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.

The genetic basis of hypertrophic cardiomyopathy in cats and humans

“…Besides wall thickening, another hallmark of the disease is impaired diastolic function due to the hypertrophy itself, myocardial fibrosis and altered calcium kinetics in the cell. 13 HCM in humans (and germane to this discussion, also in Maine Coon cats) is also usually associated with histological changes such as myocyte disarray, a diagnostic feature of the disease, where individual myocytes adopt bizarre shapes and relationships to one another. 14 Small coronary vessel disease and myocardial fibrosis are also usually present.…”

Hypertrophic Cardiomyopathy

“…Preliminary studies in animal models of HCM suggested possible benefits of angiotensin II receptor blockers, 3-hydroxy-3-methyglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), mineralocorticoid receptor blockers, and anti-oxidant N-acetylcysteine 122–124, 240–242 . Despite the beneficial effects of some of these approaches in the models, preliminary studies in humans have been largely disappointing.…”

Can heart function lost to disease be regenerated by therapeutic targeting of cardiac scar tissue?

“…A number of established clinical interventions appear to modulate fibrosis in an “off-target” manner, including angiotensin converting enzyme inhibitors [168], angiotensin receptor blockers [169], and statins [170–174], which have been shown to reduce fibrosis and inhibit detrimental myocardial remodeling. One study suggests that the anti-fibrotic effect of statins is mediated by inhibiting TGF-β-induced differentiation of fibroblasts to myofibroblasts [175].…”