Papers - KAIKITA Koichi
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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.