Kosuke Fukao

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)

Effects of calcium channel blockers on glucose tolerance, inflammatory state, and circulating progenitor cells in non-diabetic patients with essential hypertension: a comparative study between azelnidipine and amlodipine on glucose tolerance and endothelial function--a crossover trial (AGENT).

BackgroundHypertension is associated with impaired glucose tolerance and insulin resistance. Medical treatment that interferes with various steps in the renin-angiotensin system improves glucose tolerance and insulin resistance. However, it remains unclear if long-acting calcium channel blockers (CCBs) such as azelnidipine and amlodipine affect glucose tolerance and insulin resistance in clinical practice.MethodsSeventeen non-diabetic patients with essential hypertension who had controlled blood pressure levels using amlodipine (5 mg/day) were enrolled in this study. After randomization, either azelnidipine (16 mg/day) or amlodipine (5 mg/day) was administered in a crossover design for 12-weeks. At baseline and the end of each CCB therapy, samples of blood and urine were collected and 75 g oral glucose tolerance test (OGTT) was performed. In addition, hematopoietic progenitor cells (HPCs) were measured at each point by flow cytometry and endothelial functions were measured by fingertip pulse amplitude tonometry using EndoPAT.ResultsAlthough blood pressure levels were identical after each CCB treatment, the heart rate significantly decreased after azelnidipine administration than that after amlodipine administration (P < 0.005). Compared with amlodipine administration, azelnidipine significantly decreased levels of glucose and insulin 120 min after the 75 g OGTT (both P < 0.05). Serum levels of high-sensitivity C-reactive protein (P = 0.067) and interleukin-6 (P = 0.035) were decreased. Although endothelial functions were not different between the two medication groups, the number of circulating HPCs was significantly increased after azelnidipine administration (P = 0.016).ConclusionsThese results suggest that azelnidipine treatment may have beneficial effects on glucose tolerance, insulin sensitivity, the inflammatory state, and number of circulating progenitor cells in non-diabetic patients with essential hypertension.

Omega 3 Polyunsaturated Fatty Acids Suppress the Development of Aortic Aneurysms Through the Inhibition of Macrophage-Mediated Inflammation

BACKGROUND Dietary intake of ω3 polyunsaturated fatty acids (ω3-PUFAs) reduces progression of atherosclerosis and prevents future cardiovascular events. Macrophages are key players in the pathogenesis of aortic aneurysm. The effects of ω3-PUFAs on abdominal aortic aneurysm (AAA) formation and macrophage-mediated inflammation remain unclear. METHODS AND RESULTS: The AAA model was developed by angiotensin II infusion in apolipoprotein E-deficient mice. Mice were supplemented with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA). The development of AAA lesions and macrophage infiltration in the aorta were analyzed. Gene expression of inflammatory markers in aortic tissues and peritoneal macrophages were measured by using quantitative polymerase chain reaction. AAA formation and macrophage infiltration were significantly suppressed after EPA and DHA administration. EPA administration and DHA administration significantly decreased the expression of tumor necrosis factor-α, monocyte chemoattractant protein-1, transforming growth factor-β, matrix metalloproteinases (MMP)-2, MMP-9, and vascular cell adhesion molecule-1 in the aortas. The expression of arginase 2, which is a marker of pro-inflammatory macrophages, was significantly lower and that of Ym1, which is a marker of anti-inflammatory macrophages, and was significantly higher after EPA and DHA administration. The same trends were observed in peritoneal macrophages after EPA and DHA administration. CONCLUSIONS Dietary intake of EPA and DHA prevented AAA development through the inhibition of aortic and macrophage-mediated inflammation.

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.

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 very long-chain saturated fatty acid in erythrocytes correlates with atherogenic lipoprotein profiles in subjects with metabolic syndrome

AIM Very long chain saturated fatty acid (VLCFA) levels in erythrocytes are associated with metabolic syndrome (MS). However, the relationship between levels of the VLCFA ligonoceric acid (C24:0) in erythrocytes and the atherogenic lipoprotein profiles and inflammatory state in MS remain unclear. METHODS Based on the International Diabetes Federation (IDF) definition of MS, 195 apparently healthy males were assigned to either an MS group (n=38) or a non-MS group (n=157). Fatty acid composition of erythrocytes was determined by gas liquid chromatography. RESULTS Erythrocytes from the MS group had a significantly higher level of C24:0 than cells from the non-MS group (4.06±0.48% versus 3.88±0.34%; p=0.03). C24:0 levels were significantly correlated with several components of MS. The C24:0 levels showed a significant negative correlation with LDL and HDL particle size. Multivariate linear regression analysis showed that C24:0 levels were independently correlated with LDL particle size after adjusting for age and each MS criterion. C24:0 levels were also positively correlated with log-transformed high-sensitivity CRP levels (p=0.04). CONCLUSION C24:0 levels in erythrocytes are associated with specific atherogenic lipoprotein profiles and inflammation status in subjects with MS.

Disease Duration and Severity Impacts on Long-term Cardiovascular Events in Japanese Patients with Rheumatoid Arthritis

BACKGROUND Rheumatoid arthritis (RA) increases the mortality and morbidity of cardiovascular disease (CVD). However, the relationship between RA and the risk of CVD in the Japanese population remains unclear. METHODS AND RESULTS This study comprised 571 RA patients who were admitted to Juntendo University Hospital from January 1990 to December 2000. Cardiovascular events (CVEs) were defined as cardiac death, acute coronary syndrome (ACS), symptomatic stroke, and congestive heart failure. During follow-up (mean 11.7 ± 5.8 years), 7.5% of the patients died from all causes and 11.0% experienced CVEs. The morbidity of stroke and ACS was 3.6 and 2.5 per 1000 person-years, respectively. The mean RA disease duration at enrolment was significantly longer in patients who experienced CVEs than in those who did not experience CVEs (15.0 ± 12.7 years vs. 10. 8 ± 9.7 years; p = 0.01). Physical disabilities due to RA were more severe in patients who experienced CVEs than in those who did not experience CVEs. Patients with a long RA disease duration showed significantly higher event rates (p = 0.033). Cox proportional hazards analysis identified a longer RA duration as an independent risk factor for CVD (hazard ratio 1.57, 95% CI 1.09-2.30, p = 0.02). CONCLUSION Japanese RA patients showed a relatively high incidence of CVD, despite the fact that they had few coronary risk factors. The RA disease duration was an independent risk factor for CVEs.

Effect of cardiac rehabilitation on muscle mass, muscle strength, and exercise tolerance in diabetic patients after coronary artery bypass grafting

BACKGROUND The effects of cardiac rehabilitation (CR) on muscle mass, muscle strength, and exercise tolerance in patients with diabetes mellitus (DM) who received CR after coronary artery bypass grafting (CABG) have not been fully elucidated. METHODS We enrolled 78 consecutive patients who completed a supervised CR for 6 months after CABG (DM group, n=37; non-DM group, n=41). We measured mid-upper arm muscle area (MAMA), handgrip power (HGP), muscle strength of the knee extensor (Ext) and flexor (Flex), and exercise tolerance at the beginning and end of CR. RESULTS No significant differences in confounding factors, including age, gender, ejection fraction, or number of CR sessions, were observed between the two groups. At the beginning of CR, the levels of Ext muscle strength and peak VO2 were significantly lower in the DM group than in the non-DM group. At the end of CR, significant improvement in the levels of muscle strength, HGP, and exercise tolerance was observed in both groups. However, the levels of Ext muscle strength, HGP, peak VO2, thigh circumference, and MAMA were significantly lower in the DM group than in the non-DM group. In addition, no significant improvement in thigh circumference and MAMA was observed in the DM group. At the end of CR, the levels of thigh circumference and MAMA correlated with Ext and Flex muscle strength as well as with HGP. Percent changes in the levels of Ext muscle strength were significantly correlated with those of MAMA and hemoglobin A1c. CONCLUSIONS These data suggest that improvement in muscle strength may be influenced by changes in muscle mass and high glucose levels in DM patients undergoing CR after CABG. A CR program, including muscle mass intervention and blood glucose control, may improve deterioration in exercise tolerance in DM patients after CABG.