Publications (14)98.14 Total impact
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Article: Plasma Cyclophilin A Is a Novel Biomarker for Coronary Artery Disease.
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ABSTRACT: Background: Oxidative stress induces secretion of cyclophilin A (CyPA) from vascular smooth muscle cells and it plays a crucial role in the pathogenesis of atherosclerosis in mice. Therefore, we tested our hypothesis that plasma CyPA levels are increased in patients with coronary artery diseases (CAD). Methods and Results: In 320 consecutive patients undergoing coronary angiography, we examined the relationship between plasma CyPA levels and the severity of CAD. We measured plasma CyPA by an immunoassay based on the sandwich technique. Plasma CyPA levels were significantly higher in patients with significant coronary stenosis compared to those without it (P<0.001). A positive correlation was noted between plasma CyPA levels and significant coronary stenosis. The average number of stenotic coronary arteries and the need for coronary intervention were significantly increased in the quartiles of higher CyPA levels (both P<0.001). Indeed, the plasma CyPA level significantly correlated with the presence of CAD (adjusted odds ratio for CAD, 6.20; 95% confidence interval, 3.14-12.27; P<0.001). Interestingly, plasma levels of CyPA increased according to the number of atherosclerotic risk factors, all of which induce oxidative stress. Furthermore, plasma levels of CyPA significantly reduced after medical treatment of risk factors. Finally, CyPA was strongly expressed in coronary atherosclerotic plaque in patients with myocardial infarction. Conclusions: Plasma CyPA level is a novel biomarker for oxidative stress and CAD in humans.Circulation Journal 11/2012; · 3.77 Impact Factor -
Article: Enhanced Rho-Kinase Activity in Patients With Vasospastic Angina After the Great East Japan Earthquake.
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ABSTRACT: Background: It remains unclear whether disease activity of vasospastic angina (VSA) is altered during a disaster. Methods and Results: Before and after the Great East Japan Earthquake, we examined Rho-kinase activity in circulating neutrophils of 11 VSA patients and their mental stress with the post-traumatic stress disorder (PTSD) questionnaire. Rho-kinase activity was significantly increased at 6 months after the Earthquake, and was returned to baseline level at 12 months. Importantly, percent change in Rho-kinase activity was significantly correlated with the PTSD score. Conclusions: These results indicate that the Rho-kinase activity of VSA patients was transiently enhanced associated with disaster-related mental stress.Circulation Journal 11/2012; · 3.77 Impact Factor -
Article: Involvement of rho-kinase activation in the pathogenesis of coronary hyperconstricting responses induced by drug-eluting stents in patients with coronary artery disease.
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ABSTRACT: Background: Activation of Rho-kinase plays a central role in the pathogenesis of drug-eluting stents (DES)-induced coronary hyperconstricting responses in pigs in vivo has been previously demonstrated. In the present study, Rho-kinase activation involved in those responses in patients with coronary artery disease (CAD) is examined. Methods and Results: In 24 patients with CAD who underwent coronary intervention with either DES or bare-metal stents (BMS), coronary vasomotor responses to intracoronary acetylcholine (ACh) before and after intracoronary pre-treatment with a Rho-kinase inhibitor, fasudil was examined. Coronary vasomotor responses by quantitative coronary angiography (QCA) and coronary vascular structure by optical coherence tomography (OCT) was evaluated. QCA showed that the coronary vasoconstricting responses to ACh were significantly enhanced in the DES group compared with the BMS group both at the proximal and the distal segments adjacent to the stents (proximal: BMS -13.0±10.7% vs. DES -25.4±14.3%, P=0.036; distal: BMS -24.4±12.2% vs. DES -43.8±14.7%, P=0.003). Importantly, fasudil markedly attenuated the enhanced vasoconstricting responses to ACh in the DES group (proximal 10.2±11.7%, distal 14.4±10.5% vs. before fasudil, both P<0.01). In the OCT imaging analysis, there was no significant correlation between intimal thickness and coronary vasoconstriction to ACh. Conclusions: These results indicate that Rho-kinase activation is substantially involved in the pathogenesis of the DES-induced coronary hyperconstricting responses in patients with CAD, suggesting the therapeutic importance of Rho-kinase pathway. (Circ J 2012; 76: 2552-2560).Circulation Journal 07/2012; 76(11):2552-60. · 3.77 Impact Factor -
Article: Urbanization, life style changes and the incidence/in-hospital mortality of acute myocardial infarction in Japan: report from the MIYAGI-AMI Registry Study.
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ABSTRACT: It remains to be examined whether urbanization and lifestyle changes are associated with the incidence and mortality from acute myocardial infarction (AMI) in Japan. A total of 19,921 AMI patients (male/female 14,290/5,631) registered by the MIYAGI-AMI Registry Study from 1988 to 2009 were divided into 2 groups according to their residences; inside (urban area, n=7,316) and outside (rural area, n=11,402) of Sendai City. From 1988 to 2009, the incidence of AMI (/100,000 persons/year) increased more rapidly in the rural area (24.2 to 51.4) than in the urban area (31.3 to 40.8) (P<0.001), with rapid aging in both areas. Moreover, from 1998 to 2009, the age-adjusted incidence of AMI in young (<44 years) and middle-aged (45-64 years) male patients (both P<0.05) in the rural area increased significantly, along with a markedly increased prevalence of dyslipidemia (P<0.001). Although in-hospital mortality from AMI decreased in both areas over the last 20 years (both P<0.001), it remained relatively higher in female than in male patients and was associated with higher age of the onset, longer elapsing time for admission and lower prevalence of primary coronary intervention in female patients in both areas. These results demonstrate that urbanization and lifestyle changes have been associated with the incidence and mortality from AMI, although sex differences still remain to be improved.Circulation Journal 02/2012; 76(5):1136-44. · 3.77 Impact Factor -
Article: Enhanced Rho-kinase activity in circulating neutrophils of patients with vasospastic angina: a possible biomarker for diagnosis and disease activity assessment.
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ABSTRACT: The aim of this study was to examine whether Rho-kinase activity is systemically enhanced in patients with vasospastic angina (VSA) and, if so, whether a noninvasive diagnostic method could be developed to improve practice. The activated Rho-kinase pathway plays a central role in the molecular mechanism of coronary vasospasm in animal models and patients with VSA. Recently, it has been reported that Rho-kinase activity in circulating leukocytes is associated with various diseases. Fifty-three consecutive patients with chest pain who underwent acetylcholine provocation testing for coronary spasm were examined. Patients were divided into 2 groups depending on their response to the test: VSA (n = 33) and non-VSA (n = 20) groups. Venous blood samples were collected to measure Rho-kinase activity in circulating neutrophils, determined by the extent of phosphorylation of myosin-binding subunit (MBS), a substrate of Rho-kinase. Rho-kinase activity was significantly higher in the VSA group than in the non-VSA group (phosphorylated MBS/total MBS ratio 1.33 ± 0.37 vs. 0.95 ± 0.22, p < 0.001). In the VSA group, no correlation was noted between Rho-kinase activity and high-sensitivity C-reactive protein, smoking, or accumulated number of coronary risk factors. After the 3-month medical treatment, Rho-kinase activity in the VSA group was significantly decreased to 1.08 ± 0.31 (p < 0.001). On receiver-operating characteristic curve analysis, a phosphorylated MBS ratio of 1.18 was identified as the best cutoff level to predict the diagnosis of VSA. These results indicate that Rho-kinase activity in circulating neutrophils is enhanced in patients with VSA and may be a useful biomarker for diagnosis and disease activity assessment of the vasospastic disorder.Journal of the American College of Cardiology 09/2011; 58(12):1231-7. · 14.16 Impact Factor -
Article: Long-term treatment with eicosapentaenoic acid ameliorates myocardial ischemia-reperfusion injury in pigs in vivo. -Involvement of Rho-kinase pathway inhibition-.
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ABSTRACT: Eicosapentaenoic acid (EPA), the major n-3 fatty acid in fish oil, exerts cardioprotective effects against ischemic heart disease; however, the detailed mechanisms remain to be elucidated. Rho-kinase plays an important role in the pathogenesis of cardiovascular diseases including ischemia-reperfusion (I/R) injury. Thus, the hypothesis that long-term EPA treatment ameliorates myocardial I/R injury through Rho-kinase pathway inhibition in pigs in vivo was investigated. Male pigs were treated with either a control chow or EPA (600·mg·kg⁻¹·day⁻¹) for 3 weeks (n=8 each) and were subjected to myocardial ischemia by 90-min occlusion of the left circumflex coronary artery and subsequent 60-min reperfusion. The EPA group had an increased EPA level in red blood cells (4.4 ± 0.3mol%). The EPA treatment significantly ameliorated myocardial I/R injury, including regional wall motion abnormality (EPA 5.3 ± 3.6 vs. control 35.1 ± 3.8 unit, P<0.0001), left ventricular ejection fraction (EPA 43 ± 9% vs. control 32 ± 7%, P<0.05), occurrence of ventricular arrhythmias (EPA 181 ± 73 vs. control 389 ± 51 events, P<0.0001) and histological accumulation of inflammatory cells (P<0.01). Importantly, the EPA treatment significantly inhibited myocardial Rho-kinase activity (assessed by the extent of the myosin-binding subunit phosphorylation) (EPA 0.47 ± 0.11 vs. control 0.77 ± 0.14, P<0.05) and preserved myocardial eNOS activity (EPA 0.56 ± 0.13 vs. control 0.23 ± 0.07, P<0.01) with a significant correlation noted between them. Long-term treatment with EPA ameliorates I/R injury partly through Rho-kinase pathway inhibition in vivo.Circulation Journal 05/2011; 75(8):1843-51. · 3.77 Impact Factor -
Article: Eicosapentaenoic acid reduces ischemic ventricular fibrillation via altering monophasic action potential in pigs.
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ABSTRACT: Although high intake of n-3 fatty acids is associated with reduced mortality of patients with ischemic heart disease, especially reduction in sudden cardiac death (SCD), the detailed mechanisms remain to be elucidated. Thus, the present study was designed to examine whether long-term treatment with eicosapentaenoic acid (EPA), a major component of n-3 fatty acids, reduces ischemia-induced ventricular fibrillation (VF) in pigs in vivo, and if so, what molecular mechanisms are involved. Male pigs were treated with either a control chow (control group) or a control chow plus EPA (600 mg/kg/day, PO, EPA group) for 3 weeks and were subjected to myocardial ischemia for 90 min (n=8 each) with measurement of the monophasic action potential (MAP), as a marker of ventricular electrophysiological activities. The EPA treatment significantly attenuated the occurrence of VF (control 5.1±1.7 vs. EPA 1.5±0.8 times/animal, P<0.05) and markedly reduced the mortality (control 50% vs. EPA 0%, P<0.05), with the attenuation of MAP duration shortening during ischemia (control -28.1±3.0% vs. EPA -18.2±1.4%, P<0.05). These beneficial effects of EPA were abolished by pre-treatment with cromakalim, a K(ATP) channel opener (0.3 μg/kg/min, IC). Furthermore, EPA significantly inhibited the mRNA and protein expression of Kir6.2, a major component of sarcolemmal K(ATP) channels, in both the ischemic region and non-ischemic regions. These results indicate that long-term treatment with EPA reduces ischemia-induced VF and SCD in pigs in vivo, for which attenuation of MAP duration shortening may be involved.Journal of Molecular and Cellular Cardiology 05/2011; 51(3):329-36. · 5.17 Impact Factor -
Article: Long-term treatment with nifedipine suppresses coronary hyperconstricting responses and inflammatory changes induced by paclitaxel-eluting stent in pigs in vivo: possible involvement of Rho-kinase pathway.
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ABSTRACT: Accumulating evidence indicates that coronary vasoconstricting responses are enhanced at the edges of coronary segment implanted with a drug-eluting stent (DES) compared with a bare-metal stent (BMS) in humans. We have recently demonstrated that Rho-kinase pathway plays an important role in DES-induced coronary hyperconstricting responses associated with inflammatory changes in pigs in vivo. This study examined whether long-term treatment with calcium channel blocker suppresses DES-induced coronary hyperconstricting responses in pigs in vivo. Paclitaxel-eluting stent (PES) and a BMS were randomly implanted in the left coronary arteries in male domestic pigs with and without long-acting nifedipine (NIF, 4 mg/kg/day) for 4 weeks (n = 7 each). Coronary vasomotion was evaluated by quantitative coronary angiography at least 24 h after withdrawal of NIF to avoid its direct effects on coronary vasomotion. In the control group (without NIF), coronary vasoconstricting responses to serotonin (10 and 100 µg/kg, i.c.) were significantly enhanced at the PES site compared with the BMS site (P = 0.009), which were abolished by hydroxyfasudil (90 and 300 µg/kg, i.c.), a selective Rho-kinase inhibitor. The PES-induced vasoconstricting responses were significantly inhibited in the NIF group (P = 0.019). Histological examination showed that inflammatory cell accumulation and microthrombus formation were enhanced at the PES site compared with the BMS site (P < 0.05), both of which were significantly suppressed by NIF associated with reduced Rho-kinase expression and activity (P < 0.05). These results indicate that long-term treatment with NIF suppresses PES-induced coronary abnormalities partly through Rho-kinase pathway inhibition in vivo.European Heart Journal 05/2011; 33(6):791-9. · 10.48 Impact Factor -
Article: OX40 ligand plays an important role in the development of atherosclerosis through vasa vasorum neovascularization.
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ABSTRACT: Atherosclerosis is characterized by infiltration of inflammatory cells and enhanced vasa vasorum formation, for which immunological mechanisms may be involved. OX40, a membrane-bound molecule of the tumour necrosis factor-receptor superfamily, is expressed by activated T-cells, while OX40 ligand (OX40L) is expressed in activated macrophages and endothelial cells. In this study, we thus examined whether the OX40/OX40L system is involved in the pathogenesis of atherosclerosis. We examined apolipoprotein E-deficient (ApoE(-/-)) mice and ApoE(-/-)/OX40L-double-deficient (ApoE(-/-)/OX40L(-/-)) mice fed on a high-fat diet for 8 weeks. The extent of aortic atheroma was significantly less in ApoE(-/-)/OX40L(-/-) mice compared with ApoE(-/-) mice. We also treated high-fat-fed ApoE(-/-) mice with or without MGP34 antibody (OX40L-specific neutralizing antibody) for 10 weeks. After the treatment, the extent of aortic atheroma was again significantly less in MGP34-treated mice compared with controls. Importantly, both vascular density in the aortic adventitia and vascular endothelial growth factor-induced angiogenesis in the Matrigel assay in vivo were significantly reduced in ApoE(-/-)/OX40L(-/-) mice compared with ApoE(-/-) mice. Finally, when high-fat-fed ApoE(-/-) mice were transplanted with bone marrow cells from either wild-type or OX40L(-/-) mice, the extent of aortic atheroma was comparable between the two groups. These results indicate that the vascular OX40/OX40L system plays an important role in the formation of vasa vasorum and subsequent atherosclerosis, suggesting that the vascular OX40/OX40L system might be a new therapeutic target of atherosclerosis.Cardiovascular research 12/2010; 88(3):539-46. · 5.80 Impact Factor -
Article: Cardiac shock wave therapy ameliorates left ventricular remodeling after myocardial ischemia-reperfusion injury in pigs in vivo.
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ABSTRACT: Left ventricular (LV) remodeling after acute myocardial infarction (AMI) is associated with a poor prognosis and an impaired quality of life. We have shown earlier that low-energy extracorporeal cardiac shock wave (SW) therapy improves chronic myocardial ischemia in pigs and humans and also ameliorates LV remodeling in a pig model of AMI induced by permanent coronary ligation. However, in the current clinical setting, most of the patients with AMI receive reperfusion therapy. Thus, in this study we examined whether our SW therapy also ameliorates LV remodeling after myocardial ischemia-reperfusion (I/R) injury in pigs in vivo. Pigs were subjected to a 90-min ischemia and reperfusion using a balloon catheter and were randomly assigned to two groups with or without SW therapy to the ischemic border zone (0.09 mJ/mm(2), 200 pulses/spot, 9 spots/animal, three times in the first week) (n = 15 each). Four weeks after I/R, compared with the control group, the SW group showed significantly ameliorated LV remodeling in terms of LV enlargement (131 +/- 9 vs. 100 +/- 7 ml), reduced LV ejection fraction (28 +/- 2 vs. 36 +/- 3%), and elevated left ventricular end-diastolic pressure (11 +/- 2 vs. 4 +/- 1 mmHg) (all P <0.05, n = 8 each). The SW group also showed significantly increased regional myocardial blood flow (-0.06 +/- 0.11 vs. 0.36 +/- 0.13 ml/min/g, P < 0.05), capillary density (1.233 +/- 31 vs. 1.560 +/- 60/mm(2), P < 0.001), and endothelial nitric oxide synthase activity (0.24 +/- 0.03 vs. 0.41 +/- 0.05, P < 0.05) in the ischemic border zone compared with the control group (n = 7 each). These results indicate that our SW therapy is also effective in ameliorating LV remodeling after myocardial I/R injury in pigs in vivo.Coronary artery disease 08/2010; 21(5):304-11. · 1.56 Impact Factor -
Article: Double-blind and placebo-controlled study of the effectiveness and safety of extracorporeal cardiac shock wave therapy for severe angina pectoris.
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ABSTRACT: Low-energy shock wave (SW) therapy has improved myocardial ischemia in both a porcine model and in patients with severe angina pectoris. To further confirm the effectiveness and safety of SW therapy, 8 patients with severe angina pectoris were treated with SW therapy in a double-blind, placebo-controlled and cross-over manner. SW therapy, but not placebo, significantly improved chest pain symptoms and cardiac function without any complications or adverse effects. Extracorporeal cardiac SW therapy is an effective, safe and non-invasive therapeutic option for severe angina pectoris.Circulation Journal 03/2010; 74(3):589-91. · 3.77 Impact Factor -
Article: Role of Rho-kinase in the pathogenesis of coronary hyperconstricting responses induced by drug-eluting stents in pigs in vivo.
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ABSTRACT: This study examined whether the Rho-kinase pathway is involved in the pathogenesis of coronary hyperconstricting responses induced by drug-eluting stents (DES) in pigs in vivo. Recent studies showed that coronary vasoconstricting responses are enhanced at the edge of coronary segments implanted with DES compared with bare-metal stents (BMS) in humans. We have previously shown that the activated Rho-kinase pathway plays a central role in the molecular mechanism of coronary vasospasm in animals and humans. Human coronary artery smooth muscle cells (hCASMCs) were coincubated with various concentrations of paclitaxel (10(-9) to 10(-6) mol/l, corresponding levels reported in DES-implanted arterial tissue) for 24 h. A paclitaxel-eluting stent (PES), sirolimus-eluting stent (SES), and BMS were randomly implanted in the left coronary arteries in pigs for 4 weeks. In hCASMCs, paclitaxel significantly enhanced Rho-kinase expression and activity. In a porcine model, coronary vasoconstricting responses to serotonin (10 and 100 microg/kg intracoronary administration) were significantly enhanced at the PES site compared with the BMS site (45+/-4% vs. 30+/-3%; p<0.01; n=12 each), and were abolished by hydroxyfasudil (90 and 300 microg/kg intracoronary administration), a selective Rho-kinase inhibitor. The PES enhanced inflammatory responses and microthrombus formation at the stent edge, where immunoreactivities for Rho-kinase expression and activity were increased. In organ chamber experiments, serotonin-induced contractions were significantly enhanced in rings from the PES edge site compared with the BMS edge site. The SES also caused similar coronary hyperconstricting responses to serotonin in vivo. These results suggest that the Rho-kinase pathway plays an important role in the pathogenesis of DES-induced coronary hyperconstricting responses.Journal of the American College of Cardiology 12/2009; 54(24):2321-9. · 14.16 Impact Factor -
Article: Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice.
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ABSTRACT: We have recently demonstrated that endogenous erythropoietin (Epo)/Epo receptor (EpoR) system plays an important protective role in hypoxia-induced pulmonary hypertension. However, it remains to be examined whether vascular EpoR system contributes to angiogenesis in response to ischemia. We examined angiogenesis in EpoR(-/-)-rescued mice that lack EpoR in most organs including cardiovascular system except erythroid-lineage cells. Two weeks after femoral artery ligation, blood flow recovery, activation of VEGF/VEGF receptor system, and mobilization of endothelial progenitor cells were all impaired in EpoR(-/-)-rescued mice as compared with wild-type (WT) mice. Bone marrow (BM) transplantation with WT-BM cells in EpoR(-/-)-rescued mice partially but significantly improved blood flow recovery after hindlimb ischemia. The extent of VEGF upregulation and the number of BM-derived cells in ischemic tissue were significantly less in EpoR(-/-)-rescued mice compared with WT mice even after BM reconstitution with WT-BM cells. Similarly, the recovery of blood flow was significantly impaired in recipient EpoR(-/-)-rescued mice that had been transplanted with WT-BM or EpoR(-/-)-rescued-BM as compared with recipient WT mice. Furthermore, the Matrigel implantation assay and aortic ring assay showed that microvessel growth in vitro was significantly reduced in EpoR(-/-)-rescued mice as compared with WT mice. These results indicate that vascular EpoR system also plays an important role in angiogenesis in response to hindlimb ischemia through upregulation of VEGF/VEGF receptor system, both directly by enhancing neovascularization and indirectly by recruiting endothelial progenitor cells and BM-derived proangiogenic cells.Circulation Research 04/2007; 100(5):662-9. · 9.49 Impact Factor -
Article: Important role of endogenous erythropoietin system in recruitment of endothelial progenitor cells in hypoxia-induced pulmonary hypertension in mice.
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ABSTRACT: Recent studies have suggested that endogenous erythropoietin (Epo) plays an important role in the mobilization of bone marrow-derived endothelial progenitor cells (EPCs). However, it remains to be elucidated whether the Epo system exerts protective effects on pulmonary hypertension (PH), a fatal disorder encountered in cardiovascular medicine. A mouse model of hypoxia-induced PH was used for study. We evaluated right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in mice lacking the Epo receptor (EpoR) in nonerythroid lineages (EpoR(-/-) rescued mice) after 3 weeks of exposure to hypoxia. Those mice lack EpoR in the cardiovascular system but not in the hematopoietic system. The development of PH and pulmonary vascular remodeling were accelerated in EpoR(-/-) rescued mice compared with wild-type mice. The mobilization of EPCs and their recruitment to the pulmonary endothelium were significantly impaired in EpoR(-/-) rescued mice. By contrast, reconstitution of the bone marrow with wild-type bone marrow cells ameliorated PH in the EpoR(-/-) rescued mice. Hypoxia enhanced the expression of EpoR on pulmonary endothelial cells in wild-type but not EpoR(-/-) rescued mice. Finally, hypoxia activated endothelial nitric oxide synthase in the lungs in wild-type mice but not in EpoR(-/-) rescued mice. These results indicate that the endogenous Epo/EpoR system plays an important role in the recruitment of EPCs and prevents the development of PH during chronic hypoxia in mice in vivo, suggesting the therapeutic importance of the system for the treatment of PH.Circulation 04/2006; 113(11):1442-50. · 14.74 Impact Factor
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2006–2007
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Tohoku University
- Department of Cardiovascular Medicine
Sendai, Kagoshima-ken, Japan
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