Pathophysiology and Therapy of Cardiac Dysfunction in Duchenne Muscular Dystrophy
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Pathophysiology and Therapy of Cardiac Dysfunction in Duchenne Muscular Dystrophy Daniel P. Judge,1,2,3 David A. Kass,1,4 W. Reid Thompson2,5 and Kathryn R. Wagner2,6 1 2 3 4 5 6
Division of Cardiology/Medicine, Johns Hopkins University, Baltimore, MD, USA Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA Universite´ Paris Descartes, Sorbonne Paris Cite´, Paris, France Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA Division of Cardiology/Pediatrics, Johns Hopkins University, Baltimore, MD, USA Department of Neurology, Johns Hopkins University, Baltimore, MD, USA
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 b-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.
1. Introduction Duchenne muscular dystrophy (DMD) is the most common childhood form of muscular dystrophy. It results from mutations in the gene encoding dystrophin, a sub-sarcolemmal protein that plays a key role in plasma membrane integrity and in linking the extracellular matrix (ECM) with cytosolic signaling.[1] This condition segregates in families with an X-linked
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