Simvastatin provides long‐term improvement of left ventricular function and prevents cardiac fibrosis in muscular dystrophy

Abstract

Duchenne muscular dystrophy ( DMD ), caused by absence of the protein dystrophin, is a common, degenerative muscle disease affecting 1:5000 males worldwide. With recent advances in respiratory care, cardiac dysfunction now accounts for 50% of mortality in DMD . Recently, we demonstrated that simvastatin substantially improved skeletal muscle health and function in mdx ( DMD ) mice. Given the known cardiovascular benefits ascribed to statins, the aim of this study was to evaluate the efficacy of simvastatin on cardiac function in mdx mice. Remarkably, in 12‐month old mdx mice, simvastatin reversed diastolic dysfunction to normal after short‐term treatment (8 weeks), as measured by echocardiography in animals anesthetized with isoflurane and administered dobutamine to maintain a physiological heart rate. This improvement in diastolic function was accompanied by increased phospholamban phosphorylation in simvastatin‐treated mice. Echocardiography measurements during long‐term treatment, from 6 months up to 18 months of age, showed that simvastatin significantly improved in vivo cardiac function compared to untreated mdx mice, and prevented fibrosis in these very old animals. Cardiac dysfunction in DMD is also characterized by decreased heart rate variability ( HRV ), which indicates autonomic function dysregulation. Therefore, we measured cardiac ECG and demonstrated that short‐term simvastatin treatment significantly increased heart rate variability ( HRV ) in 14‐month‐old conscious mdx mice, which was reversed by atropine. This finding suggests that enhanced parasympathetic function is likely responsible for the improved HRV mediated by simvastatin. Together, these findings indicate that simvastatin markedly improves cardiac health and function in dystrophic mice, and therefore may provide a novel approach for treating cardiomyopathy in DMD .

Cholesterol metabolism is a potential therapeutic target in Duchenne Muscular Dystrophy

“…A positive effect of the cholesterol synthesis inhibitor simvastatin on the dystrophic muscle was previously reported in the mdx mouse model 37,82 . The observed beneficial effect was attributed to reduction of oxidative stress, fibrosis and inflammation.…”

Simvastatin Attenuates Cardiac Fibrosis via Regulation of Cardiomyocyte-Derived Exosome Secretion

“…Statins (for example, SIM, atorvastatin, rosuvastatin, etc.) have been demonstrated to possess various biological functions, not only in lowering cholesterol levels but also inhibiting inflammatory response [35], preventing contrast-induced acute kidney injury (CIAKI) [36], and reducing cardiovascular risk [37] and anti-fibrosis effect [38]. SIM is the earliest statin, and is commonly used for hyperlipidemia, and is easy to obtain.…”

Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy

“…Because the fibrotic process starts so early in the disease course and the consequences of unmitigated fibrosis can be so dire, reducing fibrosis has become a major goal of cardiac-directed therapies for DMD. Pharmacological approaches that have shown the capacity to limit the accumulation of fibrosis in dystrophic mouse and patient hearts include ACE inhibitors, ARBs, mineralocorticoid receptor antagonists, and even simvastatin [94,124,125,126].…”