Makoto Hiki

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.

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.

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.

Association between myocardial triglyceride content and cardiac function in healthy subjects and endurance athletes.

Ectopic fat accumulation plays important roles in various metabolic disorders and cardiovascular diseases. Recent studies reported that myocardial triglyceride (TG) content measured by proton magnetic resonance spectroscopy (1H-MRS) is associated with aging, diabetes mellitus, and cardiac dysfunction. However, myocardial TG content in athletes has not yet been investigated. We performed 1H-MRS and cardiac magnetic resonance imaging in 10 male endurance athletes and 15 healthy male controls. Serum markers and other clinical parameters including arterial stiffness were measured. Cardiopulmonary exercise testing was also performed. There were no significant differences in clinical characteristics including age, anthropometric parameters, blood test results, or arterial stiffness between the two groups. Peak oxygen uptakes, end–diastolic volume (EDV), end–systolic volume (ESV), left ventricular (LV) mass, peak ejection rates and peak filling rates were significantly higher in the athlete group than in the control group (all P<0.02). Myocardial TG content was significantly lower in the athlete group than in the control group (0.60±0.20 vs. 0.89±0.41%, P<0.05). Myocardial TG content was negatively correlated with EDV (r = −0.47), ESV (r = −0.64), LV mass (r = −0.44), and epicardial fat volume (r = 0.47) (all P<0.05). In conclusion, lower levels of myocardial TG content were observed in endurance athletes and were associated with morphological changes related to physiological LV alteration in athletes, suggesting that metabolic imaging for measurement of myocardial TG content by 1H-MRS may be a useful technique for noninvasively assessing the “athlete’s heart”.

Effects of fenofibrate on lipid profiles, cholesterol ester transfer activity, and in-stent intimal hyperplasia in patients after elective coronary stenting

BackgroundThe association between modulation of detailed lipoprotein profiles and cholesterol ester transfer (CET) activity by peroxisome proliferator-activated receptor (PPAR)-a agonists in patients with coronary artery disease remains unclear. We assessed lipid profiles, plasma CET activity, and in-stent intimal hyperplasia after fenofibrate treatment in patients who underwent elective coronary stenting.MethodsForty-three consecutive patients who underwent elective coronary stenting were randomized to the fenofibrate group (300 mg/day for 25 weeks, n = 22) or the control group (n = 21). At baseline and follow up, CET activity and lipoprotein profiles were measured, and quantitative coronary angiography was performed.ResultsIn the fenofibrate group, the levels of large very low-density lipoprotein cholesterol, and small low-density lipoprotein (LDL) cholesterol decreased and those of small high-density lipoprotein (HDL) cholesterol increased. Besides, CET activity decreased independent of the effect of fenofibrate on total and LDL cholesterol. The reduction of CET activity significantly correlated with the increase in LDL particle size (r = 0.47, P = 0.03) and the decrease of triglycerides in large HDL subclasses (r = 0.48, P = 0.03). Although there were no significant differences in restenosis parameters between the two groups, low CET activity significantly correlated with the inhibition of neointimal hyperplasia (r = 0.56, P = 0.01).ConclusionsFenofibrate inhibited CET activity and thereby improved atherogenic lipoprotein profiles, and reduced intimal hyperplasia after coronary stenting.

Clinical significance of the measurements of urinary liver-type fatty acid binding protein levels in patients with acute coronary syndrome

BACKGROUND Recently, much attention has been focused on cardio-renal interaction. Urinary liver-type fatty acid binding protein (U-L-FABP), which is produced in the proximal tubule by renal hypoxia and oxidative stress, has been identified as a useful marker for diagnosis of acute kidney disease and a predictor of future events in chronic kidney disease. However, the clinical significance of U-L-FABP measurements in patients with acute coronary syndrome (ACS) has not been completely evaluated. METHODS AND RESULTS This study included 50 consecutive patients with ACS [37 with acute myocardial infarction (AMI) and 13 with unstable angina pectoris (UAP)] and 47 subjects without coronary artery disease (control group). U-L-FABP levels, urinary albumin (U-Alb), and other serum parameters were measured at admission and at 24 h after percutaneous coronary intervention. RESULTS U-L-FABP levels in patients with AMI were significantly higher (p=0.0019), than in control subjects, while patients with UAP did not exhibit such an increase. U-L-FABP levels at admission were positively correlated with brain natriuretic protein levels (p=0.001) and duration of hospitalization (p=0.025). At follow-up angiography, patients with restenosis had significantly higher U-L-FABP (p=0.047) and U-Alb levels (p<0.0001) than those without restenosis. After a median follow-up of 42 months, U-L-FABP levels at second measurement in patients with major adverse cardiocerebrovascular events (MACCEs) were significantly higher than those in patients without MACCEs (p=0.028). After adjusting for confounding factors, high U-L-FABP levels at second measurement were found to be independent factors for MACCEs (p=0.019). CONCLUSIONS These data suggest that patients with ACS, especially those with AMI, have high U-L-FABP levels, and that U-L-FABP measurements may be useful in identifying high-risk patients for future cardiovascular events after ACS.

Prognostic Value of Coronary Computed Tomography (CT) Angiography and Coronary Artery Calcium Score Performed Before Revascularization

Background Cardiac events after revascularization are equally attributable to recurrence at site of culprit lesions and development of nonculprit lesions. We evaluated the hypothesis that coronary computed tomography (CT) angiography and coronary artery calcium score (CACS) performed before revascularization predicts cardiac events after treatment. Methods and Results Among 2238 consecutive patients without known coronary artery disease who underwent coronary CT angiography and CACS, 359 patients underwent revascularization within 30 days after CT; in 337 of 359 (93.9%) follow-up clinical information was available. In addition to known cardiac risk factors, CT findings were evaluated as predictors of cardiac events after revascularization: CACS and the presence of CT-verified high-risk plaque (CT-HRP). Improvement of predictive accuracy by including CT findings was evaluated from a discrimination (Harrell’s C-statistics) standpoint. During the follow-up period (median: 673, interquartile range: 47 to 1529 days), a total of 98 cardiac events occurred. Cox proportional hazard model revealed that age, diabetes, triglyceride, CACS, and nonculprit CT-HRP were significant predictors of overall cardiac events. Although not statistically significant, discriminatory power was greater for the model with CACS (C-stat: 63.2%) and the model with both CACS and CT-HRP (65.8%) compared to the model including neither CACS nor CT-HRP (60.7%). Conclusions High CACS and the presence of nonculprit CT-HRP performed before revascularization are significant predictors of cardiac events after revascularization.

High hexacosanoic acid levels are associated with coronary artery disease

AIMS Levels of saturated very long chain fatty acids (VLCFAs) are associated with coronary risk factors, including metabolic syndrome (MS), atherogenic lipoproteins, and systemic inflammation. However, the relationship between circulating levels of saturated VLCFA and coronary artery disease (CAD) remains unclear. METHOD We enrolled 100 consecutive CAD patients and 40 age-, gender-, and body mass index (BMI)-matched healthy control subjects. The levels of hexacosanoic acid (C26:0), a VLCFA, in whole blood were measured by gas-liquid chromatography mass spectrometry. RESULTS C26:0 levels were significantly higher in the CAD group than in the control group (2.42±0.32 vs. 2.27±0.24 μg/ml, P=0.01) and positively correlated with BMI (r=0.23, P=0.008), triglyceride levels (r=0.22, P=0.01), and hypertension (P=0.01). CAD patients with MS showed the highest C26:0 levels adjusted by hematocrit. Furthermore, adjusted C26:0 levels in CAD patients without MS were higher than those in controls (P=0.02), suggesting that C26:0 levels increased with the presence of CAD independent of MS. Our multivariate analysis revealed that high C26:0 levels in whole blood is an independent marker for CAD even after adjustment for age, gender, BMI, lipid profiles, fasting plasma glucose, and blood pressure. CONCLUSION High C26:0 levels in whole blood may be an independent marker for identifying the risks of CAD.