title: Tadalafil Treatment Delays the Onset of Cardiomyopathy in Dystrophin-Deficient Hearts.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors: Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA Pennsylvania Muscle Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, FL Myology Institute, University of Florida College of Medicine, Gainesville, FL.
authors: David W
authors: DW
authors: Hammers
authors: Myology Institute, University of Florida College of Medicine, Gainesville, FL Clinical Studies, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA Small Animal Clinical Sciences, University of Florida College of Veterinary Medicine, Gainesville, FL.
authors: Margaret M
authors: MM
authors: Sleeper
authors: Myology Institute, University of Florida College of Medicine, Gainesville, FL Physical Therapy, University of Florida, Gainesville, FL.
authors: Sean C
authors: SC
authors: Forbes
authors: Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors: Ai
authors: A
authors: Shima
authors: Myology Institute, University of Florida College of Medicine, Gainesville, FL Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL.
authors: Glenn A
authors: GA
authors: Walter
authors: Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, FL Myology Institute, University of Florida College of Medicine, Gainesville, FL lsweeney@ufl.edu.
authors: H Lee
authors: HL
authors: Sweeney
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000000981:diagnostic imaging / Q000209:etiology / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004285:Dogs; D016189:Dystrophin / Q000172:deficiency*; D004452:Echocardiography; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000150:complications / Q000188:drug therapy; D000074287:TRPC6 Cation Channel / Q000378:metabolism; D000068581:Tadalafil / Q000627:therapeutic use*
chemical_list: D002316:Cardiotonic Agents; D016189:Dystrophin; D000074287:TRPC6 Cation Channel; D000068581:Tadalafil
keywords: dobutamine stress; dystrophin cardiomyopathy; magnetic resonance imaging; phosphodiesterase type 5 inhibition; protease; utrophin