Papers - KAIKITA Koichi
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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)