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

Abstract and Introduction

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 oorly 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.

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 pattern of inheritance, though approximately 25% of cases are due to de novo gene mutations.[2] Becker muscular dystrophy (BMD) is a related disorder caused by mutations in the same DMD gene, with later onset.[3] In BMD, mutations typically cause a reduction but not complete absence of dystrophin, thus ameliorating the phenotype. However, the cardiac disease can often be severe, with dilated cardiomyopathy (DCM) and heart failure commonly occurring in the fourth decade, with marked variability and poor correlation to the severity of skeletal muscle disease.[4] Although this article focuses primarily on DMD, it may also be relevant for BMD-associated cardiomyopathy. Cardiac dilation and dysfunction may accompany many other forms of skeletal myopathy, such as the myofibrillar myopathies and many of the limb girdle muscular dystrophies. The standard treatments for cardiomyopathy reviewed in this article generally apply to these disorders, while targeted treatments based on dystrophin deficiency may not apply as readily.

Children with DMD typically display skeletal muscle weakness by age 2–6 years.[5] Cardiomyopathy is nearly ubiquitous, although the age of onset varies considerably.[4,6] This suggests that factors other than the absence of dystrophin contribute to cardiomyopathy. Therapies addressing the skeletal muscle dysfunction and pulmonary manifestations of DMD improve survival, thus increasing the likelihood of eventually developing cardiac disease. Clinical guidelines recommend that evaluations for cardiomyopathy, arrhythmia, and heart failure be performed upon diagnosis, every 2 years thereafter until age 10 years, and then at least yearly thereafter.[7]

The cardiomyopathy that develops inDMDis characterized by normal or thinned left ventricular (LV) wall thickness and progressive decline in ejection fraction or fractional shortening. Variable degrees of LV dilation occur. Abnormal LV relaxation has also been identified as an early manifestation in DMD. In a cohort of 26 boys with DMD at age 15 years or less,Markham and colleagues[8] reported abnormal ventricular relaxation and reduced ventricular compliance by echocardiography compared with age-matched controls. Unfortunately, the mechanisms underlying heart failure in DMD remain poorly understood. For this reason, current treatment of cardiomyopathy inDMD is not targeted, but rather relies on approaches considered standard for any form of DCM.

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