cerivastatin and Coronary-Artery-Disease

Although all statin drugs lower levels of circulating low-density lipoprotein cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A, molecular differences among statins affect their metabolism, solubility, and intramembrane localization, which in turn is likely to influence their efficacy and safety. In addition, these properties may have a differential impact on the pleiotropic effects of statins, including their ability to improve endothelial function and to affect proliferation and apoptosis in vascular tissues. Many pleiotropic effects of statins appear to be due to inhibition of small guanosine triphosphate-binding proteins and/or restoration of nitric oxide bioavailability, and atorvastatin metabolites may also directly protect vascular tissues from oxidative damage. The possibility of cardiovascular benefits from antioxidant effects of atorvastatin metabolites contrasts with the lack of benefits seen in most studies of antioxidant vitamins. This article reviews some of the differences in pleiotropic effects of statins and assesses the contribution of their solubility and membrane localization as the possible basis for these differences. In addition, the possibility that statin benefits on stroke reflect pleiotropic effects is reviewed. Finally, possible reasons for differences between the effects of atorvastatin metabolites and antioxidant vitamins are considered.

Topics: Antioxidants; Atorvastatin; Cholesterol, LDL; Coronary Artery Disease; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pravastatin; Pyridines; Pyrroles; Vitamins

Endothelial dysfunction is an important feature of atherosclerosis. Inhibition of the HMG-CoA pathway and of calcium channels improves endothelial function experimentally and in the forearm circulation. Thus, we investigated the effects of a statin and/or a calcium antagonist on coronary endothelial function in patients with coronary artery disease (CAD).. In 343 patients undergoing percutaneous coronary intervention in 29 centers, acetylcholine (10(-6) to 10(-4) mol/L) was infused in a coronary segment without angiographically significant CAD. Changes in coronary diameter were measured by quantitative angiography. Endothelium-independent responses were assessed by intracoronary adenosine (1.2 mg/mL) and nitroglycerin (250 microg). Thereafter, patients were randomized in a double-blind manner to placebo, cerivastatin 0.4 mg/d, nifedipine 30 to 60 mg/d, or their combination. Studies were repeated at 6 months. In the most constricted segment, nifedipine but not cerivastatin reduced vasoconstriction to acetylcholine (18.8% versus placebo 10.0%; P<0.05). Patients not taking ACE inhibitors showed a smaller improvement in the placebo group (6.0%), but nifedipine still had an effect (17.0%; P<0.05 versus placebo). Analysis of all evaluable coronary segments revealed an 11% reduction of acetylcholine-induced vasoconstriction in patients receiving nifedipine and cerivastatin (P<0.05 versus placebo). Cerivastatin lowered LDL cholesterol by 35% (P<0.001).. The ENCORE I trial demonstrates that multicenter studies on coronary endothelial function are feasible. After 6 months' treatment, nifedipine improved coronary endothelial function in the most constricted segment. The combination of nifedipine and cerivastatin tended to improve endothelial function; however, this only reached significance in an analysis of all coronary segments.

Topics: Acetylcholine; Adult; Calcium Channel Blockers; Cholesterol; Coronary Artery Disease; Double-Blind Method; Drug Therapy, Combination; Endothelium, Vascular; Female; Follow-Up Studies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Myocardium; Nifedipine; Pyridines; Vasoconstriction

Coronary calcification measured by fast computed tomography techniques is a surrogate marker of coronary atherosclerotic plaque burden. In a cohort study, we prospectively investigated whether lipid-lowering therapy with a cholesterol synthesis enzyme inhibitor reduces the progression of coronary calcification.. In 66 patients with coronary calcifications in electron beam tomography (EBT), LDL cholesterol >130 mg/dL, and no lipid-lowering treatment, the EBT scan was repeated after a mean interval of 14 months and treatment with cerivastatin was initiated (0.3 mg/d). After 12 months of treatment, a third EBT scan was performed. Coronary calcifications were quantified using a volumetric score. Cerivastatin therapy lowered the mean LDL cholesterol level from 164+/-30 to 107+/-21 mg/dL. The median calcified volume was 155 mm3 (range, 15 to 1849) at baseline, 201 mm3 (19 to 2486) after 14 months without treatment, and 203 mm3 (15 to 2569) after 12 months of cerivastatin treatment. The median annualized absolute increase in coronary calcium was 25 mm3 during the untreated versus 11 mm3 during the treatment period (P=0.01). The median annual relative increase in coronary calcium was 25% during the untreated versus 8.8% during the treatment period (P<0.0001). In 32 patients with an LDL cholesterol level <100 mg/dL under treatment, the median relative change was 27% during the untreated versus -3.4% during the treatment period (P=0.0001).. Treatment with the cholesterol synthesis enzyme inhibitor cerivastatin significantly reduces coronary calcium progression in patients with LDL cholesterol >130 mg/dL.

Topics: Adult; Aged; Calcinosis; Cholesterol, LDL; Cohort Studies; Coronary Artery Disease; Disease Progression; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Lipids; Male; Middle Aged; Prospective Studies; Pyridines; Tomography, X-Ray Computed; Treatment Outcome