Abstract 13923: LDL-Cholesterol Lowering Increased Mortality in Mice with Inherited Cardiomyopathy
Treatment with statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) lowers low-density lipoprotein cholesterol (LDL-C) for prevention of cardiovascular disease. It has been shown that statins may also improve endothelial function, inhibit inflammation, and reduce fibrosis. Cardiac specific-inactivation of the Vinculin (Vcl)-gene by MLC2v-Cre (cVclKO) caused myocardial fibrosis, ventricular arrhythmias and heart failure. We hypothesized that statin treatment may benefit cardiac function in cVclKO mice.
Control mice and littermate cVclKO underwent either atorvastatin, pravastatin (both 5mg/kg/day, as previously described) or vehicle treatment. After two months, atorvastatin reduced LDL-C (mg/dl) compared to vehicle (vehicle 140.38 ± 0.92, atorvastatin 90.25 ± 0.77, n=7-8 each, p< 0.0008), whereas pravastatin treatment did not lower LDL-C (pravastatin 131.98 ± 1.23, n=8). Echocardiography, in two-week intervals for 6 months, showed that declining fractional shortening and wall thicknesses were similar in atorvastatin, pravastatin, or vehicle treated cVclKO, when compared to control treatment groups. Kaplan Meyer survival analysis revealed increased mortality in atorvastatin treated cVclKO compared to vehicle and pravastatin treated cVclKO (n= 20-24 each, p<0.001). Ultrastructural analysis of healthy controls after six months of treatment showed swollen and misaligned mitochondria as well as accumulation of protein aggregates (i.e., lipofuscin, inclusion bodies) only in atorvastatin treated hearts (n=4 each). In neonatal mouse ventricular myocytes (NMVM), atorvastatin (1-10μM), but not pravastatin (1-10μM), reduced protein expression of caveolin-1, epithermal growth factor receptor and insulin receptor β. Atorvastatin, but not pravastatin, decreased RhoA activation, reduced AKT (S473) and ERK1/2 (T202/Y204) survival signaling, and induced apoptosis (cleaved caspase-3, and PARP) in NMVM.
LDL-C lowering by atorvastatin increased sudden death in cVclKO and altered mitochondrial ultrastructure. Pravastatin at the given dosage was not potent enough to lower LDL-C, and did not alter survival in cVclKO. Our data suggest adverse effects of LDL-lowering in cVclKO mice with non-ischemic heart failure.
- © 2012 by American Heart Association, Inc.