Pathophysiology and Therapy of Cardiac Dysfunction in Duchenne Muscular Dystrophy

Daniel P. Judge; David A. Kass; W. Reid Thompson; Kathryn R. Wagner

Disclosures

Am J Cardiovasc Drugs. 2011;11(5):287-294. 

In This Article

2. Pathophysiology of Cardiomyopathy in Duchenne Muscular Dystrophy (DMD)

The dystrophin gene encodes one of the largest proteins in humans. It was recognized based on the pattern of inheritance of DMD as X-linked, and classical positional cloning led to its discovery.[9,10] Dystrophin is present in normal human heart, skeletal muscle, and smooth muscle.[9] It localizes to the sarcolemma in myocytes and is associated with a large complex of proteins and glycoproteins known as the dystrophin-glycoprotein complex (DGC).[11] This complex forms a link between the cytoskeleton and ECM.

One hypothesis regarding the cause of cardiomyopathy for individuals with reduced or absent dystrophin is based simply on a structural deficiency. Since dystrophin is part of the DGC, its primary role may be to hold this complex together. When deficient or absent, the dystrophin-associated glycoprotein complex may deteriorate due to the hemodynamic stress associated with normal left ventricular function. Evidence for this includes the loss of several components of the DGC from the plasmalemma when dystrophin is absent.[12] If this were the only contribution of dystrophin to normal cardiac function, then one would anticipate that cardiac dysfunction would be more uniform with regard to its age of onset and severity in DMD. In addition, if this were the only role for dystrophin, then optimal therapies should target restoration of mechanical structural integrity.

Another hypothesis for cardiac dysfunction in DMD and BMD posits that dystrophin and its associated complex of ECM glycoproteins play a regulatory role. Interactions with nitric oxide production and signaling, as well as with members of the transforming growth factor-β (TGFβ) superfamily, are topics of several recent publications.[13,14] Alterations of these regulatory functions are prominent in several ongoing investigations, and their potential roles in directed pharmacologic treatments are described further below. These putative structural and regulatory roles are not mutually exclusive, and both may contribute to heart failure in DMD and BMD.

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