Ramipril Attenuates Cardiomyopathy in Danon Disease

Background: Danon disease (DD) is an X-linked disease that causes cardiomyopathy manifested by ventricular hypertrophy, myocardial fibrosis and congestive heart failure. DD arises by mutations in LAMP2 gene causing loss of protein function, a defect in autophagy and accumulation of autophagosomes in cardiomyocytes. We have previously characterized mice carrying a “human” LAMP2^Δ6 mutation. Male mutant mice initially develop mild cardiac hypertrophy followed by progressive fibrosis and reduced systolic function. The cardiac phenotype in DD mice is aggravated by angiotensin. In this study we examined the effect of inhibiting the renin-angiotensin-aldosterone and of the sympathetic system on the cardiac phenotype in DD.

Methods: DD and wild type (WT) mice (12-14 weeks age) were treated till 30 weeks with Ramipril (10 mg/kg by gavage) or Metoprolol (~100 mg/kg in drinking water). The effect of therapy was assessed by echocardiography, quantitation of fibrosis, assessing oxidative stress through Malondialdehyde (TBARS) and gene expression analysis.

Results: Treating DD mice with Ramipril prevented left ventricular hypertrophy (maximal wall thickness MWT 0.92±0.34mm vs 1.14±0.1 in untreated DD, p<0.05, and similar to 0.92±0.1 in WT mice). The fractional shortening improved to 31.0±14.5 vs 20.6±8.3% in untreated DD, p<0.05, and similar to 27.6±8.3% in WT mice). Quantitative analysis of fibrosis in Masson Trichrome stained sections showed a decrease by Ramipril (3.8±3.6% compared to 13.4±2.5% in untreated DD p<0.05, but less than 1% in WT). Hearts of Ramipril-treated DD mice showed a decrease in Malondialdehyde content (0.78±0.41 vs 2.01±0.64 µM in untreated DD, p=0.04) and reduced expression of pro-fibrotic (Collagen a1) and pro-inflammation (TGF-beta and TLR4) genes. Treating DD mice by Metoprolol had no effect on cardiomyopathy.

Conclusion: RAAS plays an important role in development of cardiomyopathy in DD. Until specific therapy becomes available, patients may be treated by an ACE inhibitor to attenuate cardiac hypertrophy and adverse remodeling.