Hirotoshi Ohmura

Effects of troglitazone on atherogenic lipoprotein phenotype in coronary patients with insulin resistance.

Insulin resistance is associated with atherogenic lipoprotein phenotype, including small dense LDL particle, hypertriglycemia and low HDL cholesterol levels. Troglitazone, a novel insulin sensitizing agent, may improve the associated lipid profile in patients with insulin resistance. We examined the effects of troglitazone (400 mg daily for 12 weeks) in 12 non-diabetic coronary patients (60+/-10 years), all of whom had hyperinsulinemic response to an oral glucose load. Troglitazone markedly reduced the insulin response. After the treatment, plasma triglycerides decreased by 32% (P<0.05), HDL cholesterol increased by 11%, (P<0.05) and LDL peak particle diameter increased from 24.7+/-0.3 to 25.5+/-0.5 nm (P<0.01). These lipidic improvements were associated with a significant rise in postheparin lipoprotein lipase levels (175+/-52 to 217+/-69 ng/ml, P<0.01). In patients with insulin resistance syndrome, troglitazone improved the atherogenic lipoprotein phenotype as well as hyperinsulinemia. Our data suggest that troglitazone therapy could reduce the atherosclerotic risk due to insulin resistance even in non-diabetic patients.

Single Administration of α-Glucosidase Inhibitors on Endothelial Function and Incretin Secretion in Diabetic Patients With Coronary Artery Disease - Juntendo University Trial: Effects of Miglitol on Endothelial Vascular Reactivity in Type 2 Diabetic Patients With Coronary Heart Disease (J-MACH) -

Background: Post-prandial hyperglycemia, hyperlipidemia, and endothelial dysfunction play an important role in the pathogenesis of atherosclerosis. Improvement in post-prandial hyperglycemia on α-glucosidase inhibitors (α-GIs) is associated with a risk reduction of cardiovascular diseases, but the post-prandial effects of α-GIs on endothelial function and incretin secretion in type 2 diabetic patients with coronary artery disease (CAD) remain unclear. Methods and Results: The post-prandial effects of a single administration of miglitol and voglibose on endothelial function and changing levels of glucose, insulin, lipids, glucagon-like peptide (GLP)-1, and gastric inhibitory polypeptide (GIP) were compared after a standard meal loading in 11 diabetic patients with CAD, using a placebo-controlled cross-over design. The changing levels of glucose, insulin and triglycerides at 60 min were significantly lower in the miglitol group than in the voglibose and placebo groups (all P<0.01). GLP-1 levels were significantly higher at 120 min (P<0.05) and GIP levels were significantly lower at 30 min and 60 min (P<0.05) in the miglitol group compared to other treatments. The reactive hyperemia duration at 120 min was significantly maintained in the miglitol group compared to the other groups. Conclusions: A single administration of miglitol significantly improved post-prandial glucose/lipid metabolism, incretin secretion, and endothelial dysfunction in diabetic patients with CAD, suggesting that miglitol may be a useful anti-atherogenic agent (UMIN000002264).  (Circ J 2010; 74: 1471 - 1478)

Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017

Toray Industries, Inc., Tokyo, Japan Department of Diabetes, Metabolism and Endocrinology, Chiba University Graduate School of Medicine, Chiba, Japan National Center for Geriatrics and Gerontology, Aichi, Japan Department of Internal Medicine and Cardiology, Gifu Prefectural General Medical Center, Gifu, Japan Division of Diabetes and Metabolism, Department of Internal Medicine, Iwate Medical University, Iwate, Japan Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi, Japan Center for Integrated Medical Research, Hiroshima University Hospital, Hiroshima, Japan Egusa Genshi Clinic, Hiroshima, Japan Department of Cardiovascular Medicine, Juntendo University, Tokyo, Japan Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan Biomedical Informatics, Osaka University, Osaka, Japan Division of Cardiology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan Department of Community Health Systems Nursing, Ehime University Graduate School of Medicine, Ehime, Japan Department of Vascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan Department of Vascular Surgery, Saitama Medical Center, Saitama, Japan Chief Health Management Department, Mitsui Chemicals Inc., Tokyo, Japan Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan Department of Neurology, Kita-Harima Medical Center, Hyogo, Japan Department of Internal Medicine, Mizonokuchi Hospital, Teikyo University School of Medicine, Kanagawa, Japan Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan Tsukasa Health Care Hospital, Kagoshima, Japan Faculty of Nutrition, Division of Clinical Nutrition, Kobe Gakuin University, Hyogo, Japan Department of Food and Nutrition, Faculty of Human Sciences and Design, Japan Women’s University, Tokyo, Japan 25 Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan Department of Medical Statistics, Toho University, Tokyo, Japan Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan Department of Laboratory Medicine, Jikei University Kashiwa Hospital, Chiba, Japan Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan Department of Obstetrics and Gynecology, Aichi Medical University, Aichi, Japan 31 Department of Community Medicine, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan Rinku General Medical Center, Osaka, Japan

Possible role of high susceptibility of high-density lipoprotein to lipid peroxidative modification and oxidized high-density lipoprotein in genesis of coronary artery spasm

Recent study demonstrated high susceptibility of plasma LDL to lipid peroxidative modification in patients with variant angina. Oxidized stress state, especially oxidized LDL, may induce coronary artery spasm by its impairing effect of endothelium-dependent arterial relaxation, but precise mechanisms remain unclear. Study subjects included 93 patients who underwent coronary angiographic examination: 12 patients with coronary artery spasm provoked by ergonovine without organic stenosis (group I), 11 patients who did not demonstrate coronary artery spasm or organic stenosis (group II) and 70 patients with organic coronary artery stenosis (group III). Levels of plasma HDL-cholesterol and apoA-I in group I were similar to those in III but were significantly lower than those in II, although the other plasma lipid parameters were not different among the three groups. The levels of TBARS in plasma and HDL were significantly higher in group I than in II or III (2.94+/-1.56 vs. 1.91+/-0.35 or 2.23+/-0.89 nmol MDA/ml and 1.23+/-1.00 vs. 0.54+/-0.37 or 0.70+/-0.63 nmol MDA/mg protein; P < 0.05), although the levels of TBARS in LDL were not significantly different. In the monitoring curve of diene production during copper-induced lipid peroxidation of HDL, its propagation slope was steeper and levels of maximum diene absorbance was higher in group I as compared with that in II or III, but not found in those of LDL. These results suggested that high susceptibility of HDL to lipid peroxidative modification in group I may contribute to the genesis of coronary artery spasm, and oxidized HDL rather than oxidized LDL is more likely to be related to coronary artery spasm.

Relationship between exercise tolerance and muscle strength following cardiac rehabilitation: Comparison of patients after cardiac surgery and patients with myocardial infarction

BACKGROUND AND PURPOSE Previous studies have demonstrated that cardiac rehabilitation (CR) improves exercise tolerance and muscle strength in patients with myocardial infarction (MI) and in patients after cardiac surgery. However, the association between exercise tolerance and muscular strength following CR and the comparison of relationships among various disease categories has not been fully examined. The purpose of the present study was to assess the relationship between exercise tolerance and muscle strength following CR in patients after cardiac surgery and patients with MI. METHODS AND RESULTS One hundred and four patients who participated in CR for 6 months were enrolled [post-cardiac valve surgery (VALVE), n=28; post-coronary artery bypass grafting (CABG), n=42; post-acute MI, n=34]. The exercise tolerance, thigh/calf circumferences, and muscle strength were measured before and after CR. At the baseline, the thigh circumference was significantly smaller in the VALVE group than in the MI group. There were significant positive correlations between peak VO(2) and muscle torques of the lower muscles in all groups. After 6 months, peak VO(2) and muscle torque were significantly increased in all groups (p<0.001). A positive significant correlation between percent increases in peak VO(2) and muscular strength was observed in the VALVE group (r=0.51, p<0.01), but not in the other groups. In addition, the changes in peak VO(2) and calf circumference after CR were significantly higher in the VALVE group than in the MI group. CONCLUSIONS These data suggest that exercise intolerance in patients after heart valve surgery may in part depend on decreased muscular strength. Further studies are needed to assess whether the strategy of increasing muscular strength of lower limb by programmed resistance training could be effective for improving exercise intolerance in patients after heart valve surgery and symptomatic patients with heart failure.

Serum levels of remnant lipoprotein cholesterol and oxidized low-density lipoprotein in patients with coronary artery disease

BACKGROUND Oxidized low-density lipoprotein (OxLDL) and remnant lipoprotein play a crucial role in the development of atherosclerosis. Recently, a novel method for measuring remnant cholesterol levels (remnant lipoproteins cholesterol homogenous assay: RemL-C) has been established. However, the correlation between OxLDL and remnant lipoprotein, including RemL-C, has not been fully investigated. METHODS We enrolled 25 consecutive patients with documented coronary artery disease (CAD) and 20 controls. Remnant-like particle cholesterol (RLP-C) and RemL-C were used to determine the levels of remnant lipoprotein cholesterol. Serum levels of malondialdehyde-modified LDL (MDA-LDL) and OxLDL using a monoclonal antibody DLH3 (OxPC) were used to measure the concentration of circulating OxLDL. RESULTS The CAD group had high levels of fasting glucose and glycosylated hemoglobin (HbA1c), and low levels of high-density lipoprotein cholesterol compared with the control group. Serum levels of total cholesterol or LDL cholesterol were not significantly different between the two groups. The levels of RemL-C (p = 0.035), MDA-LDL (p = 0.018), and MDA-LDL/LDL-C (p = 0.036) in the CAD group were significantly higher than those in the control group. The levels of RLP-C tended to be higher in the CAD group than those in the control group (p = 0.096). Positive correlations were demonstrated between remnant lipoprotein cholesterol and OxLDL (RLP-C and MDA-LDL/LDL-C, r = 0.45, p = 0.0024, RLP-C and OxPC, r = 0.51, p = 0.0005, RemL-C and MDA-LDL/LDL-C, r = 0.42, p = 0.0044, RemL-C and OxPC, r = 0.43, p = 0.0043). Similar trends were observed in non-diabetic subjects and in subjects without metabolic syndrome. Positive correlations were also observed between RLP-C and RemL-C (r = 0.94, p < 0.0001) and between MDA-LDL/LDL-C and OxPC (r = 0.40, p = 0.0074). CONCLUSIONS These results suggest that the association between high levels of remnant lipoprotein cholesterol and high OxLDL levels might be linked to atherogenesis in patients with CAD.

Validation of homogeneous assays for HDL-cholesterol using fresh samples from healthy and diseased subjects

BACKGROUND High-density lipoprotein-cholesterol (HDL-C) is a negative risk factor for cardiovascular events. Although several homogeneous HDL-C assays are available, their accuracy has not been validated, particularly in subjects with disease. We aimed to clarify whether HDL-C concentrations measured by homogeneous assays [HDL-C (H)] agree with those determined by the reference measurement procedures [HDL-C (RMP)] using ultracentrifugation and precipitation with heparin-manganese reagent in fresh clinical samples. METHODS HDL-C concentrations in samples from 48 healthy subjects and 119 subjects with disease were determined using 12 homogeneous assays and RMPs. RESULTS All reagents showed excellent intra- and inter-assay CVs (<2.23%) for two pooled sera. Furthermore, the mean bias was within ± 1.0% in nine reagents using samples from healthy subjects and in eight reagents using samples from subjects with disease. In a single HDL-C (H) determination, the total error requirement of the National Cholesterol Education Program (95% of results < 13%) was fulfilled in nine reagents using samples from healthy subjects and six reagents in those from subjects with disease. Error component analysis revealed that only one reagent exceeded ± 10% total error in samples from healthy subjects, whereas four reagents exceeded this error in samples from subjects with disease. Correlations between HDL-C (H) and HDL-C (RMP) revealed that the slopes were within 1.00 ± 0.06 in six reagents in healthy subjects, and eight reagents in subjects with disease. CONCLUSIONS Except for three reagents, HDL-C (H) agrees well with HDL-C (RMP) in subjects with common disease, but not in those with extremely low HDL-C or abnormal HDL composition.

Impact of diabetes on muscle mass, muscle strength, and exercise tolerance in patients after coronary artery bypass grafting

BACKGROUND The impact of diabetes mellitus (DM) on muscle mass, muscle strength, and exercise tolerance in patients who had undergone coronary artery bypass grafting (CABG) has not been fully elucidated. METHODS We enrolled 329 consecutive patients who received cardiac rehabilitation (CR) after CABG (DM group, n=178; non-DM group, n=151) and measured lean body weight, mid-upper arm muscle area (MAMA), and handgrip power (HGP) at the beginning of CR. We also performed an isokinetic strength test of the knee extensor (Ext) and flexor (Flex) muscles and a cardiopulmonary exercise testing at the same time. RESULTS No significant differences in risk factors, including age, gender, number of diseased vessels, or ejection fraction were observed between the 2 groups. The levels of Ext muscle strength, peak oxygen uptake, and anaerobic threshold were significantly lower in the DM group than in the non-DM group (all p<0.05). Both peak oxygen uptake and MAMA correlated with Ext and Flex muscle strength as well as HGP (all p<0.005). The MAMA, HGP, and Ext muscle strength were lower in patients who received insulin therapy than in those who did not. Interestingly, fasting glucose levels significantly and negatively correlated with Ext muscle strength. CONCLUSIONS These data suggest that DM patients had a lower muscle strength and exercise tolerance than non-DM patients. Moreover, a high glucose level may affect these deteriorations in DM patients after CABG.

Effects of cardiac rehabilitation in patients with metabolic syndrome after coronary artery bypass grafting

BACKGROUND Cardiac rehabilitation (CR) has numerous beneficial effects, including the modification of coronary risk factors and improvement of the prognosis, in patients with coronary artery disease (CAD). Limited data are available regarding the effects of CR on the physical status and risk factors in patients with metabolic syndrome (MetS) after coronary artery bypass grafting (CABG). METHODS AND RESULTS We enrolled 32 patients with MetS after CABG, who participated in a supervised CR program for 6 months. Metabolic parameters, blood chemistry, exercise tolerance, and muscle strength of the thigh were measured before and after CR. After CR: (1) the body mass index, waist circumference, and fat weight significantly decreased; (2) peak V O(2) and anaerobic threshold were significantly increased; (3) isokinetic peak torques of knee extensor and flexor muscles significantly increased; (4) metabolic scoring defined by the number of the modified Adult Treatment Panel criteria of the US National Cholesterol Education Program was significantly improved; (5) serum concentration of high-sensitivity C-reactive protein also significantly decreased. CONCLUSIONS These results suggest that CR might be useful for patients with MetS after CABG.

High levels of saturated very long-chain fatty acid (hexacosanoic acid; C26:0) in whole blood are associated with metabolic syndrome in Japanese men

OBJECTIVE Hexacosanoic acid (C26:0) is a saturated very long-chain fatty acid and high levels of C26:0 in red blood cells are reported to be closely related with risk factors of atherosclerosis. However, the relationship between absolute levels of C26:0 in whole blood and metabolic syndrome (MS) has not been determined. MATERIALS AND METHOD We divided 218 consecutive apparently healthy male subjects into an MS group (n=78) and a non-MS group (n=140) according to the definition of the International Diabetes Federation. The levels of C26:0 in whole blood were measured by gas liquid chromatography-mass spectrometry. RESULTS The MS group had significantly higher levels of C26:0 than the non-MS group (2.42+/-0.31mug/ml vs. 2.25+/-0.29mug/ml, P=0001). There was a significant association between the levels of C26:0 and the number of factors of MS. The levels of C26:0 positively correlated with age, blood pressure, triglyceride and fasting plasma glucose. Multivariate analysis revealed that the level of C26:0 is still an independent variable for the presence of MS after adjustment for age and each criterion of MS. CONCLUSION The absolute levels of C26:0 in whole blood appear to be associated with MS independent of its component parts.