Michael D Nelson1, Florian Rader1, Xiu Tang1, Jane Tavyev1, Stanley F Nelson1, M Carrie Miceli1, Robert M Elashoff1, H Lee Sweeney1, Ronald G Victor2. 1. From The Heart Institute (M.D.N., F.R., X.T., R.G.V.), and Department of Pediatrics (J.T.), Cedars-Sinai Medical Center, Los Angeles; Departments of Human Genetics (S.F.N.) and Pathology and Laboratory Medicine (S.F.N.), David Geffen School of Medicine at UCLA, Los Angeles; Department of Microbiology Immunology and Molecular Genetics (M.C.M.), David Geffen School of Medicine and College of Letters and Sciences, UCLA, Los Angeles; Department of Biomathematics (R.M.E.), and Department of Biostatistics, School of Public Health (R.M.E.), University of California, Los Angeles; and Pennsylvania Muscle Institute (H.L.S.), Department of Medicine, University of Pennsylvania, Philadelphia. 2. From The Heart Institute (M.D.N., F.R., X.T., R.G.V.), and Department of Pediatrics (J.T.), Cedars-Sinai Medical Center, Los Angeles; Departments of Human Genetics (S.F.N.) and Pathology and Laboratory Medicine (S.F.N.), David Geffen School of Medicine at UCLA, Los Angeles; Department of Microbiology Immunology and Molecular Genetics (M.C.M.), David Geffen School of Medicine and College of Letters and Sciences, UCLA, Los Angeles; Department of Biomathematics (R.M.E.), and Department of Biostatistics, School of Public Health (R.M.E.), University of California, Los Angeles; and Pennsylvania Muscle Institute (H.L.S.), Department of Medicine, University of Pennsylvania, Philadelphia. Ronald.Victor@cshs.org.
Abstract
OBJECTIVE: To determine whether phosphodiesterase type 5 (PDE5) inhibition can alleviate exercise-induced skeletal muscle ischemia in boys with Duchenne muscular dystrophy (DMD). METHODS: In 10 boys with DMD and 10 healthy age-matched male controls, we assessed exercise-induced attenuation of reflex sympathetic vasoconstriction, i.e., functional sympatholysis, a protective mechanism that matches oxygen delivery to metabolic demand. Reflex vasoconstriction was induced by simulated orthostatic stress, measured as the decrease in forearm muscle oxygenation with near-infrared spectroscopy, and performed when the forearm muscles were rested or lightly exercised with rhythmic handgrip exercise. Then, the patients underwent an open-label, dose-escalation, crossover trial with single oral doses of tadalafil or sildenafil. RESULTS: The major new findings are 2-fold: first, sympatholysis is impaired in boys with DMD-producing functional muscle ischemia-despite contemporary background therapy with corticosteroids alone or in combination with cardioprotective medication. Second, PDE5 inhibition with standard clinical doses of either tadalafil or sildenafil alleviates this ischemia in a dose-dependent manner. Furthermore, PDE5 inhibition also normalizes the exercise-induced increase in skeletal muscle blood flow (measured by Doppler ultrasound), which is markedly blunted in boys with DMD. CONCLUSIONS: These data provide in-human proof of concept for PDE5 inhibition as a putative new therapeutic strategy for DMD. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with DMD, PDE5 inhibition restores functional sympatholysis.
OBJECTIVE: To determine whether phosphodiesterase type 5 (PDE5) inhibition can alleviate exercise-induced skeletal muscle ischemia in boys with Duchenne muscular dystrophy (DMD). METHODS: In 10 boys with DMD and 10 healthy age-matched male controls, we assessed exercise-induced attenuation of reflex sympathetic vasoconstriction, i.e., functional sympatholysis, a protective mechanism that matches oxygen delivery to metabolic demand. Reflex vasoconstriction was induced by simulated orthostatic stress, measured as the decrease in forearm muscle oxygenation with near-infrared spectroscopy, and performed when the forearm muscles were rested or lightly exercised with rhythmic handgrip exercise. Then, the patients underwent an open-label, dose-escalation, crossover trial with single oral doses of tadalafil or sildenafil. RESULTS: The major new findings are 2-fold: first, sympatholysis is impaired in boys with DMD-producing functional muscle ischemia-despite contemporary background therapy with corticosteroids alone or in combination with cardioprotective medication. Second, PDE5 inhibition with standard clinical doses of either tadalafil or sildenafil alleviates this ischemia in a dose-dependent manner. Furthermore, PDE5 inhibition also normalizes the exercise-induced increase in skeletal muscle blood flow (measured by Doppler ultrasound), which is markedly blunted in boys with DMD. CONCLUSIONS: These data provide in-human proof of concept for PDE5 inhibition as a putative new therapeutic strategy for DMD. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with DMD, PDE5 inhibition restores functional sympatholysis.
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