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 beta-myosin heavy chain-Q(403) transgenic rabbits.

Methods and results: We randomized 24 beta-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 3.9+/-0.7, 6.2+/-2.0, and 7.5+/-2.1 g (P<0.001) and 2.2+/-0.2, 3.1+/-0.5, and 3.3+/-0.5 mm (P=0.002), 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% (P<0.001). 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 beta-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.

Figure 1

Levels of activated and total stress-responsive intra-cellular signaling kinases in the heart of β-MyHC-Q⁴⁰³ transgenic rabbits. Each lane represents a cardiac protein extract from one rabbit, and 2 rabbits per group are shown. Immunoblots for ERK1/2, p38, JNK, and p70S6 kinase are shown. The upper blot in each set of panels represents levels of phosphorylated kinases, and the lower panel represents levels of total kinases. Non-tg indicates nontransgenic.

Figure 2

GTP-bound and membrane association of Ras, Rac1, and RhoA. A, Activation Ras and Rac1. Each lane represents cardiac protein extract from one rabbit. Upper blot in each set of panels shows levels of GTP-bound Ras and Rac1, and the lower blot shows levels of total Ras and Rac-1. The bottom panel represents a positive control showing activation of Ras after stimulation of mink lung epithelial cells with 10% fetal calf serum at the specified time points. Molecular size markers are indicated on the right of each panel. B, Membrane-bound, soluble, and total Ras, Rac1, and RhoA. Non-tg indicates nontransgenic.

Figure 3

Masson trichrome staining. The upper panels show low magnification (×40) and the lower panels high magnification (×400) of thin myocardial sections.

Figure 4

Northern blot showing expression of skeletal α-actin. Non-tg indicates nontransgenic.