Early Treatment with Lisinopril and Spironolactone Preserves Cardiac and Skeletal Muscle in Duchenne Muscular Dystrophy Mice: Rafael-Fortney: Spironolactone+ACEI Protects DMD Muscle

Inherited myopathies produce progressive immobility due to limb muscle degeneration, respiratory failure due to diaphragm involvement and cardiomyopathy due to myocardial disease1. The most common form is Duchenne muscular dystrophy (DMD), an X-linked disorder that leads to absence of the sarcolemmal protein dystrophin and impairs ambulation beginning in children age 3–7 years. DMD patients universally develop cardiomyopathy by the third decade of life, and present guidelines advocate periodic screening with echocardiography2, 3. Current guidelines dictate that drugs like angiotensin converting enzyme (ACE) inhibitors may be started once there is evident left ventricular (LV) systolic dysfunction, particularly reduced ejection fraction (LVEF)4. Use of drugs like aldosterone antagonists that have anti-fibrotic effects are only advocated for treatment of patients with advanced heart failure4. Recent evidence supports initiation earlier in the progression of cardiac disease albeit still only in symptomatic patients with evident LV dysfunction5. Our present study was motivated by increasing evidence suggesting that myocardial disease is developing in DMD patients well before LVEF becomes abnormal6. Observing that the early histopathological changes that occur in both skeletal and cardiac muscle invariably leads to fibrosis, we postulated that drugs with an anti-fibrotic effect may be most beneficial if started earlier in the disease course. Therefore, we implemented a prospective, blinded study to test the hypothesis that early vs. late treatment with clinically-available ACE inhibitors and aldosterone antagonists provides significantly greater myocardial protection in a mouse model of DMD. In addition, because of: 1) the reported “anti-fibrotic” properties of spironolactone and lisinopril5, 7–9, 2) the absence of any published investigations of these drugs on skeletal muscles in any muscular dystrophy model, and 3) the presence of large amounts of fibrosis in het mice, we decided to include analysis of skeletal muscle effects in addition to cardiac effects of the drug treatment in our studies.