Mir Abolfazl Ostad

Effects of oral niacin on endothelial dysfunction in patients with coronary artery disease: Results of the randomized, double-blind, placebo-controlled INEF study

High-density-lipoproteins-cholesterol (HDL-C) is invertedly related to the incidence of cardiovascular events. Recent studies suggest that HDL-C directly improves endothelial function. Nicotinic acid (niacin) effectively raises serum HDL-C. We therefore hypothesized that treatment with niacin improves endothelial dysfunction in patients with coronary artery disease (CAD). One hundred seven patients with CAD were randomly assigned to double-blinded treatment for 12 weeks with extended-release (ER)-niacin 1000 mg/day (N) or placebo (C), respectively. Flow-mediated dilation (FMD) of the brachial artery, nitroglycerin-mediated endothelium-independent dilation (NMD) and serum lipid concentrations were measured before and after treatment. Triglycerides (P=0.013), low-density-lipoprotein-cholesterol (LDL-C) (P=0.013) and HDL-C (P<0.0001) were altered by N compared to C. Niacin treatment was without effect on FMD or NMD, respectively, compared to placebo. However, post-hoc subgroup analysis revealed an improvement in FMD in patients with low HDL-C at baseline (absolute change in FMD (mean+/-S.D.) N: +3.25+/-3.88%, C: +1.03+/-2.71% in low tertile HDL-C <or=45 mg/dl. P=0.047). The present findings indicate that ER-niacin treatment improves endothelial dysfunction in patients with CAD and low HDL-C, but not with normal HDL-C.

Flow-mediated dilation in patients with coronary artery disease is enhanced by high dose atorvastatin compared to combined low dose atorvastatin and ezetimibe: Results of the CEZAR study

BACKGROUND Effects independent from cholesterol reduction on vascular function are considered to importantly contribute to the beneficial effects of statin therapy in cardiovascular disease. We aimed to evaluate the effect of high versus low dose atorvastatin on endothelial dysfunction in patients with coronary artery disease (CAD) in a setting of comparable cholesterol reduction. METHODS AND RESULTS Fifty-eight patients with CAD were randomly assigned to double-blind treatment for 8 weeks with atorvastatin 80 mg per day (A80) or atorvastatin 10mg+ezetimibe 10mg per day (A10E10), respectively. Flow-mediated vasodilation (FMD) of the brachial artery, nitroglycerin-mediated endothelium-independent vasodilation (NMD), lipid, C-reactive protein (CRP) plasma concentrations and urinary 8-iso-prostaglandin F2alpha excretion were measured before and after treatment. Total cholesterol, triglycerides and LDL-cholesterol levels were significantly reduced with no difference between A80 and A10E10. A80 caused significantly stronger improvement of FMD compared to A10E10 (absolute change FMD: A80+2.7+/-3.0% (post vs. pre p<0.001), A10E10+0.6+/-2.9% (post vs. pre p=0.25), A80 vs. A10E10 p=0.018). NMD was improved by A80 but not by A10E10 (absolute change NMD: A80+2.7+/-4.6%, A10E10+0.7+/-3.5%, p=0.12). Both treatment groups caused a comparable reduction of CRP and did not effect urinary 8-iso-prostaglandin F2alpha excretion. There was no correlation between FMD or NMD change and LDL-cholesterol change in either treatment group. CONCLUSIONS The present findings clearly suggest that in the presence of comparable LDL-lowering effects of both treatment forms, LDL-cholesterol independent effects of high dose atorvastatin therapy account for the improvement of endothelium-dependent vasodilation in patients with stable CAD.

Cyclooxygenase 2-selective and nonselective nonsteroidal anti-inflammatory drugs induce oxidative stress by up-regulating vascular NADPH oxidases.

Cyclooxygenase 2-selective inhibitors (coxibs) and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increase in cardiovascular events. The current study was designed to test the effect of coxibs and nonselective NSAIDs on vascular superoxide and nitric oxide (NO) production. mRNA expression of endothelial NO synthase (eNOS) and of the vascular NADPH oxidases was studied in spontaneously hypertensive rats (SHR) and in human endothelial cells. The expression of Nox1, Nox2, Nox4, and p22phox was increased markedly by the nonselective NSAIDs diclofenac or naproxen and moderately by rofecoxib or celecoxib in the aorta and heart of SHR. The up-regulation of NADPH oxidases by NSAIDs was associated with increased superoxide content in aorta and heart, which could be prevented by the NADPH oxidase inhibitor apocynin. NSAIDs reduced plasma nitrite and diminished the phosphorylation of vasodilator-stimulated phosphoprotein. This demonstrates a reduction in vascular NO production. Aortas from diclofenac-treated SHR showed an enhanced protein nitrotyrosine accumulation, indicative of vascular peroxynitrite formation. Peroxynitrite can uncouple oxygen reduction from NO synthesis in eNOS. Accordingly, the eNOS inhibitor NG-nitro-l-arginine methyl ester reduced superoxide content in aortas of NSAID-treated animals, demonstrating eNOS uncoupling under those conditions. Also in human endothelial cells, NSAIDs increased Nox2 expression and diminished production of bioactive NO. In healthy volunteers, NSAID treatment reduced nitroglycerin-induced, NO-mediated vasodilatation of the brachial artery. These results indicate that NSAIDs may increase cardiovascular risk by inducing oxidative stress in the vasculature, with nonselective NSAIDs being even more critical than coxibs in this respect.

Monitoring White Blood Cell Mitochondrial Aldehyde Dehydrogenase Activity: Implications for Nitrate Therapy in Humans

Recent animal data suggest that reduced lipoic acid (LA) prevents oxidative inhibition of the nitrate bioactivating enzyme, the mitochondrial aldehyde dehydrogenase (ALDH-2), and that pentaerythritol tetranitrate (PETN) does not induce nitrate tolerance because of its intrinsic antioxidative properties, thereby preserving ALDH-2 activity. We sought to determine whether ALDH-2 activity in circulating white blood cells (WBCs) can be used to monitor nitrate tolerance and whether LA can prevent nitroglycerin tachyphylaxis in humans. Eight healthy male volunteers received, in randomized order, a single dose of glyceryl trinitrate (GTN; 0.8 mg), PETN (80 mg), or GTN plus LA (600 mg) orally. GTN (30 min) and PETN (120 min) administration lead to a comparable dilation of the brachial artery (15 ± 1%). In contrast to PETN, acute GTN treatment resulted in a 60% decrease in WBC ALDH-2 activity (high-performance liquid chromatography), 30% reduction of nitrate bioactivation, and 25% decrease in serum antioxidant capacity (fluorescence assay), which all were prevented by pretreatment with LA. Mechanistic studies in rats identified oxidative stress, ALDH-2 inactivation, and vascular dysfunction as common features in acute and chronic nitrate tolerance. Treatment with GTN, but not PETN, acutely inhibits ALDH-2 activity and nitrate bioactivation in healthy volunteers. These effects were prevented by LA pretreatment, emphasizing the role of oxidative stress-triggered ALDH-2 dysfunction. Assessment of WBC ALDH-2 activity could be used as an easily accessible marker for the detection of nitroglycerin-induced tachyphylaxis in humans and may be of high clinical interest because recent data suggest that ALDH-2 activity correlates with protection from ischemic heart damage in infarct models.

Impact of exaggerated blood pressure response in normotensive individuals on future hypertension and prognosis: Systematic review according to PRISMA guideline

PURPOSE Arterial hypertension (aHT) is the leading risk factor for morbidity and mortality worldwide. Blood pressure (BP) deviation at rest is well defined and accompanies risk for cardiovascular events and cardiovascular mortality. A growing body of evidence emphasises that an exaggerated blood pressure response (EBPR) in cardiopulmonary exercise testing (CPET) could help to identify seemingly cardiovascular healthy and normotensive subjects, who have an increased risk of developing aHT and cardiovascular events in the future. MATERIALS AND METHODS The PubMed online database was searched for published studies reporting exercise-related BP and both the risk of aHT and cardiovascular events in the future. RESULTS We identified 18 original studies about EBPR in CPET, which included a total of 35,151 normotensive individuals for prediction of new onset of aHT in the future and 11 original studies with 43,012 enrolled subjects with the endpoint of cardiovascular events in the future. Although an EBPR under CPET is not well defined, a large number of studies emphasise that EBPR in CPET is associated with both new-onset aHT and cardiovascular events in the future. CONCLUSIONS A growing number of studies support the hypothesis that EBPR in CPET may be a diagnostic tool to identify subjects with an elevated risk of developing aHT and cardiovascular events in the future.

Predictive value of brachial reactive hyperemia and flow-mediated dilation in stable coronary artery disease.

BACKGROUND The purpose of this study was to determine the predictive value of a single measurement of reactive hyperemia (RH) and brachial flow-mediated dilation (FMD) in patients with established stable coronary artery disease (CAD). METHODS RH and brachial artery FMD were ultrasonographically measured in 325 patients with stable CAD. Patients were followed for cerebro-cardiovascular events. The median follow-up was 3.7 years (range 0.01-5.7 years). RESULTS Sixty-seven patients (20.6%) had an cerebro-cardiovascular event. Patients with subsequent events had lower FMD (4.9 ± 3.3% versus 6.3 ± 3.5%, p = 0.003), higher brachial artery resting diameter (5.1 ± 0.7 mm versus 4.8 ± 0.7 mm, p = 0.002) and lower NMD (11.2 ± 5.1% versus 12.8 ± 5.4%, p = 0.02), while the mean hyperemic flow velocity and shear stress did not differ from patients without cerebro-cardiovascular events. Cox proportional hazard model adjusted for sex, age, BMI, and traditional cardiovascular risk factors revealed a hazard ratio of 0.84 for lower FMD (p = 0.01). CONCLUSIONS We conclude that single spot measurements of peak RH do not provide long-term prognostic information, but evaluation of conduit artery FMD predicts long-term cerebro-cardiovascular events in patients with stable CAD. The prognostic value of FMD is incremental to traditional cardiovascular risk factors and may therefore be of clinical importance.

Hypertension is strongly associated with false-positive bicycle exercise stress echocardiography testing results

Abstract Introduction: Exercise echocardiography is a reliable routine test in patients with known or suspected coronary artery disease. However, in ∼15% of all patients, stress echocardiography leads to false-positive stress echocardiography results. We aimed to investigate the impact of hypertension on stress echocardiographic results. Methods: We performed a retrospective study of patients with suspected or known stable coronary artery disease who underwent a bicycle exercise stress echocardiography. Patients with false-positive stress results were compared with those with appropriate results. Results: 126 patients with suspected or known coronary artery disease were included in this retrospective study. 23 patients showed false-positive stress echocardiography results. Beside comparable age, gender distribution and coronary artery status, hypertension was more prevalent in patients with false-positive stress results (95.7% vs. 67.0%, p = 0.0410). Exercise peak load revealed a borderline-significance with lower loads in patients with false-positive results (100.0 (IQR 75.0/137.5) vs. 125.0 (100.0/150.0) W, p = 0.0601). Patients with false-positive stress results showed higher systolic (2.05 ± 0.69 vs. 1.67 ± 0.39 mmHg/W, p = 0.0193) and diastolic (1.03 ± 0.38 vs. 0.80 ± 0.28 mmHg/W, p = 0.0165) peak blood pressure (BP) per wattage. In a multivariate logistic regression test, hypertension (OR 17.6 [CI 95% 1.9–162.2], p = 0.0115), and systolic (OR 4.12 [1.56–10.89], p = 0.00430) and diastolic (OR 13.74 [2.46–76.83], p = 0.00285) peak BP per wattage, were associated with false-positive exercise results. ROC analysis for systolic and diastolic peak BP levels per wattage showed optimal cut-off values of 1.935mmHg/W and 0.823mmHg/W, indicating false-positive exercise echocardiographic results with AUCs of 0.660 and 0.664, respectively. Conclusions: Hypertension is a risk factor for false-positive stress exercise echocardiographic results in patients with known or suspected coronary artery disease. Presence of hypertension was associated with 17.6-fold elevated risk of false-positive results.

Interferon- and ribavirin-free therapy with new direct acting antivirals (DAA) for chronic hepatitis C improves vascular endothelial function

INTRODUCTION Chronic Hepatitis C virus infection (HCV) is associated with extrahepatic manifestations and an increased prevalence in cardiovascular disease. New direct acting antivirals (DAA) have revolutionized HCV treatment with high rates of sustained virological response (SVR). Recently it was demonstrated, that SVR reduces morbidity and overall mortality more than can be solely explained by hepatic effects, suggesting that treatment with DAA also affects cardiovascular disease. The aim of this pilot study was to identify possible underlying mechanisms behind the HCV-associated cardiovascular mortality reported by others. METHODS AND RESULTS 20 HCV patients (10 genotype GT1, 10 GT3) were treated with interferon (IFN)- and ribavirin (RBV)-free DAA regimens for 12 weeks (SVR12). Primary endpoint was an improvement in endothelial function (flow-mediated dilation, FMD) at SVR12 compared to baseline. Patient demographics, FMD, markers for endothelial function and inflammation, coagulation and oxidative stress were measured at baseline, end of treatment and SVR12. All patients achieved SVR12. There was a significant increase in FMD from 9.4 ± 5.2% at baseline to 11.9 ± 4.5% at SVR12 (p = 0.04). Concomitantly, there were significant reductions in levels of endothelium-derived adhesion molecules E-selectin, VCAM-1 and ICAM-1. While APRI values were also significantly lower, liver stiffness did not change significantly. There were no relevant changes in systemic inflammation, oxidative stress, insulin resistance or coagulation pathways. CONCLUSIONS Successful DAA therapy was associated with improvements in endothelial function and a reduction of soluble adhesion molecules. Our findings indicate that HCV infection affects the endothelium and that DAA-treatment reverses these effects and enhances endothelial function.