Faculty Profiles - MIYOSHI Toru

Papers - MIYOSHI Toru

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Association of serum levels of arachidonic acid and eicosapentaenoic acid with prevalence of major adverse cardiac events after acute myocardial infarction.

Masayuki Ueeda, Takenori Doumei, Yoichi Takaya, Nobuhiko Ohnishi, Atsushi Takaishi, Satoshi Hirohata, Toru Miyoshi, Ryoko Shinohata, Shinichi Usui, Shozo Kusachi

Heart and vessels 26 ( 2 ) 145 - 52 2011.3

Language：English Publishing type：Research paper (scientific journal)

We studied the association of serum levels of arachidonic acid (AA) and eicosapentaenoic acid (EPA) with the prevalence of major adverse cardiac events (MACE) after acute myocardial infarction (AMI). We measured serum AA and EPA on admission in 146 consecutive AMI patients. The primary clinical endpoint was occurrence of MACE, defined as cardiac death, occurrence of heart failure, reinfarction, recurrent angina pectoris, and requirement of coronary intervention. Common logarithmic transformed serum levels of AA (logAA) and EPA (logEPA) were used in the analyses. The optimum cutoff point of each fatty acid used to distribute patients into two groups for Kaplan-Meier analysis was determined by receiver operating characteristic curves analysis. MACE occurred in 40 patients (27.4%). Kaplan-Meier analysis disclosed that the group with a logAA above the cutoff point [145.3 μg/mL (logAA 2.162)] showed a higher prevalence of MACE than those with a logAA below the cutoff point (P < 0.01). Conversely, the prevalence of MACE was significantly higher in the group with a logEPA below the cutoff point [52.3 μg/mL (logEPA 1.719)] compared to the group with a logEPA above it (P < 0.01). Similar to logAA, logAA/logEPA showed significant differences in the MACE-free curve between the two groups (cutoff 1.301, P < 0.001). Cox proportional hazards regression analysis suggested that logAA, logEPA, and logAA/logEPA were independently associated with the prevalence of MACE. Although the present study included a limited number of patients with single-time point measurement, the results suggested an association of logAA, logEPA, and logAA/logEPA with the prevalence of MACE after AMI. The present study warrants further studies involving a large number of patients to confirm that the serum levels of these fatty acids and their ratios are predictors of MACE after AMI.

DOI： 10.1007/s00380-010-0038-8

AHR, a novel acute hypoxia-response sequence, drives reporter gene expression under hypoxia in vitro and in vivo. International journal

Mehmet Zeynel Cilek, Satoshi Hirohata, Omer Faruk Hatipoglu, Hiroko Ogawa, Toru Miyoshi, Junko Inagaki, Takashi Ohtsuki, Hiroshi Harada, Shigeshi Kamikawa, Shozo Kusachi, Yoshifumi Ninomiya

Cell biology international 35 ( 1 ) 1 - 8 2011.1

Language：English Publishing type：Research paper (scientific journal)

ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) is an early immediate gene. We have previously reported that ADAMTS1 was strongly induced by hypoxia. In this study, we investigated whether ADAMTS1 promoter-driven reporter signal is detectable by acute hypoxia. We constructed the GFP (green fluorescent protein) expression vector [AHR (acute hypoxia-response sequence)-GFP] under the control of ADAMTS1 promoter and compared it with the constitutive GFP-expressing vector under the control of CMV (cytomegalovirus promoter-GFP). We transduced AHR-GFP and examined whether GFP signals can be detected under the acute hypoxia. When the human umbilical vein [HUVEC (human umbilical vein endothelial cells)] was transduced under normoxia, there were few GFP signals, while CMV-GFP showed considerable GFP signals. When HUVEC was stimulated with hypoxia, GFP signals from AHR-GFP gene were induced under hypoxic conditions. Notably, the GFP signals peaked at 3 h under hypoxia. In ischaemic hind limb model, transduced AHR-GFP showed hypoxic induction of GFP signals. In summary, we have demonstrated that the AHR system induced the reporter gene expression by acute hypoxia, and its induction is transient. This is the first report showing the unique acute hypoxia-activated gene expression system.

DOI： 10.1042/CBI20100290

Circulating KCNH2 current-activating factor in patients with heart failure and ventricular tachyarrhythmia. International journal

Hiroki Sugiyama, Kazufumi Nakamura, Hiroshi Morita, Satoshi Akagi, Yoshinori Tani, Yusuke Katayama, Nobuhiro Nishii, Toru Miyoshi, Satoshi Nagase, Kunihisa Kohno, Kengo Fukushima Kusano, Tohru Ohe, Junko Kurokawa, Tetsushi Furukawa, Hiroshi Ito

PloS one 6 ( 5 ) e19897 2011

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: It is estimated that approximately half of the deaths in patients with HF are sudden and that the most likely causes of sudden death are lethal ventricular tachyarrhythmias such as ventricular tachycardia (VT) or fibrillation (VF). However, the precise mechanism of ventricular tachyarrhythmias remains unknown. The KCNH2 channel conducting the delayed rectifier K(+) current (I(Kr)) is recognized as the most susceptible channel in acquired long QT syndrome. Recent findings have revealed that not only suppression but also enhancement of I(Kr) increase vulnerability to major arrhythmic events, as seen in short QT syndrome. Therefore, we investigated the existence of a circulating KCNH2 current-modifying factor in patients with HF. METHODOLOGY/PRINCIPAL FINDINGS: We examined the effects of serum of HF patients on recombinant I(Kr) recorded from HEK 293 cells stably expressing KCNH2 by using the whole-cell patch-clamp technique. Study subjects were 14 patients with non-ischemic HF and 6 normal controls. Seven patients had a history of documented ventricular tachyarrhythmias (VT: 7 and VF: 1). Overnight treatment with 2% serum obtained from HF patients with ventricular arrhythmia resulted in a significant enhancement in the peaks of I(Kr) tail currents compared to the serum from normal controls and HF patients without ventricular arrhythmia. CONCLUSIONS/SIGNIFICANCE: Here we provide the first evidence for the presence of a circulating KCNH2 channel activator in patients with HF and ventricular tachyarrhythmias. This factor may be responsible for arhythmogenesis in patients with HF.

DOI： 10.1371/journal.pone.0019897

Identification of Soat1 as a quantitative trait locus gene on mouse chromosome 1 contributing to hyperlipidemia. International journal

Zongji Lu, Zuobiao Yuan, Toru Miyoshi, Qian Wang, Zhiguang Su, Catherine C Chang, Weibin Shi

PloS one 6 ( 10 ) e25344 2011

Language：English Publishing type：Research paper (scientific journal)

We previously identified two closely linked quantitative trait loci (QTL) on distal chromosome 1 contributing to major variations in plasma cholesterol and triglyceride levels in an intercross derived from C57BL/6 (B6) and C3H/HeJ (C3H) apolipoprotein E-deficient (apoE(-/-)) mice. Soat1, encoding sterol o-acyltransferase 1, is a functional candidate gene located underneath the proximal linkage peak. We sequenced the coding region of Soat1 and identified four single nucleotide polymorphisms (SNPs) between B6 and C3H mice. Two of the SNPs resulted in amino-acid substitutions (Ile147Val and His205Tyr). Functional assay revealed an increased enzyme activity of Soat1 in peritoneal macrophages of C3H mice relative to those of B6 mice despite comparable protein expression levels. Allelic variants of Soat1 were associated with variations in plasma cholesterol and triglyceride levels in an intercross between B6.apoE(-/-) and C3H.apoE(-/-) mice. Inheritance of the C3H allele resulted in significantly higher plasma lipid levels than inheritance of the B6 allele. Soat1 variants were also significantly linked to major variations in plasma esterified cholesterol levels but not with free cholesterol levels. Trangenic expression of C3H Soat1 in B6.apoE(-/-) mice resulted in elevations of plasma cholesterol and triglyceride levels. These results indicate that Soat1 is a QTL gene contributing to hyperlipidemia.

DOI： 10.1371/journal.pone.0025344

Fragmented QRS is associated with torsades de pointes in patients with acquired long QT syndrome. International journal

Kayo Haraoka, Hiroshi Morita, Yukihiro Saito, Norihisa Toh, Toru Miyoshi, Nobuhiro Nishii, Satoshi Nagase, Kazufumi Nakamura, Kunihisa Kohno, Kengo F Kusano, Kenji Kawaguchi, Tohru Ohe, Hiroshi Ito

Heart rhythm 7 ( 12 ) 1808 - 14 2010.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Acquired long QT syndrome (LQTS) is a disease due to a secondary repolarization abnormality induced by various predisposing factors. In contrast to congenital LQTS, risk factors that produce acquired LQTS include organic heart diseases that often exhibit depolarization abnormality. Although various repolarization parameters have been evaluated in acquired LQTS, the existence of depolarization abnormality in association with torsades de pointes (TdP) has not been reported. OBJECTIVE: The purpose of this study was to evaluate both repolarization (QT components) and depolarization parameters (fragmented QRS [fQRS]) in acquired LQTS patients with markedly prolonged QT interval. METHODS: Seventy patients with acquired severe QT prolongation (QTc ≥ 550 ms) were studied. Thirty-two patients had syncope or TdP (syncope group). Thirty-eight patients did not have any symptoms (asymptomatic group). The existence of fQRS and QT components (QT, QTc, Tpe [interval between peak and end of T wave] intervals, and U-wave voltage) was analyzed. RESULTS: The syncope group had more frequent fQRS (81%) than did the asymptomatic group (21%, P < .01) and the incidence of fQRS was not different before and after removal of predisposing factors. The incidence of organic heart disease was not different between the two groups. No differences in QTc interval were noted between the syncope and asymptomatic groups, although the syncope group had longer QT and Tpe intervals and higher U wave than the asymptomatic group (P < .01). CONCLUSION: Acquired predisposing factors promoted repolarization abnormality (especially prolongation of QT and Tpe intervals), and the existence of fQRS had an important role in the development of TdP in patients with acquired LQTS.

DOI： 10.1016/j.hrthm.2010.09.008

Connective tissue growth factor induction in a pressure-overloaded heart ameliorated by the angiotensin II type 1 receptor blocker olmesartan. International journal

Mutsumi Iwamoto, Satoshi Hirohata, Hiroko Ogawa, Takashi Ohtsuki, Ryoko Shinohata, Toru Miyoshi, Faruk O Hatipoglu, Shozo Kusachi, Kazuhide Yamamoto, Yoshifumi Ninomiya

Hypertension research : official journal of the Japanese Society of Hypertension 33 ( 12 ) 1305 - 11 2010.12

Language：English Publishing type：Research paper (scientific journal)

Connective tissue growth factor (CTGF) is a secreted protein that regulates fibrosis. We hypothesized that CTGF is induced in a pressure-overloaded (PO) heart and that blocking the angiotensin II type 1 receptor would reduce CTGF expression. Accordingly, we administered olmesartan and compared its effects with other antihypertensive drugs in a PO heart. CTGF induction was determined in a rat PO model, and olmesartan, hydralazine or saline was continuously administered. The effects of olmesartan on CTGF induction, myocyte hypertrophy and fibrosis were evaluated. The effect of olmesartan on cardiac function was also examined in CTGF- and transforming growth factor-beta 1 (TGF-β1)-infused rats. CTGF was increased in the PO heart 3 days after aortic banding and was markedly distributed around the perivascular fibrotic area. After 28 days, blood pressure was not significantly different in the olmesartan and hydralazine groups, but olmesartan treatment reduced CTGF distribution in PO hearts. Olmesartan was associated with a significantly reduced myocyte hypertrophy index (4.77±0.48 for olmesartan and 6.05±1.45 for saline, P<0.01), fibrosis area (32.0±15.5% compared with the saline group, P<0.05) and serum TGF-β1 level (62.6±10.6 ng ml⁻¹ for olmesartan and 84.4±7.2 ng ml⁻¹ for hydralazine, P<0.05). In addition, cardiac function was significantly preserved in the olmesartan group compared with the saline group. Finally, olmesartan ameliorated the cardiac dysfunction in CTGF- and TGF-β1-infused rats. Olmesartan attenuated CTGF induction, reduced perivascular fibrosis and ameliorated cardiac dysfunction in a PO heart. Our results provide insight into the beneficial effects of olmesartan on PO hearts, independent of blood-pressure lowering.

DOI： 10.1038/hr.2010.189

Significant relationship between changes in brachial-ankle pulse wave velocity relative to blood pressure elevation and coronary artery disease. International journal

Issei Komatsubara, Shinichi Inoue, Rie Koumoto, Shigeru Matano, Tomoki Kitawaki, Satoshi Hirohata, Toru Miyoshi, Hiroko Ogawa, Ryoko Shinohata, Shozo Kusachi

Coronary artery disease 21 ( 7 ) 407 - 13 2010.11

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: Based on well-established physiological theories, we studied correlations between changes in brachial-ankle pulse wave velocity (baPWV) relative to blood pressure (BP) elevation (elasticity of large-to-medium-sized arteries), and coronary artery disease (CAD). METHODS: The baPWV (in centimeters/second) and BP (in millimeters of mercury) were determined in 101 patients before, during, and/or after a cold pressor test using a volume-plethysmographic system. RESULTS: Significantly higher rates of increase in PWV relative to changes in BP were observed in the CAD(+) group than in the CAD(-) group when mean BP [median (25th-75th percentiles): 14.8 (8.3-24.9) vs. 8.6 (5.7-11.4) cm/s/mmHg, P<0.0001], and systolic [10.1 (6.0-17.5) vs. 6.4 (4.4-10.6) cm/s/mmHg, P=0.0023] and diastolic BP [21.0 (14.0-34.4) vs. 10.8 (6.8-16.1) cm/s/mmHg, P<0.0001] were used as BP indices. Similarly, the rates of increase in baPWV showed a significant correlation with the extent of CAD. The rate of increase in baPWV obtained using the mean, systolic and diastolic BP as indices showed an area under the receiver operating characteristic curve of 0.68-0.76, sensitivity of 65-75%, and specificity of 65-75% for the detection of CAD. The area under the receiver operating characteristic curve, sensitivity, and specificity for the rate of increase were slightly higher than those for baseline baPWV and baseline baPWV/baseline BP ratio, but not to a significant degree. CONCLUSION: The rate of increase in baPWV relative to BP elevation determined by cold pressor test is significantly and moderately correlated with CAD. To identify patients with CAD, the rate of increase in baPWV relative to changes in BP can provide considerable, but limited, information.

DOI： 10.1097/MCA.0b013e32833e1c19

Serum Adipocyte Fatty Acid-Binding Protein is Associated With Coronary Lesion Complexity in Patients With Coronary Artery Disease

Masayuki Doi, Toru Miyoshi, Mutsumi Iwamoto, Kunio Nogami, Kajiya Masashi, Ko Takeda, Satoshi Hirohata, Shozo Kusachi, Hiroshi Ito

CIRCULATION 122 ( 21 ) 2010.11

Remote ischemic preconditioning(RIPC)により血管弛緩反応が惹起される

圓光賢希, 中村一文, 柚木佳, 杜徳尚, 三好亨, 西井伸洋, 永瀬聡, 河野晋久, 森田宏, 草野研吾, 伊藤浩, 寒川睦子

日本心臓病学会誌 5 ( Suppl.I ) 257 - 257 2010.8

Serum adipocyte fatty acid-binding protein is independently associated with coronary atherosclerotic burden measured by intravascular ultrasound. International journal

Toru Miyoshi, Go Onoue, Atsushi Hirohata, Satoshi Hirohata, Shinichi Usui, Kazuyoshi Hina, Hiroshi Kawamura, Masayuki Doi, Kengo Fukushima Kusano, Shozo Kusachi, Yoshifumi Ninomiya

Atherosclerosis 211 ( 1 ) 164 - 9 2010.7

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: Adipocyte fatty acid-binding protein (A-FABP) has been shown to have an effect on insulin resistance, lipid metabolism, and atherosclerosis in animals. We therefore investigated the association between the serum A-FABP level and coronary atherosclerosis. METHODS: One hundred twenty-five consecutive patients with coronary artery disease (CAD) were enrolled after coronary angiography. Plaque volume in non-culprit coronary arteries was determined using intravascular ultrasound and expressed as percent plaque volume (%PV). Voluntary blood donors (n=120), matched for age and gender, served as controls. Serum levels of A-FABP, adiponectin, and inflammatory markers were measured by enzyme-linked immunosorbent assay. RESULTS: The serum A-FABP level in CAD patients was significantly higher than in control subjects (median [25th-75th percentiles], 27.2 [20.5-37.1] ng/mL vs. 18.9 [14.6-24.5] ng/mL) (p<0.01). Serum A-FABP showed 0.74 of the area under the curve in the receiver operating characteristic curve for the detection of CAD, with 76% specificity and 65% sensitivity with a cut-off value of 20.1 ng/mL. Further, in CAD patients, serum A-FABP had a significant correlation with %PV in all subjects (r=0.33, p<0.01). Serum A-FABP was positively correlated with the body mass index, serum interleukin-6 and high-sensitive CRP, and negatively correlated with HDL-cholesterol and serum adiponectin in CAD patients. Stepwise regression analysis revealed that serum A-FABP was independently associated with %PV. CONCLUSION: Increased serum A-FABP was significantly associated with a greater coronary plaque burden. Our findings revealed that the measurement of serum A-FABP could be utilized for the evaluation of the extent of coronary atherosclerosis.

DOI： 10.1016/j.atherosclerosis.2010.01.032

Combination therapy of calcium channel blocker and angiotensin II receptor blocker reduces augmentation index in hypertensive patients. International journal

Masayuki Doi, Toru Miyoshi, Satoshi Hirohata, Shigeshi Kamikawa, Shinichi Usui, Youko Kaji, Kosuke Sakane, Hiroko Ogawa, Yoshifumi Ninomiya, Shozo Kusachi

The American journal of the medical sciences 339 ( 5 ) 433 - 9 2010.5

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: The optimal combination treatment for hypertension has not been established. We investigated the effect of a calcium channel blocker or a diuretic added to angiotensin II receptor blockers (ARBs) on the augmentation index (AI), as a marker of arterial stiffness and wave reflection, in hypertensive patients. METHODS: Thirty-seven patients treated with ARBs were randomly allocated to either of the 2 groups receiving an ARB plus azelnidipine (AZ group) or trichlormethiazide (TCM group). Changes in brachial blood pressure (BP), AI, high-sensitive C-reactive protein (hsCRP), and serum asymmetric dimethylarginine, as an endogenous nitric oxide synthase inhibitor, were determined. RESULTS: Systolic and diastolic blood pressure after 6 months were significantly reduced in both the groups similarly; however, after adjustment for baseline covariates, the extent of the reduction in AI (%) in the AZ group was significantly greater than in the TCM group (between-group difference was 3.2; 95%CI: 0.2-6.3; P = 0.03). The reduction of high-sensitive C-reactive protein (mg/L) and serum asymmetric dimethylarginine (micromol/L) was significantly greater in the AZ group than in the TCM group (between-group difference was 0.18 and 0.05; 95%CI: -0.01 to 0.36 and -0.01 to 0.11; P = 0.04 and 0.02, respectively). Further, when patients were analyzed according to age younger than 60 years or older than 60 years, the reduction in AI in the AZ group aged older than 60 years was significantly greater than in the TCM group. CONCLUSION: The results suggest that azelnidipine has a more beneficial effect on vascular properties in combination therapy with ARB than trichlormethiazide.

DOI： 10.1097/MAJ.0b013e3181d658c4

Type IV collagen induces expression of thrombospondin-1 that is mediated by integrin alpha1beta1 in astrocytes. International journal

Tomoko Yonezawa, Shunji Hattori, Junko Inagaki, Masae Kurosaki, Tomoyuki Takigawa, Satoshi Hirohata, Toru Miyoshi, Yoshifumi Ninomiya

Glia 58 ( 7 ) 755 - 67 2010.5

Language：English Publishing type：Research paper (scientific journal)

Following brain injury, thrombospondin-1 (TSP-1) is involved in angiogenesis and synaptic recovery. In this study, we used a cold injury-model and found that TSP-1 mRNA was markedly upregulated after brain injury. Immunohistochemistry showed that TSP-1 was upregulated in both the core of the lesion and in the perilesional area of injured brain tissue. Numerous astrocytes immunopositive for glial fibrillary acidic protein (GFAP) were found in the perilesional area, and TSP-1 was also expressed in almost all astrocytes surrounding blood vessels at 4 days after injury. Next, we examined the influence of vascular basement membrane components on TSP-1 expression. When astrocytes were cultured on type IV collagen, TSP-1 was significantly upregulated compared with the expression when cells were grown on laminin, fibronectin, or poly-L-lysine. This increase occurred exclusively when astrocytes were grown on the native form of type IV collagen but not on the heat-denatured form or the non-collagenous 1 domain. Further, integrin alpha1 and beta1 mRNAs were upregulated concomitantly with GFAP mRNA, and integrin alpha1 protein was localized to the endfeet of astrocytes that surrounded blood vessels in the injured brain. Using function-blocking antibodies, we found that the effect of type IV collagen was attributed to integrin alpha1beta1 in primary astrocytes. Collectively, our results suggest that vascular basement membrane components substantially impact gene expression in astrocytes during brain tissue repair.

DOI： 10.1002/glia.20959

Cardio-ankle vascular index is independently associated with the severity of coronary atherosclerosis and left ventricular function in patients with ischemic heart disease.

Toru Miyoshi, Masayuki Doi, Satoshi Hirohata, Kosuke Sakane, Shigeshi Kamikawa, Tomoki Kitawaki, Youko Kaji, Kengo Fukushima Kusano, Yoshifumi Ninomiya, Shozo Kusachi

Journal of atherosclerosis and thrombosis 17 ( 3 ) 249 - 58 2010.3

Language：English Publishing type：Research paper (scientific journal)

AIM: The cardio-ankle vascular index (CAVI) has been proposed as a new noninvasive marker of arterial stiffness independent of blood pressure. We investigated the association of the CAVI with coronary atherosclerosis and left ventricular (LV) systolic and diastolic function in patients with ischemic heart disease (IHD). METHODS: A total of 206 consecutive subjects undergoing coronary angiography were enrolled. CAVI measurement and echocardiography were performed simultaneously. Patients having significant coronary stenosis were classified into the IHD group. RESULTS: CAVI in the IHD group (n=133) was significantly higher than in the non-IHD group(n=73)(9.1+/-1.3 vs. 8.7+/-1.2, p=0.02). In all IHD patients, CAVI was negatively correlated with LV ejection fraction (LVEF)(r=-0.31, p<0.01), LV mass index (r=0.24, p<0.01) and angiographic scores of coronary atherosclerosis. Stepwise regression analysis revealed that CAVI was independently associated with LVEF, along with a history of myocardial infarction, LV mass index, and left atrial diameter in all IHD patients (p<0.01). In the sub-analysis of IHD patients with preserved LVEF, CAVI was correlated with echocardiographic parameters regarding LV diastolic function. Multivariate analysis demonstrated that the increased CAVI was significantly associated with LV diastolic dysfunction in patients with preserved LVEF. CONCLUSION: CAVI, a new parameter of aortic stiffness, was independently associated with LV systolic and diastolic function as well as coronary artery disease in IHD patients.

Impact of olmesartan on progression of coronary atherosclerosis a serial volumetric intravascular ultrasound analysis from the OLIVUS (impact of OLmesarten on progression of coronary atherosclerosis: evaluation by intravascular ultrasound) trial. International journal

Atsushi Hirohata, Keizo Yamamoto, Toru Miyoshi, Kunihiko Hatanaka, Satoshi Hirohata, Hitoshi Yamawaki, Issei Komatsubara, Masaaki Murakami, Eiki Hirose, Shinji Sato, Keisuke Ohkawa, Makoto Ishizawa, Hirosuke Yamaji, Hiroshi Kawamura, Shozo Kusachi, Takashi Murakami, Kazuyoshi Hina, Tohru Ohe

Journal of the American College of Cardiology 55 ( 10 ) 976 - 82 2010.3

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: The aim of this study was to evaluate the impact of olmesartan on progression of coronary atherosclerosis. BACKGROUND: Prior intravascular ultrasound (IVUS) trial results suggest slowing of coronary atheroma progression with some medicines but have not shown convincing evidence of regression with angiotension-II receptor blocking agents. METHODS: A prospective, randomized, multicenter trial-OLIVUS (Impact of OLmesartan on progression of coronary atherosclerosis: evaluation by IntraVascular UltraSound)-was performed in 247 stable angina pectoris patients with native coronary artery disease. When these patients underwent percutaneous coronary intervention for culprit lesions, IVUS was performed in their nonculprit vessels (without angiographically documented coronary stenosis [<50%]). Patients were randomly assigned to receive 10 to 40 mg of olmesartan or control and treated with a combination of beta-blockers, calcium channel blockers, diuretics, nitrates, glycemic control agents, and/or statins per physician's guidance. Serial IVUS examinations (baseline and 14-month follow-up) were performed to assess coronary atheroma volume. Volumetric IVUS analyses included lumen, plaque, vessel volume, percent atheroma volume (PAV), percent change in total atheroma volume (TAV) and PAV. RESULTS: Patient characteristics and blood pressure control were identical between the 2 groups. However, follow-up IVUS showed significantly decreased TAV and percent change in PAV in the olmesartan group (5.4% vs. 0.6 % for TAV and 3.1% vs. -0.7% for percent change in PAV, control vs. olmesartan, p < 0.05 for all). CONCLUSIONS: These observations suggest a positive role in a potentially lower rate of coronary atheroma progression through the administration of olmesartan, an angiotension-II receptor blocking agent, for patients with stable angina pectoris.

DOI： 10.1016/j.jacc.2009.09.062

Effect of cilnidipine on normal to marginally elevated urine albumin-creatinine ratio in asymptomatic non-diabetic hypertensive patients: an exponential decay curve analysis. International journal

Takaaki Nakatsu, Shinji Toyonaga, Keiichi Mashima, Yoko Yuki, Aya Nishitani, Hiroko Ogawa, Toru Miyoshi, Satoshi Hirohata, Reishi Izumi, Shozo Kusachi

Clinical drug investigation 30 ( 10 ) 699 - 706 2010

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: High-normal urinary albumin excretion has been reported to have clinical significance with respect to progression of proteinuria and hypertension. OBJECTIVE: We analysed the effect of cilnidipine (10 mg/day) on morning systolic blood pressure (SBP) and urine albumin-creatinine ratio (UACR) in 16 non-diabetic hypertensive patients with a normal to marginally elevated UACR (mean +/- SD 29.4 +/- 21.7; range 7.5-72.9 mg/g creatinine). METHODS: Sequential home BP and UACR data were fitted to a simple exponential function as follows: where y is SBP (mmHg) or UACR (mg/g creatinine); alpha is the extent of the SBP (mmHg)- or UACR (mg/g creatinine)-lowering effect; beta (days) is the time-constant for SBP or UACR decrease; t is the number of days after the start of cilnidipine administration; and gamma is the finally stabilized SBP (mmHg) or UACR (mg/g creatinine). RESULTS: Mean +/- SD morning SBP and UACR decreased by 20.4 +/- 11.4 mmHg and 15.2 +/- 13.1 mg/g creatinine, respectively, as determined by coefficient alpha. The mean +/- SD time-constant for UACR decrease was significantly longer than that for BP decrease (43.5 +/- 22.9 vs 15.4 +/- 7.1 days). UACR reduction correlated with pre-treatment UACR values (correlation coefficient [R] = 0.88, p < 0.01) but not with BP decrease. CONCLUSIONS: The present study demonstrated that cilnidipine reduced UACR in hypertensive patients with normal to marginally elevated UACR independent of its BP-lowering effect.

DOI： 10.2165/11538510-000000000-00000

ADAMTS-1 is an Endothelial Cell-specific Hypoxia-inducible Gene

Satoshi Hirohata, Faruk O. Hatipoglu, Toru Miyoshi, Hiroko Ogawa, Masanari Obika, Shigeshi Kamikawa, Shozo Kusachi, Hiroshi Itoh, Yoshifumi Ninomiya

CIRCULATION 120 ( 18 ) S1172 - S1172 2009.11

A Novel Cationic Protein Reduced Infracted Size and Protected Myocytes From Oxidative Stress Through Modification of Akt Signaling

Shigeshi Kamikawa, Satoshi Hirohata, Syougo Watanabe, Takashi Ohtsuki, Toru Miyoshi, Hiroko Ogawa, Shozo Kusachi, Masaharu Senoo, Yoshifumi Ninomiya, Hiroshi Itoh

CIRCULATION 120 ( 18 ) S888 - S889 2009.11

Association of Increased Plasma Adipocyte Fatty Acid-binding Protein With Coronary Artery Disease in Men

Shunichi Higashiya, Masayuki Doi, Kunio Nogami, Mutsumi Iwamoto, Akihisa Yumoto, Kou Takeda, Masayuki Ueeda, Toru Miyoshi, Satoshi Hirohata, Shozo Kusachi, Yoshifumi Ninomiya, Hiroshi Ito

CIRCULATION 120 ( 18 ) S397 - S398 2009.11

Augmentation index is associated with B-type natriuretic peptide in patients with paroxysmal atrial fibrillation. International journal

Youko Kaji, Toru Miyoshi, Masayuki Doi, Satoshi Hirohata, Shigeshi Kamikawa, Kosuke Sakane, Tomoki Kitawaki, Shozo Kusachi, Kengo Fukushima Kusano, Hiroshi Ito

Hypertension research : official journal of the Japanese Society of Hypertension 32 ( 7 ) 611 - 6 2009.7

Language：English Publishing type：Research paper (scientific journal)

B-type natriuretic peptide (BNP) levels have been shown to be elevated in patients with paroxysmal atrial fibrillation (PAF); however, the underlying mechanisms have not been fully elucidated. Earlier, we reported that an increase in the augmentation index (AI), which is an index of wave reflection and arterial stiffness, is associated with PAF. In this study, we investigate the relationship between the BNP level and AI in patients with PAF. We enrolled 92 patients with a history of PAF and 90 age- and gender-matched individuals without PAF. AI was calculated using applanation tonometry of the radial artery when all patients were on sinus rhythm. Plasma BNP levels were measured simultaneously. An arterial stiffness parameter, the cardio-ankle vascular index (CAVI), was also evaluated. The increased AI in patients with PAF correlated with the elevation of the BNP level (r=0.47, P<0.01). When PAF patients were classified into tertiles on the basis of the BNP level, the left atrial volume index, left ventricular mass index, AI and CAVI increased, and mitral annular e' velocity (e'), as an index of left ventricular diastolic pressure, decreased with BNP tertiles. AI was also associated with e' and left ventricular mass index. Multiple regression analysis showed that the AI in PAF patients independently correlated with BNP levels. This study showed that AI was an independent correlate of the BNP level in PAF patients. Left ventricular diastolic dysfunction, which linked to an increase in arterial stiffness, may be involved in the elevated BNP level.

DOI： 10.1038/hr.2009.62

ADAMTS1 is a unique hypoxic early response gene expressed by endothelial cells. International journal

Omer F Hatipoglu, Satoshi Hirohata, M Zeynel Cilek, Hiroko Ogawa, Toru Miyoshi, Masanari Obika, Kadir Demircan, Ryoko Shinohata, Shozo Kusachi, Yoshifumi Ninomiya

The Journal of biological chemistry 284 ( 24 ) 16325 - 16333 2009.6

Language：English Publishing type：Research paper (scientific journal)

ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) is a member of the matrix metalloproteinase family. We have previously reported that ADAMTS1 was strongly expressed in myocardial infarction. In this study, we investigated whether hypoxia induced ADAMTS1 and investigated its regulatory mechanism. In hypoxia, the expression level of ADAMTS1 mRNA and protein rapidly increased in endothelial cells, but not in other cell types. Interestingly, the induction of ADAMTS1 by hypoxia was transient, whereas vascular endothelial growth factor induction by hypoxia in human umbilical vein endothelial cells (HUVEC) increased in a time-dependent manner. CoCl2, a transition metal that mimics hypoxia, induced ADAMTS1 in HUVEC. The phosphatidylinositol 3-kinase inhibitor LY294002 dose-dependently inhibited the increase of ADAMTS1 mRNA expression in hypoxia. We characterized the promoter region of ADAMTS1, and the secreted luciferase assay system demonstrated that hypoxia induced luciferase secretion in the culture medium 4.6-fold in HUVEC. In the promoter region of ADAMTS1, we found at least three putative hypoxia-inducible factor (HIF) binding sites, and the chromatin immunoprecipitation assay revealed HIF-1 binding to HIF binding sites in the promoter region of ADAMTS1 under hypoxia. Recombinant ADAMTS1 protein promoted the migration of HUVEC under hypoxic conditions. In summary, we found that ADAMTS1 is transiently induced by hypoxia in endothelial cells, and its transcription is mediated by HIF-1 binding. Our data indicate that ADAMTS1 is a novel acute hypoxia-inducible gene.

DOI： 10.1074/jbc.M109.001313

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