Cardiac effects of statins—advancements and open questions (original) (raw)
Related papers
Statin mediated protection of the ischemic myocardium
Vascular Pharmacology, 2005
Hypercholesterolemia is a major risk factor in the development of cardiovascular disease and HMG-CoA reductase inhibitors (i.e. statins) were originally designed to reduce serum cholesterol levels and thus reduce this risk factor. However, it has become increasingly apparent that the effects of statins extend well beyond their lipid lowering actions, and these pleiotropic effects have a major role in protecting the myocardium against ischemic injury. There have been a large number of clinical studies demonstrating the safety and efficacy of statins in reducing total mortality as well as many other secondary endpoint markers in patients with cardiovascular disease. In addition, statins appear to benefit patients with a variety of clinical conditions such as acute coronary syndromes and severe heart failure. Recent experimental studies demonstrated that stains can rapidly (i.e. within hours) upregulate endothelial nitric oxide synthase (eNOS) activity and nitric oxide (NO) production. These landmark studies of statins and eNOS function set the foundation for the investigation of the protective effects of statins. Many experimental studies investigating the effects of statins on eNOS and cardiac injury in the setting of ischemia and reperfusion have been performed in an attempt to determine the extent of the protection as well as the mechanism of the protection. This review article will focus on our current understanding of statin-mediated protection of the myocardium against ischemiareperfusion injury and infarction. D
Pleiotropic effects of statins: A boulevard to cardioprotection
Arabian Journal of Chemistry, 2016
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, referred to as ''statins'' have been extensively reported to possess lipid lowering effects by inhibiting the synthesis of cholesterol by liver and thereby increasing hepatic cholesterol uptake and reducing circulating lipid levels. Growing body of evidences have shown that apart from lipid lowering effects, statins possess various pleiotropic effects that include improvement in endothelial dysfunction, increased expression of endothelial nitric oxide synthase (eNOS), enhanced bioavailability of nitric oxide (NO), potent antioxidant potential and anti-inflammatory properties. In relation to cardiovascular pathologies, statins have been shown to inhibit atrial myocardial remodeling, prevent atrial fibrillation, conserve NO production in heart failure, reduce activity of small G-proteins in cardiac hypertrophy and protect the myocardium from lethal ischemia/reperfusion (I/R) injury. The mechanisms underlying the cardioprotective potential include phosphatidyl inositol (PI3)-kinase/Akt/eNOS pathway, subsequent activation of ATP sensitive potassium (K ATP) channels by NO resulting in improved myocardial metabolism, release of endogenous adenosine by increasing the activity of adenosine forming enzyme ecto-5V-nucleotidase, inhibition of reactive oxygen species (ROS) production, decrease in oxidative stress and attenuation of apoptosis. The present review article demonstrates the pleiotropic effects of statins beyond their lipid lowering effects. Moreover, the underlying mechanisms involved in stain-induced cardioprotection have been delineated.
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...
… and Vascular Biology, 2011
Objective-Clinical trials of statins during myocardial infarction (MI) have differed in their therapeutic regimes and generated conflicting results. This study evaluated the role of the timing and potency of statin therapy on its potential mechanisms of benefit during MI. Methods and Results-ST-elevation MI patients (nϭ125) were allocated into 5 groups: no statin; 20, 40, or 80 mg/day simvastatin starting at admission; or 80 mg/day simvastatin 48 hours after admission. After 7 days, all patients switched their treatment to 20 mg/day simvastatin for an additional 3 weeks and then underwent flow-mediated dilation in the brachial artery. As of the second day, C-reactive protein (CRP) differed between non-statin users (12.0Ϯ4.1 mg/L) and patients treated with 20 (8.5Ϯ4.0 mg/L), 40 (3.8Ϯ2.5 mg/L), and 80 mg/day (1.4Ϯ1.5 mg/L), and the daily differences remained significant until the seventh day (PϽ0.0001). The higher the statin dose, the lower the elevation of interleukin-2 and tumor necrosis factor-␣, the greater the reduction of 8-isoprostane and low-density lipoprotein(Ϫ), and the greater the increase in nitrate/nitrite levels during the first 5 days (PϽ0.001). Later initiation of statin was less effective than its early introduction in relation to attenuation of CRP, interleukin-2, tumor necrosis factor-␣, 8-isoprostane, and low-density lipoprotein(Ϫ), as well as in increase in nitrate/nitrite levels (PϽ0.0001). At the 30th day, there was no longer a difference in lipid profile or CRP between groups; the flow-mediated dilation, however, was proportional to the initial statin dose and was higher for those who started the treatment early (Pϭ0.001). Conclusion-This study demonstrates that the timing and potency of statin treatment during MI are key elements for their main mechanisms of benefit. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00906451.
Atherosclerosis Supplements, 2011
Objective-Clinical trials of statins during myocardial infarction (MI) have differed in their therapeutic regimes and generated conflicting results. This study evaluated the role of the timing and potency of statin therapy on its potential mechanisms of benefit during MI. Methods and Results-ST-elevation MI patients (nϭ125) were allocated into 5 groups: no statin; 20, 40, or 80 mg/day simvastatin starting at admission; or 80 mg/day simvastatin 48 hours after admission. After 7 days, all patients switched their treatment to 20 mg/day simvastatin for an additional 3 weeks and then underwent flow-mediated dilation in the brachial artery. As of the second day, C-reactive protein (CRP) differed between non-statin users (1.2Ϯ4.
Statin therapy and myocardial no-reflow
British Journal of Pharmacology, 2006
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 lipid lowering actions. However, it has now become increasingly clear that the beneficial effects of statins are not related to the lipid lowering effects, but rather to a number of pleiotropic actions. Of particular interest, statins have been shown to increase bioavailability of nitric oxide and protect against vascular inflammation and cardiac cell death in a number of cardiovascular disease states. In this present issue of the British Journal of Pharmacology, Zhao and colleagues provide a novel mechanism of action for statins with the observation that simvastatin reduces myocardial 'no-reflow' after ischemia and reperfusion by activating the mitochondrial K ATP channel. The findings of the present study have very profound implications for the treatment of cardiovascular disease. This commentary discusses the implications of these findings and how they relate to the established cardioprotective actions of statins.
Circulation, 2004
Background— Endothelial nitric oxide (eNO) bioavailability is severely reduced after myocardial infarction (MI) and in heart failure. Statins enhance eNO availability by both increasing eNO production and reducing NO inactivation. We therefore studied the effect of statin treatment on eNO availability after MI and tested its role for endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular (LV) dysfunction, remodeling, and survival after MI. Methods and Results— Wild-type (WT) and eNO synthase (eNOS) −/− mice with extensive anterior MI were randomized to treatment with vehicle (V) or atorvastatin (Ator, 50 mg/kg QD by gavage) for 4 weeks starting on day 1 after MI. Ator markedly improved endothelium-dependent, NO-mediated vasorelaxation; mobilization of endothelial progenitor cells; and myocardial neovascularization of the infarct border in WT mice after MI while having no effect in eNOS −/− mice. LV dysfunction and interstitial fibrosis were markedl...
Cardiovascular Research, 2005
Objectives: Statins attenuate myocardial ischemic injury by activating nitric oxide synthase (NOS). It is unknown whether cyclooxygenase-2 (COX2), which mediates late ischemic preconditioning, also mediates statins-induced cardioprotection. We investigated the involvement of the prostaglandins and NOS in the cardioprotective effect of atorvastatin (ATV) in the rat. Methods: Sprague-Dawley rats were randomized to a 3-day oral treatment with ATV 10 mg/kg, valdecoxib, a selective COX2 inhibitor (VAL) 3 mg/kg, ATV+VAL or water alone. Rats underwent 30-min myocardial ischemia followed by 4-h reperfusion. Results: Infarct size was smaller in the ATV group (31.3F1.9%) than controls (44.5F3.1%; p=0.011) and VAL (44.5F3.1%; p=0.008). VAL attenuated the protective effect of ATV when administered together (40.2F2.5%). ATV pretreatment increased myocardial content of 6-keto-PGF 1a (69.5F1.5 pg/mg) and PGE 2 (57.9F0.6 pg/mg) compared with controls (16.2F0.2 and 42.1F2.0 pg/mg, respectively) and ATV+VAL (15.8F0.3 and 39.9F1.9 pg/mg, respectively). ATV increased myocardial content of cytosolic phospholipase A 2 (cPLA 2 ) (174.8F0.5%), COX2 (446.2F0.9%), PGI 2 synthase (201.8F1.1%) and PGE 2 synthase (122F0.7%), whereas ATV+VAL did not (123.0F7.9%, 93.8F8.5%, 103.0F1.6% and 99.0F0%, respectively). ATV did not change the myocardial content of eNOS and nNOS, but increased the concentration of phosphorylated eNOS (231.8F2.4%) and iNOS (154.5F1.2%). This effect was not blocked by coadministration of VAL (231.5F3.0% and 154.5F1.8%, respectively). Conclusions: Our results suggest that the prostaglandins are essential for mediating the myocardial protective effects of ATV and their production is downstream to eNOS phosphorylation and iNOS.