Faculty Profiles - MIYOSHI Toru

Papers - MIYOSHI Toru

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One of six patients with non-ischemic heart disease exhibit provoked coronary spasms: non-ischemic heart disease associated with ischemia?

Shozo Sueda, Toru Miyoshi, Yasuhiro Sasaki, Tomoki Sakaue, Hirokazu Habara, Hiroaki Kohno

Internal medicine (Tokyo, Japan) 54 ( 3 ) 281 - 6 2015

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

OBJECTIVE: The majority of cardiologists do not perform spasm provocation tests in patients with non-ischemic heart disease (non-IHD) or non-obstructive coronary artery disease (non-ob-CAD). We herein examined the frequency of provoked spasms in non-IHD and non-ob-CAD patients, including those with atypical chest pain (Aty), valvular heart disease (Val), hypertrophic cardiomyopathy (HCM), congestive heart failure (CHF), and others (Oth). METHODS & RESULTS: We performed acetylcholine (ACh) spasm provocation tests over a period of 22 years (1991-2012) among 1,440 patients, including 981 IHD and 459 non-IHD subjects. A total of 43 patients with significant organic stenosis were excluded, and the remaining 416 patients with non-IHD or non-ob-CAD disease were assessed. ACh was injected in incremental doses of 20/50/80 μg into the right coronary artery (RCA) and 20/50/100/(200) μg into the left coronary artery (LCA). Positive coronary spasms were defined as transient luminal narrowing of >99%. Positive coronary spasms were noted in 17.3% of the non-IHDs patients (72/416), compared to 11.4% (15/132), 19% (8/42), 16.7% (5/30), 23.9% (16/67), and 19.3% (28/145), in the patients in the Aty, Val, HCM, CHF, and Oth groups, respectively. The rate of positive provoked spasms was higher in men than women, although not significantly [20.6% (46/223) vs. 13.4% (26/193), ns], and significantly higher in the late period (2001-2012) than in the early period (1991-2000) (36.8% vs. 7.0%, p<0.001). CONCLUSION: Physicians should perform spasm provocation tests in patients with IHD as well as non-IHD with non-ob-CAD, as one of six non-IHD patients in this study exhibited provoked coronary spasms.

DOI： 10.2169/internalmedicine.54.2660

Aortic vascular graft infection caused by Cardiobacterium valvarum: a case report. International journal

Hideharu Hagiya, Susumu Kokeguchi, Hiroko Ogawa, Tomohiro Terasaka, Kosuke Kimura, Koichi Waseda, Yoshihisa Hanayama, Kaori Oda, Hisatoshi Mori, Toru Miyoshi, Fumio Otsuka

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 20 ( 12 ) 804 - 9 2014.12

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

A 53-year-old man with a past medical history of total arch replacement surgery and severe aortic regurgitation presented with a 1-month history of persistent general malaise, anorexia, body weight loss and night sweats. His recent history included gingival hyperplasia for 6 years, gingivitis after tooth extraction 3 years before, prolonged inflammatory status for 4 months, fundal hemorrhage and leg tenderness for 2 months. A pathogen was detected from blood culture, but conventional microbiological examination failed to identify the pathogen. The organism was eventually identified as Cardiobacterium valvarum by 16S rRNA analysis, and the patient was diagnosed with infective endocarditis and prosthetic vascular graft infection. The patient received intravenous antibiotic therapy using a combination of ceftriaxone and levofloxacin for 5 weeks and was discharged with a good clinical course. C. valvarum is a rare human pathogen in clinical settings. Only 10 cases have been reported to date worldwide, and therefore, the clinical characteristics of C. valvarum infection are not fully known. This is a first well-described case of C. valvarum infection in Japan, and further, a first report of aortic prosthetic vascular graft infection worldwide. Identification of C. valvarum is usually difficult due to its phenotypic characteristics, and molecular approaches would be required for both clinicians and microbiologists to facilitate more reliable diagnosis and uncover its clinical picture more clearly.

DOI： 10.1016/j.jiac.2014.07.008

Early eicosapentaenoic acid treatment after percutaneous coronary intervention reduces acute inflammatory responses and ventricular arrhythmias in patients with acute myocardial infarction: a randomized, controlled study. International journal

Masayuki Doi, Kazumasa Nosaka, Toru Miyoshi, Mutsumi Iwamoto, Masahito Kajiya, Keisuke Okawa, Rie Nakayama, Wataru Takagi, Ko Takeda, Satoshi Hirohata, Hiroshi Ito

International journal of cardiology 176 ( 3 ) 577 - 82 2014.10

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

OBJECTIVE: We examined whether early loading of eicosapentaenoic acid (EPA) reduces clinical adverse events by 1 month, accompanied by a decrease in C-reactive protein (CRP) values in patients with acute myocardial infarction (MI). BACKGROUND: Acute MI triggers an inflammatory reaction, which plays an important role in myocardial injury. EPA could attenuate the inflammatory response. METHODS: This prospective, open-label, blinded endpoint, randomized trial consisted of 115 patients with acute MI. They were randomly assigned to the EPA group (57 patients) and the control group (58 patients). After percutaneous coronary intervention (PCI), 1800 mg/day of EPA was initiated within 24h. The primary endpoint was composite events, including cardiac death, stroke, re-infarction, ventricular arrhythmias, and paroxysmal atrial fibrillation within 1 month. RESULTS: Administration of EPA significantly reduced the primary endpoint within 1 month (10.5 vs 29.3%, p=0.01), especially the incidence of ventricular arrhythmias (7.0 vs 20.6%, p=0.03). Peak CRP values after PCI in the EPA group were significantly lower than those in the control group (median [interquartile range], 8.2 [5.6-10.2] mg/dl vs 9.7 [7.6-13.9] mg/dl, p<0.01). Logistic regression analysis showed that EPA use was an independent factor related to ventricular arrhythmia until 1 month, with an odds ratio of 0.29 (95% confidence interval, 0.09 to 0.96, p=0.04). CONCLUSIONS: Early EPA treatment after PCI in the acute stage of MI reduces the incidence of ventricular arrhythmias, and lowers CRP values.

DOI： 10.1016/j.ijcard.2014.08.055

Add-on ezetimibe reduces small dense low-density lipoprotein cholesterol levels without affecting absorption of eicosapentaenoic acid in patients with coronary artery disease: a pilot study. International journal

Motoki Kubo, Toru Miyoshi, Tomonari Kimura, Yoko Noda, Kunihisa Kohno, Kazufumi Nakamura, Hiroshi Morita, Hiroshi Ito

American journal of cardiovascular drugs : drugs, devices, and other interventions 14 ( 5 ) 387 - 92 2014.10

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

BACKGROUND: Residual risk of cardiovascular disease from increased small dense low-density lipoprotein (sdLDL)-cholesterol levels and low n-3 polyunsaturated fatty acid (PUFA) levels is a considerable therapeutic issue. The purpose of this study was to evaluate the effect of ezetimibe as an add-on to statins and supplemental eicosapentaenoic acid (EPA) on sdLDL cholesterol and absorption of EPA in patients with coronary artery disease. METHODS: The study population consisted of ten male patients who were concurrently receiving statins and EPA 1,800 mg/day. Serum lipids and PUFAs, including EPA and arachidonic acid, were measured in blood samples collected before ezetimibe (baseline), 4 weeks after starting 10-mg/day ezetimibe, and 4 weeks after discontinuing ezetimibe. RESULTS: Ezetimibe significantly decreased sdLDL-cholesterol levels after 4 weeks of treatment (baseline 35 ± 13 mg/dl; treatment 27 ± 9 mg/dl), but the levels returned to baseline after discontinuation of ezetimibe (37 ± 13 mg/dl). The concentration of EPA did not significantly change during the study. CONCLUSION: Ezetimibe shows great promise as an add-on therapy to statins to reduce sdLDL-cholesterol-related residual risk of cardiovascular disease without affecting absorption of supplemental EPA in patients with coronary artery disease.

DOI： 10.1007/s40256-014-0082-3

Pioglitazone prevents the endothelial dysfunction induced by ischemia and reperfusion in healthy subjects. International journal

Yuka Sakatani, Toru Miyoshi, Hiroki Oe, Yoko Noda, Yuko Ohno, Kazufumi Nakamura, Yukihiro Saito, Kazuhiro Osawa, Hiroshi Morita, Kunihisa Kohno, Hiroshi Ito

Journal of cardiovascular pharmacology 64 ( 4 ) 326 - 31 2014.10

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

BACKGROUND: No study has investigated whether pioglitazone (an agonist of peroxisome proliferator-activated receptor gamma) protects against ischemia and reperfusion (IR)-induced endothelial dysfunction in humans. METHODS AND RESULTS: In the first crossover study, 20 volunteers were randomized to 1 week of pioglitazone (30 mg/d, postoperatively) or control (no treatment). In the second single-arm study, 15 volunteers received pioglitazone and the cyclooxygenase-2 inhibitor meloxicam for 1 week. On day 7, endothelium-dependent flow-mediated dilation (FMD) of the distal brachial artery was measured before and after IR (15 minutes of ischemia followed by 15 minutes of reperfusion in the proximal upper arm). Pre-IR brachial-artery diameter and FMD were similar across the 2 sessions (control, pioglitazone) in protocol 1 and between the 2 protocols. IR significantly blunted FMD after no treatment (pre-IR FMD: 10.2% ± 2.6%; post-IR FMD: 3.5% ± 1.9%, P < 0.01) but not after pioglitazone administration (pre-IR FMD: 9.7% ± 2.5%; post-IR FMD: 8.8% ± 2.9%, P = 0.11). This protective effect was accompanied by an increase in serum levels of the antioxidant enzyme extracellular superoxide dismutase and was not affected by concomitant administration of the cyclooxygenase-2 inhibitor meloxicam (P = 0.10). CONCLUSIONS: In humans, pioglitazone provides potent protection against IR-induced endothelial dysfunction.

DOI： 10.1097/FJC.0000000000000124

Omega-3 fatty acids improve postprandial lipemia and associated endothelial dysfunction in healthy individuals - a randomized cross-over trial. International journal

Toru Miyoshi, Yoko Noda, Yuko Ohno, Hiroki Sugiyama, Hiroki Oe, Kazufumi Nakamura, Kunihisa Kohno, Hiroshi Ito

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 68 ( 8 ) 1071 - 7 2014.10

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

BACKGROUND: Postprandial elevation of triglycerides impairs endothelial function and contributes to the development of atherosclerosis. We investigated the effects of omega-3 fatty acids on postprandial endothelial function and lipid profiles. METHODS: Healthy volunteers [10] were given supplementation at 4g/day omega-3 fatty acids (or were not treated) for 4 weeks in a randomised crossover study. Postprandial levels of various lipids were monitored and endothelial function assessed by brachial artery flow-mediated dilation during fasting and after a standard cookie test. RESULTS: Omega-3 fatty acids reduced postprandial endothelial dysfunction compared with the control diet (flow-mediated dilation at 4h=-0.5±1.2 vs. -2.0±1.6%, P=0.03). Postprandial levels of triglycerides, apolipoprotein B-48, and remnant lipoprotein-cholesterol increased in untreated subjects, peaked at 2-4h, and returned to baseline at 8h, whereas low-density lipoprotein-cholesterol levels did not change. Supplementation with omega-3 fatty acids significantly suppressed postprandial elevation of triglycerides (incremental area under the curve=220±209 vs. 374±216mg/h/dL, P=0.04) and remnant lipoprotein-cholesterol (incremental area under the curve=21.7±13.8 vs. 13.3±12.9mg/h/dL, P=0.04). Supplementation with omega-3 fatty acids significantly suppressed the increase in triglyceride content in chylomicrons as well as in very-low-density lipoproteins from baseline to 4h after the cookie test. CONCLUSION: Omega-3 fatty acids significantly decreased postprandial triglyceride elevation and postprandial endothelial dysfunction, suggesting that omega-3 fatty acids may have vascular protective effects in postprandial state.

DOI： 10.1016/j.biopha.2014.10.008

DPP-4 inhibitor and alpha-glucosidase inhibitor equally improve endothelial function in patients with type 2 diabetes: EDGE study. International journal

Kazufumi Nakamura, Hiroki Oe, Hajime Kihara, Kenei Shimada, Shota Fukuda, Kyoko Watanabe, Tsutomu Takagi, Kei Yunoki, Toru Miyoshi, Kumiko Hirata, Junichi Yoshikawa, Hiroshi Ito

Cardiovascular diabetology 13 110 - 110 2014.7

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

BACKGROUND: Alpha glucosidase inhibitor (GI) attenuates postprandial hyperglycemia (PPH) and reduces the risk of cardiovascular events in patients with impaired glucose tolerance or type 2 diabetes. Dipeptidyl peptidase 4 (DPP-4) inhibitors also attenuate PPH. PPH is one of the factors leading to endothelial dysfunction which is an early event in the pathogenesis of atherosclerosis. Furthermore, DPP-4 inhibitors protect endothelial function through a GLP-1-dependent mechanism. However, the impact of these two types of drugs on endothelial dysfunction in patients with type 2 diabetes has not been fully elucidated. We compared the effects of sitagliptin, a DPP-4 inhibitor, and voglibose, an alpha GI, on endothelial function in patients with diabetes. METHODS: We conducted a randomized prospective multicenter study in 66 patients with type 2 diabetes who did not achieve the treatment goal with sulfonylurea, metformin or pioglitazone treatment; 31 patients received sitagliptin treatment and 35 patients, voglibose treatment. The flow-mediated dilatation (FMD) of the brachial artery was measured in the fasting state at baseline and after 12 weeks of treatment. The primary endpoint was a change in FMD (ΔFMD) from the baseline to the end of follow-up. The effects of sitagliptin and voglibose on FMD were assessed by ANCOVA after adjustment for the baseline FMD, age, sex, current smoking, diabetes duration and body mass index. Secondary efficacy measures included changes in HbA1c, GIP, GLP-1, C-peptide, CD34, lipid profile, oxidative stress markers, inflammatory markers and eGFR and any adverse events. RESULTS: ΔFMD was significantly improved after 12 weeks of treatment in both groups, and there was no significant difference in ΔFMD between the two groups. There were no significant differences in changes in HbA1c, GIP, GLP-1, C-peptide, lipid profile, oxidative stress marker, inflammatory marker and eGFR between the two groups. Compared with voglibose, sitagliptin significantly increased the circulating CD34, a marker of endothelial progenitor cells. Adverse events were observed in 5 patients in only the voglibose group (diarrhea 1, nausea 1, edema 2 and abdominal fullness 1). CONCLUSIONS: Sitagliptin improved endothelial dysfunction just as well as voglibose in patients with type 2 diabetes. Sitagliptin had protective effects on endothelial function without adverse events. TRIAL REGISTRATION: registered at http://www.umin.ac.jp/ctrj/ under UMIN000003951.

DOI： 10.1186/s12933-014-0110-2

Additional diagnostic value of first-pass myocardial perfusion imaging without stress when combined with 64-row detector coronary CT angiography in patients with coronary artery disease. International journal

Kazuhiro Osawa, Toru Miyoshi, Yasushi Koyama, Katsushi Hashimoto, Shuhei Sato, Kazufumi Nakamura, Nobuhiro Nishii, Kunihisa Kohno, Hiroshi Morita, Susumu Kanazawa, Hiroshi Ito

Heart (British Cardiac Society) 100 ( 13 ) 1008 - 15 2014.7

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

OBJECTIVE: Multi-detector coronary CT angiography (CCTA) can detect coronary stenosis, but it has a limited ability to evaluate myocardial perfusion. We evaluated the usefulness of first-pass CT-myocardial perfusion imaging (MPI) in combination with CCTA for diagnosing coronary artery disease (CAD). METHODS: A total of 145 patients with suspected CAD were enrolled. We used 64-row multi-detector CT (Definition Flash, Siemens). The same coronary CCTA data were used for first-pass CT-MPI without drug loading. Images were reconstructed by examining the signal densities at diastole as colour maps. Diagnostic accuracy was assessed by comparison with invasive coronary angiography. RESULTS: First-pass CT-MPI in combination with CCTA significantly improved diagnostic performance compared with CCTA alone. With per-vessel analysis, the sensitivity, specificity, positive predictive value and negative predictive value increased from 81% to 85%, 87% to 94%, 63% to 79% and 95% to 96%, respectively. The area under the receiver operating characteristic curve for detecting CAD also increased from 0.84 to 0.89 (p=0.02). First-pass CT-MPI was particularly useful for assessing segments that could not be directly evaluated due to severe calcification and motion artefacts. CONCLUSIONS: First-pass CT-MPI has an additional diagnostic value for detecting coronary stenosis, in particular in patients with severe calcification.

DOI： 10.1136/heartjnl-2013-305468

Bezafibrate improves postprandial hypertriglyceridemia and associated endothelial dysfunction in patients with metabolic syndrome: a randomized crossover study. International journal

Yuko Ohno, Toru Miyoshi, Yoko Noda, Hiroki Oe, Norihisa Toh, Kazufumi Nakamura, Kunihisa Kohno, Hiroshi Morita, Hiroshi Ito

Cardiovascular diabetology 13 71 - 71 2014.4

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

BACKGROUND: Postprandial elevation of triglyceride-rich lipoproteins impairs endothelial function, which can initiate atherosclerosis. We investigated the effects of bezafibrate on postprandial endothelial dysfunction and lipid profiles in patients with metabolic syndrome. METHODS: Ten patients with metabolic syndrome were treated with 400 mg/day bezafibrate or untreated for 4 weeks in a randomized crossover study. Brachial artery flow-mediated dilation (FMD) and lipid profiles were assessed during fasting and after consumption of a standardized snack. Serum triglyceride and cholesterol contents of lipoprotein fractions were analyzed by high-performance liquid chromatography. RESULTS: Postprandial FMD decreased significantly and reached its lowest value 4 h after the cookie test in both the bezafibrate and control groups, but the relative change in FMD from baseline to minimum in the bezafibrate group was significantly smaller than that in the control group (-29.0 ± 5.9 vs. -42.9 ± 6.2%, p = 0.04). Bezafibrate significantly suppressed postprandial elevation of triglyceride (incremental area under the curve (AUC): 544 ± 65 vs. 1158 ± 283 mg h/dl, p = 0.02) and remnant lipoprotein cholesterol (incremental AUC: 27.9 ± 3.5 vs. 72.3 ± 14.1 mg h/dl, p < 0.01). High-performance liquid chromatography analysis revealed that postprandial triglyceride content of the chylomicron and very low-density lipoprotein fractions was significantly lower in the bezafibrate group than in the control group (p < 0.05). CONCLUSION: Bezafibrate significantly decreased postprandial endothelial dysfunction, and elevations of both exogenous and endogenous triglycerides in patients with metabolic syndrome, suggesting that bezafibrate may have vascular protective effects in these patients. CLINICAL TRIAL REGISTRATION: Unique Identifiers: UMIN000012557.

DOI： 10.1186/1475-2840-13-71

Low serum level of secreted frizzled-related protein 5, an anti-inflammatory adipokine, is associated with coronary artery disease. International journal

Toru Miyoshi, Masayuki Doi, Shinichi Usui, Mutsumi Iwamoto, Masahito Kajiya, Ko Takeda, Kazumasa Nosaka, Rie Nakayama, Keisuke Okawa, Wataru Takagi, Kazufumi Nakamura, Satoshi Hirohata, Hiroshi Ito

Atherosclerosis 233 ( 2 ) 454 - 459 2014.4

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

OBJECTIVE: Secreted frizzled-related protein 5 (SFRP5) is an anti-inflammatory adipokine that is associated with insulin resistance in animals. To extend these observations to humans, we investigated the association of serum SFRP5 levels in subjects with and without coronary artery disease (CAD). METHODS: Subjects (n=185, 68±11 years, 79% male) suspected of having CAD were enrolled in the study and were divided into two groups, CAD and non-CAD subjects, according to the results of their coronary angiographies. Serum SFRP5 levels of the subjects were measured by an enzyme-linked immunosorbent assay. RESULTS: The serum SFRP5 levels in the subjects with CAD were significantly lower than those in the non-CAD subjects (median [interquartile range]: 47.7 [26.6] vs. 52.4 [29.6] ng/mL, respectively; p=0.02). The serum SFRP5 levels significantly correlated with body mass index, the homeostasis model of assessment of insulin resistance, adiponectin levels, and CAD severity. Multivariate logistic regression analysis revealed that a decreased serum SFRP5 level (log transformed) was independently associated with CAD for all subjects (adjusted odds ratio, 0.36; 95% confidence interval, 0.14-0.94; p=0.03). CONCLUSION: Serum SFRP5 levels are significantly associated with CAD in humans, suggesting that low SFRP5 levels may contribute to CAD.

DOI： 10.1016/j.atherosclerosis.2014.01.019

Differential association of visceral adipose tissue with coronary plaque characteristics in patients with and without diabetes mellitus. International journal

Kazuhiro Osawa, Toru Miyoshi, Yasushi Koyama, Shuhei Sato, Noriaki Akagi, Yusuke Morimitsu, Motoki Kubo, Hiroki Sugiyama, Kazufumi Nakamura, Hiroshi Morita, Susumu Kanazawa, Hiroshi Ito

Cardiovascular diabetology 13 61 - 61 2014.3

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

BACKGROUND: Excess visceral adipose tissue (VAT) is closely associated with the presence of coronary artery plaques that are vulnerable to rupture. Patients with diabetes mellitus (DM) have more VAT than patients without DM, but the extent to which VAT contributes to the characteristics of coronary plaques before and after the development of DM is not fully understood. METHODS: We retrospectively evaluated 456 patients (60% male, age 64 ± 16 years) who were suspected to have cardiovascular disease and underwent 64-slice computed tomography angiography (CTA). Seventy-one (16%) patients had vulnerable plaques (CT density < 50 Hounsfield Units, positive remodeling index > 1.05, and adjacent spotty areas of calcification). RESULTS: Patients were divided into tertiles according to the VAT area. There were stepwise increases in noncalcified and vulnerable plaques with increasing tertiles of VAT area in patients without DM, but not in patients with DM. Multivariate analysis showed that a larger VAT area was significantly associated with a higher risk of vulnerable plaque in patients without DM (odds ratio 3.17, 95% confidence interval 1.08-9.31, p = 0.04), but not in patients with DM. CONCLUSIONS: The VAT area is associated with the characteristics of coronary plaques on CTA in patients without DM, but not in patients with DM. VAT may be a significant cardiometabolic risk factor that is associated with plaque vulnerability before the development of DM. CTA findings may help to improve risk stratification in such patients.

DOI： 10.1186/1475-2840-13-61

Olmesartan reduces inflammatory biomarkers in patients with stable coronary artery disease undergoing percutaneous coronary intervention: results from the OLIVUS trial.

Toru Miyoshi, Atsushi Hirohata, Shinichi Usui, Keizo Yamamoto, Takashi Murakami, Issei Komatsubara, Shozo Kusachi, Tohru Ohe, Kazufumi Nakamura, Hiroshi Ito

Heart and vessels 29 ( 2 ) 178 - 85 2014.3

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

The OLmesartan on the progression of coronary atherosclerosis: evaluation by IntraVascular UltraSound (OLIVUS) trial demonstrated that an angiotensin II receptor blocker, olmesartan, reduces the rate of coronary atheroma progression as evaluated by intravascular ultrasound in patients with stable angina pectoris undergoing percutaneous coronary intervention. This substudy examined the impact of olmesartan on serum biomarkers and the relationship between biomarker changes and atheroma progression. Patients in the OLIVUS trial (n = 247) were randomly assigned to a control group or the olmesartan group. A subgroup of these patients (n = 135, 55 %) was analyzed at baseline and at 14 months. Patients' characteristics and blood-pressure control were identical between the control group (n = 65) and the olmesartan group (n = 70), and also between the subpopulation and total population. The change in the level of high-sensitivity C-reactive protein (hs-CRP) (mg/l) and adiponectin (μg/ml) was significantly greater in the olmesartan group than in the control group (between-group differences: 0.5 and -0.7; 95 % confidence interval: 0.2-0.8 and -1.3 to -0.1; P = 0.001 and 0.02, respectively). Multiple regression analysis revealed that the nominal changes in total atheroma volume and percent atheroma volume were significantly associated with the nominal change in hs-CRP in the olmesartan group but not in the control group. Olmesartan reduced hs-CRP in patients with stable angina, and this correlated with the change in coronary atheroma.

DOI： 10.1007/s00380-013-0343-0

Effect of vildagliptin, a dipeptidyl peptidase 4 inhibitor, on cardiac hypertrophy induced by chronic beta-adrenergic stimulation in rats. International journal

Toru Miyoshi, Kazufumi Nakamura, Masashi Yoshida, Daiji Miura, Hiroki Oe, Satoshi Akagi, Hiroki Sugiyama, Kaoru Akazawa, Tomoko Yonezawa, Jun Wada, Hiroshi Ito

Cardiovascular diabetology 13 43 - 43 2014.2

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

BACKGROUND: Heart failure with left ventricular (LV) hypertrophy is often associated with insulin resistance and inflammation. Recent studies have shown that dipeptidyl peptidase 4 (DPP4) inhibitors improve glucose metabolism and inflammatory status. We therefore evaluated whether vildagliptin, a DPP4 inhibitor, prevents LV hypertrophy and improves diastolic function in isoproterenol-treated rats. METHODS: Male Wistar rats received vehicle (n = 20), subcutaneous isoproterenol (2.4 mg/kg/day, n = 20) (ISO), subcutaneous isoproterenol (2.4 mg/kg/day + oral vildagliptin (30 mg/kg/day, n = 20) (ISO-VL), or vehicle + oral vildagliptin (30 mg/kg/day, n = 20) (vehicle-VL) for 7 days. RESULTS: Blood pressure was similar among the four groups, whereas LV hypertrophy was significantly decreased in the ISO-VL group compared with the ISO group (heart weight/body weight, vehicle: 3.2 ± 0.40, ISO: 4.43 ± 0.39, ISO-VL: 4.14 ± 0.29, vehicle-VL: 3.16 ± 0.16, p < 0.05). Cardiac catheterization revealed that vildagliptin lowered the elevated LV end-diastolic pressure observed in the ISO group, but other parameters regarding LV diastolic function such as the decreased minimum dp/dt were not ameliorated in the ISO-VL group. Histological analysis showed that vildagliptin attenuated the increased cardiomyocyte hypertrophy and perivascular fibrosis, but it did not affect angiogenesis in cardiac tissue. In the ISO-VL group, quantitative PCR showed attenuation of increased mRNA expression of tumor necrosis factor-α, interleukin-6, insulin-like growth factor-l, and restoration of decreased mRNA expression of glucose transporter type 4. CONCLUSIONS: Vildagliptin may prevent LV hypertrophy caused by continuous exposure to isoproterenol in rats.

DOI： 10.1186/1475-2840-13-43

Spasm provocation tests performed under medical therapy: a new approach for treating patients with refractory coronary spastic angina on emergency admission.

Shozo Sueda, Hiroaki Kohno, Toru Miyoshi, Yasuhiro Sasaki, Tomoki Sakaue, Hirokazu Habara

Internal medicine (Tokyo, Japan) 53 ( 16 ) 1739 - 47 2014

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

Objective There are no objective methods for evaluating the severity of vasospasms in patients with refractory coronary spastic angina (R-CSA) under adequate medical therapy. We examined whether spasm provocation tests performed under adequate medication are useful for evaluating the severity of disease in R-CSA patients on emergency admission. Methods and Results We performed spasm provocation tests before and after the administration of medical therapy in eight R-CSA patients, including one ventricular fibrillation survivor (VF-S) and seven patients with unstable angina (UAP) on emergency readmission. We also performed these tests only after medical therapy on urgent admission in four R-CSA patients, including two patients with UAP, one patient with VF-S and one patient with acute coronary syndrome. All 12 R-CSA patients had been medicated with ≥ 2 vasodilator drugs. Positive coronary spasms were defined as >99% transient narrowing. The coronary artery spasms disappeared in three patients under medication, and mitigation of vasospasticity was observed in three patients. In these six cases we continued the same medications. Meanwhile in two patients, we recommended a consultation for psychosomatic medicine. In contrast, the remaining six R-CSA patients exhibited higher levels of vasospasticity, irrespective of the administration of aggressive medical therapy, in which the doses of vasoactive drugs were increased in order to suppress coronary artery spasms. Conclusion In some R-CSA patients on emergency admission, performing spasm provocation tests under medical therapy is useful for determining the subsequent treatment strategy. Therefore, this test may become a new tool in the treatment of R-CSA.

Arterial stiffness determined according to the cardio-ankle vascular index is associated with paroxysmal atrial fibrillation: a cross-sectional study. International journal

Toru Miyoshi, Masayuki Doi, Yoko Noda, Yuko Ohno, Kosuke Sakane, Shigeshi Kamikawa, Youko Noguchi, Hiroshi Ito

Heart Asia 6 ( 1 ) 59 - 63 2014

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

BACKGROUND: Several lines of evidence suggest that atrial fibrillation (AF) may be a consequence of vascular disease. We investigated the relationship between cardio-ankle vascular index (CAVI), a new index of arterial stiffness, and the presence of paroxysmal AF (PAF). METHODS AND RESULTS: 181 outpatients (91 patients with PAF and 90 age- and gender-matched subjects without PAF) were analysed for their sinus rhythm. The CAVI was significantly higher in patients with PAF than in subjects without PAF (9.0±1.0 vs 8.7±0.8, p<0.01). In all subjects, the CAVI was significantly correlated with the left ventricular mass index (r=0.30, p<0.01), left atrial diameter (r=0.22, p<0.01), and augmentation index, a parameter of wave reflection (r=0.32, p<0.01), in addition to age, systolic blood pressure and pulse pressure. Logistic analysis demonstrated that the CAVI was independently associated with PAF even after adjustment for confounding factors. The adjusted OR of PAF was 1.8 for each unit increase in the CAVI (p=0.01). CONCLUSIONS: Our finding suggests that increased arterial stiffness may be involved in the maintenance of AF.

DOI： 10.1136/heartasia-2014-010503

Serum adipocyte fatty acid-binding protein is independently associated with complex coronary lesions in patients with stable coronary artery disease.

Masahito Kajiya, Toru Miyoshi, Masayuki Doi, Shinichi Usui, Mutsumi Iwamoto, Ko Takeda, Kazumasa Nosaka, Rie Nakayama, Satoshi Hirohata, Shozo Kusachi, Kazufumi Nakamura, Hiroshi Ito

Heart and vessels 28 ( 6 ) 696 - 703 2013.11

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

The association between circulating adipocyte fatty acid-binding protein (A-FABP) levels and coronary artery disease (CAD) is reported. We assessed whether plasma A-FABP levels are associated with angiographic coronary lesion morphology in patients with stable CAD. Serum A-FABP levels were analyzed in 115 patients with stable CAD (mean age 69 ± 10 years; 80 % men). These patients were angiographically studied and divided into two groups: simple lesions (n = 34) and complex lesions (n = 81). We also compared 50 age- and gender-matched controls with no evidence of CAD. Serum A-FABP levels in patients with stable CAD were significantly higher than those in controls. In patients with stable CAD, serum A-FABP levels were significantly higher in patients with complex lesions than in those with simple lesions: median (25th-75th percentile), 23.4 (17.7-30.8) vs 18.2 (12.2-24.7) ng/ml, P < 0.01. Serum A-FABP levels were also significantly associated with angiographic scores of extent of coronary lesion (r = 0.21, P = 0.02). Multiple logistic analysis that included dyslipidemia, statin therapy, and extent score demonstrated that serum A-FABP was independently associated with complex lesions. The multiple adjusted odds ratio for a complex lesion with a serum A-FABP level (per doubling) was 2.38 (95 % confidence interval, 1.03-6.41; P = 0.03). High serum A-FABP levels were significantly associated with complex coronary lesions in patients with stable CAD, suggesting that high A-FABP levels may be involved in coronary plaque vulnerability.

DOI： 10.1007/s00380-012-0310-1

[Treatment of hypertriglyceridemia with omega-3 fatty acids].

Toru Miyoshi, Hiroshi Ito

Nihon rinsho. Japanese journal of clinical medicine 71 ( 9 ) 1650 - 4 2013.9

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

Omega-3 fatty acids such as eicosapentaenoic acid(EPA) and docosahexaenoic acid(DHA) have important biologic functions, including effects on membranes, eicosanoid metabolism, and gene transcription. Studies indicate that the use of EPA and DHA lowered triglyceride levels, which is accomplished by decreasing the production of hepatic triglycerides and increasing the clearance of plasma triglycerides. Recent clinical studies showed that intake of omega-3 fatty acids reduced cardiovascular events. In addition, combination therapy with omega-3 fatty acids and a statin is a safe and effective way to improve lipid levels and cardiovascular prognosis beyond the benefits provided by statin therapy alone. Our focus is to review the potential mechanisms by which these fatty acids reduce cardiovascular disease risk.

Serum cystatin C as a biomarker of cardiac diastolic dysfunction in patients with cardiac disease and preserved ejection fraction

Nosaka Kazumasa, Nakamura Kazufumi, Kusano Kengo, Toh Norihisa, Tada Takeshi, Miyoshi Toru, Doi Masayuki, Kohno Kunihisa, Morita Hiroshi, Ito Hiroshi

Congestive Heart Failure 19 ( 4 ) E35 - E39 2013.8

Reduced diurnal variation of heart rate is associated with increased plasma B-type natriuretic peptide level in patients with atrial fibrillation. International journal

Shigeshi Kamikawa, Toru Miyoshi, Masayuki Doi, Naoko Orita, Mutsuko Sangawa, Takaaki Nakatsu, Youko Noguchi, Satoshi Hirohata, Shozo Kusachi, Kazufumi Nakamura, Hiroshi Ito

Clinical cardiology 36 ( 7 ) 394 - 400 2013.7

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

BACKGROUND: The plasma B-type natriuretic peptide (BNP) level has been shown to be increased in patients with chronic atrial fibrillation (AF) independent of left ventricular ejection fraction (LVEF). The purpose of this study is to evaluate the relationship between the plasma BNP level and heart rate variation in patients with AF. HYPOTHESIS: The plasma BNP level is associated with heart rate variation in patients with AF. METHODS: A total of 102 patients with AF and preserved LVEF were included from 2 hospitals. The ambulatory electrocardiographic recording and measurement of plasma BNP levels were performed simultaneously. Echo-Doppler parameters were measured as the average of 10 consecutive cardiac cycles. RESULTS: A difference in the mean heart rate between night and day (DIFF) and the standard deviation of the 5-miniute mean R-R interval (SDARR) were significantly associated with log-transformed BNP levels (r = -0.411, P < 0.001 and r = -0.243, P = 0.049, respectively). In echocardiography, the ratio of E velocity to early diastolic velocity, which reflects left ventricular (LV) filling pressure, was significantly correlated with the DIFF and SDARR, along with the log-transformed BNP level. Stepwise multiple linear regression analysis revealed that the DIFF and age were independent factors related with the BNP level (P < 0.01). CONCLUSIONS: The reduced diurnal variation of heart rate was significantly associated with increased BNP, which is linked to LV diastolic dysfunction in patients with AF.

DOI： 10.1002/clc.22128

Alogliptin ameliorates postprandial lipemia and postprandial endothelial dysfunction in non-diabetic subjects: a preliminary report. International journal

Yoko Noda, Toru Miyoshi, Hiroki Oe, Yuko Ohno, Kazufumi Nakamura, Norihisa Toh, Kunihisa Kohno, Hiroshi Morita, Kengo Kusano, Hiroshi Ito

Cardiovascular diabetology 12 8 - 8 2013.1

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

BACKGROUND: Postprandial hyperlipidemia impairs endothelial function and participates in the development of atherosclerosis. We investigated the postprandial effects of a dipeptidyl peptidase IV inhibitor, alogliptin, on endothelial dysfunction and the lipid profile. METHODS: A randomized cross-over trial design in 10 healthy volunteers (8 males and 2 females, 35 ± 10 years) was performed. The postprandial effects before and after a 1-week treatment of 25 mg/day alogliptin on endothelial function were assessed with brachial artery flow-mediated dilation (FMD) and changing levels of lipids, apolipoprotein B48 (apoB-48), glucose, glucagon, insulin, and glucagon-like peptide-1 (GLP-1) during fasting and at 2, 4, 6, and 8 h after a standard meal loading test. RESULTS: Alogliptin treatment significantly suppressed the postprandial elevation in serum triglyceride (incremental area under the curve [AUC]; 279 ± 31 vs. 182 ± 32 mg h/dl, p = 0.01), apoB-48 (incremental AUC; 15.4 ± 1.7 vs. 11.7 ± 1.1 μg h/ml, p = 0.04), and remnant lipoprotein cholesterol (RLP-C) (incremental AUC: 29.3 ± 3.2 vs. 17.6 ± 3.3 mg h/dl, p = 0.01). GLP-1 secretion was significantly increased after alogliptin treatment. Postprandial endothelial dysfunction (maximum decrease in%FMD, from -4.2 ± 0.5% to -2.6 ± 0.4%, p = 0.03) was significantly associated with the maximum change in apoB-48 (r = -0.46, p = 0.03) and RLP-C (r = -0.45, p = 0.04). CONCLUSION: Alogliptin significantly improved postprandial endothelial dysfunction and postprandial lipemia, suggesting that alogliptin may be a promising anti-atherogenic agent.

DOI： 10.1186/1475-2840-12-8

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