cerivastatin and Calcinosis

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

Although lipid-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) decreases the progression of coronary artery and aortic valve calcification, the mechanism of action of these drugs to inhibit the calcification process remains unclear. In this study, we investigated the effect of statins such as cerivastatin and atorvastatin on vascular calcification by utilizing an in vitro model of inflammatory vascular calcification. Cerivastatin and atorvastatin dose-dependently inhibited in vitro calcification of human vascular smooth muscle cells (HVSMCs) induced by the following inflammatory mediators (IM): interferon-gamma, 1alpha,25-dihydroxyvitamin D3, tumor necrosis factor-alpha, and oncostatin M. These statins also depressed expression of alkaline phosphatase (ALP) in HVSMCs induced by these factors. Mevalonate and geranylgeranylpyrophosphate reversed the inhibitory effect of cerivastatin on ALP expression in HVSMCs, while farnesylpyrophosphate showed no effect on the ALP activities inhibited by this drug, suggesting that inhibition of Rho and its downstream target, Rho kinase may mediate the inhibitory effect of cerivastatin. Cerivastatin prevented RhoA activation in HVSMCs induced by the IM. A specific inhibitor of Rho kinase (Y-27632) inhibited in vitro calcification and induction of ALP in HVSMCs. These findings provide a possible mechanism of statins to prevent the progression of calcification in inflammatory vascular diseases such as atherosclerosis and cardiac valvular calcification.

Topics: Alkaline Phosphatase; Atorvastatin; Calcinosis; Dose-Response Relationship, Drug; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Mevalonic Acid; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Polyisoprenyl Phosphates; Pyridines; Pyrroles; Sesquiterpenes