Search

Background and Aims: This study investigated the association of leukocyte subtype counts with vascular endothelial dysfunction and future cardiovascular events in patients with coronary artery disease (CAD)., Methods: The study included 389 consecutive CAD patients (259 male, 130 female; mean age, 70.1 ± 9.9 years). The patients underwent coronary angiography, and measurement of blood parameters, including leukocyte subtype counts., Results: There were 84 cardiovascular events during a mean follow-up of 586 ± 378 days. Kaplan-Meier analysis showed a higher probability of cardiovascular events in the high-monocyte group (≥360/mm 3 ) compared with the low-monocyte group (<360/mm 3 ) (log-rank test, p = 0.047). Multivariate Cox hazard analysis identified a high monocyte count as an independent predictor of cardiovascular events (hazard ratio: 1.63, 95% confidence interval:1.05-2.51, p = 0.028). Peripheral endothelial function in 355 of the CAD patients was assessed by reactive hyperemia peripheral arterial tonometry index (RHI) to examine the association of ln-RHI with leukocyte subtype counts. Total leukocyte, monocyte and neutrophil counts were significantly higher in CAD patients with low ln-RHI (<0.57: the mean ln-RHI value) compared with those with high ln-RHI (≥0.57). Univariate analyses revealed that ln-RHI in CAD patients was positively correlated with ln-total leukocyte (r = -0.187, p < 0.001), ln-monocyte (r = 0.316, p < 0.001), and neutrophil (r = -0.175, p = 0.001) counts. Multiple regression analysis showed that the monocyte count was a significant and independent factor associated with ln-RHI (adjusted R 2  = 0.126, p < 0.001)., Conclusions: A high monocyte count was an independent and incremental predictor of cardiovascular events in CAD patients. The monocyte count was also significantly correlated with peripheral endothelial dysfunction in CAD patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Aims: Although dual low-density lipoprotein cholesterol (LDL-C)-lowering therapy (DLLT) with statin-ezetimibe combination showed clinical benefit in patients with acute coronary syndrome (ACS) confirming "the lower, the better," the underlying mechanisms of DLLT are still unknown., Methods: PRECISE-IVUS trial evaluated the effects of DLLT on IVUS-derived coronary atherosclerosis and lipid profile, compared with atorvastatin monotherapy, quantifying the coronary plaque response in 100 ACS patients. We explored the potential predictors of plaque regression., Results: Lower total cholesterol, LDL-C, triglyceride, remnant-like particles cholesterol, and stronger reduction of small dense LDL-C and cholesterol absorption markers were observed in patients with plaque regression compared to those with progression. Multivariate analysis revealed that achieved LDL-C was the strongest predictor for coronary plaque regression (95% CI: 0.944-1.000, p = 0.05), followed by age (95% CI: 0.994-1.096, p = 0.09)., Conclusions: Incremental LDL-C lowering by DLLT was associated with stronger coronary plaque regression, reconfirming that lowering LDL-C to levels below previous targets provided additional clinical benefit., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Aims: Whether adverse effect of statins on glycaemic indices is common to all statins remains controversial and as yet data for pitavastatin are limited. We sought to assess the effects of pitavastatin on glycaemia and new-onset diabetes (NOD) in non-diabetic individuals using data from RCT pooled together by means of a meta-analysis., Materials and Methods: We searched Medline, Cochrane, Embase and clinical trials registries websites until November-2014 for ≥12-week follow-up placebo or statin-controlled RCT of pitavastatin that included participants without diabetes and reported on fasting blood glucose (FBG), HbA1c or NOD. We additionally sought studies by consulting with Kowa Ph. Ltd. The association of pitavastatin with the outcomes were estimated by random-effects meta-analyses. Heterogeneity was assessed by the I(2) statistic and sensitivity and subgroup analyses, and publication bias with funnel plots and Egger and Harbord Tests., Results: 15 studies (approx. 1600 person-years) were included. No significant differences associated with pitavastatin (vs. control) were observed for FBG (MD -0.01 mg/dL [95%CI -0.77, 0.74], I(2) = 0%), HbA1c (MD -0.03% [95%CI -0.11, 0.05], I(2) = 43%) or NOD (RR 0.70 [95%CI 0.30, 1.61]; RD 0.0 [95%CI -0.004, 0.003]; I(2) = 0%). Sensitivity and subgroup analyses (including type of control [placebo or other statin], pitavastatin dose or follow-up] did not yield significant results. Potential publication bias may occur for NOD., Conclusions: In the present meta-analysis pitavastatin did not adversely affect glucose metabolism or diabetes development compared with placebo or other statins., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

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., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: Early statin therapy after acute coronary syndrome reduces atherothrombotic vascular events. This study aimed to compare the effects of hydrophilic and hydrophobic statins on myocardial salvage and left ventricular (LV) function in patients with ST-elevated myocardial infarction (STEMI)., Methods: Seventy-five STEMI patients who had received emergency reperfusion therapy were enrolled and randomized into the hydrophilic statin group (rosuvastatin; 5 mg/day, n = 38) and hydrophobic statin group (atorvastatin; 10 mg/day, n = 37) for 6 months. LV ejection fraction (LVEF), and B-type natriuretic peptide (BNP) and co-enzyme Q10 (CoQ10) levels were measured at baseline and the end of treatment. The myocardial salvage index was assessed by single photon emission computed tomography with (123-)I-β-methyl-iodophenylpentadecanoic acid (ischemic area-at-risk at onset of STEMI: AAR) and (201-)thallium scintigraphy (area-at-infarction at 6 months: AAI) [myocardial salvage index = (AAR-AAI) × 100/AAR (%)]., Results: Onset-to-balloon time and maximum creatine phosphokinase levels were comparable between the groups. After 6 months, rosuvastatin (-37.6% ± 17.2%) and atorvastatin (-32.4% ± 22.4%) equally reduced low-density lipoprotein-cholesterol (LDL-C) levels (p = 0.28). However, rosuvastatin (+3.1% ± 5.9%, p < 0.05), but not atorvastatin (+1.6% ± 5.7%, p = 0.15), improved LVEF. Rosuvastatin reduced BNP levels compared with atorvastatin (-53.3% ± 48.8% versus -13.8% ± 82.9%, p < 0.05). The myocardial salvage index was significantly higher in the rosuvastatin group than the atorvastatin group (78.6% ± 29.1% versus 52.5% ± 38.0%, p < 0.05). CoQ10/LDL-C levels at 6 months were increased in the rosuvastatin group (+23.5%, p < 0.01) and percent changes in CoQ10/LDL-C were correlated with the myocardial salvage index (r = 0.56, p < 0.01)., Conclusion: Rosuvastatin shows better beneficial effects on myocardial salvage than atorvastatin in STEMI patients, including long-term cardiac function, associated with increasing CoQ10/LDL-C., Clinical Trial Registration: URL http://www.umin.ac.jp/ctr/index.htm Unique Identifier: UMIN000003893., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Coenzyme Q10 levels are low in patients with coronary artery disease (CAD), and increasing or preserving coenzyme Q10 could be a beneficial strategy. Exercise and statins improve high-density lipoprotein cholesterol (HDL-C) levels. However, statins inhibit coenzyme Q10 biosynthesis, and the combination of statins with coenzyme Q10 supplementation increases HDL-C compared to statins alone. We compared the effects of two statins (rosuvastatin and atorvastatin) combined with exercise on coenzyme Q10 and HDL-C levels in CAD patients., Methods: After randomizing 28 CAD patients to rosuvastatin (n=14) and atorvastatin (n=14) groups, patients performed weekly in-hospital aerobic exercise and daily home exercise for 20 weeks. We measured serum lipids, ubiquinol, and exercise capacity., Results: Both statins equally improved exercise capacity and lowered low-density lipoprotein cholesterol and triglyceride levels. Rosuvastatin significantly increased HDL-C (rosuvastatin, +12 ± 9 mg/dL [+30%], atorvastatin, +5 ± 5 mg/dL [+13%], p=0.014) and apolipoprotein A1 (ApoA1) (rosuvastatin, +28.3 ± 20.7 mg/dL, atorvastatin, +13.4 ± 12.0 mg/dL, p=0.030) compared to atorvastatin. Atorvastatin significantly decreased serum ubiquinol (731 ± 238 to 547 ± 219 nmol/L, p=0.001), but rosuvastatin (680±233 to 668 ± 299 nmol/L, p=0.834) did not. There was a significant positive correlation between changes in ubiquinol and ApoA1 (r=0.518, p=0.005). Multivariate regression analysis showed that changes in ubiquinol correlated significantly with changes in ApoA1 after adjusting for age, sex, body mass index, and smoking (β=0.502, p=0.008)., Conclusions: Compared to atorvastatin, rosuvastatin combined with exercise significantly preserved ubiquinol levels associated with an increase in HDL-C. Rosuvastatin with regular exercise could be beneficial for CAD patients., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: The Impact of Nicorandil in Angina (IONA) trial demonstrated that the use of nicorandil, an anti-anginal drug, reduced future cardiovascular events in patients with stable angina. We hypothesized that nicorandil has beneficial effects on coronary arterial plaque characteristics and atherosclerogenesis., Methods and Results: Preintervention intravascular ultrasound-virtual histology was performed prospectively in 65 consecutive patients with stable angina pectoris. There were no differences in coronary risk factors between the nicorandil (n = 16) and non-nicorandil (n = 49) groups. However, the nicorandil group demonstrated a larger %fibrous tissue (68 ± 10 vs. 62 ± 11%, P = 0.049) and a smaller %necrotic core tissue (11 ± 7 vs. 16 ± 10%, P = 0.049) compared with the non-nicorandil group. Multiple regression analysis showed that %necrotic core tissue (P = 0.045) was negatively and %fibrous tissue (P = 0.026) was positively associated with the use of nicorandil independent of statin use. We also analyzed the effect of nicorandil on atherosclerotic lesion formation in a mouse model of atherosclerosis. Lipid profiles were unaffected, but the area of atherosclerotic lesion and plaque necrosis were significantly reduced following 8-week nicorandil treatment in ApoE-deficient mice fed an atherogenic diet. Nicorandil significantly reduced the expression levels of endoplasmic reticulum stress markers, C/EBP homologous protein (CHOP) and glucose regulated protein/BiP (GRP78) in atherosclerotic lesions. Nicorandil significantly attenuated tunicamycin-induced CHOP upregulation in cultured THP-1 macrophages., Conclusions: Nicorandil exerts its anti-atherogenic effect by mechanisms different from those of statins. Long-term nicorandil treatment is a potentially suitable second-line prevention therapy for patients with coronary artery disease., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: Several studies in experimental animals have shown that statins stabilize atheromatous plaques by increasing fibrous-cap thickness. However, direct evidence linking the use of statins to the incidence of plaque rupture in humans is lacking. We investigated whether statin treatment before the onset of ST-elevation myocardial infarction (STEMI) influences the incidence of plaque rupture detected by intravascular ultrasound (IVUS)., Methods: The study enrolled 458 patients with STEMI who were admitted within 6h from symptom onset. IVUS interrogation was performed before percutaneous coronary intervention., Results: Plaque ruptures were detected in 262 patients (57%). Patients with statin pretreatment (n=68) had a lower incidence of plaque rupture than those without (37% vs. 61%, p<0.001). Univariate analysis revealed that smoking (p=0.003), lower high-density lipoprotein cholesterol (p=0.001), and a lack of statin pretreatment (p<0.001) were associated with a higher incidence of plaque rupture. Multivariate logistic regression analysis identified statin pretreatment as a negative determinant of plaque rupture independent of age, gender, coronary risk factors, and all other medications (odds ratio 0.35; 95% CI 0.19-0.66, p=0.001). Positive remodeling was also associated with plaque rupture (p<0.001), and the relationship between statin pretreatment and a lower incidence of plaque rupture persisted after adjustment for positive remodeling (odds ratio 0.42; 95% CI 0.22-0.80, p=0.009)., Conclusions: Statin treatment before the onset of STEMI is associated with a lower incidence of plaque rupture, suggesting that the prevention of plaque rupture may be a crucial mechanism underlying clinical benefits associated with statins., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objectives: We sought to assess the association between inflammation in pericardial fat (PF) and coronary artery disease (CAD) by pathological examination and clinical evaluation with cardiac computed tomography (CT)., Background: Inflammation of adipose tissue is involved in cardio-metabolic disorders and shows high density in CT., Methods: We quantified, by immunohistochemical means, the PF inflammation in 39 autopsy cases by counting leukocyte common antigen (LCA)-positive cells. We then measured the CT density of PF in 39 patients with acute coronary syndromes and 69 patients suspected of CAD., Results: Pericoronary PF had significantly more LCA-positive cells in CAD autopsy cases (n=21) than non-CAD cases (n=18) (44 ± 21 vs. 24 ± 22 cells/mm(2), p=0.006). The CT density of PF around culprit lesions was significantly higher than non-culprit lesions in patients with acute coronary syndromes (-72 ± 11 vs. -82 ± 14 HU, p=0.002), which may reflect PF inflammation. Among patients suspected of CAD, the pericardial CT density gradient (PDG; difference in CT density between pericoronary PF and PF apart from coronary arteries) was significantly greater in CAD patients (n=30) than non-CAD patients (n=39) (22 ± 16 vs. 16 ± 10 HU, p=0.046). Multiple logistic regression analysis demonstrated that the PF inflammation index (PFI; PDG × PF volume, which could be the integrated index of inflammatory activity and abundance of PF) was significantly associated with the presence of CAD (odds ratio [95% confidence interval]; 1.234 [1.012-1.503] per 1000 HU cm(3), p=0.037) independent of other metabolic risk factors such as hypertension, dyslipidemia, and diabetes., Conclusions: Active inflammation in PF correlates with CAD. PF inflammation may be involved in pathogenesis of CAD., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The purpose of this study was to examine the association of pericardial fat with the presence of coronary plaques., Background: Waist circumference, reflecting abdominal obesity, is a risk factor of metabolic syndrome and coronary artery disease (CAD). Adipose tissue secretes many factors implicated in atherogenesis, however, the role of pericardial fat (ectopic visceral fat around coronary arteries) in the pathogenesis of CAD is not clear., Methods: We measured total pericardial fat volume (PFV) and determined presence and characteristics of coronary plaques using 64-slice computed tomography in 171 consecutive patients suspected of CAD (101 men; mean age, 66+/-11 years, +/-SD)., Results: PFV correlated with age (p<0.05), body mass index (p<0.05), waist circumference (p<0.01), and high-density lipoprotein cholesterol (p<0.01) by multivariate regression analysis. PFV was significantly larger in patients with coronary plaques, even nonstenotic or noncalcified ones, than those without plaques (any plaques, n=123; 201+/-71cm(3), nonstenotic plaques, n=51; 192+/-63, noncalcified plaques, n=32; 196+/-56 vs. no plaque, n=48; 144+/-45, p<0.001, respectively). Multivariate backward logistic regression analysis demonstrated that PFV, but not waist circumference, significantly associated with the presence of any coronary plaques (odds ratio [OR]; 2.876, 95% confidence interval [95% CI]; 1.614-5.125, p<0.001), nonstenotic plaques confirmed by coronary angiography (OR; 3.423, 95% CI; 1.764-6.642, p<0.001), and noncalcified plaques (OR; 3.316, 95% CI; 1.435-7.661, p<0.01)., Conclusions: PFV correlated significantly with the presence of nonstenotic and noncalcified coronary plaques assessed by multislice computed tomography. Pericardial fat is more highly associated with early development of CAD than simple anthropometric measures of abdominal obesity., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Reduced incidence of type-2 diabetes has been shown in patients treated with pravastatin. Adiponectin can exhibit beneficial effects on glucose metabolism. We investigated whether pravastatin could improve glucose tolerance associated with increasing adiponectin levels in patients with impaired glucose tolerance (IGT). This study consisted of 40 coronary artery disease (CAD) patients with IGT assessed by oral glucose tolerance test (OGTT). Patients were randomized to receive pravastatin (n=20) or no lipid-lowering medications (control group, n=20) for 6 months, after which OGTT was repeated and adiponectin levels were measured. Pravastatin treatment significantly decreased levels of total cholesterol (16%), low-density lipoprotein cholesterol (23%) and high-sensitivity C-reactive protein (37%) (p<0.01, respectively). At 2h in OGTT, pravastatin significantly improved hyperglycemia (-14%) and hyperinsulinemia (-23%). Pravastatin treatment significantly elevated plasma adiponectin levels (35%; p<0.001) but not in the control group. The glucose reduction at 2h post-OGTT was significantly associated with increased levels of adiponectin (r=-0.462; p=0.003). Pravastatin treatment is an independent predictor for improvement of post-loaded hyperglycemia (odds ratio; 5.7; 95% confidence interval 1.7-19.3; p=0.003) and achieved beneficial conversion from IGT to normal glucose tolerance (40%; p=0.03). Pravastatin exhibits beneficial effects on glucose metabolism especially in the postprandial state associated with increasing plasma adiponectin levels in CAD patients with IGT.

There is conflicting information about whether mortality after AMI is higher in women than men. We investigated the significance of plasma adiponectin concentrations on major adverse cardiac events (MACE) after acute myocardial infarction (AMI) to delineate any differences between men and women. The study patients consisted of 114 men and 42 women with AMI. The incidence of MACE was significantly higher in women than men during the entire follow-up period (p<0.05). Compared with men for post-AMI MACE, the hazard ratio for women was 5.6 after adjustment for prognostic factors. Killip class (p<0.001) and sex differences (p<0.05) were independent predictors of MACE at 1 year post-AMI. Plasma adiponectin levels in women were significantly higher than men on admission (8.66 microg/mL [range: 6.6-14.08] versus 4.71 microg/mL [range: 3.47-7.27], p<0.0001) and during the post-AMI course (all p<0.0001). Multivariate analysis identified plasma adiponectin level on admission as an independent predictor of MACE in men (p<0.001) and the difference between plasma adiponectin levels at discharge and on admission in women (p<0.05). Patterns of serial changes in plasma adiponectin concentrations are different between men and women and plasma adiponectin concentrations can be used to predict future adverse cardiac events in AMI patients.

Smooth muscle cells play an important role in human vascular diseases. Several lines of evidence demonstrate that circulating smooth muscle precursor cells contribute to intimal hyperplasia in animal models. We obtained large spindle cells expressing alpha-smooth muscle actin (alpha-SMA), denoted here as "smooth muscle-like cells" (SMLC), from human peripheral blood mononuclear cells (PBMC). SMLC derived from human PBMC proliferated readily and expressed pro-inflammatory genes during early culture. After long-term culture, SMLC could contract and express characteristic smooth muscle cell markers. We found peripheral blood mononuclear cell expressing alpha-smooth muscle actin in the circulating blood that bore CD14 and CD105. Sorted CD14/CD105 double-positive PBMC could differentiate into SMLC. The number of CD14-CD105-bearing PBMC increased significantly in patients with coronary artery disease compared to patients without coronary artery disease. These results support the novel concept that smooth muscle precursor cells exist in circulating human blood and may contribute to the pathogenesis of vascular diseases.