Pathophysiology and Therapy of Cardiac Dysfunction in Duchenne Muscular Dystrophy
- 1 October 2011
- journal article
- review article
- Published by Springer Science and Business Media LLC in American Journal of Cardiovascular Drugs
- Vol. 11 (5), 287-294
- https://doi.org/10.2165/11594070-000000000-00000
Abstract
Cardiac dysfunction is a frequent manifestation of Duchenne muscular dystrophy (DMD) and a common cause of death for individuals with this condition. Early diastolic dysfunction and focal fibrosis proceed to dilated cardiomyopathy (DCM), complicated by heart failure and arrhythmia in most patients. Improvements in the management of respiratory insufficiency in DMD have improved lifespan and overall prognosis, but heart failure and sudden death continue to impact survival and quality of life for people with DMD. Since the specific mechanisms resulting in heart failure for people with DMD are poorly understood, current treatments are not targeted, but rely on approaches that are considered standard for DCM. These approaches include angiotensin-converting enzyme (ACE) inhibitors and β-adrenoceptor antagonists. Data from one trial in DMD support the use of ACE inhibitors before the onset of left ventricular dysfunction. Angiotensin receptor blockers have shown similar efficacy to ACE inhibitors in numerous studies of dilated cardiomyopathy, and are a good choice for patients who cannot tolerate ACE inhibition. The pathogenesis of DMD-associated cardiomyopathy may be similar to other genetic disorders of the cytoskeletal complex of ventricular myocytes, though unique features offer targeted opportunities to impact treatment. Novel areas of investigation are focused on the regulatory role of dystrophin in relation to neuronal nitric oxide synthase (nNOS) and transient receptor potential canonical channels (TRPC). Inhibition of phosphodiesterase-5 (PDE5) addresses several aspects of regulatory dysfunction induced by dystrophin deficiency, and studies with PDE5-inhibitors have shown benefits in murine models of DMD. PDE5-inhibitors are currently under investigation in at least one study in humans. This article focuses on mechanisms of cardiac dysfunction, as well as potential targets for pharmacologic manipulation to prevent or improve cardiomyopathy in DMD.Keywords
This publication has 68 references indexed in Scilit:
- Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial managementThe Lancet Neurology, 2010
- Genotype-phenotype analysis in 2,405 patients with a dystrophinopathy using the UMD-DMD database: a model of nationwide knowledgebaseHuman Mutation, 2009
- Current treatment of adult Duchenne muscular dystrophyBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2007
- Abnormalities of Diastolic Function Precede Dilated Cardiomyopathy Associated with Duchenne Muscular DystrophyJournal of the American Society of Echocardiography, 2006
- 107th ENMC International Workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy. 7th–9th June 2002, Naarden, the NetherlandsNeuromuscular Disorders, 2003
- Skeletal, cardiac, and smooth muscle failure in Duchenne muscular dystrophyPediatric Neurology, 1996
- Membrane organization of the dystrophin-glycoprotein complexCell, 1991
- Dystrophin: The protein product of the duchenne muscular dystrophy locusCell, 1987
- Complete cloning of the duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individualsCell, 1987
- Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy geneNature, 1986