Tadalafil treatment delays the onset of cardiomyopathy in dystrophin‐deficient hearts

DW Hammers, MM Sleeper, SC Forbes… - Journal of the …, 2016 - Am Heart Assoc
DW Hammers, MM Sleeper, SC Forbes, A Shima, GA Walter, HL Sweeney
Journal of the American Heart Association, 2016Am Heart Assoc
Background Cardiomyopathy is a leading cause of mortality among Duchenne muscular
dystrophy patients and lacks effective therapies. Phosphodiesterase type 5 is implicated in
dystrophic pathology, and the phosphodiesterase type 5 inhibitor tadalafil has recently been
studied in a clinical trial for Duchenne muscular dystrophy. Methods and Results Tadalafil
was evaluated for the prevention of cardiomyopathy in the mdx mouse and golden retriever
muscular dystrophy dog models of Duchenne muscular dystrophy. Tadalafil blunted the …
Background
Cardiomyopathy is a leading cause of mortality among Duchenne muscular dystrophy patients and lacks effective therapies. Phosphodiesterase type 5 is implicated in dystrophic pathology, and the phosphodiesterase type 5 inhibitor tadalafil has recently been studied in a clinical trial for Duchenne muscular dystrophy.
Methods and Results
Tadalafil was evaluated for the prevention of cardiomyopathy in the mdx mouse and golden retriever muscular dystrophy dog models of Duchenne muscular dystrophy. Tadalafil blunted the adrenergic response in mdx hearts during a 30‐minute dobutamine challenge, which coincided with cardioprotective signaling, reduced induction of μ‐calpain levels, and decreased sarcomeric protein proteolysis. Dogs with golden retriever muscular dystrophy began daily tadalafil treatment prior to detectable cardiomyopathy and demonstrated preserved cardiac function, as assessed by echocardiography and magnetic resonance imaging at ages 18, 21, and 25 months. Tadalafil treatment improved golden retriever muscular dystrophy histopathological features, decreased levels of the cation channel TRPC6, increased total threonine phosphorylation status of TRPC6, decreased m‐calpain levels and indicators of calpain target proteolysis, and elevated levels of utrophin. In addition, we showed that Duchenne muscular dystrophy patient myocardium exhibited increased TRPC6, m‐calpain, and calpain cleavage products compared with control human myocardium.
Conclusions
Prophylactic use of tadalafil delays the onset of dystrophic cardiomyopathy, which is likely attributed to modulation of TRPC6 levels and permeability and inhibition of protease content and activity. Consequently, phosphodiesterase type 5 inhibition is a candidate therapy for slowing the development of cardiomyopathy in Duchenne muscular dystrophy patients.
Am Heart Assoc