CS) using a highly sensitive assay in 90 nonischemic HF patients and 47 non-HF patients. Transcardiac cTnT and plasma B-type natriuretic peptide (BNP) release were described as the differences between CS and Ao cTnT levels [ΔcTnT (CS-Ao)] and BNP levels [ΔBNP (CS-Ao)], respectively. Coronary flow reserve (CFR) was measured in 68 HF patients using an intracoronary Doppler guidewire. Results ΔcTnT (CS-Ao) levels were available in 76 HF patients and 28 non-HF patients (84% vs. 60%; p = 0.001), and higher in HF patients than non-HF patients (p < 0.001). Among HF patients, log[ΔcTnT (CS-Ao)] correlated with log[ΔBNP (CS-Ao)] (r = 0.368, p = 0.001), pulmonary capillary wedge pressure (r = 0.253, p = 0.03) and left ventricular end-diastolic pressure (LVEDP) (r = 0.321, p = 0.005). Multivariate regression analysis identified LVEDP as an independent parameter that correlated with ΔcTnT (CS-Ao). ΔcTnT (CS-Ao) levels were available in 58 HF patients who were evaluated for CFR. Coronary microvascular dysfunction, diagnosed by CFR <2.0, was observed in 18 HF patients. ΔcTnT (CS-Ao) was higher in patients with coronary microvascular dysfunction (4.8 [2.0 to 8.1] ng/l) than those without (2.0 [1.2 to 4.6] ng/l; p = 0.04). Conclusions cTnT release from failing myocardium correlated with diastolic load and coronary microvascular dysfunction in nonischemic HF patients. © 2013 by the American College of Cardiology Foundation Published by Elsevier Inc.
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Sato K., Kaikita K., Nakayama N., Horio E., Yoshimura H., Ono T., Ohba K., Tsujita K., Kojima S., Tayama S., Hokimoto S., Matsui K., Sugiyama S., Yamabe H., Ogawa H.
Journal of the American Heart Association 2 ( 4 ) e000227 2013.8
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American Heart Association
The aim of this study was to elucidate the correlation between angiographic coronary vasomotor responses to intracoronary acetylcholine (ACh) injection, clinical features, and long-term prognosis in patients with vasospastic angina (VSA). This is a retrospective, observational, single-center study of 1877 consecutive patients who underwent ACh-provocation test between January 1991 and December 2010. ACh-provoked coronary spasm was observed in 873 of 1637 patients included in the present analysis. ACh-positive patients were more likely to be older male smokers with dyslipidemia, to have a family history of ischemic heart disease, and to have a comorbidity of coronary epicardial stenosis than were ACh-negative patients. ACh-positive patients were divided into 2 groups: those with focal (total or subtotal obstruction, n=511) and those with diffuse (severe diffuse vasoconstriction, n=362) spasm patterns. Multivariable logistic regression analysis identified female sex and low comorbidity of coronary epicardial stenosis to correlate with the ACh-provoked diffuse spasm pattern in patients with VSA. Kaplan-Meier survival curve indicated better 5-year survival rates free from major adverse cardiovascular events in patients with diffuse spasm pattern compared with those with focal spasm pattern (P=0.019). Multivariable Cox hazard regression analysis identified diffuse spasm pattern as a negative predictor of major adverse cardiovascular events in patients with VSA. ACh-induced diffuse coronary spasm was frequently observed in female VSA patients free of severe coronary epicardial stenosis and was associated with better prognosis than focal spasm. These results suggest the need to identify the ACh-provoked coronary spasm subtypes in patients with VSA.
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Fujisue K., Sugiyama S., Ono T., Matsuzawa Y., Akiyama E., Sugamura K., Matsubara J., Kurokawa H., Kaikita K., Iwashita S., Sumida H., Hokimoto S., Oniki K., Nakagawa K., Matsui K., Ogawa H.
Circulation: Cardiovascular Interventions 6 ( 4 ) 452 - 459 2013.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation: Cardiovascular Interventions
Background-Dual antiplatelet therapy with aspirin and clopidogrel is widely used in patients with coronary stents. High residual platelet reactivity (high RPR) after dual antiplatelet therapy is associated with increased cardiovascular events. Endothelial function could affect platelet reactivity in vivo. We hypothesized that endothelial dysfunction could be associated with high RPR after dual antiplatelet therapy in patients with stable coronary artery disease. Methods and Results-We screened patients with stable coronary artery disease for cytochrome P450 (CYP) 2C19 genotypes and enrolled 103 patients who lacked CYP2C19*2 or *3 loss-of-function allele to minimize the effect of this gene on high RPR. All patients received aspirin (100 mg/d) and clopidogrel (75 mg/d for long-term treatment or a loading dose of 300 mg) before the following tests. Platelet aggregability was assessed as P2Y12 reaction unit using the VerifyNow System. High RPR was defined as P2Y12 reaction unit =230. Peripheral endothelial function was expressed as reactive hyperemia index using reactive hyperemia peripheral arterial tonometry. Fifty-three patients exhibited high RPR. High RPR patients were significantly older, had higher levels of B-type natriuretic peptide, and were predominantly hypertensive compared with non-high RPR patients. Reactive hyperemia index was significantly lower in high RPR patients (0.46±0.15) compared with non-high RPR patients (0.61±0.18; P<0.001). Linear regression analysis demonstrated significant negative correlation between reactive hyperemia index and P2Y12 reaction unit (r=-0.32; P=0.001). Multivariable logistic regression analysis identified reactive hyperemia index as an independent and significant determinant of high RPR (odds ratio, 0.55; 95% confidence interval, 0.39-0.78; P=0.001). Conclusions-In patients with stable coronary artery disease, endothelial function was significantly impaired in high RPR patients. Endothelial dysfunction is independently correlated with high RPR after dual antiplatelet therapy. © 2013 American Heart Association, Inc.
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ランブル様収縮期雑音を聴取した1例 Reviewed
三角郁夫＊，宇宿弘輝，楠原健一，六反田拓，赤星隆一郎，松本充博，安田久代，海北幸一，掃本誠治，杉山正悟，小川久雄
日本心臓病学会誌 8 ( 2 ) 168 - 170 2013.6
Language：Japanese Publishing type：Research paper (scientific journal)
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Matsubara J., Sugiyama S., Akiyama E., Iwashita S., Kurokawa H., Ohba K., Maeda H., Fujisue K., Yamamoto E., Kaikita K., Hokimoto S., Jinnouchi H., Ogawa H.
Circulation Journal 77 ( 5 ) 1337 - 1344 2013.5
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: Dipeptidyl peptidase 4 (DPP4) inhibitors are used for treatment of diabetes mellitus (DM). We hypothesized that sitagliptin, a DPP4-inhibitor, could improve endothelial dysfunction in DM patients with coronary artery disease (CAD). Methods and Results: The 40 patients with CAD and uncontrolled DM, aged 68.7±9.4 years (mean ± standard deviation) (50% males, hemoglobin A1c [HbA ] 7.4±1.0%) were assigned to either additional treatment with sitagliptin (50 mg/day, n=20) or aggressive conventional treatment (control, n=20) for 6 months. Endothelial function was assessed by the reactive hyperemia peripheral arterial tonometry index (RHI). The clinical characteristics at baseline were not different between the groups. After treatment, fasting blood glucose and insulin levels, and lipid profiles were not different between the groups. HbA levels significantly improved similarly in both groups. The percent change in RHI was greater in the sitagliptin group than in the control group (62.4±59.2% vs. 15.9±22.0%, P<0.01). Furthermore, treatment with sitagliptin resulted in a significant decrease in the high-sensitivity C-reactive protein (hsCRP) level, but no such change was noted in the control group. Linear regression analysis demonstrated a significant negative relation between changes in RHI and hsCRP, but not between RHI and HbA . Conclusions: Sitagliptin significantly improved endothelial function and inflammatory state in patients with CAD and uncontrolled DM, beyond its hypoglycemic action. These findings suggest that sitagliptin has beneficial effects on the cardiovascular system in DM patients. 1c 1c 1c
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Yamamuro M., Yamamoto K., Kan H., Takashio S., Tayama S., Kaikita K., Hokimoto S., Sumida H., Sugiyama S., Ogawa H.
Journal of Atherosclerosis and Thrombosis 20 ( 3 ) 238 - 244 2013.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Atherosclerosis and Thrombosis
Aim: The concomitant use of angiotensin II receptor blocker (ARB) with low doses of hydrochlorothiazide (HCTZ) may provide additional antihypertensive activity. HCTZ induces hypokalemia and hyperglycemia, while ARB slightly induces hyperkalemia. Recently, it has been reported that ARB/ HCTZ did not worsen fasting blood sugar levels; however, the detailed glucose tolerance change effect with combination therapy of ARB/HCTZ compared to ARB alone therapy remains to be investigated. Methods: Treated non-diabetes mellitus (DM) hypertensive patients taking a common dose of ARB regimens, not achieving blood pressure (BP) goals, were switched to 50 mg Losartan/12.5 mg HCTZ combinations, and the 75 g oral glucose tolerance test (75 g OGTT) was performed before switching and after switching at 3 months. Results: This study included 30 patients aged 66.5±8.7 years, 67% women. Pre-switching BP 146.6± 17.0/ 88.4±10.4 mmHg decreased and was maintained at a steady state, reaching 131.4±1.0/73.8± 8.8 mmHg (p < 0.001) 3 months later. After switching, blood glucose levels on the 75 g OGTT at fasting, 30, 60 and 120 minutes were significantly decreased. Homeostasis model assessment as an index of insulin resistance and the whole body insulin sensitivity index were significantly ameliorated. Conclusions: On the 75 g OGTT, 50 mg Losartan with 12.5 mg HCTZ combinations did not worsen glucose tolerance; moreover, they improved BP, insulin resistance and sensitivity in non-DM Japanese patients with essential hypertension uncontrolled with ARBs alone.
DOI： 10.5551/jat.14464
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Early diastolic overinflation in diastolic mitral regurgitation Reviewed
Misumi I., Usuku H., Kusuhara K., Rokutanda T., Akahoshi R., Matsumoto M., Kimura K., Yasuda H., Kaikita K., Hokimoto S., Sugiyama S., Ogawa H.
Journal of Echocardiography 11 ( 1 ) 32 - 33 2013.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Echocardiography
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Tabata N., Tsujita K., Mizobe M., Hirakawa K., Tanaka T., Yamamuro M., Yamamoto E., Kaikita K., Tayama S., Hokimoto S., Sugiyama S., Ogawa H.
Journal of Cardiology Cases 6 ( 5 ) e154 - e157 2012.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology Cases
Intra-aortic balloon counterpulsation (IABP) has been used in various cardiovascular conditions including cardiogenic shock. Prophylactic systemic heparinization has been commonly utilized to prevent thrombotic complications. There are a number of anticoagulants in addition to heparin; however, there is little consensus and few data to support the safety of alternative anticoagulation during IABP management. We report here on the case of a 47-year-old woman with cardiogenic shock. She had a medical history of heparin-induced thrombocytopenia (HIT) type II and soon after admission she deteriorated into cardiogenic shock of unknown etiology. This patient survived by IABP circulatory support with alternative argatroban anticoagulant therapy; and there were no signs of thrombus or thromboembolism in this patient or on the catheter itself. Our report suggests that alternative anticoagulation by argatroban may be a safe and effective therapeutic option in seriously ill patients requiring IABP support and nonheparin anticoagulation. © 2012 Japanese College of Cardiology.
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Akiyama E., Sugiyama S., Matsuzawa Y., Konishi M., Suzuki H., Nozaki T., Ohba K., Matsubara J., Maeda H., Horibata Y., Sakamoto K., Sugamura K., Yamamuro M., Sumida H., Kaikita K., Iwashita S., Matsui K., Kimura K., Umemura S., Ogawa H.
Journal of the American College of Cardiology 60 ( 18 ) 1778 - 1786 2012.10
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American College of Cardiology
Objectives: The purpose of this study was to investigate whether peripheral endothelial dysfunction could predict the occurrence of cardiovascular events in patients with heart failure (HF) with normal left ventricular ejection fraction (HFNEF). Background: Endothelial dysfunction plays an important role in HF, but the relation between peripheral endothelial dysfunction and prognosis in HFNEF remains unknown. Methods: We conducted a prospective cohort study of 321 patients with HFNEF. We evaluated cardiac function by echocardiography measuring the ratio of early transmitral flow velocity to tissue Doppler early diastolic mitral annular velocity (E/e'), noninvasively assessed peripheral endothelial function by reactive hyperemia-peripheral arterial tonometry (RH-PAT) as the RH-PAT index (RHI), and followed cardiovascular events. Results: A total of 59 patients had a cardiovascular event. Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular events in the low RHI group than in the high RHI group (mean follow-up: 20 months; log-rank test: p < 0.001). Multivariate Cox hazard analysis identified RHI (per 0.1) (hazard ratio [HR]: 0.80; 95% confidence interval [CI]: 0.67 to 0.94; p = 0.007), E/e' (Ln[E/e'] [per 0.1]) (HR: 1.15; 95% CI: 1.04 to 1.26; p = 0.006), and B-type natriuretic peptide (BNP) (Ln[BNP] [per picogram/milliliter]) (HR: 1.81; 95% CI: 1.44 to 2.28; p < 0.001) as independent predictors of cardiovascular events. The C-statistics for cardiovascular events substantially increased when the RHI was added to the HFNEF prognostic 5 factors (PF5) - age, diabetes, New York Heart Association classification, HF hospitalization history, and left ventricular ejection fraction - which were identified in the I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction Study) (PF5 alone: 0.671; PF5 + RHI: 0.712). The net reclassification index was significant after addition of the RHI (19.0%, p = 0.01). Conclusions: Peripheral endothelial dysfunction independently correlated with future cardiovascular events, adding incremental clinical significance for risk stratification in patients with HFNEF. (Endothelial Dysfunction Assessed by Reactive Hyperemia Peripheral Arterial Tonometry and Heart Failure with Preserved Left Ventricular Ejection Fraction; UMIN000002640) © 2012 American College of Cardiology Foundation.
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Ohba K., Sugiyama S., Sumida H., Nozaki T., Matsubara J., Matsuzawa Y., Konishi M., Akiyama E., Kurokawa H., Maeda H., Sugamura K., Nagayoshi Y., Morihisa K., Sakamoto K., Tsujita K., Yamamoto E., Yamamuro M., Kojima S., Kaikita K., Tayama S., Hokimoto S., Matsui K., Sakamoto T., Ogawa H.
Journal of the American Heart Association 1 ( 5 ) e002485 2012.10
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American Heart Association
Angina without significant stenosis, or nonobstructive coronary artery disease, attracts clinical attention. Microvascular coronary artery spasm (microvascular CAS) can cause nonobstructive coronary artery disease. We investigated the clinical features of microvascular CAS and the therapeutic efficacy of calcium channel blockers. Three hundred seventy consecutive, stable patients with suspected angina presenting nonobstructive coronary arteries (<50% diameter) in coronary angiography were investigated with the intracoronary acetylcholine provocation test, with simultaneous measurements of transcardiac lactate production and of changes in the quantitative coronary blood flow. We diagnosed microvascular CAS according to lactate production and a decrease in coronary blood flow without epicardial vasospasm during the acetylcholine provocation test. We prospectively followed up the patients with calcium channel blockers for microvascular coronary artery disease. We identified 50 patients with microvascular CAS who demonstrated significant impairment of the endothelium-dependent vascular response, which was assessed by coronary blood flow during the acetylcholine provocation test. Administration of isosorbide dinitrate normalized the abnormal coronary flow pattern in the patients with microvascular CAS. Multivariate logistic regression analysis indicated that female sex, a lower body mass index, minor-borderline ischemic electrocardiogram findings at rest, limited-baseline diastolic-to-systolic velocity ratio, and attenuated adenosine triphosphate-induced coronary flow reserve were independently correlated with the presence of microvascular CAS. Receiver-operating characteristics curve analysis revealed that the aforementioned 5-variable model showed good correlation with the presence of microvascular CAS (area under the curve: 0.820). No patients with microvascular CAS treated with calcium channel blockers developed cardiovascular events over 47.8±27.5 months. Microvascular CAS causes distinctive clinical features and endothelial dysfunction that are important to recognize as nonobstructive coronary artery disease so that optimal care with calcium channel blockers can be provided. URL: www.umin.ac.jp/ctr. Unique identifier: UMIN000003839.
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Significance of coronary vasospasm in the perioperative management of non-cardiac surgery Reviewed
Nagayoshi Y., Kawano H., Kojima S., Soejima H., Kaikita K., Nakayama M., Sumida H., Sugiyama S., Ogawa H.
Circulation Journal 76 ( 8 ) 1965 - 1971 2012.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background:The number of patients undergoing non-cardiac surgery has been increasing. Thus, the reduction of cardiac events is important during the perioperative period. The prevalence of Japanese patients with coronary vasospasm is higher as compared with Western countries. The present study reported the role of coronary vasospasm in the perioperative period in a Japanese university hospital. Methods and Results:A total of 77,745 consecutive patients who underwent non-cardiac surgery in Kumamoto University Hospital between April 2003 and March 2010 were retrospectively examined. Forty-two cases in which patients underwent coronary catheterization due to cardiovascular events in the perioperative period were reviewed, and data were collected on the type of surgery, urgency of surgery, cardiac risk factors, previous history and the cardiology consultation. The Revised Cardiac Risk Index (RCRI) was also calculated. A total of 18 patients were diagnosed as having definite vasospastic angina. In the definite vasospastic angina group, 9 patients had cardiovascular events intraoperatively. Six patients were in the group undergoing high-risk surgery. The RCRI score in the definite vasospastic angina group was 0.5±0.6 (mean ± SEM), and only 2 patients had a preoperative consultation with a cardiologist. Conclusions:Coronary vasospasm is not often encountered, but it can be a cause of cardiac trouble in the perioperative period. It should be taken into consideration at the time of planning of operation in Japanese patients even if they apparently have low cardiac risk.
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Kimura Y., Ohba K., Sumida H., Tsujita K., Hirose T., Maruyama H., Hirai S., Kaikita K., Hokimoto S., Sugiyama S., Ogawa H.
Internal Medicine 51 ( 14 ) 1845 - 1850 2012.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Internal Medicine
A 54-year-old man was referred to a local hospital, located about 90 km from our hospital, with cardiogenic shock due to left main coronary artery infarction (LMCA-MI). Percutaneous coronary intervention (PCI) was performed under intra-aortic balloon pumping (IABP) support, but resulted in insufficient reperfusion and his condition worsened. The helicopter emergency medical service (HEMS) rapidly transported the patient to our hospital. After percutaneous cardio-pulmonary support system (PCPS) insertion, PCI could establish the coronary flow. A series of intensive therapies saved the patient. The cooperation of medical and emergency service system following revascularization and intensive care saved the patient with LMCA-MI accompanied by cardiogenic shock. © 2012 The Japanese Society of Internal Medicine.
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Subsequent silent plaque rupture of nonculprit lesion in a patient with acute myocardial infarction Reviewed
Takaoka N., Tsujita K., Kaikita K., Tayama S., Hokimoto S., Sugiyama S., Ogawa H.
International Journal of Cardiology 157 ( 3 ) e60 - 2 2012.6
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
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Takashio S., Yamamuro M., Kojima S., Izumiya Y., Kaikita K., Hokimoto S., Sugiyama S., Tsunoda R., Nakao K., Ogawa H.
American Journal of Cardiology 109 ( 11 ) 1651 - 1656 2012.6
Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Cardiology
Although the prognosis of patients with stress (takotsubo) cardiomyopathy is relatively favorable, serious complications occur in some patients. It is generally accepted that electrocardiography is an essential tool for the diagnosis of stress cardiomyopathy, with findings highly suggestive of the characteristics of myocardial damage. We tested the hypothesis that the quantitative analysis of electrocardiograhic changes can predict complications in stress cardiomyopathy. The study subjects were 85 patients with stress cardiomyopathy. A total of 34 patients developed <1 in-hospital complications (heart failure, intraventricular pressure gradient [>30 mm Hg], cardiogenic shock, ventricular tachycardia/fibrillation, and embolism). Patients with complications were likely to have a higher heart rate (96 ± 25 vs 76 ± 17 beats/min, p <0.001), larger sum of ST-segment elevation in 12 leads (median 10.5 mm; interquartile range 5.0 to 17.5 vs 3.0 mm, interquartile range 0 to 7.0; p <0.001) and extension of ST-segment elevation to limb leads (50% vs 12%, p <0.001) than those without complications. Multivariate logistic regression analysis identified heart rate (odds ratio 1.05, 95% confidence interval 1.02 to 1.07, p = 0.001) and sum of ST-segment elevation in 12 leads (odds ratio 1.24, 95% confidence interval 1.11 to 1.39, p <0.001) as significant and independent predictors of complications. Receiver operating characteristic analysis selected 5.5 mm as the best cutoff value of sum of ST-segment elevation in 12 leads for the prediction of complications, with a sensitivity and specificity of 74% and 73%, respectively, and area under the curve of 0.81 (95% confidence interval 0.72 to 0.90, p <0.001). The results suggest that the extent and magnitude of ST-segment elevation on the electrocardiogram are potentially useful predictors of in-hospital complications in patients with stress cardiomyopathy. © 2012 Elsevier Inc.
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冠動脈形成術後の心房細動の抗凝固療法：抗血小板薬との併用はどうするか
海北幸一
治療 94 ( 6 ) 1120 - 1124 2012.6
Authorship：Lead author Publishing type：Research paper (scientific journal)
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Onoue Y., Izumiya Y., Takashio S., Ono T., Morihisa K., Tsujita K., Yamamoto E., Yamamuro M., Kaikita K., Tayama S., Hokimoto S., Sumida H., Sugiyama S., Ogawa H.
Internal Medicine 51 ( 10 ) 1215 - 1219 2012.5
Language：English Publishing type：Research paper (scientific journal) Publisher：Internal Medicine
Shock patients with restrictive cardiomyopathy due to cardiac amyloidosis are refractory to medical treatment. Here, we report a case of early initiation of intra-aortic balloon pumping (IABP) in a patient with cardiac amyloidosis who developed postoperative shock. Continuous hemodiafiltration was also applied to control circulating fluid volume. The mechanical treatments allowed reduction of the doses of catecholamine and diuretics and resulted in full recovery. It is reasonable to initiate IABP and hemofiltration dialysis during the early stages for the appropriate control of hemodynamics and fluid in shock patients with cardiac amyloidosis. © 2012 The Japanese Society of Internal Medicine.
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Obscured meshwork structure after treatment for heart failure: A case study Reviewed
Rokutanda T., Misumi I., Hanaoka Y., Akahoshi R., Matsumoto M., Takeda N., Obayashi H., Kaikita K., Yamamuro M., Sugiyama S., Ogawa H.
Internal Medicine 51 ( 9 ) 1049 - 1053 2012.5
Language：English Publishing type：Research paper (scientific journal) Publisher：Internal Medicine
An 87-year-old man with heart failure was admitted to our hospital. A transthoracic echocardiography showed diffuse mild left ventricular (LV) hypokinesis and LV noncompaction at the apex. A threedimensional transthoracic echocardiography confirmed a trabecular meshwork. After treatment for heart failure, LV end-systolic dimension decreased and trabeculae seemed to converge and became obscure in endsystole. This is a rare case suggesting mechanism of obscured LV noncompaction after treatment for heart failure. © 2012 The Japanese Society of Internal Medicine.
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Tsujita K., Miyazaki T., Kaikita K., Chitose T., Takaoka N., Soejima H., Tayama S., Hokimoto S., Sugiyama S., Ogawa H.
Cardiovascular Intervention and Therapeutics 27 ( 2 ) 121 - 126 2012.5
Language：English Publishing type：Research paper (scientific journal) Publisher：Cardiovascular Intervention and Therapeutics
A 45-year-old premenopausal woman presented with acute myocardial infarction (MI). An intravascular ultrasound (IVUS) revealed that her distal right coronary artery was occluded by spontaneous coronary artery dissection (SCAD). She did not have any specific condition related to SCAD. At follow-up cardiac catheterization, an acetylcholine provocation test was applied to examine the etiology of SCAD, and definitive coronary vasospasm was induced with chest symptoms and significant electrocardiographic change. A Ca-channel blocker was administered and since then chest pain has subsequently so far been relieved. The current case suggests the significance of the IVUS in detecting etiology of MI in younger patients and the potential association between SCAD and coronary vasospasm. © 2012 Japanese Association of Cardiovascular Intervention and Therapeutics.
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Simultaneous pressure recording in mid-ventricular obstructive hypertrophic cardiomyopathy Reviewed
Hanaoka Y., Misumi I., Rokutanda T., Akahoshi R., Matsumoto M., Sakamoto T., Kaikita K., Yamamuro M., Sugiyama S., Ogawa H.
Internal Medicine 51 ( 4 ) 387 - 390 2012.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Internal Medicine
A 70-year-old man was diagnosed with mid-ventricular obstructive hypertrophic cardiomyopathy (MVOHCM) with apical aneurysm and paradoxic jet flow. At cardiac catheterization, pressure study showed that there was a markedly high pressure-gradient of 90 mmHg between the apex and the base in systole. Apical pressure was 350 mmHg after premature ventricular contraction. The apical aneurysm was already dilated and spherical in late systole; the absence of active relaxation was considered to be the cause of the paradoxic jet flow. In this report, we suggest the pathogenesis of left ventricular apical aneurysm and paradoxic jet flow in MVOHCM. © 2012 The Japanese Society of Internal Medicine.
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Marked decrease in BNP levels in 2 related patients with reversible dilated cardiomyopathy Reviewed
Misumi I., Fujimoto K., Miyao Y., Matsumoto M., Rokutanda T., Hanaoka Y., Kaikita K., Yamamuro M., Sugiyama S., Ogawa H.
Journal of Cardiology Cases 5 ( 1 ) e65 - e68 2012.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology Cases
Two male patients, one in his thirties and the other in his fifties, were admitted to different hospitals for congestive heart failure (CHF). In both patients, laboratory findings indicated high plasma B-type natriuretic peptide (BNP) levels (266.0 and 902.7. pg/mL, respectively) and echocardiography showed large left ventricular diastolic dimensions (LVDd) (67 and 73. mm, respectively) and low ejection fractions (EF) (26% and 18%, respectively). Coronary arteriography revealed no organic stenosis in either patient. Following treatment, plasma BNP levels decreased to below the limit of measurement (4. pg/mL) in both patients and echocardiography revealed improved LVDd (61 and 52. mm, respectively) and EF (41% and 45%, respectively). Because these patients are related, genetic factors might have affected low plasma BNP levels. Moreover, these results suggest that marked decrease in plasma BNP during follow up may be an indicator of preserved neurohormonal and organ systems. © 2011 Japanese College of Cardiology.
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Matsubara J., Sugiyama S., Sugamura K., Nakamura T., Fujiwara Y., Akiyama E., Kurokawa H., Nozaki T., Ohba K., Konishi M., Maeda H., Izumiya Y., Kaikita K., Sumida H., Jinnouchi H., Matsui K., Kim-Mitsuyama S., Takeya M., Ogawa H.
Journal of the American College of Cardiology 59 ( 3 ) 265 - 276 2012.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American College of Cardiology
The aim of this study was to investigate the antiatherogenic effects of the dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin (DFS). The new class of antitype 2 diabetes drugs, dipeptidyl peptidase-4 inhibitors, improves glucose metabolism by increasing levels of active glucagon-like peptide (GLP)-1. Endothelial function was examined by acetylcholine-induced endothelium- dependent vasorelaxation using aortic rings and atherosclerotic lesion development in the entire aorta in apolipoprotein Edeficient mice fed a high-fat diet with or without DFS, and the antiatherogenic effects of DFS were investigated in cultured human macrophages and endothelial cells. Plasma levels of active GLP-1 were measured in patients with or without coronary artery disease. DFS significantly improved endothelial dysfunction (89.9 ± 3.9% vs. 79.2 ± 4.3% relaxation at 10 mol/l acetylcholine, p < 0.05) associated with increased endothelial nitric oxide synthase phosphorylation and reduced atherosclerotic lesion area (17.7% [15.6% to 25.8%] vs. 24.6% [19.3% to 34.6%], p < 0.01) compared with vehicle treatment. In cultured human macrophages, DFS significantly increased GLP-1-induced cytosolic levels of cyclic adenosine monophosphate compared with GLP-1 alone, resulted in inhibiting phosphorylation of c-jun N-terminal kinase and extracellular signal-regulated kinase 1/2 and nuclear factor-kappa B p65 nuclear translocation through the cyclic adenosine monophosphate/protein kinase A pathway, and suppressed proinflammatory cytokines (i.e., interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha) and monocyte chemoattractant protein-1 production in response to lipopolysaccharide. DFS-enhanced GLP-1 activity sustained endothelial nitric oxide synthase phosphorylation and decreased endothelial senescence and apoptosis compared with GLP-1 alone. In the human study, fasting levels of active GLP-1 were significantly lower in patients with coronary artery disease than those without (3.10 pmol/l [2.40 to 3.62 pmol/l] vs. 4.00 pmol/l [3.10 to 5.90 pmol/l], p < 0.001). A DPP-4 inhibitor, DFS, exhibited antiatherogenic effects through augmenting GLP-1 activity in macrophages and endothelium. © 2012 American College of Cardiology Foundation. -4
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Chitose T., Hokimoto S., Oshima S., Nakao K., Fujimoto K., Miyao Y., Shimomura H., Tsunoda R., Maruyama H., Hirose T., Yamamoto K., Mizobe M., Kaikita K., Nakamura S., Ogawa H.
Circulation Journal 76 ( 1 ) 71 - 78 2012.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: The aim of this study was to examine the effect of proton-pump inhibitor (PPI) on clinical outcomes in Japanese patients who undergo coronary stent implantation. Methods and Results: A total of 1,270 patients (males 915, 69 years) were enrolled and dual antiplatelet therapy of aspirin and a thienopyridine derivative was prescribed (clopidogrel 630, ticlopidine 640). Patients were divided into 2 groups treated with or without PPI. PPI was administered in 331 cases (26%), and non-PPI in 939 (74%). There were no significant differences in cardiovascular death (PPI vs. non-PPI: 5 vs. 11 cases), nonfatal myocardial infarction (3 vs. 5), and stroke (3 vs. 16) between PPI and non-PPI groups, but the ratio of gastrointestinal events had a higher tendency in non-PPI group compared with PPI group (1 vs. 17, P=0.08). In subgroup analysis of patients taking clopidogrel, or patients with acute coronary syndrome, there was no significant difference in the ratio of cardiovascular events (7 vs. 16, 6 vs. 17, NS). The non-PPI group had a tendency of an increased risk of gastrointestinal events compared with the PPI group (0 vs. 9, P=0.06; 1 vs. 7, P=0.14). Conclusions: In contrast to the negative drug interaction of PPI reported elsewhere, in the present study the intake of PPI was not associated with an increased risk for adverse clinical outcomes in patients treated with stents.
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経皮的冠動脈ステント留置術を受けた透析患者において，糖尿病は臨床転帰に影響を及ぼすか Reviewed
永野雅英，掃本誠治＊，大嶋秀一，中尾浩一，藤本和輝，宮尾雄治，下村英紀，角田隆輔，丸山秀樹，廣瀬豊樹，中村夏樹，境野成次，岡秀樹，山本展誉，森上靖洋，松村敏幸，梶原一郎，小森顕一，枇杷剛，小出俊一，溝部道生，千年忠祐，山本浩一朗，海北幸一，杉山正悟，中村淳，小川久雄
日本心臓病学会誌 7 263 - 267 2012
Language：Japanese Publishing type：Research paper (scientific journal)
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Ono T., Kaikita K., Hokimoto S., Iwashita S., Yamamoto K., Miyazaki Y., Horio E., Sato K., Tsujita K., Abe T., Deguchi M., Tayama S., Sumida H., Sugiyama S., Yamabe H., Nakamura S., Nakagawa K., Ogawa H.
Thrombosis Research 128 ( 6 ) e130 - 6 2011.12
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Thrombosis Research
Introduction: Carriers of reduced-function CYP2C19 allele on antiplatelet therapy show diminished platelet inhibition and higher rate of clinical risk. The purpose of this study was to determine cut-off levels of VerifyNow P2Y12 system associated with effective inhibition of on-clopidogrel platelet aggregation to predict carriers of CYP2C19 reduced-function allele among patients undergoing percutaneous coronary intervention (PCI). Materials and Methods: We enrolled 202 consecutive patients with stable coronary artery disease (CAD) undergoing PCI and treated with clopidogrel. All patients underwent CYP2C19 genotyping and measurement of residual platelet aggregation by VerifyNow system. Results: Carriers of CYP2C19 reduced-function allele constituted 131 (65%) of 202 CAD patients. Platelet inhibition measured by P2Y12 reaction units (PRU) and %inhibition was diminished in carriers compared with noncarriers (PRU: 290.0 ± 81.2 vs 217.6 ± 82.4, p < 0.001, %inhibition: 17.9 ± 17.8 vs 35.5 ± 22.8, p < 0.001, respectively). Multiple logistic regression analysis identified PRU and %inhibition as significant predictors of carrier state [odds ratio (OR) 4.95; 95% confidence interval (95%CI): 2.49 to 9.85; p < 0.001, OR 5.55; 95%CI: 2.80 to 10.99; p < 0.001, respectively]. Receiver-operating characteristic analysis showed that PRU and %inhibition were significant predictors of carrier state [area under the curve (AUC) 0.736 (95%CI: 0.664 to 0.808; p < 0.001), AUC 0.727 (95%CI: 0.651 to 0.803; p < 0.001), respectively]. The cut-off levels of PRU and %inhibition were 256 and 26.5% for the identification of carriers. Conclusions: Our results suggested that the cut-off levels of PRU and %inhibition to discriminate carriers of CYP2C19 reduced-function allele from noncarriers are potentially useful clinically to provide optimal clopidogrel therapy in patients with stable CAD undergoing PCI. © 2011 Elsevier Ltd. All rights reserved.
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Onoue Y., Tsujita K., Hokimoto S., Kaikita K., Sugiyama S., Ogawa H.
Journal of Cardiology Cases 4 ( 3 ) e163 - e167 2011.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology Cases
Fibromuscular dysplasia (FMD) is one of the etiologies of renal artery stenosis (RAS) and secondary hypertension. Balloon angioplasty has emerged as the mainstay of treatment because patients with FMD usually show substantial clinical and anatomic response to renal angioplasty without stenting. We report a 21-year-old male case of FMD-induced RAS treated with intravascular ultrasound- and pressure gradient-guided renal angioplasty. Ultrasonic imaging of the stenotic renal artery clearly visualized adventitial fibrotic band surrounding the negative remodeled renal artery and the accompanying atherosclerotic plaque. The findings suggest that atherosclerotic change can occur in young patients with renal FMD that is basically considered to be nonatherosclerotic. Pressure gradient measurement is also useful in confirming hemodynamic improvement during angioplasty. © 2011 Japanese College of Cardiology.
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Passive exercise using whole-body periodic acceleration enhances blood supply to ischemic hindlimb Reviewed
Rokutanda T., Izumiya Y., Miura M., Fukuda S., Shimada K., Izumi Y., Nakamura Y., Araki S., Hanatani S., Matsubara J., Nakamura T., Kataoka K., Yasuda O., Kaikita K., Sugiyama S., Kim-Mitsuyama S., Yoshikawa J., Fujita M., Yoshiyama M., Ogawa H.
Arteriosclerosis, Thrombosis, and Vascular Biology 31 ( 12 ) 2872 - 2880 2011.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Arteriosclerosis, Thrombosis, and Vascular Biology
Objective-Whole-body periodic acceleration (WBPA) has been developed as a passive exercise technique to improve endothelial function by increasing shear stress through repetitive movements in spinal axis direction. We investigated the effects of WBPA on blood flow recovery in a mouse model of hindlimb ischemia and in patients with peripheral arterial disease. Methods and results-After unilateral femoral artery excision, mice were assigned to either the WBPA (n=15) or the control (n=13) group. WBPA was applied at 150 cpm for 45 minutes under anesthesia once a day. WBPA significantly increased blood flow recovery after ischemic surgery, as determined by laser Doppler perfusion imaging. Sections of ischemic adductor muscle stained with anti-CD31 antibody showed a significant increase in capillary density in WBPA mice compared with control mice. WBPA increased the phosphorylation of endothelial nitric oxide synthase (eNOS) in skeletal muscle. The proangiogenic effect of WBPA on ischemic limb was blunted in eNOS-deficient mice, suggesting that the stimulatory effects of WBPA on revascularization are eNOS dependent. Quantitative real-time polymerase chain reaction analysis showed significant increases in angiogenic growth factor expression in ischemic hindlimb by WBPA. Facilitated blood flow recovery was observed in a mouse model of diabetes despite there being no changes in glucose tolerance and insulin sensitivity. Furthermore, both a single session and 7-day repeated sessions of WBPA significantly improved blood flow in the lower extremity of patients with peripheral arterial disease. Conclusion-WBPA increased blood supply to ischemic lower extremities through activation of eNOS signaling and upregulation of proangiogenic growth factor in ischemic skeletal muscle. WBPA is a potentially suitable noninvasive intervention to facilitate therapeutic angiogenesis. © 2011 American Heart Association, Inc.
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Repetitive early stent thrombosis in a patient with the CYP2C19<sup>*</sup>3/<sup>*</sup>3 genotype Reviewed
Takashio S., Hokimoto S., Kaikita K., Fujimoto K., Misumi I., Nakagawa K., Ogawa H.
Journal of Cardiology Cases 4 ( 1 ) e16 - e19 2011.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology Cases
A 45-year-old man presented with acute inferior myocardial infarction and underwent emergent coronary angiography (CAG). CAG revealed total occlusion of both the proximal right coronary artery (RCA) and distal left circumflex artery, and two bare-metal stents were deployed in the RCA. After the procedure, dual antiplatelet therapy (DAT) with 100 mg aspirin and 75 mg clopidogrel daily were given as usual, however, stent thrombosis occurred three times and he underwent repeat interventions. To investigate the cause of repeated stent thrombosis, the platelet function during DAT was measured. The result showed that he did not achieve an adequate antiplatelet effect. Clopidogrel is a prodrug that requires biotransformation by cytochrome P450 (CYP) enzyme in the liver. Recently, the carriers of CYP2C19 2 or 3 null-of-function allele, have been shown to demonstrate an increased risk of cardiovascular events, including stent thrombosis, compared with non-carriers. This patient carried the CYP2C19 3/ 3 genotype. This is the first report of repetitive stent thrombosis in a poor metabolizer carrying two loss-of-function alleles (CYP2C19 3/ 3). © 2011 Japanese College of Cardiology. * * * * * *
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Enomoto K., Yamabe H., Toyama K., Matsuzawa Y., Yamamuro M., Uemura T., Morihisa K., Iwashita S., Kaikita K., Sugiyama S., Ogawa H.
Journal of Cardiology 58 ( 1 ) 69 - 73 2011.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
Background and purpose: Cardiac resynchronization therapy (CRT) is a beneficial strategy to improve severe cardiac dysfunction in patients with congestive heart failure (CHF). The improvement of endothelial function in CHF patients treated with CRT is reflected in the mortality risk reduction. However the precise mechanisms of the relationship between CRT and vascular endothelial function have not been well discussed. Methods and subjects: Twenty-two severe consecutive CHF patients associated with dilated cardiomyopathy [New York Heart Association (NYHA) class 3.3 ± 0.5, left ventricular ejection fraction (LVEF) 24.4 ± 5.9%] were included in this study. We evaluated endothelial function, measured by reactive hyperemia peripheral arterial tonometry (RH-PAT), between optimal medical therapy alone group (medical therapy group: n = 10) and CRT group (n = 12) at the study enrolment and 12 weeks later. Furthermore we analyzed the association between the RH-PAT and cardiac function. Essential results: Both therapies significantly and equally improved NYHA class, LVEF, end-diastolic left ventricular dimension and plasma levels of brain natriuretic peptide (BNP). CRT significantly increased RH-PAT index (medical therapy group: 1.5 ± 0.2 to 1.5 ± 0.3, p = 0.824; CRT group: 1.4 ± 0.2 to 1.7 ± 0.4, p = 0.003) and cardiac output (medical therapy group: 3.3 ± 1.1 to 3.5 ± 1.0, p = 0.600; CRT group: 2.7 ± 0.6 to 4.3 ± 1.5, p = 0.001), compared to the medical therapy group. There was significant positive correlation between the change in RH-PAT index and cardiac output (r = 0.600, p = 0.003). Conclusions: CRT significantly improved endothelial function through the improvement of cardiac output in CHF patients, compared to optimal medical therapy. © 2011 Japanese College of Cardiology.
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Miyazaki Y., Kaikita K., Endo M., Horio E., Miura M., Tsujita K., Hokimoto S., Yamamuro M., Iwawaki T., Gotoh T., Ogawa H., Oike Y.
Arteriosclerosis, Thrombosis, and Vascular Biology 31 ( 5 ) 1124 - 1132 2011.5
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Arteriosclerosis, Thrombosis, and Vascular Biology
Objective- To investigate whether and how the endoplasmic reticulum (ER) stress-induced, CCAAT/enhancer-binding protein-homologous protein (CHOP)-mediated pathway regulates myocardial ischemia/reperfusion injury. Methods and Results- Wild-type and chop-deficient mice underwent 50 minutes of left coronary artery occlusion followed by reperfusion. Expression of chop and spliced x-box binding protein-1 (sxbp1) mRNA was rapidly and significantly increased in reperfused myocardium of wild-type mice. chop-deficient mice exhibited markedly reduced injury size after reperfusion compared with wild-type mice, accompanied by a decreasing number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cardiomyocytes. Interestingly, myocardial inflammation, as assessed by expression of inflammatory cytokines and chemokines and numbers of infiltrated inflammatory cells, was also attenuated in chop-deficient mice. Moreover, expression of interleukin-6 mRNA in response to lipopolysaccharide was enhanced by simultaneous stimulation with thapsigargin, a potent ER stressor, in wild-type cardiomyocytes but not in chop-deficient cardiomyocytes. Finally, we found that superoxide was produced in reperfused myocardium and that intravenous administration of edaravone, a free radical scavenger, immediately before reperfusion significantly suppressed the superoxide overproduction and subsequent expression of sxbp1 and chop mRNA, followed by reduced injury size in wild-type mice. Conclusion- The ER stress-induced, CHOP-mediated pathway, which is activated in part by superoxide overproduction after reperfusion, exacerbates myocardial ischemia/reperfusion injury by inducing cardiomyocyte apoptosis and myocardial inflammation. Copyright © 2011 American Heart Association. All rights reserved.
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Hypercholesterolemia and hypoadiponectinemia are associated with necrotic core-rich coronary plaque Reviewed
Kojima S., Kojima S., Maruyoshi H., Nagayoshi Y., Kaikita K., Sumida H., Sugiyama S., Funahashi T., Ogawa H.
International Journal of Cardiology 147 ( 3 ) 371 - 376 2011.3
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background: Hypercholesterolemia is a risk factor for coronary artery disease and closely linked to unstable plaque. Hypoadiponectinemia is frequently observed in patients with metabolic syndrome complicated with macroangiopathy and predicts poor clinical outcome. Spectral analysis of intravascular ultrasonography radiofrequency (IVUS-Virtual Histology [VH]) allows quantitative analysis of plaque composition. The purpose of this study was to verify the effects of low-density lipoprotein (LDL) cholesterol level on plaque morphology, and test the hypothesis that adiponectin influences coronary plaque volume and composition. Methods: Preintervention IVUS-VH using a continuous pullback was performed in 92 coronary vessels in 92 patients with coronary artery disease. The morphological distribution of plaque was evaluated prospectively in a 60-mm segment of coronary vessels containing the culprit lesion. Results: Serum LDL cholesterol levels correlated positively with necrotic core volume (r = 0.217, P = 0.037) and percent necrotic core tissue (r = 0.308, P = 0.003), while plasma adiponectin levels correlated negatively with plaque volume (r = - 0.297, P = 0.004) and necrotic core volume (r = - 0.306, P = 0.003). Multiple regression analyses showed close association between necrotic core volume and statin-use (β = - 21.68, P = 0.004) and adiponectin levels (β = - 31.25, P = 0.038), and that percent necrotic core tissue was influenced by statin-use (β = - 4.595, P = 0.026) and LDL cholesterol levels (β = 0.092, P = 0.031). Conclusions: Adiponectin is closely linked to coronary plaque volume. Hypercholesterolemia and hypoadiponectinemia correlate with necrotic core lesions and may contribute to increased risk of coronary plaque vulnerability. Statins can affectively prevent necrotic core plaque formation associated with hypercholesterolemia and hypoadiponectinemia. © 2009 Elsevier Ireland Ltd. All rights reserved.
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Yamamoto K., Hokimoto S., Chitose T., Morita K., Ono T., Kaikita K., Tsujita K., Abe T., Deguchi M., Miyagawa H., Saruwatari J., Sumida H., Sugiyama S., Nakagawa K., Ogawa H.
Journal of Cardiology 57 ( 2 ) 194 - 201 2011.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
Background and purpose: CYP2C19*2 loss-of-function allele in Caucasians may be associated with wide interindividual variability in platelet response to clopidogrel, and the incidence of gene mutation varies with racial differences, especially between Asians and Caucasians. The aim was to examine the impact of CYP2C19 genotype on the residual platelet reactivity in Japanese patients with coronary heart disease (CHD) during antiplatelet therapy. Methods and results: We measured the CYP2C19 genotype and platelet aggregation in 201 patients with stable CHD. Moreover, we examined the relation of CYP2C19 polymorphism to cardiovascular events in 98 patients treated with stent implantation. The distribution of CYP2C19 genotype was 37%, 33%, 11%, 11%, 7%, and 1% in CYP2C19*1/*1, *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3, respectively. Residual platelet reactivity was lower in patients during dual antiplatelet therapy (DAT) than in those with aspirin (3975±1569 aggregation units. minute (AU min) vs 5850±938 AU min, p<0.05). In the DAT group, the platelet reactivity decreased significantly in the wild-type homozygotes (CYP2C19*1/*1), subsequently in the *2, or *3 heterozygotes (*1/*2, *1/*3), and was not well inhibited in the *2, and/or *3 homozygotes (*2/*2, *2/*3, *3/*3; 3194±1570 AU min, 4148±1400 AU min, and 5088±1080 AU min, respectively). However, when the duration of DAT was used to divide subjects into 2 groups, <7 days, and >7 days, patients carrying the variant allele showed significantly decreased platelet reactivities at >7 days compared with those at <7 days. Moreover, the incidence of cardiovascular events was higher in patients carrying at least one variant allele than in wild-type homozygotes. Conclusions: CYP2C19 polymorphism may be associated with high residual platelet reactivity and the occurrence of cardiovascular events. © 2011 Japanese College of Cardiology.
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Matsubara J., Sugiyama S., Nozaki T., Sugamura K., Konishi M., Ohba K., Matsuzawa Y., Akiyama E., Yamamoto E., Sakamoto K., Nagayoshi Y., Kaikita K., Sumida H., Kim-Mitsuyama S., Ogawa H.
Journal of the American College of Cardiology 57 ( 7 ) 861 - 869 2011.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American College of Cardiology
Objectives: This study investigated the clinical significance of plasma pentraxin 3 (PTX3) levels in patients with heart failure with normal ejection fraction (HFNEF) and whether PTX3 is produced from coronary circulation. Background: Pentraxin 3 is a novel inflammatory marker and a member of pentraxin superfamily including C-reactive protein (CRP). The relationship between inflammatory markers and HFNEF remains unclear. Methods: We measured peripheral blood levels of PTX3, high-sensitivity CRP, tumor necrosis factor-alpha, and interleukin-6 in 323 patients comprising 82 HFNEF, 70 heart failure (HF) with reduced EF, and 171 non-HF patients. Levels of PTX3 were also measured at the aortic root and the coronary sinus in 75 patients. Results: The levels of PTX3, tumor necrosis factor-alpha, and interleukin-6, but not high-sensitivity CRP, were significantly higher in HFNEF patients than in non-HF patients. Multivariate logistic regression analysis identified only high levels of PTX3 as the independent inflammatory marker correlated with the presence of HFNEF in patients with normal left ventricular (LV) EF (odds ratio [OR]: 1.49, 95% confidence interval [CI]: 1.11 to 1.98, p < 0.01) and with the presence of left ventricular diastolic dysfunction (LVDD) in non-HF patients (OR: 1.23, 95% CI: 1.02 to 1.50, p < 0.05). Levels of PTX3 at the coronary sinus were significantly higher than at the aortic root in HFNEF patients (p < 0.05) and in non-HF patients with LVDD (p < 0.01), but not different in non-HF patients without LVDD (p = 0.33). Conclusions: Pentraxin 3 is significantly elevated in HFNEF patients and produced in the coronary circulation in patients with LVDD. Pentraxin 3, but not high-sensitivity CRP, is an independent inflammatory marker correlated with the presence of LVDD and HFNEF. (The Clinical Significance of Plasma Pentraxin 3 levels for Patients with Diastolic Heart Failure; UMIN000002170) © 2011 American College of Cardiology Foundation.
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Long-term use of oral nicorandil stabilizes coronary plaque in patients with stable angina pectoris Reviewed
Izumiya Y., Kojima S., Kojima S., Araki S., Usuku H., Matsubara J., Sakamoto K., Tsujita K., Nagayoshi Y., Kaikita K., Sugiyama S., Ogawa H.
Atherosclerosis 214 ( 2 ) 415 - 421 2011.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Atherosclerosis
Objective: The Impact of Nicorandil in Angina (IONA) trial demonstrated that the use of nicorandil, an anti-anginal drug, reduced future cardiovascular events in patients with stable angina. We hypothesized that nicorandil has beneficial effects on coronary arterial plaque characteristics and atherosclerogenesis. Methods and Results: Preintervention intravascular ultrasound-virtual histology was performed prospectively in 65 consecutive patients with stable angina pectoris. There were no differences in coronary risk factors between the nicorandil (n = 16) and non-nicorandil (n = 49) groups. However, the nicorandil group demonstrated a larger %fibrous tissue (68 ± 10 vs. 62 ± 11%, P = 0.049) and a smaller %necrotic core tissue (11 ± 7 vs. 16 ± 10%, P = 0.049) compared with the non-nicorandil group. Multiple regression analysis showed that %necrotic core tissue (P = 0.045) was negatively and %fibrous tissue (P = 0.026) was positively associated with the use of nicorandil independent of statin use. We also analyzed the effect of nicorandil on atherosclerotic lesion formation in a mouse model of atherosclerosis. Lipid profiles were unaffected, but the area of atherosclerotic lesion and plaque necrosis were significantly reduced following 8-week nicorandil treatment in ApoE-deficient mice fed an atherogenic diet. Nicorandil significantly reduced the expression levels of endoplasmic reticulum stress markers, C/EBP homologous protein (CHOP) and glucose regulated protein/BiP (GRP78) in atherosclerotic lesions. Nicorandil significantly attenuated tunicamycin-induced CHOP upregulation in cultured THP-1 macrophages. Conclusions: Nicorandil exerts its anti-atherogenic effect by mechanisms different from those of statins. Long-term nicorandil treatment is a potentially suitable second-line prevention therapy for patients with coronary artery disease. © 2010 Elsevier Ireland Ltd.
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Double-blind, placebo-controlled phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease Reviewed
Goto S＊, Ogawa H, Takeuchi M, Flather MD, Bhatt DL; J-LANCELOT (Japanese-Lesson from Antagonizing the Cellular Effect of Thrombin) Investigators (including Kaikita K)
European Heart Journal 31 2601 - 2613 2010.8
Language：English Publishing type：Research paper (scientific journal)
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Waveform of ophthalmic artery doppler flow predicts the severity of systemic atherosclerosis Reviewed
Maruyoshi H., Kojima S., Kojima S., Nagayoshi Y., Horibata Y., Kaikita K., Sugiyama S., Ogawa H.
Circulation Journal 74 ( 6 ) 1251 - 1256 2010.6
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: Doppler imaging of ophthalmic artery (OA), the first major branch of the internal carotid artery, provides anatomical advantages due to the vertical angle to the body surface and absence of ultrasonic obstacles. It was hypothesized that the Doppler waveform indices of OA correlate with severity of systemic atherosclerosis. Methods and Results: The study subjects were 180 patients who underwent cardiac catheterization and OA Doppler imaging (90 patients with coronary artery disease (CAD) and 90 control patients). The ratio of stroke volume to pulse pressure, an index of arterial compliance, was closely associated with the ratio of systolic to diastolic mean velocity (Sm/Dm) in OA. The level of Sm/Dm increased in proportion with the increase in number of stenosed coronary arteries (0-vessel disease 2.1±0.3, 1-vessel disease 2.3±0.3, multi-vessel disease 2.6±0.5, P<0.0001). The Sm/Dm level in OA correlated positively with age, pulse pressure, pulse wave velocity, resistive index and pulsatility index in OA. The best Sm/Dm cut-off to predict CAD was 2.3, and patients with Sm/Dm >2.3 had 8.0-fold risk for CAD. Conclusions: The waveform indices of OA are clinically useful for evaluating the severity of CAD and may help explain the missing link between OA circulation and systemic arterial compliance.
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循環器疾患
三浦光年, 海北幸一, 小川久雄
臨牀と研究 87 ( 6 ) 766 - 770 2010.6
Publishing type：Research paper (scientific journal)
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Digital Assessment of Endothelial Function and Ischemic Heart Disease in Women Reviewed
Matsuzawa Y., Sugiyama S., Sugamura K., Nozaki T., Ohba K., Konishi M., Matsubara J., Sumida H., Kaikita K., Kojima S., Nagayoshi Y., Yamamuro M., Izumiya Y., Iwashita S., Matsui K., Jinnouchi H., Kimura K., Umemura S., Ogawa H.
Journal of the American College of Cardiology 55 ( 16 ) 1688 - 1696 2010.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American College of Cardiology
Objectives: We investigated the utility of digital reactive hyperemia peripheral arterial tonometry (RH-PAT) in predicting ischemic heart disease (IHD), including obstructive coronary artery disease (CAD) and nonobstructive coronary artery disease (NOCAD), in women. Background: IHD is the leading cause of mortality, and its pathogenesis is diverse in women. Fingertip RH-PAT is a new device that provides noninvasive, automatic, and quantitative evaluation of endothelial dysfunction. Methods: RH-PAT was measured using Endo-PAT2000 (Itamar Medical, Caesarea, Israel) before cardiac catheterization in 140 stable women scheduled for hospitalization to examine chest pain. NOCAD was diagnosed by angiography with measurement of coronary blood flow and cardiac lactate production during intracoronary acetylcholine provocation test and cardiac scintigraphy with stress tests. Results: Sixty-eight women (49%) had obstructive CAD and 42 women (30%) had NOCAD. RH-PAT indexes were significantly attenuated in both obstructive CAD and NOCAD as compared with non-IHD (n = 30) (obstructive CAD: median 1.57, interquartile range [IQR] 1.42 to 1.76; NOCAD: median 1.58, IQR 1.41 to 1.78; non-IHD: median 2.15, IQR 1.85 to 2.48, p < 0.001). By multivariate logistic regression analysis, only RH-PAT index was significantly associated with IHD, including obstructive CAD and NOCAD (odds ratio 0.51; 95% confidence interval: 0.38 to 0.68; p < 0.001). In receiver-operating characteristic analysis, RH-PAT index was a significant predictor of IHD (area under the curve 0.86; p < 0.001). Furthermore, only RH-PAT was useful for the prediction of NOCAD after excluding obstructive CAD (area under the curve 0.85; p < 0.001; RH-PAT index of <1.82 had 81% sensitivity and 80% specificity). Conclusions: RH-PAT indexes were significantly attenuated in women with IHD. Digital RH-PAT can predict patients with IHD, especially NOCAD before angiography. RH-PAT is potentially useful for identifying high-risk women for IHD. (Endothelial Dysfunction and Coronary Artery Spasm; NCT00619294). © 2010 American College of Cardiology Foundation.
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Miura M., Kaikita K., Matsukawa M., Soejima K., Fuchigami S., Miyazaki Y., Ono T., Uemura T., Tsujita K., Hokimoto S., Sumida H., Sugiyama S., Matsui K., Yamabe H., Ogawa H.
Thrombosis and Haemostasis 103 ( 3 ) 623 - 629 2010.3
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Thrombosis and Haemostasis
High plasma level of von Willebrand factor (VWF) is a marker of future cardiovascular events in patients at high risk of coronary artery disease (CAD). The purpose of this study was to examine the changes and the prognostic value of plasma VWF-cleaving protease (ADAMTS13) levels in patients with CAD. Plasma VWF and ADAMTS13 levels were measured in 225 patients with CAD (152 men and 73 women, age, 70.3 ± 8.9 years, mean ± SD) and 100 patients without CAD who were age-and gender-matched to the CAD patients (60 men and 40 women, age, 68.6 ± 8.9 years). The CAD patients had higher VWF and lower ADAMTS13 antigen levels compared to patients without CAD. During 22.3 ± 10.4 months follow-up period, 20 major adverse cardiac and cerebrovascular events (MACCE) occurred in 222 patients with CAD who could be followed up. Kaplan-Meier analysis demonstrated that CAD patients with high plasma VWF antigen levels were significantly more likely to develop MACCE. Furthermore, eight cardiac and cerebrovascular thrombotic events [acute coronary syndrome (n=4) and cerebral infarction (n=4)] occurred in CAD patients with both high plasma VWF and low ADAMTS13 antigen levels. Multivariate Cox hazards regression analysis identified high plasma VWF and low ADAMTS13 antigen levels as significant and independent predictors of future MACCE and thrombotic events during the follow-up period in CAD patients. Our findings suggest that low plasma ADAMTS13 as well as high VWF level is a useful predictor of cardiac and cerebrovascular events in CAD patients. © Schattauer 2010.
DOI： 10.1160/TH09-08-0568
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Arima Y., Kojima S., Kusuhara K., Nagayoshi Y., Kawano H., Kaikita K., Sugiyama S., Kinoshita Y., Ogawa H.
Journal of Cardiology Cases 1 ( 1 ) e45 - e48 2010.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology Cases
A 76-year-old woman with a diagnosis of dilated-phase hypertrophic cardiomyopathy was admitted to our hospital for exacerbation of congestive heart failure. After admission, she developed cardiac arrest and the electrocardiogram showed pulseless electrical activity. Cardiopulmonary resuscitation was started immediately; however, return of spontaneous circulation was achieved 56 min after cardiopulmonary arrest. Therapeutic hypothermia was considered as an adjunct therapy, together with intensive treatment. The target temperature of 33.0 °C was achieved 10 h after cardiopulmonary arrest. Core temperature was maintained between 33.0 and 35.0 °C for 72 h with no cardiac arrhythmia detected during this period. Re-warming was initiated at a rate of 1 °C/day. On day 6, the core temperature returned to 37 °C and recovery of consciousness was achieved on day 9. No impairment of neurological function was noted. She had no heart failure-related symptoms and B-type natriuretic peptide level decreased from 4174 pg/mL on admission to 450 pg/mL at discharge. Therapeutic hypothermia may be a promising post-resuscitation therapy for comatose survivors of in-hospital cardiac arrest with non-ventricular fibrillation leading to improvement in neurological outcome. © 2009 Japanese College of Cardiology.
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Clinical factors affecting serum potassium concentration in cardio-renal decompensation syndrome Reviewed
Ueno H., Yoshimura M., Nakayama M., Yamamuro M., Nishijima T., Kusuhara K., Nagayoshi Y., Kojima S., Kaikita K., Sumida H., Sugiyama S., Ogawa H.
International Journal of Cardiology 138 ( 2 ) 174 - 181 2010.1
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background: Renin-angiotensin-aldosterone system (RAAS) inhibitors are currently indispensable for the treatment of heart failure. It is well known that hyperkalemia is likely to occur in renal failure; however, it has not yet been clarified how the serum potassium concentration changes as heart failure progresses. Currently, the cardio-renal decompensation syndrome holds that the serum potassium concentration is altered similarly by both heart failure and renal failure; however, there are no definitive reports on this. In order to use RAAS inhibitors more safely and effectively in heart failure, it is necessary to understand the factors affecting serum potassium concentration in the clinical setting. Methods and results: We examined the clinical factors affecting serum potassium concentration in 1035 consecutive patients with cardiovascular disease who were hospitalized in our institution. Multiple regression analysis showed that the independent factors associated with an elevated serum potassium concentration were renal insufficiency evaluated by estimated glomerular filtration rate (eGFR) (P < 0.0001), diabetes mellitus evaluated by HbA (P = 0.0005) and the use of RAAS inhibitors (P = 0.0010). The independent factors associated with a decreased serum potassium concentration were mean blood pressure (P < 0.0001), heart failure evaluated by log BNP (P = 0.0164) and the use of diuretics (P = 0.0232). Conclusions: The serum potassium concentration decreases with the severity of heart failure if renal function is preserved. From the perspective of potassium homeostasis, we could use the RAAS inhibitors more aggressively in patients with heart failure who do not have renal failure. © 2008 Elsevier Ireland Ltd. All rights reserved. 1c
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Cannabinoid 1 receptor blockade reduces atherosclerosis with enhances reverse cholesterol transport Reviewed
Sugamura K., Sugiyama S., Fujiwara Y., Matsubara J., Akiyama E., Maeda H., Ohba K., Matsuzawa Y., Konishi M., Nozaki T., Horibata Y., Kaikita K., Sumida H., Takeya M., Ogawa H.
Journal of Atherosclerosis and Thrombosis 17 ( 2 ) 141 - 147 2010
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Atherosclerosis and Thrombosis
Aim: A recent clinical study using coronary intravascular ultrasound showed that rimonabant, a cannabinoid 1 (CB1) receptor antagonist, significantly reduced total atheroma volume, suggesting that CB1 receptor blockade could be beneficial in anti-atherogenic therapy. The reverse cholesterol transport (RCT) system plays important roles in atherogenesis. We investigated whether CB1 receptor blockade could modulate atherogenesis in mice. Methods and Results: Oral administration of rimonabant (8 mg/kg/day) to apolipoprotein E-deficient mice for 3 months significantly reduced the relative area of atherosclerotic lesions in the aorta (vehicle; 12.6 ± 4.0% vs. rimonabant; 9.7 ± 2.3, n = 12 each, p < 0.05) with an increase in serum adiponectin levels (15.6 ± 2.3 μg/mL vs. 12.2 ± 2.1, n = 12 each, p < 0.001), without affecting body weight or serum cholesterol levels. Rimonabant tended to increase serum high-density lipoprotein cholesterol (HDL-C) (p = 0.05). The relative area of atherosclerotic lesions in the aorta correlated inversely with serum HDL-C levels (r = -0.45, n = 24, p < 0.05). Rimonabant upregulated the mRNA expression levels of various components of the RCT system on THP-1 cell-derived macrophages (scavenger receptor B1: 1.15 ± 0.12 fold, n = 6; p < 0.05, ATP-binding cassette [ABC] transporter G1: 1.23 ± 0.11 fold, n = 6; p < 0.01), but not ABCA1 (1.13 ± 0.20 fold, n = 6; p = 0.13). Conclusion: CB1 receptor blockade reduced atherosclerosis in apoE-deficient mice through an increase in serum adiponectin levels and activation of the RCT system. CB1 receptor blockade may be therapeutically beneficial for atherogenesis by increasing the serum adiponectin level and enhancing of the RCT system.
DOI： 10.5551/jat.2865
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Standard-dose statin therapy provides incremental clinical benefits in normocholesterolemic diabetic patients Reviewed
Kojima S＊, Sakamoto T, Ogawa H, Kitagawa A, Matsui K, Shimomura H, Kimura K, Ogata Y, Sakaino N; multicenter study for aggressive lipid-lowering strategy by HMG-CoA reductase inhibitors investigators (including Kaikita K)
Circulation Journal 74 ( 4 ) 779 - 785 2010
Language：English Publishing type：Research paper (scientific journal)
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Nakamura Y., Yamada Y., Shimomura H., Nagayoshi Y., Tsujita K., Yamashita T., Fukuda M., Ohba K., Nako H., Ogura Y., Chitose T., Yamaguchi M., Nagata T., Soejima H., Kaikita K., Sugiyama S., Ogawa H.
Journal of Cardiology 54 ( 3 ) 416 - 424 2009.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
Background: Monocyte chemoattractant protein-1 (MCP-1) plays an important role in the pathogenesis of acute coronary syndrome. We have recently demonstrated that the administration of edaravone before reperfusion attenuated reperfusion injury in patients with acute myocardial infarction (AMI). Methods: Plasma MCP-1 levels were measured in 45 consecutive patients with AMI (edaravone group, n = 25; control group, n = 20). In the edaravone group, 30 mg edaravone was intravenously infused just before reperfusion. Plasma samples were obtained before and at 24 h, 3, 5, 7, and 14 days after reperfusion. Cardiovascular events were defined as cardiac death, subacute thrombosis, or fatal arrhythmia. Heart failure requiring rehospitalization was evaluated at 12 months after reperfusion. Results: Plasma MCP-1 levels were not different between the two groups before reperfusion. Compared with the placebo group, the edaravone group had statistically lower maximum creatine kinase-MB levels (218 ± 31 IU/l versus 145 ± 21 IU/l, p < 0.05) and plasma MCP-1 levels on day 3 after reperfusion (873 ± 118 pg/ml versus 516 ± 66 pg/ml, p < 0.05). Heart failure requiring rehospitalization occurred in four patients in the control group, but did not occur in the edaravone group (p < 0.05). At 12 months after reperfusion, left ventricular ejection fraction was statistically higher in the edaravone group than in the control group (62 ± 2% versus 54 ± 3%, p < 0.05). Conclusion: Edaravone suppressed plasma MCP-1, improved left ventricular ejection fraction, and reduced rehospitalization due to heart failure. Suppression of plasma MCP-1 level by edaravone might induce better prognosis for AMI patients. © 2009 Japanese College of Cardiology.
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Nagayoshi Y., Kawano H., Hokamaki J., Uemura T., Soejima H., Kaikita K., Sugiyama S., Yamabe H., Shioji I., Sasaki S., Kuroda Y., Ogawa H.
Free Radical Research 43 ( 12 ) 1159 - 1166 2009.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Free Radical Research
Various oxidative stress markers have been measured to evaluate the status of heart failure (HF). However, the relationships between these markers and the aetiology of HF have not been fully investigated. This study compared 8-hydroxy-2′-deoxyguanosine (8-OHdG) and biopyrrins levels in patients with ischemic and non-ischemic HF. Study subjects were divided into a coronary artery disease (CAD) group (n70), a non-CAD group (n61) and a control group (n33). In the CAD group, 8-OHdG and biopyrrins levels increased with the severity of the New York Heart Association (NYHA) functional class and log BNP levels correlated with 8-OHdG and biopyrrins levels. However, non-CAD patients with NYHA class III/IV had significantly lower 8-OHdG levels than CAD patients with NYHA class III/IV and the levels did not correlate with log BNP levels. In the CAD group, 8-OHdG levels reflected the severity of atherosclerosis. These results indicate that the properties of oxidative stress markers should be carefully taken into consideration for the assessment of HF status.
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Fukunaga T., Soejima H., Irie A., Fukushima R., Oe Y., Kawano H., Sumida H., Kaikita K., Sugiyama S., Nishimura Y., Ogawa H.
Circulation Journal 73 ( 10 ) 1914 - 1919 2009.10
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: Dendritic cells (DCs) stimulate T-cells to participate in the inflammatory processes that promote the destruction of vulnerable plaques. The relationship between circulating levels of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in patients with acute coronary syndrome (ACS) was evaluated. Methods and Results: Biood samples were obtained from 39 patients with ACS, 41 patients with stable angina pectoris (SAP) and 43 controls. The proportion of mDCs tended to be lower in the ACS group than in the SAP group and controls. Interleukin-12 levels associated with mDCs were significantly higher in the ACS group than in control group. The proportion of pDCs was significantly lower in the ACS groups than in the other two groups. Interferon-α levels secreted by pDCs, however, were not significantly different among the 3 groups. The ratio of mDCs to pDCs ≥4 is an important value for distinguishing ACS from SAP patients and control patients through receiver operating characteristic analysis (sensitivity; 85.0%, specificity; 83.4%). Conclusions: The ratio of mDCs to pDCs may be a useful marker for detecting ACS and the existence of vulnerable plaques.
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Tabata M., Kadomatsu T., Fukuhara S., Miyata K., Ito Y., Endo M., Urano T., Zhu H.J., Tsukano H., Tazume H., Kaikita K., Miyashita K., Iwawaki T., Shimabukuro M., Sakaguchi K., Ito T., Nakagata N., Yamada T., Katagiri H., Kasuga M., Ando Y., Ogawa H., Mochizuki N., Itoh H., Suda T., Oike Y.
Cell Metabolism 10 ( 3 ) 178 - 188 2009.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Cell Metabolism
Recent studies of obesity have provided new insights into the mechanisms underlying insulin resistance and metabolic dysregulation. Numerous efforts have been made to identify key regulators of obesity-linked adipose tissue inflammation and insulin resistance. We found that angiopoietin-like protein 2 (Angptl2) was secreted by adipose tissue and that its circulating level was closely related to adiposity, systemic insulin resistance, and inflammation in both mice and humans. Angptl2 activated an inflammatory cascade in endothelial cells via integrin signaling and induced chemotaxis of monocytes/macrophages. Constitutive Angptl2 activation in vivo induced inflammation of the vasculature characterized by abundant attachment of leukocytes to the vessel walls and increased permeability. Angptl2 deletion ameliorated adipose tissue inflammation and systemic insulin resistance in diet-induced obese mice. Conversely, Angptl2 overexpression in adipose tissue caused local inflammation and systemic insulin resistance in nonobese mice. Thus, Angptl2 is a key adipocyte-derived inflammatory mediator that links obesity to systemic insulin resistance. © 2009 Elsevier Inc. All rights reserved.
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Hokimoto S., Matsui K., Oshima S., Noda K., Kaikita K., Sumida H., Sugiyama S., Ogawa H.
Journal of Cardiology 54 ( 1 ) 71 - 75 2009.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
Background: The aim of this study was to examine the effects of gastric medicines on gastroduodenal injury during antiplatelet therapy after coronary intervention. Methods: A total of 501 patients were enrolled and as dual antiplatelet therapy, aspirin and thienopyridine were administered. Patients were divided into four groups: histamine H2-receptor antagonists (H2RA); proton pump inhibitors (PPI); other gastromucosal protective agents (GMP); or nothing (None), and follow-up lasted 8-20 months. Results: H2RA were prescribed in 212 cases (42%), PPI in 150 (30%), GMP in 56 (11%), and None in 83 (17%). Significant findings by endoscopy were recognized in 18 cases and upper gastrointestinal bleeding requiring hospitalization occurred in 7 patients (1.4%; H2RA in 4, GMP in 2, and None in 1). There were no gastrointestinal injuries in the PPI group. To minimize the effect of selection bias on gastroduodenal lesions, the propensity score analysis for clinical characteristics was used. The results of propensity score matching showed that administration of PPI reduced the incidence of gastrointestinal lesions compared with that of the non-PPI group. Conclusion: Administration of PPI reduced the incidence of gastrointestinal lesions compared with that of the non-PPI group. © 2009 Japanese College of Cardiology.
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Uemura T., Kaikita K., Yamabe H., Soejima K., Matsukawa M., Fuchigami S., Tanaka Y., Morihisa K., Enomoto K., Sumida H., Sugiyama S., Ogawa H.
Thrombosis Research 124 ( 1 ) 28 - 32 2009.5
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Thrombosis Research
Introduction: Previous studies have shown raised plasma von Willebrand factor (VWF) levels in patients with atrial fibrillation (AF). However, little is known about changes of VWF associated with VWF-cleaving protease (ADAMTS13) in AF. The aim of this study was to examine the relationship between changes in plasma VWF and ADAMTS13 levels, and left atrial remodeling in AF patients. Materials and Methods: We measured plasma VWF and ADAMTS13 antigen levels in 70 paroxysmal AF (PAF) patients, 56 chronic AF (CAF) patients, and 55 control subjects. Results: Plasma VWF levels (mU/ml) were significantly higher in CAF and PAF patients compared with the controls (2103 ± 743, 1930 ± 676, 1532 ± 555, respectively, P < 0.0001 in CAF vs. controls, P = 0.001 in PAF vs. control), while ADAMTS13 levels (mU/ml) were significantly lower in CAF and PAF patients compared with the controls (795 ± 169, 860 ± 221, 932 ± 173, respectively, P = 0.0002 in CAF vs. controls, P = 0.04 in PAF vs. control). The VWF/ADAMTS13 ratio was significantly higher in patients with CAF than PAF or controls (2.81 ± 1.30, 2.34 ± 0.92, 1.73 ± 0.83, respectively; P = 0.01 in CAF vs. PAF, P < 0.0001 in CAF vs. controls). There was a significant correlation between the VWF/ADAMTS13 ratio and left atrial diameter (positive correlation; r = 0.275, P = 0.0002) and left atrial appendage flow velocity (negative correlation; r = - 0.345, P = 0.0018). Conclusions: These findings suggest that the imbalance between plasma VWF and ADAMTS13 levels caused by left atrial remodeling might be closely associated with intra-atrial thrombus formation in AF patients. © 2008 Elsevier Ltd. All rights reserved.
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Morihisa K., Yamabe H., Uemura T., Tanaka Y., Enomoto K., Kawano H., Nagayoshi Y., Kaikita K., Sumida H., Sugiyama S., Ogawa H.
PACE - Pacing and Clinical Electrophysiology 32 ( 4 ) 484 - 493 2009.4
Language：English Publishing type：Research paper (scientific journal) Publisher：PACE - Pacing and Clinical Electrophysiology
Background: The precise nature of the upper turnaround part of atrioventricular nodal reentrant tachycardia (AVNRT) is not entirely understood. Methods: In nine patients with AVNRT accompanied by variable ventriculoatrial (VA) conduction block, we examined the electrophysiologic characteristics of its upper common pathway. Results: Tachycardia was induced by atrial burst and/or extrastimulus followed by atrial-His jump, and the earliest atrial electrogram was observed at the His bundle site in all patients. Twelve incidents of VA block: Wenckebach VA block (n = 7), 2:1 VA block (n = 4), and intermittent (n = 1) were observed. In two of seven Wenckebach VA block, the retrograde earliest atrial activation site shifted from the His bundle site to coronary sinus ostium just before VA block. Prolongation of His-His interval occurred during VA block in 11 of 12 incidents. After isoproterenol administration, 1:1 VA conduction resumed in all patients. Catheter ablation at the right inferoparaseptum eliminated antegrade slow pathway conduction and rendered AVNRT noninducible in all patients. Conclusion: Selective elimination of the slow pathway conduction at the inferoparaseptal right atrium may suggest that the subatrial tissue linking the retrograde fast and antegrade slow pathways forms the upper common pathway in AVNRT with VA block. © 2009 Wiley Periodicals, Inc.
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Smoking cessation is associated with increased plasma adiponectin levels in men Reviewed
Otsuka F., Kojima S., Maruyoshi H., Kojima S., Matsuzawa Y., Funahashi T., Kaikita K., Sugiyama S., Kimura K., Umemura S., Ogawa H.
Journal of Cardiology 53 ( 2 ) 219 - 225 2009.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
Objectives: Low levels of adiponectin, an adipocytokine with anti-diabetic and anti-atherogenic properties, are associated with increased risk of future myocardial infarction in men. Previous studies have demonstrated that cigarette smoking is involved in the development of insulin resistance, and current smokers have been shown to have reduced plasma adiponectin levels. However, the influence of smoking cessation on adiponectin levels remains unknown. We sought to assess whether smoking cessation is associated with increased plasma adiponectin levels in men. Methods: The study includes 72 men (47 non-smokers and 25 current smokers at baseline) with stable angina pectoris who underwent percutaneous coronary intervention and follow-up coronary angiography 6 months later. During the 6-month follow-up period, all 47 non-smokers remained non-smokers, while 15 men of the 25 baseline current smokers successfully quit smoking. We evaluated plasma adiponectin levels at coronary intervention and 6 months later. Results: Plasma adiponectin levels at coronary intervention were comparable to those after 6 months in non-smokers (4.22 [3.15-6.43] vs. 4.58 [3.03-6.26] μg/mL, P = 0.124) and in persistent smokers (4.77 [4.25-10.53] vs. 5.16 [4.11-8.10] μg/mL, P = 0.721). Meanwhile, an increase in adiponectin level was observed in patients who quit smoking for 6 months (4.24 [3.30-5.70] vs. 5.50 [4.03-8.00] μg/mL, P = 0.002). Univariate analysis revealed that the percent increase in adiponectin levels correlated positively with smoking cessation (P = 0.003) and negatively with additional use of β-blockers (P = 0.049). In addition, increases in adiponectin levels were closely associated with increase in high-density lipoprotein cholesterol (P = 0.148), decrease in triglycerides (P = 0.140), and additional use of renin-angiotensin system inhibitors (P = 0.069). Multivariate analysis demonstrated that smoking cessation was an independent determinant of the increase in adiponectin (P = 0.036). Conclusions: Smoking cessation is associated with increased plasma adiponectin levels in men with stable angina, suggesting that the significance of smoking cessation may be partly explained by the increase in adiponectin level. © 2008 Japanese College of Cardiology.
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Effects of imidapril therapy on endogenous fibrinolysis in patients with recent myocardial infarction Reviewed
Soejima H, Ogawa H＊, Yasue H, Suefuji H, Kaikita K
Clinical Cardiology 20 ( 5 ) 441 - 445 2009.2
Authorship：Last author Language：English Publishing type：Research paper (scientific journal)
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Sugamura K., Sugiyama S., Nozaki T., Matsuzawa Y., Izumiya Y., Miyata K., Nakayama M., Kaikita K., Obata T., Takeya M., Ogawa H.
Circulation 119 ( 1 ) 28 - 36 2009.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation
Cannabinoid 1 (CB1) receptor blockade with rimonabant represents a clinical therapeutic strategy for obesity. Recently, the role of the endocannabinoid system has been described in peripheral organs. We sought to determine whether the endocannabinoid system could be involved in human atherosclerosis and whether CB1 receptor blockade could modulate proinflammatory activity in macrophages. Methods and Results-mRNA expression levels of CB1 receptor in coronary atherectomy samples were significantly higher in patients with unstable angina than in those with stable angina (3.62±2.96-fold; n=7; P<0.05). Immunoreactive area analysis of the coronary artery showed that CB1 receptor expression was greater in lipid-rich atheromatous plaques than in fibrous plaques, especially in CD68 macrophages (9.5± 1.2% versus 0.6±0.6%; n=5; P<0.01). Levels of blood endocannabinoids were significantly higher in patients with coronary artery disease (n=20) than those without coronary artery disease (n=20) (median [interquartile range]: anandamide, 1.048 pmol/mL [0.687 to 1.387 pmol/mL] versus 0.537 pmol/mL [0.468 to 0.857 pmol/mL], P<0.01; 2-arachidonoyl glycerol, 13.30 pmol/mL [6.65 to 16.21 pmol/mL] versus 7.67 pmol/mL [6.39 to 10.03 pmol/mL], P<0.05). In cultured macrophages, expression of CB1 receptor was significantly increased during monocyte-macrophage differentiation (1.78±0.13-fold; n=6; P<0.01). CB1 receptor blockade in macrophages induced a significant increase in cytosolic cAMP (29.9± 13.0%; n=4; P<0.01), inhibited phosphorylation of c-Jun N-terminal kinase (-19.1±12.6%, n=4; P<0.05), and resulted in a significant decrease in the production of proinflammatory mediators (interleukin-lβ, -28.9± 10.9%; interleukin-6, -24.8±7.6%; interleukin-8, -22.7±5.2%; tumor necrosis factor-α, -13.6±4.8%; matrix metalloproteinase-9, -16.4±3.8%; n=4 to 8; P<0.01). Conclusions-Patients with coronary artery disease demonstrated the activation of the endocannabinoid system with elevated levels of blood endocannabinoids and increased expression of CB1 receptor in coronary atheroma. CB1 receptor blockade exhibited antiinflammatory effects on macrophages, which might provide beneficial effects on atherogenesis. (Circulation. 2009;119:28-36.) © 2009 American Heart Association, Inc.
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Idiopathic left ventricular aneurysm accompanied by lethal arrhythmia:Report of two cases Reviewed
Morihisa Kenji, Sumida Hitoshi, Sugiyama Seigo, Ogawa Hisao, Yamabe Hiroshige, Enomoto Koji, Uemura Takashi, Tanaka Yasuaki, Matsuzawa Yasushi, Nagayoshi Yasuhiro, Kaikita Koichi, Kawano Hiroaki
Shinzo 41 ( 9 ) 1012 - 1017 2009
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japan Heart Foundation
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Uemura T., Yamabe H., Tanaka Y., Morihisa K., Kawano H., Kaikita K., Sumida H., Sugiyama S., Ogawa H.
Internal Medicine 47 ( 20 ) 1799 - 1802 2008.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Internal Medicine
Ventricular tachycardia originating from the right ventricular outflow tract (RVOT) is considered benign, but sometimes it causes polymorphic ventricular tachycardia and ventricular fibrillation, resulting in sudden cardiac death. A 58-year-old woman without structural heart disease was admitted for evaluation of recurrent episodes of syncope. Surface ECG showed frequent repetitive premature ventricular contraction (PVC) of RVOT origin. Polymorphic ventricular tachycardia triggered by the same PVC was documented by Holter ECG during an episode of syncope. Radiofrequency catheter ablation was performed to eradicate this PVC. No polymorphic ventricular tachycardia has developed after the procedure, and the patient has had no recurrence of syncope. © 2008 The Japanese Society of Internal Medicine.
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冠攣縮性狭心症の診断と治療に関するガイドライン
小川久雄, 赤阪隆史, 奥村謙, 川嶋成乃亮, 川筋道雄, 木村一雄, 斎藤穎, 下川宏明, 末田章三, 嶽山陽一, 田辺恭彦, 土橋和文, 野出孝一, 服部隆一, 水野杏一, 三羽邦久, 室原豊明, 毛利正博, 山岸正和, 吉村道博, 井上晃男, 雪吹周生, 大下晃, 海北幸一, 河野宏明, 小島淳, 小菅雅美, 副島弘文, 財田滋穂, 中山雅文, 安田聡, 岸田浩, 友池仁暢, 土師一夫, 横山光宏.
Circulation journal 72 1195 - 1252 2008.11
Publishing type：Research paper (scientific journal)
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Ueno H., Nakayama M., Kojima S., Kusuhara K., Nagayoshi Y., Yamamuro M., Nishijima T., Usuku H., Kaikita K., Sumida H., Yamabe H., Sugiyama S., Yoshimura M., Ogawa H.
Heart and Vessels 23 ( 4 ) 243 - 248 2008.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Heart and Vessels
The prevalence of anemia in patients with heart failure (HF) increases according to disease severity as a consequence of renal insufficiency, cytokine production, plasma volume expansion, and/or malnutrition. B-type natriuretic peptide (BNP) has been recognized as a biochemical marker of ventricular dysfunction. The aim of this study was to evaluate the clinical significance of anemia in HF patients and furthermore, to investigate whether a significant correlation exists between anemia, BNP, and poor clinical outcomes in HF patients. We studied 185 consecutive HF patients. We assessed the occurrence of major adverse cardiac events (MACE) post hospital discharge. Anemia was defined as Hb concentrations <12.9 g/dl in men and <11.3 g/dl in women, respectively. Kaplan-Meier analysis revealed that anemia and high BNP levels (>259 pg/ml) were significantly associated with the occurrence of MACE. Multiple logistic analysis revealed that the most predictive independent risk factor for the occurrence of MACE was high BNP levels, followed by anemia (relative risk [RR] = 2.803 and 2.241, respectively). We divided the patients with or without anemia and high or low BNP levels into four groups according to their respective Hb and BNP levels. The hazard ratio for MACE in the group with anemia and high BNP levels was 10.3 in comparison to the group without anemia and with low BNP levels (P = 0.0002). Both anemia and high plasma levels of BNP are significantly and independently associated with the occurrence of MACE in HF patients; furthermore, the synergistic effect of anemia combined with high BNP levels significantly predicts an enhanced risk for MACE. © Springer Japan 2008.
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Nakayama M., Kudoh T., Kaikita K., Yoshimura M., Oshima S., Miyamoto Y., Takeya M., Ogawa H.
Atherosclerosis 198 ( 2 ) 426 - 433 2008.6
Language：English Publishing type：Research paper (scientific journal) Publisher：Atherosclerosis
Objective: Morbidity and mortality rates are still high among patients with acute coronary syndrome (ACS); moreover, it is clinically difficult to determine precisely which patients will progress satisfactorily. Unstable plaque is characterized by an increased number of activated inflammatory cells, including macrophages and lymphocytes, and an increased release of numerous inflammatory mediators and proteolytic enzymes. Mononuclear cells consist of monocytes/macrophages and lymphocytes and are able to be experimentally isolated. We searched for a specific risk factor for ACS in the peripheral blood mononuclear cells (PBMCs). Methods and results: We examined the expression of 12,625 genes in PBMCs utilizing a gene chip microarray system in ACS patients in acute and chronic stable phases. The gene expression profiles revealed that class A macrophage scavenger receptors (SR-A), among the immune response factors and the receptor activity markers, were the most strongly increased in the acute phase. We examined SR-A gene expression levels of PBMCs using real time RT-PCR in 122 consecutive patients: 32 ACS patients; 41 stable angina patients; and, 49 control subjects. The SR-A gene expression levels of the PBMCs were highest in the ACS patients (p < 0.0001). The occurrence of a reattack of a cardiovascular event was significantly lower in the low SR-A group than in the high SR-A group (p < 0.001). Conclusion: SR-A gene expression level in the PBMCs specifically increases in patients with ACS, and provides a predictive marker for a reattack of a cardiovascular event. © 2007 Elsevier Ireland Ltd. All rights reserved.
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Honda T., Kaikita K., Tsujita K., Hayasaki T., Matsukawa M., Fuchigami S., Sugiyama S., Sakashita N., Ogawa H., Takeya M.
Journal of Molecular and Cellular Cardiology 44 ( 5 ) 915 - 926 2008.5
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Molecular and Cellular Cardiology
Although considerable attention has focused on obesity, insulin resistance and abnormal lipid metabolism as coronary risk factors, it remains unclear how these pathogenic factors affect the inflammatory response after myocardial ischemia-reperfusion. This study was conducted to evaluate whether these metabolic disorders exacerbate myocardial ischemia-reperfusion injury, and to determine if ischemia-reperfusion injury could be modified with the thiazolidinedione, pioglitazone. Experiments were performed in KK-A and C57BL/6J mice subjected to 40 min of ischemia followed by reperfusion. Infiltration of inflammatory cells in ischemic myocardium, and infarct size 3 days after reperfusion were significantly higher in KK-A than C57BL/6J mice (p < 0.05 and p < 0.001, respectively). Furthermore, expression of chemokines, inflammatory cytokines and extracellular matrix proteins in ischemic myocardium was significantly higher in KK-A than C57BL/6J mice 1 day after reperfusion. Pioglitazone treatment of KK-A mice for 14 days significantly reduced the accumulation of inflammatory cells in ischemic myocardium, and infarct size 3 days after reperfusion compared to vehicle treatment (p < 0.05 and p < 0.05, respectively). Pioglitazone also attenuated expression of chemokines, inflammatory cytokines and extracellular matrix proteins in ischemic myocardium 1 day after reperfusion. In vitro experiments demonstrated that tumor necrosis factor-α (TNF-α) was significantly higher in cultured peritoneal macrophages from KK-A than C57BL/6J mice, and pioglitazone significantly reduced TNF-α in macrophages from both types of mice. These findings suggest that metabolic disorders exacerbate ischemia-reperfusion injury as a result of overexpression of inflammatory mediators, and this effect might be improved, in part by the anti-inflammatory effects of pioglitazone. © 2008 Elsevier Inc. All rights reserved. y y y y y
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HDLコレステロールやLDLコレステロールは冠動脈内プラークの体積や組成を反映する.
小島淳, 小島志乃ぶ, 永吉靖央, 海北幸一, 角田等, 杉山正悟, 小川久雄.
超音波医学 35 S256 2008.4
Publishing type：Research paper (scientific journal)
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Fuchigami S., Kaikita K., Soejima K., Matsukawa M., Honda T., Tsujita K., Nagayoshi Y., Kojima S., Nakagaki T., Sugiyama S., Ogawa H.
Thrombosis Research 122 ( 5 ) 618 - 623 2008.2
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Thrombosis Research
Introduction: Increased plasma levels of von Willebrand factor (VWF) have been reported in acute myocardial infarction (AMI). Recently, we showed reduced activity of a VWF-cleaving protease (ADAMTS13) in AMI patients. However, there is no information as to whether ADAMTS13 affects the pathogenesis of unstable angina (UA). Thus, the purpose of this study was to examine changes in plasma VWF and ADAMTS13 levels in UA patients. Materials and methods: Plasma VWF and ADAMTS13 levels (mU/ml) were measured in 45 patients with UA, 55 with stable exertional angina (SEA) and 47 with chest pain syndrome (CPS) at the time of coronary angiography. Levels were also measured in 15 UA patients after 6 months of follow-up. Results: VWF antigen levels (mU/ml) increased significantly in UA patients compared with SEA or CPS (2129.3 ± 739.5, 1571.8 ± 494.2 and 1569.5 ± 487.0, respectively; P < 0.0001 in UA vs. SEA or CPS). ADAMTS13 antigen levels (mU/ml) were significantly lower in UA patients than SEA or CPS (737.3 ± 149.5, 875.3 ± 229.0 and 867.7 ± 195.5, respectively; P < 0.01 in UA vs. SEA or CPS). Furthermore, there was a significant inverse correlation between VWF and ADAMTS13 antigen levels (r = -0.302, P = 0.0002). The antigen levels at 6 months of follow-up were not different compared to the acute phase in the 15 UA patients that had repeated blood sampling. Conclusions: These findings suggest that there is prolonged thrombogenicity in UA patients represented as an imbalance between VWF and ADAMTS13 activity. © 2008 Elsevier Ltd. All rights reserved.
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Soejima H., Irie A., Fukunaga T., Oe Y., Kojima S., Kaikita K., Kawano H., Sugiyama S., Yoshimura M., Kishikawa H., Nishimura Y., Ogawa H.
Circulation Journal 71 ( 12 ) 1879 - 1884 2007.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: T cells in peripheral blood reflect the systemic inflammatory response in patients with heart failure (HF). In a rat model of HF, osteopontin is dramatically increased in the left ventricular myocardium, so the association between osteopontin and HF was examined in the present study. Methods and Results: Peripheral blood was collected from 93 patients with heart disease and 38 controls. Left ventricular ejection fraction (LVEF) was calculated using a modified Simpson's rule. The 93 patients were classified into 3 classes according to the New York Heart Association (NYHA) functional classification. Osteopontin-expressing CD4 T cells were quantified by flow cytometry. Plasma osteopontin levels (ng/ml) and the frequencies of osteopontin-expressing CD4 T cells (%) were higher in patients with HF than in controls (800±554, 575±229, p=0.016 and 27.3±12.2, 16.7±10.0, p<0.001). Furthermore, the plasma osteopontin levels and the frequencies of osteopontin-expressing CD4 T cells increased in proportion to the severity of the NYHA functional class. The frequencies of osteopontin-expressing CD4 T cells were significantly correlated with LVEF (r=-0.336, p=0.0048) and log plasma brain natriuretic peptide levels (r=0.305, p=0.0025). Conclusions: Osteopontin expression of circulating CD4 T cells and plasma osteopontin levels reflect the severity of HF. Osteopontin could be a new target in the assessment of HF. + + + + +
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血液バイオマーカーからのアプローチ
海北幸一、小川久雄
細胞 39 ( 14 ) 590 - 593 2007.12
Authorship：Lead author Publishing type：Research paper (scientific journal)
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Suzuki S., Yoshimura M., Nakayama M., Abe K., Yamamuro M., Nagayoshi Y., Kojima S., Kaikita K., Sugiyama S., Yasue H., Ogawa H.
Pharmacogenetics and Genomics 17 ( 11 ) 919 - 930 2007.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Pharmacogenetics and Genomics
OBJECTIVE: Coronary spasm plays an important role in the pathogenesis of variant angina and also ischemic heart diseases in general, and it is more likely to occur in angiographically normal coronary arteries than in stenotic coronary arteries. We previously found a -786T/C polymorphism in the 5′-flanking region of the endothelial nitric oxide synthase (eNOS) gene and reported that this polymorphism is associated with coronary spasm. We report on an investigation of the genetic factor(s) associated with coronary spasm utilizing a genome-wide case-control study. METHODS AND RESULTS: We recruited 411 consecutive Japanese women (201 with coronary spasm; 210 controls) who were all underwent an acetylcholine provocation test. For single nucleotide polymorphism analysis (SNP), 116 204 SNPs were genotyped for 100 women (50 with coronary spasm; 50 controls) utilizing the Affymetrix GeneChip 100 K Set. Case-control studies were performed with 311 women (151 with coronary spasm; 160 controls) using the 10 lowest permutation P value SNPs from the initial SNP analysis. Finally, we discovered SNP rs10498345, a genetic marker for coronary spasm in Japanese women (Odds ratio=0.43, P=9.48×10). Haplotype analysis showed that haplotype H2, the only haplotype containing the protective A allele at SNP rs10498345, was most strongly associated with coronary spasm (permutation P value <1×10). SNP rs10498345 was strongly associated with the vasoconstrictor response to acetylcholine. Northern blot analysis revealed a novel 4.7 kb RNA transcript, which lacked poly (A), nearby SNP rs10498345. CONCLUSIONS: SNP rs10498345 was strongly associated with coronary spasm in Japanese women utilizing genome-wide SNP analysis. © 2007 Lippincott Williams & Wilkins, Inc.
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Matsukawa M., Kaikita K., Soejima K., Fuchigami S., Nakamura Y., Honda T., Tsujita K., Nagayoshi Y., Kojima S., Shimomura H., Sugiyama S., Fujimoto K., Yoshimura M., Nakagaki T., Ogawa H.
American Journal of Cardiology 100 ( 5 ) 758 - 763 2007.9
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Cardiology
Von Willebrand factor (VWF), a cofactor in platelet adhesion and aggregation, increases hemostasis and thrombosis. Recently, a metalloprotease that cleaves VWF multimers has been identified, namely ADAMTS13. The aim of this study was to investigate the relation between serial changes in plasma VWF and ADAMTS13 and the prognosis after acute myocardial infarction (AMI). We measured serial changes of plasma VWF and ADAMTS13 antigen levels in 92 patients with AMI and 40 control subjects. VWF levels were significantly higher in patients with AMI compared with controls (p <0.01) on admission, peaked 3 days after admission, and remained high for 14 days. In contrast, on admission, ADAMTS13 levels were significantly lower in patients with AMI compared with controls (p <0.0001), with minimum antigen levels reached after 3 days, and remained lower for 14 days. The ratio of VWF/ADAMTS13 antigen levels was higher in patients with AMI compared with controls throughout the time course. Cox hazards analysis revealed that the early increase of VWF and VWF/ADAMTS13 ratio levels and the early decrease of ADAMTS13 levels were significant predictors of future thrombotic events during the 1-year follow-up period. Kaplan-Meier analysis demonstrated that patients with major decreases of ADAMTS13 levels and high increases of VWF/ADAMTS13 levels had significantly greater probabilities for development of thrombotic events (p = 0.0104 and 0.0209, respectively). In conclusion, these findings suggest that monitoring the changes of VWF and ADAMTS13 antigen levels in the early phase might be valuable for predicting and preventing thrombosis during 1-year follow-up in patients with AMI. © 2007 Elsevier Inc. All rights reserved.
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Honda T., Sugiyama S., Sakamoto T., Kaikita K., Ogawa H.
Circulation Journal 71 ( 8 ) 1263 - 1267 2007.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: Patients with hypertrophic cardiomyopathy (HCM) frequently complain of angina-like symptoms in the absence of organic coronary stenoses. Coronary spasm might cause myocardial ischemia in HCM patients. Delta-sarcoglycan plays a crucial role in the pathogenesis of HCM and coronary spasm in a mouse model. Methods and Results: This is a retrospective, single-center study with a small sample size. Seventy patients with HCM underwent coronary angiography and received acetylcholine provocation test. Coronary risk factors and 5′-untranslated region (UTR) G to C polymorphism on delta-sarcoglycan gene (n=64) were evaluated in the HCM patients. In 31 (44.3%) of 70 HCM patients, coronary spasm was induced by the provocation. None of the coronary risk factors was significantly different between the coronary spasm group and the non-coronary spasm group. The 5′-UTR gene polymorphism was associated with the occurrence of coronary spasm with an additive effect on the coexistence (p=0.025). Multiple logistic regression analysis showed that the C allele of 5′-UTR polymorphism was a significant risk factor for coronary spasm in patients with HCM (odds ratio, 3.1; 95% confidence interval, 1.0 to 9.5; p=0.045) that was independent of traditional coronary risk factors. Conclusions: The 5′-UTR polymorphism on delta-sarcoglycan gene was associated with coronary spasm in Japanese patients with HCM.
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Fukunaga T., Soejima H., Irie A., Sugamura K., Oe Y., Tanaka T., Nagayoshi Y., Kaikita K., Sugiyama S., Yoshimura M., Nishimura Y., Ogawa H.
American Journal of Cardiology 100 ( 3 ) 483 - 488 2007.8
Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Cardiology
The percentage of CD4 T cells in blood is correlated with left ventricular dysfunction and decreased ejection fraction in heart disease. The aim of this study was to determine the relation between activation of CD4 T cells and New York Heart Association functional classes in chronic heart failure (HF) and differences in inflammatory activation between ischemic cardiomyopathy (IC) and idiopathic dilated cardiomyopathy (IDC). Blood samples were obtained from 47 patients with HF and 20 controls. Percentages of interferon-γ-positive CD4 T cells (representative type 1 T-helper cells) and interleukin-4-positive CD4 T cells (representative type 2 T-helper cells) were analyzed using 3-color flow cytometry. The proportion of interferon-γ-positive CD4 T cells was higher in patients with HF (28.96 ± 12.90%) than in controls (18.12 ± 5.28, p = 0.0006), but there was no difference in percentage of interleukin-4-positive CD4 T cells between the 2 groups. The proportion of interferon-γ-positive CD4 T cells and plasma B-type natriuretic peptide levels increased with worsening of New York Heart Association functional class in the IC and IDC groups. The proportion of interferon-γ-positive CD4 T cells in the IC group (33.88 ± 13.33%) was higher than in the IDC group (22.33 ± 8.88%, p = 0.002); however, plasma B-type natriuretic peptide levels were higher in the IDC group (358.0 pg/ml, 327.5 to 1,325.7) than in the IC group (82.7 pg/ml, 34.7 to 252.9, p = 0.019). In conclusion, we demonstrated pronounced type 1 T-helper cell activation in patients with HF in proportion to severity of HF and that the specificity of T-cell activation differs between patients with IC and those with IDC. © 2007 Elsevier Inc. All rights reserved. + + + + + + + +
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Tsujita K., Kaikita K., Hayasaki T., Honda T., Kobayashi H., Sakashita N., Suzuki H., Kodama T., Ogawa H., Takeya M.
Circulation 115 ( 14 ) 1904 - 1911 2007.4
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation
BACKGROUND - Class A macrophage scavenger receptor (SR-A) is a macrophage-restricted multifunctional molecule that optimizes the inflammatory response by modulation of the activity of inflammatory cytokines. This study was conducted with SR-A-deficient (SR-A) mice to evaluate the relationship between SR-A and cardiac remodeling after myocardial infarction. METHODS AND RESULTS - Experimental myocardial infarction (MI) was produced by ligation of the left coronary artery in SR-A and wild-type (WT) male mice. The number of mice that died within 4 weeks after MI was significantly greater in SR-A mice than in WT mice (P=0.03). Importantly, death caused by cardiac rupture within 1 week after MI was 31% (17 of 54 mice) in SR-A mice and 12% (6 of 51 mice) in WT mice (P=0.01). In situ zymography demonstrated augmented gelatinolytic activity in the infarcted myocardium in SR-A mice compared with WT mice. Real-time reverse transcription-polymerase chain reaction at day 3 after MI showed that the expression of matrix metalloproteinase-9 mRNA increased significantly in the infarcted myocardium in SR-A mice compared with WT mice. Furthermore, SR-A mice showed augmented expression of tumor necrosis factor-α and reduction of interleukin-10 in the infarcted myocardium at day 3 after MI. In vitro experiments also demonstrated increased tumor necrosis factor-α and decreased interleukin-10 expression in activated SR-A macrophages. CONCLUSIONS - The present findings suggest that SR-A deficiency might cause impairment of infarct remodeling that results in cardiac rupture via insufficient production of interleukin-10 and enhanced expression of tumor necrosis factor-α and of matrix metalloproteinase-9. SR-A might contribute to the prevention of cardiac rupture after MI. © 2007 American Heart Association, Inc.
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Sugamura K., Sugiyama S., Kawano H., Horio E., Ono S., Kojima S., Kaikita K., Sagishima K., Sakamoto T., Yoshimura M., Kinoshita Y., Ogawa H.
Journal of Cardiology 48 ( 6 ) 345 - 352 2006.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
A 20-year-old female survived fulminant myocarditis with 56 hr of non-responsive cardiac arrest and was able to resume a normal life with cardiac resynchronization therapy (CRT). On admission, she had developed cardiogenic shock refractory to pharmacological intervention. Percutaneous cardiopulmonary support was initiated with intraaortic balloon pumping. She developed complete cardiac standstill unresponsive to ventricular pacing. After 56 hr of cardiac arrest, ventricular fibrillation occurred and her ventricle started to respond to pacing therapy. She could leave the intensive care unit, although she continued to have severe heart failure refractory to medical intervention. She presented with paradoxical ventricular motion with a low cardiac output, so CRT was performed. After the initiation of CRT, her heart failure symptoms improved and she could return home.
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Okuma T., Terasaki Y., Sakashita N., Kaikita K., Kobayashi H., Hayasaki T., Kuziel W.A., Baba H., Takeya M.
International Journal of Experimental Pathology 87 ( 6 ) 475 - 483 2006.12
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Experimental Pathology
To clarify the role of the monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2) signalling pathway in hyperoxia-induced acute lung injury, CCR2-deficient (CCR2-/-) and wild-type (CCR2+/+) mice were exposed to 85% O for up to 6 days. At day 3, body weight significantly decreased and total protein concentration in bronchoalveolar lavage fluid (BALF) was higher in CCR2-/- mice compared with CCR2+/+ mice. Cumulative survivals were significantly lower in CCR2-/- mice than in CCR2+/+ mice. However, the two groups showed no significant differences in both histological changes and number of macrophages in BALF. Real-time reverse transcriptase-polymerase chain reaction revealed increased mRNA levels of MCP-1, interleukin-1β thioredoxin-1, and inducible nitric oxide synthase (iNOS) in lung tissues in CCR2-/- mice compared with CCR2+/+ mice. Increased iNOS mRNA levels in alveolar macrophages exposed to 85% O for 48 h in vivo or in vitro were significantly higher in CCR2-/- mice than in CCR2+/+ mice. These results suggest that the MCP-1/CCR2 signalling pathway is protective against hyperoxia-induced tissue injury by suppressing induction of iNOS and consequent production of reactive oxygen species by activated alveolar macrophages. © 2006 Blackwell Publishing Ltd. 2 2
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Reduced von Willebrand factor-cleaving protease (ADAMTS13) activity in acute myocardial infarction Reviewed
Kaikita K＊, Soejima K, Matsukawa M, Nakagaki T, Ogawa H
J Thromb Haemost 4 ( 11 ) 2490 - 2493 2006.8
Authorship：Lead author, Corresponding author Language：English Publishing type：Research paper (scientific journal)
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Long-term efficacy of edaravone in patients with acute myocardial infarction Reviewed
Tsujita K., Shimomura H., Kaikita K., Kawano H., Hokamaki J., Nagayoshi Y., Yamashita T., Fukuda M., Nakamura Y., Sakamoto T., Yoshimura M., Ogawa H.
Circulation Journal 70 ( 7 ) 832 - 837 2006.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: The effect of edaravone, a free radical scavenger, on long-term prognosis and its efficacy with regards to scavenging injurious free radicals in patients with acute myocardial infarction (AMI) was examined. Methods and Results: One hundred and one initial AMI patients were randomly assigned to receive 30 mg edaravone (n=50) or a placebo (n=51) intravenously just before reperfusion. The infarct size, using serum biomarkers and Q-wave formations, and the incidence of reperfusion arrhythmia between the groups were compared. Cardiovascular event-free curves were estimated by using the Kaplan-Meier method. In addition, the serum thioredoxin levels, an oxidative stress marker, to assess the antioxidant effect of edaravone was determined. In all cases, successful reperfusion was obtained within 6h after the onset of symptoms. Infarct size and reperfusion arrhythmia were significantly attenuated in the edaravone group compared with the placebo group (p=0.035 and p=0.031). The cumulative event-free rate was significantly higher in the edaravone group than in the placebo group (p=0.045). Serum thioredoxin levels were significantly lower in the edaravone group than in the placebo group throughout the acute phase. Conclusions: The present study suggests that the edaravone administration just prior to reperfusion might reduce oxidative stress and improve the long-term clinical outcomes of AMI patients.
DOI： 10.1253/circj.70.832
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Hayasaki T., Kaikita K., Okuma T., Yamamoto E., Kuziel W.A., Ogawa H., Takeya M.
Circulation Journal 70 ( 3 ) 342 - 351 2006.3
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: Monocyte chemoattractant protein-1 (MCP-1) and its major receptor, CC chemokine receptor 2 (CCR2), have been shown to contribute to left ventricular remodeling after myocardial infarction. However, it is unknown whether CCR2 deficiency protects the myocardium after myocardial ischemia-reperfusion. The purpose of the present study was to investigate the effects of CCR2 deficiency on myocardial ischemia-reperfusion injury in mice. Methods and Results: Experiments were performed in CCR2 and wild-type mice subjected to 45 min of ischemia followed by reperfusion. Macrophage infiltration in ischemic lesions was markedly reduced in CCR2 mice compared with wild-type mice (p<0.01). The infarct size was significantly reduced in CCR2 mice compared with wild-type mice at 3 days after reperfusion (p<0.001). In situ zymography revealed augmented gelatinolytic activity at 3 days after reperfusion in wild-type mice, but significantly less activity in CCR2 mice. NADPH oxidase activity, the intensity of nitrotyrosine staining and expression of inducible nitric oxide synthase and thioredoxin-1 were significantly increased in ischemic myocardium in wild-type mice compared with CCR2 mice, indicating a role for CCR2 in oxidative stress after ischemia-reperfusion. Conclusions: Inhibition of the MCP-1/CCR2 pathway may be a useful strategy for attenuating myocardial ischemia-reperfusion injury. -/- -/- -/- -/- -/-
DOI： 10.1253/circj.70.342
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Floating coronary artery thrombus prior to the onset of acute myocardial infarction Reviewed
Maruyoshi H., Sugiyama S., Araki S., Kojima S., Hayasaki T., Kaikita K., Fukushima S., Kageshita T., Sakamoto T., Yoshimura M., Ono T., Ogawa H.
Internal Medicine 45 ( 3 ) 173 - 174 2006.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Internal Medicine
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Hypoadiponectinemia is associated with coronary artery spasm in men Reviewed
Maruyoshi H., Kojima S., Otsuka F., Funahashi T., Kaikita K., Sugiyama S., Sakamoto T., Yoshimura M., Shimomura I., Ogawa H.
Circulation Journal 69 ( 9 ) 1154 - 1156 2005.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: The relationship between adiponectin and coronary spastic angina (CSA), both of which are closely involved in coronary endothelial dysfunction, has not been elucidated. Methods and Results: Plasma adiponectin concentrations were examined in 55 men with CSA and 55 with chest pain syndrome (CPS). The plasma log-adiponectin levels were significantly lower in patients with CSA than with CPS (0.61±0.28 vs 0.80±0.21• g•/ml, p<0.0001). The prevalence of smoking was significantly higher in the CSA patients than in those with CPS (50.9% vs 29.1%, p=0.0195). In multiple logistic regression analysis, log-adiponectin (p=0.0008) and smoking (p=0.0210) were independent determinants of CSA. Conclusions: Hypoadiponectinemia is a potential risk factor for CSA in men, independent of smoking.
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Komohara Y., Terasaki Y., Kaikita K., Suzuki H., Kodama T., Takeya M.
Developmental Dynamics 232 ( 1 ) 67 - 74 2005.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Developmental Dynamics
Elimination of apoptotic cells is an important mechanism to maintain proper embryonal morphogenesis. The class A scavenger receptor type I, II (CD204), one of the major receptors expressed on macrophages, is a receptor actively involved in recognition and ingestion of apoptotic cells. To clarify the role of CD204 in embryonic morphogenesis, we performed immunohistochemical and immunoelectron microscopic studies using CD204-deficient mouse embryos. In control mice, almost all macrophages expressed CD204 from embryonic day 9.5 (E9.5). Phagocytes engulfing dead cells in the E13.5 interdigit region showed strong expression of CD204, indicating that CD204 was actively involved in apoptotic cell clearance. However, CD204 is not essential for the embryonic clearance of apoptotic cells, because CD204-deficient embryos developed normally without any retardation in footplate remodeling. Up-regulation of CD36 in CD204-deficient fetal macrophages suggested that CD36 substitutes for CD204 function. We also found that mesenchymal cells frequently engulfed apoptotic cells especially in early embryonal stages. These data suggest that CD204 is partially but not essentially involved in apoptotic cell clearance in embryogenesis. During early embryonal development, mesenchymal cells, rather than macrophages, play a major role in apoptotic cell clearance. © 2004 Wiley-Liss, Inc.
DOI： 10.1002/dvdy.20206
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Okuma T., Terasaki Y., Kaikita K., Kobayashi H., Kuziel W.A., Kawasuji M., Takeya M.
Journal of Pathology 204 ( 5 ) 594 - 604 2004.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Pathology
Macrophage infiltration is implicated in various types of pulmonary fibrosis. One important pathogenetic process associated with pulmonary fibrosis is injury to basement membranes by matrix metalloproteinases (MMPs) that are produced mainly by macrophages. In this study, C-C chemokine receptor 2-deficient (CCR2-/-) mice were used to explore the relationship between macrophage infiltration and MMP activity in the pathogenesis of pulmonary fibrosis, using the bleomycin-induced model of this disease process. CCR2 is the main (if not only) receptor for monocyte chemoattractant protein-1/C-C chemokine ligand 2 (MCP-1/CCL2), which is a critical mediator of macrophage trafficking, and CCR2-/-mice demonstrate defective macrophage migration. Pulmonary fibrosis was induced in CCR2-/- and wild-type (CCR2+/+) mice by intratracheal instillation of bleomycin. No significant differences in the total protein concentration in bronchoalveolar lavage (BAL) fluid, or in the degree of histological lung inflammation, were observed in the two groups until day 7. Between days 3 and 21, however, BAL fluid from CCR2-/- mice contained fewer macrophages than BAL fluid from CCR2+/+ mice. Gelatin zymography of BAL fluid and in situ zymography revealed reduced gelatinolytic activity in CCR2-/-mice. Immunocytochemical staining showed weaker expression of MMP-2 and MMP-9 in macrophages in BAL fluid from CCR2-/- mice at day 3. Gelatin zymography of protein extracted from alveolar macrophages showed reduced gelatinolytic activity of MMP-2 and MMP-9 in CCR2-/- mice. At days 14 and 21, lung remodelling and the hydroxyproline content of lung tissues were significantly reduced in CCR2-/- mice. These results suggest that the CCL2/CCR2 functional pathway is involved in the pathogenesis of bleomycin-induced pulmonary fibrosis and that CCR2 deficiency may improve the outcome of this disease by regulating macrophage infiltration and macrophage-derived MMP-2 and MMP-9 production. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
DOI： 10.1002/path.1667
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Kaikita K., Hayasaki T., Okuma T., Kuziel W.A., Ogawa H., Takeya M.
American Journal of Pathology 165 ( 2 ) 439 - 447 2004.8
Authorship：Lead author, Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Pathology
A key component of cardiac remodeling after acute myocardial infarction (MI) is the inflammatory response, which modulates cardiac tissue repair. The purpose of this study was to investigate the relationship between the monocytic inflammatory response and left ventricular remodeling after MI using mice deficient in CC chemokine receptor 2 (CCR2), the primary receptor for the critical regulator of CC chemokine ligand 2. Immunohistochemical analysis revealed rapid infiltration of macrophages into infarcted tissue within 7 days in wild-type (WT) mice. However, this process was greatly impaired in CCR2-deficient (CCR2 ) mice. Echocardiography demonstrated beneficial effects of CCR2 deficiency on left ventricular remodeling at 7 and 28 days after MI. In situ zymography showed augmented gelatinolytic activity in WT mice within 7 days after MI, whereas gelatinolytic activity was barely detectable in CCR2 mice. Moreover, the distribution of gelatinolytic activity in serial sections was very similar to the distribution of macrophages rather than neutrophils. Expression of matrix metalloproteinases and tumor necrosis factor-α mRNAs was up-regulated in infarcted regions from WT mice compared to CCR2 mice at 3 days after MI. Direct inhibition of CCR2 functional pathway might contribute to the attenuation of left ventricular remodeling after MI. -/- -/- -/-
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Effects of Nicorandil on Endogenous Fibrinolytic Capacity in Patients with Coronary Artery Disease Reviewed
Sakamoto T., Kaikita K., Miyamoto S., Kojima S., Sugiyama S., Yoshimura M., Ogawa H.
Circulation Journal 68 ( 3 ) 232 - 235 2004.3
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: Nicorandil is a hybrid-type anti-anginal drug that combines a KATP channel opener and a nitric oxide donor. Recently the IONA study reported that nicorandil improves the prognosis of patients with stable angina pectoris. Methods and Results: To examine the effects of nicorandil on endogenous fibrinolysis, plasma concentrations of tissue-type plasminogen activator (t-PA) antigen, type-1 plasminogen activator inhibitor (PAI-1) antigen and PAI activity were measured in consecutive 11 patients (7 men and 4 women, mean age 63 years, ranges 41-84 years) with coronary artery disease. Nicorandil (15 mg/day) was administered orally to each patient for 2 weeks. Venous blood samples were obtained from each patient before and after the administration of the drug in the early morning before eating. There were no significant changes in the plasma concentrations of t-PA (12.4±1.9 to 9.8±1.5) or PAI-1 (26.3±3.9 to 21.5±4.9) antigens (ng/ml, mean±SEM) before and after nicorandil administration. On the other hand, the plasma activity of PAI (IU/ml, mean±SEM) decreased significantly after the treatment (12.9±3.2 to 5.6±1.9, p=0.039). Conclusions: It is well known that PAI activity determines the whole fibrinolytic capacity and oral administration of nicorandil decreased PAI activity in patients with coronary artery disease. This finding suggests that nicorandil improves the fibrinolytic capacity and may reduce the risk of coronary thrombus formation in such patients.
DOI： 10.1253/circj.68.232
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Suzuki S., Sugiyama S., Usuku H., Hirai N., Kaikita K., Sakashita N., Sakamoto T., Yoshimura M., Ogawa H.
Internal Medicine 43 ( 3 ) 199 - 203 2004.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Internal Medicine
We report a 67-year-old Japanese man who presented with worsening heart failure with asymptomatically transient ischemic ST-segment depression. Left ventriculography showed diffuse hypokinesis; asymptomatic coronary artery spasm was evoked by the acetylcholine provocation test. Endomyocardial biopsy exhibited hypertrophic cardiomyocytes and scattered microscopic focal myocardial necrosis with amyloid-deposition. Transient ST-segment depression improved after treatment with a calcium antagonist, but cardiac contraction was still impaired. We hypothesize that asymptomatic coronary spasm may cause irreversible cardiac damage and heart failure with amyloid-deposition; the presence or absence of coronary spasm in heart failure patients should be clarified in order to determine therapeutic strategy.
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KAIKITA K
J Mol Cell Cardiol 34 ( 6 ) 617 - 627 2002.6
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)
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KAIKITA K
Circulation 104 ( 7 ) 839 - 844 2001.8
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)
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Soejima H., Ogawa H., Suefuji H., Kaikita K., Takazoe K., Miyamoto S., Kajiwara I., Shimomura H., Sakamoto T., Yoshimura M., Nakamura S.
American Journal of Cardiology 87 ( 12 ) 1408 - 1411 2001.6
Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Cardiology
In conclusion, this study demonstrates that losartan and enalapril improved hypercoagulability in patients with AMI associated with improvement in impaired fibrinolysis.
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Ogawa H., Sakamoto T., Nishiyama K., Soejima H., Kaikita K., Takazoe K., Miyamoto S., Kugiyama K., Yoshimura M., Yasue H.
Japanese Circulation Journal 64 ( 3 ) 170 - 176 2000.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Japanese Circulation Journal
The cell surface expression of intercellular adhesion molecule-1 (ICAM- 1) is upregulated following activation during inflammatory responses, mediating both cell migration and activation. The involvement of inflammation in unstable angina is suggested by the presence of activated circulating leukocytes. To examine whether plasma soluble ICAM-1 (sICAM-1) levels increase in the coronary circulation of patients with coronary organic stenosis and coronary spasm, plasma sICAM-1 levels were measured in the coronary sinus (CS) and the aortic root (Ao) simultaneously in 10 patients with 90% or more coronary narrowing and coronary spasm (coronary spastic angina (CSA) with organic stenosis), in 11 patients with coronary spasm and no significant coronary narrowing (CSA without organic stenosis), in 16 patients with stable exertional angina, and in 13 control subjects. The plasma sICAM-1 levels (ng/ml) in the CS increased in CSA with organic stenosis (230±26) as compared with CSA without organic stenosis (158±14), stable exertional angina (130±9) and control subjects (121±10) (p<0.01). The levels in the Ao also increased in CSA with organic stenosis (208±24) as compared with CSA without organic stenosis (149±13), stable exertional angina (130±11) and control subjects (121±10) (p<0.01). Furthermore, the plasma sICAM-1 levels were higher in the CS than in the Ao only in CSA with organic sterosis. These results suggest that activation of leukocytes occurs through the induction of ICAM-1 in the coronary circulation in the patients with CSA with organic stenosis.
DOI： 10.1253/jcj.64.170
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Difference in fibrinolytic activity between multivessel coronary spasm and one-vessel coronary spasm Reviewed
Ogawa H., Suefuji H., Takazoe K., Soejima H., Sakamoto T., Miyamoto S., Kaikita K., Yoshimura M., Kugiyama K., Yasue H.
American Journal of Cardiology 85 ( 1 ) 98 - 101 2000.1
Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Cardiology
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Increased plasma level of soluble E-selectin in acute myocardial infarction Reviewed
Suefuji H., Ogawa H., Yasue H., Sakamoto T., Miyao Y., Kaikita K., Soejima H., Misumi K., Miyamoto S., Kataoka K.
American Heart Journal 140 ( 2 ) 243 - 248 2000
Language：English Publishing type：Research paper (scientific journal) Publisher：American Heart Journal
Background: E-selectin, also known as endothelial cell leukocyte adhesion molecule-1, is a member of the selectin family of adhesion molecules and is expressed on vascular endothelial cells in inflammatory reactions. The induction of surface E-selectin expression by endothelial cells is considered a marker of activation. Methods and Results: We examined the plasma soluble E-selectin (sE-selectin) level in 41 patients within 6 hours after the onset of acute myocardial infarction (AMI) and in 37 patients with stable exertional angina and 27 control patients. Blood samples were obtained on admission, after reperfusion therapy, and at 4 hours, 8 hours, 12 hours, 24 hours, 48 hours, 3 days, 5 days, 1 week, and 2 weeks after admission in the AMI group. In this group, 21 patients had a history of prodromal unstable angina before infarction and 20 had sudden onset of infarction. The plasma sE-selectin level (ng/mL) on admission was higher in the AMI group than in the stable exertional angina group and control group (38.5 ± 3.1 vs 28.5 ± 1.5, P < .01, 26.0 ± 1.8, P < .01, respectively). In addition, plasma sE-selectin levels were higher in the patients with AMI with prodromal unstable angina than in those with a sudden onset of infarction on admission (44.7 ± 5.4 vs 32.0 ± 2.1, P < .05). The plasma sE-selectin level decreased slowly during the chronic phase both in patients with AMI with prodromal unstable angina (from 44.7 ± 5.4 to 33.8 ± 3.4, P < .01) and those with a sudden onset of infarction (from 32.0 ± 2.1 to 24.9 ± 2.4, P <.01). Conclusions: These results suggest that an increase of sE-selectin may reflect enhanced endothelial cell activation in patients with AMI. The higher sE-selectin level in patients with AMI with prodromal unstable angina may have been associated with repeated episodes of myocardial ischemia and reperfusion.
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Soejima H., Ogawa H., Yasue H., Kaikita K., Takazoe K., Nishiyama K., Misumi K., Miyamoto S., Yoshimura M., Kugiyama K., Nakamura S., Tsuji I.
Journal of the American College of Cardiology 34 ( 4 ) 983 - 988 1999.10
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American College of Cardiology
OBJECTIVES: We investigated the effects of enalapril therapy on plasma tissue factor (TF), tissue factor pathway inhibitor (TFPI) and monocyte chemoattractant protein-1 (MCP-1) levels in patients with acute myocardial infarction. BACKGROUND: Macrophages express TF in human coronary atherosclerotic plaques. Both TF and TFPI are major regulators of coagulation and thrombosis. Monocyte chemoattractant protein-1 is a monocyte and macrophage chemotactic and activating factor. METHODS: In a randomized, double-blind, placebo-controlled study beginning about two weeks after myocardial infarction, 16 patients received four weeks of placebo (placebo group) and another 16 patients received four weeks of enalapril 5 mg daily therapy (enalapril group). We performed blood sampling after administration of the doses. RESULTS: There were no significant differences in the serum angiotensin-converting enzyme (ACE) activity, plasma TF, free TFPI or MCP-1 levels before administration between the enalapril and placebo groups. In the enalapril group, ACE activity (IU/liter) (14.0 before, 5.2 on day 3, 5.8 on day 7, 6.3 on day 28), TF levels (pg/ml) (223, 203, 182, 178) and MCP-1 levels (pg/ml) (919, 789, 790, 803) significantly decreased by day 28. However, the free TFPI levels (ng/ml) (28.2, 26.5, 26.8, 28.4) did not change. These four variables were unchanged during the study period in the placebo group. CONCLUSIONS: This study demonstrated that administration of enalapril reduces the increased procoagulant activity in patients with myocardial infarction associated with inhibition of the activation and accumulation of macrophages and monocytes.
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Takazoe K., Ogawa H., Yasue H., Sakamoto T., Oshima S., Arai H., Moriyama Y., Shimomura H., Hirai N., Kaikita K., Soejima H., Misumi K., Hosoda K.
Thrombosis Research 95 ( 1 ) 37 - 47 1999.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Thrombosis Research
Protein C is one of the most important antithrombotic components. After activation by the thrombin-thrombomodulin complex on endothelial cells, activated protein C (APC) inactivates factors Va and VIIIa, which leads to the inhibition of thrombin formation. We examined the association of plasma levels of APC with the responsiveness to coronary thrombolytic therapy of the infarct-related coronary artery in patients with acute myocardial infarction (AMI). Plasma levels of APC, thrombin-antithrombin III complex (TAT), and plasminogen activator inhibitor (PAI) activity were measured in 32 consecutive AMI patients who underwent coronary angiography followed by thrombolytic therapy, and compared to the measurements in 23 control subjects. On admission, APC levels (ng/mL) were significantly elevated in patients with AMI, as compared with controls (2.5±0.4 vs. 1.2±0.2, 1.3±0.2, respectively, p<0.01). At discharge, plasma levels in AMI patients decline to values not significantly different from those in controls. (1.2±0.2, 1.3±0.2, respectively). TAT levels (ng/mL) were different among the groups in a fashion similar to that of APC (14.1±3.1 on admission vs. 3.3±0.4 at discharge, 1.8±0.1 in the control subjects, respectively, p<0.01). PAI activity levels (IU/mL) were higher on admission than at discharge and higher than the control subjects (19.7±1.8 vs. 10.5±1.0, 5.4±0.7, respectively, p<0.01). Thirty-two patients with AMI were classified into two groups according to the results of thrombolysis: the success group (24 patients) and the failure group (eight patients). APC levels were higher in the failure group than in the success group (5.1±0.7 vs. 1.6±0.2, p<0.01). TAT levels were also higher in the failure group than in the success group (30.8±9.6 vs. 8.6±1.7, p<0.01). PAI activity levels (IU/mL) were lower in the failure group than in the success group (13.5±3.1 vs. 21.7±2.1, p<0.05). There were correlations between APC and TAT levels both on admission (r=0.75, p<0.0001) and at discharge (r=0.71, p<0.0001). Elevated APC was thought to correlate with increased thrombin generation in patients with AMI. This study demonstrated that there was a significant relation between plasma APC level and the responsiveness to thrombolytic therapy of the impact artery. This study may also indicate that increased thrombin generation is a cause of the resistance to thrombolytic therapy.
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Co-localization of tissue factor and tissue factor pathway inhibitor in coronary atherosclerosis Reviewed
Kaikita K., Takeya M., Ogawa H., Suefuji H., Yasue H., Takahashi K.
Journal of Pathology 188 ( 2 ) 180 - 188 1999.6
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Pathology
Tissue factor (TF) initiates the extrinsic pathway of blood coagulation by acting as a cofactor for Factor VII. Inhibition of the Factor VIIa-TF complex is mediated by the tissue factor pathway inhibitor (TFPI), which is a serine protease inhibitor with three Kunitz-type domains. The localization of TF and TFPI protein has been examined immunohistochemically in various atherosclerotic lesions of coronary arteries from 22 autopsy cases and their messenger RNA expression has been confirmed by reverse transcription- polymerase chain reaction. Four types of atherosclerotic lesion (types I, II, III, and IV) were classified according to the method described by Stary et al. TF and TFPI were localized in endothelial cells, macrophages, macrophage- derived foam cells, and smooth muscle cells in the intimal lesions, medial smooth muscle cells, and endothelial cells of the microvessels in the adventitia. Immunohistochemical double staining revealed the co-localization of TF and TFPI in the endothelial cells and macrophages in four types of atherosclerotic lesions. In type III and IV lesions, the number of TF- and TFPI-positive cells was increased, accompanied by extracellular localization of TF and TFPI in the lipid core of atherosclerotic plaques. Fibrin deposition was found around TF- and TFPI-positive macrophages and in the lipid core of atherosclerotic plaques. TF and TFPI messenger RNA were detected more frequently in coronary arteries with type III and IV lesions than in those with type I and II lesions. The co-localization of TF and TFPI was demonstrated in various atherosclerotic lesions of coronary arteries and was shown to be intimately related to fibrin deposition in advanced atherosclerotic plaques. The co-localization of TF and TFPI may thus be closely associated with thrombogenicity in atherosclerotic lesions of coronary arteries.
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Soejima H., Ogawa H., Yasue H., Kaikita K., Nishiyama K., Misumi K., Takazoe K., Miyao Y., Yoshimura M., Kugiyama K., Nakamura S., Tsuji I., Kumeda K.
Circulation 99 ( 22 ) 2908 - 2913 1999.6
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation
Background - This study was designed to evaluate the plasma levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in patients with unstable angina and investigate whether there is a relationship between these levels and unfavorable outcome. Methods and Results - The plasma TF and free TFPI antigen levels were determined in plasma samples taken from 51 patients with unstable angina, 56 with stable exertional angina, and 55 with chest pain syndrome. The plasma TF and free TFPI antigen levels were higher in the unstable angina group than in the stable exertional angina and chest pain syndrome group. There was a good correlation between TF and TFPI. We established borderline as maximum level in the patients with chest pain syndrome. Seven patients (of the 22 in the high TF group) required revascularization to control their unstable angina during in-hospital stay. On the other hand, only 1 of the 29 patients in the low TF group required myocardial revascularization. Four patients of the 14 patients in the high free TFPI group required myocardial revascularization during in-hospital stay, and 4 of the 37 patients in the low free TFPI group required myocardial revascularization. We compared the TF and free TFPI levels between the cardiac event (+) group and cardiac event (-) group. TF levels were significantly higher in the cardiac event (+) group than in the cardiac event (-) group. Conclusions - We have demonstrated that not only the plasma TF levels but also the plasma-free TFPI levels are elevated in patients with unstable angina. Patients with unstable angina and heightened TF and free TFPI are at increased risk for unfavorable outcomes. The heightened TF level was a more important predictor in patients with unstable angina.
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Ogawa H., Yasue H., Miyao Y., Sakamoto T., Soejima H., Nishiyama K., Kaikita K., Suefuji H., Misumi K., Takazoe K., Kugiyama K., Yoshimura M.
American Journal of Cardiology 83 ( 1 ) 38 - 42 1999.1
Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Cardiology
It has been suggested that active inflammation plays an important role in the pathogenesis of acute coronary syndromes, including unstable angina. Intracellular adhesion molecule-1 (ICAM-1) is a major ligand on the endothelial cells for adherence of the activated polymorphonuclear leukocytes. Recently, it has been demonstrated that the soluble form of ICAM- 1 has been detected in human serum and has been increased in many other inflammatory or autoimmune disorders. To evaluate the involvement of ICAM-1 in unstable angina, we examined plasma soluble ICAM-1 (sICAM-I) levels in coronary circulation. The plasma sICAM-1 levels in the coronary sinus and aortic root were simultaneously examined in 20 patients with unstable angina, 19 patients with stable exertional angina, and 16 control subjects. The plasma levels of sICAM-1 were measured by enzyme-linked immunosorbent assay. The mean plasma sICAM-1 levels (nanograms per milliliter) both in the coronary sinus and aortic root were significantly higher (p <0.01) in patients with unstable angina than in those with stable exertional angina and in control subjects (217 ± 14 vs 126 ± 8; 120 ± 10 in the coronary sinus, 202 ± 13 vs 125 ± 9; 123 ± 10 in the aortic root). Furthermore, the mean value was higher in the coronary sinus than in the aortic root in patients with unstable angina. There were no significant differences in the values between in the coronary sinus and aortic root in patients with stable exertional angina and control subjects. Thus, sICAM-1 release is increased, especially in coronary circulation in unstable angina.
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Soejima H., Ogawa H., Yasue H., Nishiyama K., Kaikita K., Misumi K., Takazoe K., Kugiyama K., Tsuji I., Kumeda K., Nakamura S.
Thrombosis Research 93 ( 1 ) 17 - 25 1999.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Thrombosis Research
The hypercoagulability is associated with expression of tissue factor in patients with angina. Tissue factor pathway inhibitor regulates the extrinsic coagulation pathway mediated by tissue factor. Plasma samples were obtained from 14 patients with angina pectoris and 9 with chest pain syndrome before and 5, 30, 60, and 120 minutes after administration of heparin (50 IU/kg). The tissue factor and prothrombin fragment 1+2 levels before administration were elevated in patients with angina pectoris and were reduced to the levels of chest pain syndrome after the administration. The free tissue factor pathway inhibitor levels after the administration were higher in patients with angina pectoris than in patients with chest pain syndrome. Plasma tissue factor pathway inhibitor levels correlated positively with plasma tissue factor and prothrombin fragment 1+2 levels. We showed that plasma-free TFPI levels after administration of heparin, which may indicate endothelial cell associated TFPI levels, increased in patients with angina pectoris compared with patients with chest pain syndrome. Increased endothelial cell associated TFPI was associated with hypercoagulability in patients with angina pectoris. These may help to explain the reduction in thrombotic risk associated with the use of heparin.
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Serial changes in plasma levels of soluble P-selectin in patients with acute myocardial infarction Reviewed
Shimomura H., Ogawa H., Arai H., Moriyama Y., Takazoe K., Hirai N., Kaikita K., Hirashima O., Misumi K., Soejima H., Nishiyama K., Yasue H.
American Journal of Cardiology 81 ( 4 ) 397 - 400 1998.2
Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Cardiology
The present study examines whether an acute inflammatory response occurs during acute myocardial infarction (AMI) by measuring soluble P-selectin levels. We examined plasma soluble P-selectin levels in 16 consecutive patients with AMI, in 15 patients with angina, and in 13 control subjects with chest pain but normal coronary arteries and no coronary spasm. In patients with AMI, blood samples were obtained immediately after admission and at 1, 4, 24, and 48 hours, and 1 week after initiation of reperfusion therapy. The plasma soluble P-selectin levels were significantly higher in the AMI group on admission than in the other 2 groups (83 ± 13 ng/ml, p <0.01). The plasma soluble P-selectin levels at baseline were not significantly different between the angina and control groups (28 ± 4 vs 24 ± 5 ng/ml, p = NS). Plasma soluble P-selectin levels reached their peak significantly at 4 hours after initiation of the reperfusion therapy in patients with AMI. The peak level was significantly higher than the level on admission (115 ± 17 vs 83 ± 13 ng/ml, p <0.05). The plasma soluble P- selectin levels were higher in the AMI group than in the angina and control groups over the time course (p <0.01). Our data indicate that the plasma soluble P-selectin levels are increased in patients with AMI, and that the levels are increases after reperfusion therapy more than before reperfusion. We suggest that the increase in the plasma soluble P-selectin levels may be caused by the activation of endothelial cells and platelets after myocardial ischemia and reperfusion during AMI.
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Moriyama Y., Ogawa H., Oshima S., Takazoe K., Honda Y., Hirashima O., Arai H., Sakamoto T., Sumida H., Suefuji H., Kaikita K., Yasue H.
Japanese Circulation Journal 61 ( 4 ) 308 - 314 1997
Language：English Publishing type：Research paper (scientific journal) Publisher：Japanese Circulation Journal
Recent clinical trials have demonstrated that the administration of angiotensin-converting enzyme (ACE) inhibitors to patients with myocardial infarction reduces the incidence of recurrent myocardial infarction. It has also been reported that an elevated level of plasminogen activator inhibitor (PAI) appears to constitute a marker of the risk of recurrent coronary thrombosis. To determine whether the ACE inhibitor captopril reduces plasma PAI inhibitor activity, we measured changes in plasma PAI activity (IU/ml), tissue plasminogen activator (t-PA) antigen (ng/ml), and serum ACE activity (IU/L) in 14 survivors of myocardial infarction receiving captopril therapy (37.5 mg daily) and compared them with the values in 15 placebo-treated patients chosen at random. Blood sampling was performed at 07.00 h. In the captopril-treated group, serum ACE activity decreased significantly, from 14.0 + 0.8 to 11.5 + 1.2 IU/L 24 h after captopril therapy (p<0.01), and those of PAI activity and t-PA antigen also decreased significantly - from 11.9 + 2.8 to 5.5+2.2 IU/ml (p<0.02) and from 9.9 + 1.0 to 7.5 + 0.9 ng/ml (p<0.05), respectively 48 h after captopril therapy. However, the levels of ACE activity, PAI activity, and t-PA antigen remained unchanged during the study period in the placebo group. Thus, our data indicate that the administration of captopril to patients with acute myocardial infarction may result in a reduced frequency of recurrent coronary thrombosis by increasing fibrinolytic capacity. © 1997, The Japanese Circulation Society. All rights reserved.
DOI： 10.1253/jcj.61.308
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Kaikita K., Ogawa H., Yasue H., Sakamoto T., Miyao Y., Suefuji H., Soejima H., Tayama S., Hayasaki K., Honda T., Kamijikkoku S.
Japanese Circulation Journal 61 ( 9 ) 741 - 748 1997
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Japanese Circulation Journal
Intercellular adhesion molecule-1 (ICAM-1) is a major ligand for 2 members of the CD18 family of leukocyte integrin adhesion molecules and mediates adhesion between leukocytes and stimulated endothelial cells. We examined plasma soluble ICAM-1 (sICAM-1) levels in 30 patients with acute myocardial infarction (AMI) within 6 h of symptom onset, 21 patients with unstable angina (UA), 35 patients with stable exertional angina (SEA) and 21 control subjects. Plasma sICAM-1 levels (ng/ml) were significantly higher in both the acute and chronic phases of AMI and in the UA group than in the SEA and the control groups (195+14, 198+16 in the acute and chronic phases of AMI, 188+11 in the UA group vs 142+7 in the SEA group, 141 + 10 in the control group, p<0.01). Plasma sICAM-1 levels were significantly higher in AMI patients when preceded by unstable angina than when not preceded by unstable angina at any point over the time course except 1 week after admission (p<0.01 vs admission, 12 h, 2 days, 3 days, 5 days, 2 weeks, 3 weeks. P<0.05 vs 24 h). These results suggest that the increase in sICAM-1 is associated with repeated episodes of myocardial ischemia and reperfusion not leading to myocardial necrosis. The increase in sICAM-1 may play an important role as an inflammatory component in the pathogenesis of the ischemic myocardium. © 1997, The Japanese Circulation Society. All rights reserved.
DOI： 10.1253/jcj.61.741
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Increased plasma tissue factor levels in acute myocardial infarction Reviewed
Suefuji H., Ogawa H., Yasue H., Kaikita K., Soejima H., Motoyama T., Mizuno Y., Oshima S., Saito T., Tsuji I., Kumeda K., Kamikubo Y., Nakamura S.
American Heart Journal 134 ( 2 I ) 253 - 259 1997
Language：English Publishing type：Research paper (scientific journal) Publisher：American Heart Journal
Background: Tissue factor (TF) is a low molecular weight glycoprotein that initiates the clotting cascade and is considered to be a major regulator of coagulation, hemostasis and thrombosis Methods and Results: We examined plasma TF levels in 31 consecutive patients with acute myocardial infarction (AMI) (within 6 hours after the onset of symptoms), 27 patients with stable exertional angina, and 27 control subjects. Ten patients with AMI had a history of unstable angina before infarction, and 21 had a sudden onset of infarction. The plasma TF level was higher in the AMI group than in the stable exertional angina and control groups (240 ± 112 vs 184 ± 46 pg/ml [p < 0.05] vs 177 ± 37 pg/ml, p < 0.01, respectively). TF levels were decreased in the chronic phase (2 weeks after admission) compared with the acute phase of infarction (from 240 ± 112 pg/ml to 222 ± 97 pg/ml, p < 0.05). In addition, plasma TF levels were higher in patients with AMI with prodromal unstable angina than in patients with a sudden onset of infarction (300 ± 169 pg/ml vs 212 ± 57 pg/ml, p < 0.05). TF levels were similar in the acute and chronic phases in the patients with AMI with prodromal unstable angina (300 ± 169 pg/ml vs 290 ± 136 pg/ml, p = not significant) but were decreased in the chronic phase in the patients with AMI with sudden onset (from 212 ± 57 pg/ml to 190 ± 49 pg/ml, p < 0.05). Conclusion: Increased plasma TF levels in patients with AMI may reflect enhanced intravascular procoagulant activity. The higher TF levels in patients with AMI with prodromal unstable angina may be associated with repeated episodes of myocardial ischemia and reperfusion.
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Oshima S., Ogawa H., Mizuno Y., Yamashita S., Noda K., Saito T., Sumida H., Suefuji H., Kaikita K., Soejima H., Yasue H.
American Heart Journal 134 ( 5 I ) 961 - 966 1997
Language：English Publishing type：Research paper (scientific journal) Publisher：American Heart Journal
This study sought to determine whether early treatment with angiotensin- converting enzyme (ACE) inhibitors in patients with acute myocardial infarction (AMI) is useful for the improvement of fibrinolytic function, as well as left ventricular function. This study was designed to examine the levers of plasma plasminogen activator inhibitor (PAI) activity and serum ACE activity during the course of 2 weeks in 40 patients with AMI within 12 hours after the onset of the symptom and who randomly received early treatment with either the ACE inhibitor imidapril or a placebo (20 patients in the imidapril group and 20 in me placebo group). The levels of serum ACE activity in the imidapril group decreased significantly (p < 0.01) 8 hours after the administration of imidapril, and the levels 24 hours after administration were significantly lower than those in the placebo group (3.6 ± 0.6 IU/L vs 7.4 ± 0.8 IU/L; p < 0.001). The plasma PAI activity increased gradually to peak levels 16 hours after the administration of imidapril and placebo. The levels in the placebo group decreased gradually but remained high during the study period. On the other hand, the levels of PAI activity in the imidapril group decreased rapidly and those 48 hours after administration were significantly lower than those in the placebo group (7.9 ± 1.9 IU/ml vs 18.4 ± 3.5 IU/ml; p < 0.01). The levels of left ventricular election fraction about 2 weeks after admission were significantly higher in the imidapril group than in the placebo group (65.9% ± 2.5% vs 49.1% ± 4.4%; p < 0.01). This study showed that imidapril, an ACE inhibitor, might be useful for the improvement of fibrinolytic function and left ventricular function in the acute phase of myocardial infarction.
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Tissue factor expression on macrophages in coronary plaques in patients with unstable angina Reviewed
Kaikita K., Ogawa H., Yasue H., Takeya M., Takahashi K., Saito T., Hayasaki K., Horiuchi K., Takizawa A., Kamikubo Y., Nakamura S.
Arteriosclerosis, Thrombosis, and Vascular Biology 17 ( 10 ) 2232 - 2237 1997
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Arteriosclerosis, Thrombosis, and Vascular Biology
Tissue factor is a membrane-bound glycoprotein that functions in the oxtrinsic pathway of blood coagulation by acting as a cofactor for factor VII, and the resulting complex leads to thrombin production in vivo. The purpose of the present study is to determine whether macrophages express tissue factor in human coronary atherosclerotic plaques. We examined directional coronary atherectomy specimens from 24 patients with unstable angina and 23 with stable exertional angina. In these specimens, macrophages were detected in 22 (92%) of 24 patients with unstable angina versus 12 (52%) of 23 with stable exertional angina (P=.003). The percentage of macrophage infiltration area was significantly larger in patients with unstable angina than in those with stable exertional angina (17±3% versus 6±2%, P=.008). The immunohistochemical double staining revealed the expression of tissue factor on macrophages in 18 (75%) of 24 patients with unstable angina versus 3 (13%) of 23 with stable exertional angina (P<.0001). Thrombus was identified in 20 (83%) of 24 patients with unstable angina versus 12 (52%) of 23 with stable exertional angina (P=.02). Fibrin deposition was mainly observed around macrophages expressing tissue factor in the patients with unstable angina. We have shown that tissue factor expression on macrophages was more frequent in coronary atherosclerotic plaques in patients with unstable angina. Tissue factor expressed on macrophages may play an important role in the thrombogenicity in coronary atherosclerotic plaques of these patients.
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Effects of enalapril on tissue factor in patients with uncomplicated acute myocardial infarction Reviewed
Soejima H., Ogawa H., Yasue H., Suefuji H., Kaikita K., Tsuji I., Kumeda K., Aoyama N.
American Journal of Cardiology 78 ( 3 ) 336 - 340 1996.8
Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Cardiology
In a randomized, double-blind, placebo-controlled study beginning 4 weeks after uncomplicated acute myocardial infarction, it was established that the baseline plasma tissue factor antigen level was significantly higher in patients with myocardial infarction than in control subjects, and enalapril therapy significantly reduced the elevated plasma tissue factor antigen level. This may be associated with the reduction in the risk of coronary thrombosis seen with the use of angiotensin-converting enzyme inhibitors.
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Suefuji H., Ogawa H., Yasue H., Imoto N., Sakamoto T., Miyao Y., Kaikita K., Soejima H., Nishiyama K.
Coronary Artery Disease 7 ( 2 ) 167 - 172 1996
Language：English Publishing type：Research paper (scientific journal) Publisher：Coronary Artery Disease
Background: Lipoprotein (a) [Lp(a)] is an independent risk factor for coronary artery disease and niceritrol (a prodrug of nicotinic acid) is known to reduce Lp(a) levels. Patients with coronary artery disease often have impairment of the fibrinolytic system. Methods: To elucidate the effect of niceritrol on fibrinolysis and Lp(a) levels, we examined plasminogen activator inhibitor (PAI) activity, tissue-type plasminogen activator (t-PA) antigen, and serum Lp(a) levels before and after administration of niceritrol to coronary artery disease patients with high baseline Lp(a) levels (≤ 20 mg/dl). Niceritrol was administered to 26 patients for 12 weeks at 750 mg/day. Fasting blood samples were obtained at 0800 h from each patient before treatment, after administration of niceritrol for 12 weeks and 4 weeks after the discontinuation of therapy. Results: There were significant reductions in PAI activity (9.9 ± 1.8 compared with 5.4 ± 1.6 IU/ml, P < 0.01), t-PA antigen levels (10.0 ± 0.5 compared with 8.8 ± 0.6 ng/ml, P < 0.05), and Lp(a) levels (49.3 ± 5.9 compared with 42.5 ± 5.4 mg/dl, P < 0.01) after 12 weeks of niceritrol administration. Four weeks after the discontinuation of niceritrol treatment, all these parameters returned to baseline. Conclusions: This study demonstrated that niceritrol administration decreases PAI activity and t-PA antigen levels together with Lp(a) levels in patients with coronary artery disease. These observations suggest that niceritrol administration may tend to normalize fibrinolysis in such patients.
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Hokimoto S., Yasue H., Fujimoto K., Yamamoto H., Nakao K., Kaikita K., Sakata R., Miyanioto E.
Circulation 94 ( 7 ) 1513 - 1518 1996
Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation
Background: Local ACE in the heart may be important in the pathophysiological state after myocardial infarction (MI). It is unknown, however, whether ACE is expressed in myocytes of the human heart. Methods and Results: Using a newly generated polyclonal antibody to a synthetic peptide corresponding to part of the human endothelial ACE sequence, we examined the localization of ACE in left ventricles of patients (n=10) with MI obtained at left ventricular aneurysmectomy or autopsy and in the hearts of control subjects at autopsy (n=10). The avidin-biotinylated peroxidase complex method was used for the immunohistochemical staining for ACE. In the left ventricles, positively stained myocytes for ACE were found in 8 of the 10 patients with MI. ACE immunoreactivity was seen in the remaining viable myocytes located near the infarct scar of the aneurysmal left ventricle and in nonmyocytes such as fibroblasts, macrophages, vascular smooth muscle cells, and endothelial cells within the scarred tissue. On the other hand, no immunoreactivity for ACE was detected in the ventricular myocytes of all control hearts obtained at autopsy. Conclusions: We observe immunohistochemical staining for ACE in the left ventricular myocytes of the region adjacent to the infarct scar and in nonmyocytes. These results indicate that ACE is markedly increased on the edge of the infarct scar and suggest that local ACE may be important in the ventricular remodeling after MI.
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Soluble P-selectin is released into the coronary circulation after coronary spasm Reviewed
Kaikita K., Ogawa H., Yasue H., Sakamoto T., Suefuji H., Sumida H., Okumura K.
Circulation 92 ( 7 ) 1726 - 1730 1995.10
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Circulation
Background: The glycoprotein P-selectin is an adhesion molecule involved in the property change of leukocytes at the initiation of the inflammatory process. The purpose of the present study was to determine whether acute myocardial ischemia induced by coronary spasm causes an acute inflammatory response in the coronary circulation. Methods and Results: We examined plasma soluble P-selectin levels in the coronary sinus and the aortic root simultaneously in 16 patients with coronary spastic angina before and after left coronary artery spasm induced by intracoronary injection of acetylcholine and in 15 patients with stable exertional angina before and after acute myocardial ischemia induced by rapid atrial pacing. Ten control patients with chest pain but normal coronary arteries and no coronary spasm also received intracoronary acetylcholine. Plasma soluble P-selectin levers were increased significantly in the coronary sinus (32.8 ± 3.6 to 52.8 ± 5.9 ng/mL, P<.001) and in the aortic root (34.6±3.7 to 41.9±4.4 ng/mL, P<.05) after the attacks in the coronary spastic angina group but remained unchanged in the stable exertional angina group after the attacks and in the control group after the administration of acetylcholine. Furthermore, the coronary sinus-arterial difference of soluble P-selectin increased significantly after the attacks in the coronary spastic angina group (1.8 ± 2.2 to 10.9 ± 2.7 ng/mL, P<.001). Conclusions: Our data indicate that soluble P-selectin is released into the coronary circulation after coronary artery spasm. We conclude that coronary artery spasm may induce the leukocyte adhesion in the coronary circulation and may lead to myocardial damage.
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A Case of 5-Fluorouracil Cardiotoxicity Simulating Acute Myocardial Infarction Reviewed
Mizuno Y., Hokamura Y., Kimura T., Kimura Y., Kaikita K., Yasue H.
Japanese Circulation Journal 59 ( 5 ) 303 - 307 1995
Language：English Publishing type：Research paper (scientific journal) Publisher：Japanese Circulation Journal
5-Fluorouracil (5-FU) is widely used in the treatment of various solid tumors. However, 5-FU cardiotoxicity is being reported with increasing frequency. The main symptom of cardiotoxicity is chest pain at rest with ischemic electrocardiographic changes. Up until now, the underlying mechanism has been suspected to be coronary artery spasm. However, this chest pain associated with 5-FU has several characteristics that are incompatible with coronary artery spasm; eg, inefficacy of calcium-channel blocker and a slow increase in cardiac enzyme levels. We experienced a case of 5-FU-induced cardiotoxicity which showed clinical findings consistent with acute myocardial infarction. Based on the clinical findings, coronary angiography, and left ventricular angiography in a prolonged attack, we concluded that the cardiotoxicity in this case was not due to ischemia caused by coronary artery spasm. © 1995, The Japanese Circulation Society. All rights reserved.
DOI： 10.1253/jcj.59.303