Endothelial Protection, AT1 Blockade and Cholesterol-Dependent Oxidative Stress: The EPAS Trial (original) (raw)
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Circulation, 2011
Background-Treatment with statins improves clinical outcome, but the exact mechanisms of pleiotropic statin effects on vascular function in human atherosclerosis remain unclear. We examined the direct effects of atorvastatin on tetrahydrobiopterin-mediated endothelial nitric oxide (NO) synthase coupling in patients with coronary artery disease. Methods and Results-We first examined the association of statin treatment with vascular NO bioavailability and arterial superoxide (O 2 ·Ϫ ) in 492 patients undergoing coronary artery bypass graft surgery. Then, 42 statin-naïve patients undergoing elective coronary artery bypass graft surgery were randomized to atorvastatin 40 mg/d or placebo for 3 days before surgery to examine the impact of atorvastatin on endothelial function and O 2 ·Ϫ generation in internal mammary arteries. Finally, segments of internal mammary arteries from 26 patients were used in ex vivo experiments to evaluate the statin-dependent mechanisms regulating the vascular redox state. Statin treatment was associated with improved vascular NO bioavailability and reduced O 2 ·Ϫ generation in internal mammary arteries. Oral atorvastatin increased vascular tetrahydrobiopterin bioavailability and reduced basal and N-nitro-L-arginine methyl ester-inhibitable O 2 ·Ϫ in internal mammary arteries independently of low-density lipoprotein lowering. In ex vivo experiments, atorvastatin rapidly improved vascular tetrahydrobiopterin bioavailability by upregulating GTP-cyclohydrolase I gene expression and activity, resulting in improved endothelial NO synthase coupling and reduced vascular O 2 ·Ϫ . These effects were reversed by mevalonate, indicating a direct effect of vascular hydroxymethylglutaryl-coenzyme A reductase inhibition.
The evolving role of statins in the management of atherosclerosis
Journal of the American College of Cardiology, 2000
Significant advances in the management of cardiovascular disease have been made possible by the development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors-"statins." Initial studies explored the impact of statin therapy on coronary artery disease (CAD) progression and regression. Although the angiographic changes were small, associated clinical responses appeared significant. Subsequent large prospective placebocontrolled clinical trials with statins demonstrated benefit in the secondary and primary prevention of CAD in subjects with elevated cholesterol levels. More recently, the efficacy of statins has been extended to the primary prevention of CAD in subjects with average cholesterol levels. Recent studies also suggest that statins have benefits beyond the coronary vascular bed and are capable of reducing ischemic stroke risk by approximately one-third in patients with evidence of vascular disease. In addition to lowering low-density lipoprotein (LDL) cholesterol, statin therapy appears to exhibit pleiotropic effects on many components of atherosclerosis including plaque thrombogenicity, cellular migration, endothelial function and thrombotic tendency. Growing clinical and experimental evidence indicates that the beneficial actions of statins occur rapidly and yield potentially clinically important antiischemic effects as early as one month after commencement of therapy. Future investigations are warranted to determine threshold LDL values in primary prevention studies, and to elucidate effects of statins other than LDL lowering. Finally, given the rapid and protean effects of statins on determinants of platelet reactivity, coagulation, and endothelial function, further research may establish a role for statin therapy in acute coronary syndromes.
American Heart Journal, 2005
Background Recent data suggest an early outcome benefit with reduction in cholesterol using statin therapy in patients with coronary artery disease (CAD). This may be caused by effects of low-density lipoprotein cholesterol (LDL-C) reduction on endothelial function and vascular reactivity in the coronary bed. The aim of this randomized placebo-controlled study was to examine the early effects of important reductions in LDL-C on myocardial perfusion and peripheral endothelial function. Methods and Results Seventy-two patients with CAD and LDL-C between 3.0 and 5.9 mmol/L (116-228 mg/dL) were randomized to receive simvastatin 20 mg daily, pravastatin 40 mg daily, or placebo for 8 weeks. At baseline, 2 weeks, and 8 weeks, patients underwent dynamic positron emission tomography perfusion imaging to quantify the retention of rubidium-82 as a measure of myocardial flow at rest and after dipyridamole stress. Patients also underwent brachial artery ultrasound to measure endothelium-dependent flow-mediated vasodilatation. At 2 and 8 weeks, the simvastatin and pravastatin groups showed a significant reduction (P b .001) in LDL-C compared with placebo. At 8 weeks, simvastatin led to an improvement in flow-mediated vasodilatation compared with placebo (6.86% F 4.4% vs 3.44% F 4.0%, P b .05), whereas pravastatin was not significantly different than placebo (5.62% F 4.1% vs 3.44% F 4.0%, P = NS). Despite this improvement in peripheral endothelial function with simvastatin, there were no significant differences observed in global stress flow and coronary flow reserve at 8 weeks with either drug. Conclusions Short-term LDL reduction with simvastatin therapy improves peripheral endothelial function in patients with stable CAD, although an early effect on coronary vascular reactivity could not be demonstrated.
Journal of Pharmacology and Toxicology, 2023
Atherosclerosis and its complications represent the major cause of death in developed countries. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A [HMGCoA] reductase and consequently inhibitors of cholesterol biosynthesis. Statins have been described as the most potent class of drugs to reduce serum cholesterol levels. In clinical trials, statins are beneficial in primary and secondary prevention of coronary heart disease. Statins, were initially designed as cholesterol-lowering drugs. However, these drugs, besides their lipid-lowering properties, exert a number of protective effects on the cardiovascular system that emerged over the past years. The benefits observed with statin treatment appear to be greater than that might be expected from reduction in lipid levels alone, suggesting effects beyond cholesterol lowering. These cholesterol-independent effects have been called "pleiotropic". The cholesterol-independent or "pleiotropic" effects of statins involve improvement of endothelial function, stability of atherosclerotic plaques, decrease of oxidative stress and inflammation, and inhibition of thrombogenic response. These pleiotropic effects of statins have been proposed as key properties of these drugs to reduce cardiovascular morbidity and mortality. The present review will emphasize the molecular mechanisms underlying the effects of statins on endothelial function and oxidative stress. In particular, inhibition of small GTP-binding proteins, Rho, Ras and Rac, which are regulated by isoprenoids [farnesyl pyrophosphate and geranylgeranyl pyrophosphate], seems to play an important role in mediating the pleiotropic effects of statins.
The role of statins in endothelial dysfunction in hypertension
Current Opinion in Cardiology, 2006
Purpose of review Hypertension and dyslipidemia frequently coexist, and endothelial dysfunction is associated with the pathophysiology of both atherosclerosis and hypertension. Evidence is convincing for an overlapping role of oxidative stress, renin-angiotensin system activation, and dyslipidemia in the genesis of endothelial dysfunction. Recent findings Ample experimental and human data suggest that common cellular pathways are involved in the pathogenesis of hypertension, increased vascular resistance, and plaque formation. Multiple interventions such as dietary modification, exercise, antioxidants, and antihypertensive drugs improve endothelial dysfunction in hypertension. Statin drugs are a cornerstone of dyslipidemia therapy. Studies have demonstrated that statins correct endothelial function and vascular stiffening and may be useful in reducing blood pressure to target levels. Summary Statins may be a useful adjunct in the treatment of hypertension in patients with dyslipidemia and possibly those with normal cholesterol levels.
Impact of Statins in Ischemic Heart Disease
2011
Mortality and morbidity are still high in cardiovascular disease. Myocardial ischemia reperfusion injury leading to myocardial infarction is one of the most frequent causes of the death in human. Atherosclerosis is the major risk factor for cardiovascular disease. Coronary artery disease is a common and serious condition due to an underlying pathology of atherosclerosis, which is caused mainly by increased levels of low-density lipoprotein that accumulate in the walls of the coronary arteries. The main treatment option for high cholesterol levels is a group of cholesterol-lowering drugs called HMGCoA reductase inhibitors (statins). They act mainly on the liver enzymes responsible for cholesterol synthesis, reducing the production of cholesterol. HMG-CoA reductase inhibitors (statins) have now become one of the most powerful pharmacological strategies in the treatment of cardiovascular diseases. Originally, the cardioprotective effects of statins were thought to be mediated through l...
Atherosclerosis, 2009
Statins have been demonstrated to significantly affect the prognosis and outcome of patients with risk factors to atherosclerosis (in primary and secondary prevention trials). Several clinical and recently basic studies have suggested an extra-beneficial effect of the statins in the prevention of atherosclerosis and coronary artery disease. These studies showed that statins may affect the cardiovascular system beyond their effect on the lipid profile, and it was suggested that they affect the immunological system and vascular inflammation. Many of the beneficial pleiotropic effects of statins occur as a result of modulated endothelial function and reduced inflammatory processes. Attempting to understand these properties of statins is an exciting field of research that will also improve our understanding of vascular biology in health and disease, and thus enable the better use of this drug class in clinical practice.
Journal of clinical medicine research, 2014
Accumulating evidence suggests that inflammatory mechanisms play a central role in the development, progression and outcome of atherosclerosis. Recent evidence suggests that statins improve anti-inflammatory, anti-thrombotic and endothelial functions, along with their lipid-decreasing effects. We examined the effect of statins on endothelial function using biochemical markers of endothelial dysfunction and brachial artery flow-mediated dilatation (FMD). Thirty male patients presenting with acute coronary syndrome (ACS) and 26 age-matched healthy control subjects aged 40 - 60 years who were not on any medication were enrolled in the study. The patient group was started on atorvastatin (40 mg/day) without consideration of their low-density lipoprotein (LDL)-cholesterol levels. Endothelin, sICAM and E-selectin from stored serum samples were measured using commercially available enzyme-linked immunosorbant assays (ELISAs). Endothelial function was assessed using brachial artery FMD. Pri...