Simvastatin Induces Regression of Cardiac Hypertrophy and Fibrosis and Improves Cardiac Function in a Transgenic Rabbit Model of Human Hypertrophic Cardiomyopathy

Abstract

Background-Hypertrophic cardiomyopathy is a genetic disease characterized by cardiac hypertrophy, myocyte disarray, interstitial fibrosis, and left ventricular (LV) dysfunction. We have proposed that hypertrophy and fibrosis, the major determinants of mortality and morbidity, are potentially reversible. We tested this hypothesis in ␤-myosin heavy chain-Q 403 transgenic rabbits. Methods and Results-We randomized 24 ␤-myosin heavy chain-Q 403 rabbits to treatment with either a placebo or simvastatin (5 mg · kg -1 · d -1 ) for 12 weeks and included 12 nontransgenic controls. We performed 2D and Doppler echocardiography and tissue Doppler imaging before and after treatment. Demographic data were similar among the groups. Baseline mean LV mass and interventricular septal thickness in nontransgenic, placebo, and simvastatin groups were 3.9Ϯ0.7, 6.2Ϯ2.0, and 7.5Ϯ2.1 g (PϽ0.001) and 2.2Ϯ0.2, 3.1Ϯ0.5, and 3.3Ϯ0.5 mm (Pϭ0.002), respectively. Simvastatin reduced LV mass by 37%, interventricular septal thickness by 21%, and posterior wall thickness by 13%. Doppler indices of LV filling pressure were improved. Collagen volume fraction was reduced by 44% (PϽ0.001). Disarray was unchanged. Levels of activated extracellular signal-regulated kinase (ERK) 1/2 were increased in the placebo group and were less than normal in the simvastatin group. Levels of activated and total p38, Jun N-terminal kinase, p70S6 kinase, Ras, Rac, and RhoA and the membrane association of Ras, RhoA, and Rac1 were unchanged. Conclusions-Simvastatin induced the regression of hypertrophy and fibrosis, improved cardiac function, and reduced ERK1/2 activity in the ␤-myosin heavy chain-Q 403 rabbits. These findings highlight the need for clinical trials to determine the effects of simvastatin on cardiac hypertrophy, fibrosis, and dysfunction in humans with hypertrophic cardiomyopathy and heart failure.

Gene expression changes associated with fibronectin-induced cardiac myocyte hypertrophy

“…3). This is a novel observation in cardiac myocytes and may be a mechanism by which cholesterol synthesis inhibitors prevent cardiac hypertrophy (41,44), in addition to their effect in the isoprenylation of small G proteins, such as Ras and RhoA (30).…”

Spectrum of Pleiotropic Effects of Statins in Heart Failure

“…It was postulated that simvastatin was able to provide protection by down-regulating the levels of ERK1/2 kinases, which have been implicated in hypertrophic growth. [56] Dhal salt sensitive rats develop cardiac hypertrophy and congestive heart failure after a being fed a high salt diet. When these rats were fed a high salt diet and given cerivastatin they displayed decreased left ventricular wall thickness and myocardial fibrosis, as well as decreased heart weight, and LV diameter, and improved LV function at 17 weeks (Figure 2).…”

Disrobing the Emperor (Heart) Without Destroying the Dignity of Super-Normality

“…Placebocontrolled studies with losartan 10 and simvastatin 11 showed a marked reduction in the phenotype of fibrosis and hypertrophy and improved ventricular function in genetic animal models of human FHCM. Both drugs have approved safety profiles in humans for treatment of other diseases, which, if shown to be effective in clinical trials of patients with FHCM, would beckon the need for independent preclinical diagnosis.…”