Hirofumi Maeda

A dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin, improves endothelial function and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice.

OBJECTIVES The aim of this study was to investigate the antiatherogenic effects of the dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin (DFS). BACKGROUND The new class of anti-type 2 diabetes drugs, dipeptidyl peptidase-4 inhibitors, improves glucose metabolism by increasing levels of active glucagon-like peptide (GLP)-1. METHODS Endothelial function was examined by acetylcholine-induced endothelium-dependent vasorelaxation using aortic rings and atherosclerotic lesion development in the entire aorta in apolipoprotein E-deficient mice fed a high-fat diet with or without DFS, and the antiatherogenic effects of DFS were investigated in cultured human macrophages and endothelial cells. Plasma levels of active GLP-1 were measured in patients with or without coronary artery disease. RESULTS DFS significantly improved endothelial dysfunction (89.9 ± 3.9% vs. 79.2 ± 4.3% relaxation at 10(-4) mol/l acetylcholine, p < 0.05) associated with increased endothelial nitric oxide synthase phosphorylation and reduced atherosclerotic lesion area (17.7% [15.6% to 25.8%] vs. 24.6% [19.3% to 34.6%], p < 0.01) compared with vehicle treatment. In cultured human macrophages, DFS significantly increased GLP-1-induced cytosolic levels of cyclic adenosine monophosphate compared with GLP-1 alone, resulted in inhibiting phosphorylation of c-jun N-terminal kinase and extracellular signal-regulated kinase 1/2 and nuclear factor-kappa B p65 nuclear translocation through the cyclic adenosine monophosphate/protein kinase A pathway, and suppressed proinflammatory cytokines (i.e., interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha) and monocyte chemoattractant protein-1 production in response to lipopolysaccharide. DFS-enhanced GLP-1 activity sustained endothelial nitric oxide synthase phosphorylation and decreased endothelial senescence and apoptosis compared with GLP-1 alone. In the human study, fasting levels of active GLP-1 were significantly lower in patients with coronary artery disease than those without (3.10 pmol/l [2.40 to 3.62 pmol/l] vs. 4.00 pmol/l [3.10 to 5.90 pmol/l], p < 0.001). CONCLUSIONS A DPP-4 inhibitor, DFS, exhibited antiatherogenic effects through augmenting GLP-1 activity in macrophages and endothelium.

Physical fitness Its contribution to serum high density lipoprotein

The effects of exercise conditioning on serum high density lipoprotein cholesterol (HDL-C) were studied using 20 members of a regular joggers club and other healthy non-member subjects of varying degrees of habitual physical activity (253 males and 391 females). Both the HDL-C and HDL-C/serum total cholesterol (TC) levels were significantly higher with the 20 regular joggers than with the sedentary controls matched for age, TC, serum triglycerides (TG) and weight index (WI). A significant correlation was found between HDL-C/TC and the exercise conditioning value obtained by using the results of the 12-min performance test as an index among the non-member subjects. In order to ascertain the relative significance of exercise conditioning in influencing HDL-C/TC, a multiple regression analysis was conducted using HDL-C/TC as the variable criterion. The results showed that TG affected HDL-C/TC the most among both males and females, while exercise conditioning affected it second among males and fourth among females.

Microvascular coronary artery spasm presents distinctive clinical features with endothelial dysfunction as nonobstructive coronary artery disease.

Background Angina without significant stenosis, or nonobstructive coronary artery disease, attracts clinical attention. Microvascular coronary artery spasm (microvascular CAS) can cause nonobstructive coronary artery disease. We investigated the clinical features of microvascular CAS and the therapeutic efficacy of calcium channel blockers. Methods and Results Three hundred seventy consecutive, stable patients with suspected angina presenting nonobstructive coronary arteries (<50% diameter) in coronary angiography were investigated with the intracoronary acetylcholine provocation test, with simultaneous measurements of transcardiac lactate production and of changes in the quantitative coronary blood flow. We diagnosed microvascular CAS according to lactate production and a decrease in coronary blood flow without epicardial vasospasm during the acetylcholine provocation test. We prospectively followed up the patients with calcium channel blockers for microvascular coronary artery disease. We identified 50 patients with microvascular CAS who demonstrated significant impairment of the endothelium-dependent vascular response, which was assessed by coronary blood flow during the acetylcholine provocation test. Administration of isosorbide dinitrate normalized the abnormal coronary flow pattern in the patients with microvascular CAS. Multivariate logistic regression analysis indicated that female sex, a lower body mass index, minor–borderline ischemic electrocardiogram findings at rest, limited–baseline diastolic-to-systolic velocity ratio, and attenuated adenosine triphosphate–induced coronary flow reserve were independently correlated with the presence of microvascular CAS. Receiver-operating characteristics curve analysis revealed that the aforementioned 5-variable model showed good correlation with the presence of microvascular CAS (area under the curve: 0.820). No patients with microvascular CAS treated with calcium channel blockers developed cardiovascular events over 47.8±27.5 months. Conclusions Microvascular CAS causes distinctive clinical features and endothelial dysfunction that are important to recognize as nonobstructive coronary artery disease so that optimal care with calcium channel blockers can be provided. Clinical Trial Registration URL: www.umin.ac.jp/ctr. Unique identifier: UMIN000003839.

Endothelial function and cardiovascular events in chronic kidney disease

BACKGROUND As patients with chronic kidney disease (CKD) are at high risk of developing coronary artery disease (CAD), it is important to stratify their cardiovascular risk. We investigated whether peripheral endothelial dysfunction is associated with the presence of CAD in patients with CKD and is a predictor of cardiovascular events. METHODS We enrolled 383 CKD patients with at least one coronary risk factor. Peripheral endothelial function was assessed by reactive hyperemia peripheral arterial tonometry index (RHI). The presence of CAD was determined by coronary angiography. Cardiovascular events were assessed during follow-up. RESULTS Ln-RHI was significantly lower in risk factor-matched CKD patients (n=323) than risk factor-matched non-CKD patients (n=323) (0.527 ± 0.192 vs. 0.580 ± 0.218, p=0.001). In CKD patients (n=383), Ln-RHI was significantly lower in CAD (0.499 ± 0.183, n=262) than non-CAD (0.582 ± 0.206, n=121) (p<0.001) patients. Multivariate logistic regression analysis identified Ln-RHI as an independent factor associated with the presence of CAD (p=0.001). During a mean follow-up period of 30 months, 90 cardiovascular events were recorded in CKD patients. Multivariate Cox hazard analysis identified low-Ln-RHI as an independent predictor of cardiovascular events (hazard ratio=2.70, 95% confidence interval=1.62-4.51, p<0.001). The predictive value of combined Ln-RHI and Framingham risk score (FRS) was evaluated by net reclassification index (NRI) and C-statistics, which showed significant improvement (NRI=22%, p<0.001) (C-statistics: FRS=0.49, FRS+Ln-RHI=0.62, p=0.005). CONCLUSIONS Endothelial function was significantly impaired in CKD patients and correlated with the presence of CAD. Severe endothelial dysfunction was an independent and incremental predictor of cardiovascular events in CKD.

Prognostic significance of peripheral microvascular endothelial dysfunction in heart failure with reduced left ventricular ejection fraction

BACKGROUND Endothelial dysfunction plays a crucial role in heart failure (HF), but the association between peripheral microvascular endothelial function assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) and prognosis remains unknown in HF with reduced left ventricular (LV) ejection fraction (HFREF). We prospectively investigated the association between peripheral microvascular endothelial function and HF-related near-future cardiovascular outcomes in HFREF patients. METHODSANDRESULTS The 362 HFREF patients (LVEF <50%) were followed for HF-related events (composite of cardiovascular death and HF hospitalization) up to 3 years. A natural logarithmic-scaled RH-PAT index (Ln-RHI) was obtained for each patient. A total of 82 HF-related events were recorded. The lower-RHI group (Ln-RHI ≤0.49, median) experienced a higher rate of HF-related events compared with the higher-RHI group by Kaplan-Meier analysis (30.9% vs. 14.4%, log-rank test: P<0.001). Multivariable Cox hazard analysis identified Ln-RHI as an independent predictor for HF-related events (per 0.1, hazard ratio: 0.84, 95% confidence interval: 0.75-0.95, P=0.005). Adding Ln-RHI to the Meta-analysis Global Group in Chronic HF risk score (MAGGICs) and Seattle Heart Failure Model (SHFM), powerful prognostic predictors of HF, significantly improved the net reclassification index (MAGGICs: 20.11%, P=0.02, SHFM: 24.88%, P<0.001), and increased the C-statistics for prediction of HF-related events (MAGGICs+Ln-RHI: from 0.612 to 0.670, SHFM+Ln-RHI: from 0.662 to 0.695). CONCLUSIONS Peripheral microvascular endothelial dysfunction assessed by RH-PAT was associated with future HF-related events in HFREF.

Reactive Oxygen Metabolites are Closely Associated With the Diagnosis and Prognosis of Coronary Artery Disease

Background Reactive oxygen species (ROS) are associated with development of coronary artery disease (CAD). However, theres no useful biomarker of ROS in CAD. Methods and Results We recruited 395 consecutive CAD patients who were performed coronary angiography (262 male and 133 female, age 70.2±10), and we measured serum derivatives of reactive oxidative metabolites (DROM) were measured. Two hundred twenty‐seven non‐CAD patients were also enrolled. We performed follow‐up study in these 395 CAD patients and case‐control study after risk factor and 1:1 pair matching (both, n=163). As subgroup analysis, DROM were also measured at the aortic root and the coronary sinus in 59 CAD patients. DROM were significantly higher in CAD patients (n=163, median [inter‐quartile range, IQR]=338 [302 to 386]) than in risk factor‐matched non‐CAD patients (n=163, 311 [282 to 352.5], effect size=0.33, P<0.001). During a mean follow‐up period of 20 months of 395 CAD patients, 83 cardiovascular events were recorded. Kaplan‐Meier analysis showed a higher probability of cardiovascular events in the high‐DROM group (>346 U.CARR) than in the low‐DROM group (≤346 U.CARR) (P=0.001 [log‐rank test]). Multivariate Cox hazard analysis identified ln‐DROM as an independent predictor for cardiovascular events (hazard ratio: 10.8, 95% confidence interval: 2.76 to 42.4, P=0.001). The transcardiac gradient of DROM was significantly higher in CAD patients than in non‐CAD patients (−2.0 [−9.0 to 9.0] versus 8 [−8.0 to 28.3], effect size=0.21, P=0.04), indicating that DROM production in coronary circulation is associated with development of CAD. Conclusion DROM are increased in CAD patients and associated with future cardiovascular events. DROM might provide clinical benefits for risk stratification of CAD. Clinical Trial Registration URL: http://www.umin.ac.jp/ctr/. Unique identifier: UMIN000012990.

Telmisartan enhances mitochondrial activity and alters cellular functions in human coronary artery endothelial cells via AMP-activated protein kinase pathway.

OBJECTIVE Mitochondrial dysfunction plays an important role in cellular senescence and impaired function of vascular endothelium, resulted in cardiovascular diseases. Telmisartan is a unique angiotensin II type I receptor blocker that has been shown to prevent cardiovascular events in high risk patients. AMP-activated protein kinase (AMPK) plays a critical role in mitochondrial biogenesis and endothelial function. This study assessed whether telmisartan enhances mitochondrial function and alters cellular functions via AMPK in human coronary artery endothelial cells (HCAECs). METHODS AND RESULTS In cultured HCAECs, telmisartan significantly enhanced mitochondrial activity assessed by mitochondrial reductase activity and intracellular ATP production and increased the expression of mitochondria related genes. Telmisartan prevented cellular senescence and exhibited the anti-apoptotic and pro-angiogenic properties. The expression of genes related anti-oxidant and pro-angiogenic properties were increased by telmisartan. Telmisartan increased endothelial NO synthase and AMPK phosphorylation. Peroxisome proliferator-activated receptor gamma signaling was not involved in telmisartan-induced improvement of mitochondrial function. All of these effects were abolished by inhibition of AMPK. CONCLUSIONS Telmisartan enhanced mitochondrial activity and exhibited anti-senescence effects and improving endothelial function through AMPK in HCAECs. Telmisartan could provide beneficial effects on vascular diseases via enhancement of mitochondrial activity and modulating endothelial function through AMPK activation.

Incremental Prognostic Significance of the Elevated Levels of Pentraxin 3 in Patients With Heart Failure With Normal Left Ventricular Ejection Fraction

Background Pentraxin 3 (PTX3) is a novel inflammatory marker produced by various cell types including those of the vasculature and the heart. The relationship between inflammatory markers and prognosis of patients with heart failure with normal ejection fraction (HFNEF) remains unknown. We investigated whether plasma PTX3 levels can predict future cardiovascular events in patients with HFNEF. Methods and Results Plasma PTX3, high‐sensitivity C‐reactive protein, and B‐type natriuretic peptide levels were measured prospectively in 360 stable patients with HFNEF. The subsequent incidence of cardiovascular events, including cardiovascular death, nonfatal myocardial infarction (MI), unstable angina pectoris, nonfatal ischemic stroke, hospitalization for heart failure decompensation, and coronary revascularization, was determined. During a mean 30‐month follow‐up, 106 patients experienced cardiovascular events. These events were more frequent in patients with high plasma PTX3 levels (>3.0 ng/mL) than low levels (≤3.0 ng/mL). Multivariable Cox hazard analysis showed that PTX3 (hazard ratio: 1.16; 95% CI: 1.05 to 1.27; P<0.01) and B‐type natriuretic peptide (hazard ratio: 1.08; 95% CI: 1.03 to 1.14; P<0.001), but not high‐sensitivity C‐reactive protein levels, were significant predictors of future cardiovascular events. Multivariable Cox analysis with the forced inclusion model, including 5 previously identified prognostic factors, found that PTX3 was a significant predictor of cardiovascular events (hazard ratio: 1.16; 95% CI: 1.06 to 1.27; P<0.01). The C‐statistics for cardiovascular events substantially increased from 0.617 to 0.683 when PTX3 was added to the 5 previously identified prognostic factors. Conclusions High plasma PTX3 levels, but not other inflammatory markers, are correlated with future cardiovascular events in patients with HFNEF. PTX3 may be a useful biomarker for assessment of risk stratification in HFNEF. Clinical Trial Registration URL: http://www.umin.ac.jp; Unique identifier: UMIN000002170.

Relationship between inter-arm blood pressure differences and future cardiovascular events in coronary artery disease.

Objective: Recent studies have shown that inter-arm blood pressure differences (IAD) may be a risk factor for cardiovascular events; however, none have addressed them in patients with coronary artery disease (CAD). Methods: We measured blood pressure bilaterally with the ankle brachial index (ABI) in 657 patients with suspected CAD and assessed the presence of CAD by coronary angiography, and the severity of coronary atherosclerosis with the Gensini score. Results: Mean IADs were significantly greater in risk factor matched patients with CAD than in those without it (P = 0.01), whereas Gensini scores were significantly greater in those with high IAD (≥10 mmHg) than in those with low-IAD (P = 0.01) according to cross-sectional analysis. Patients with high IAD had a significantly greater probability of cardiovascular events than those in whom it was low (log-rank test, P < 0.01, mean follow-up range; 827.3 ± 268.1 days). The presence of hypertension, ABI, usage of calcium channel blocker and high IAD were independent predictors of cardiovascular events according to longitudinal analysis (IAD; hazard ratio: 2.90, 95% confidence interval: 1.41–5.94, P < 0.01) in these patients. Patients with high IAD and peripheral artery disease had the highest Gensini scores according to cross-sectional analysis (P < 0.01) and highest probability of cardiovascular events according to longitudinal analysis (log-rank test, P < 0.001). Conclusion: IADs were increased in CAD patients and correlated with its severity. Greater than 10 mmHg of IAD was independently associated with future cardiovascular events. Assessing IAD by ABI measurement may facilitate risk stratification in CAD patients.

Low-Normal Serum Sodium and Heart Failure-Related Events in Patients With Heart Failure With Preserved Left Ventricular Ejection Fraction.

BACKGROUND Hyponatremia has been shown to be a prognostic factor in heart failure (HF) with preserved ejection fraction (HFpEF). Serum sodium (sNa) cut-off, however, is not defined in HFpEF. Therefore, we investigated the relationship between sNa and HF-related events (cardiovascular death and hospitalization for HF decompensation) in HFpEF patients. METHODSANDRESULTS We assessed cardiac function using echocardiography and measured sNa in HFpEF patients with New York Heart Association class II (n=321) or III (n=84) in a compensated condition after implementing medical therapy for HF. During a mean follow-up of 27 months, 73 patients developed HF-related events. On multivariate Cox hazard analysis including established predictors in HF, sNa level as a continuous variable was identified as an independent predictor for HF-related events in HFpEF (per 1.0 mmol/L: HR, 0.93; 95% CI: 0.87-0.98; P<0.01). Kaplan-Meier analysis demonstrated significantly higher probability of HF-related events in the lower sNa group (sNa <140 mmol/L) than in the higher sNa group (sNa ≥140 mmol/L; P<0.001, log-rank test). Further, the low-normal sNa group (135 mmol/L<sNa<140 mmol/L) was significantly associated with HF-related events compared with the higher sNa group (P<0.001, log-rank test). CONCLUSIONS sNa as a continuous variable was independently correlated with future HF-related events in HFpEF. Low-normal sNa could provide important prognostic information for practical risk stratification in HFpEF.