Introduction
Duchenne muscular dystrophy (DMD), an X-linked recessive disorder affecting approximately 1 in 3,600 to 6000 live male births, results from a mutation in the gene which encodes dystrophin, a sarcolemmal protein abundant in skeletal and cardiac muscle cells1-4. Absence of dystrophin results in progressive necrosis, apoptosis and fibrosis of muscle tissues leading to progressive degenerative muscle disorder5, 6. DMD is a rare but devastating disease resulting in progressive loss of ambulation, respiratory failure, DMD-associated cardiomyopathy (DMD-CM) and premature death7, 8. Since the discovery of the dystrophin gene more than three decades ago, the field has been dominated by expectation of a “cure”. However, despite considerable effort directed toward gene therapy and marked advancements in understanding, these insights have not translated into a cure yet9-15. Clinically, DMD is characterized by progressive skeletal muscle weakness, with loss of ambulation between the ages of 7 and 13 years; death secondary to cardiac or respiratory failure typically occurs in the second to third decade of life 16-18. The progression of DMD-CM does not correlate to the severity of skeletal muscle weakness, and early manifestations of heart failure (HF) in DMD patients often go unrecognized due to lack of classic HF signs and symptoms 18, 19. Currently, the only recommended therapy remains corticosteroid at a young age to prolong ambulation20-22. Use of corticosteroids and supportive respiratory care21, 23, 24have improved outcomes in DMD patients such that DMD-CM is now the leading cause of death25-29. Historically, most clinical and basic research programs have focused on the skeletal myopathy with less attention to the cardiac phenotype. This omission is rather astonishing since patients with DMD possess an absolute genetic risk of developing cardiomyopathy19, 30-33. Late referrals and treatment initiation occur because of lack of HF symptoms due to skeletal muscle myopathy limiting the utility of HF symptoms by the New York Heart Association (NYHA) classification even in advance stages of DMD-CM. In addition, routine cardiac evaluation by echocardiographic (TTE) only detect cardiac dysfunction late in the disease course34, 35. Indeed, one explanation for the paucity of cardiac therapeutic trials for DMD-CM has been the lack of a suitable end-point of therapy.
While the disease process in the heart begins in infancy and is progressive, global dysfunction by ejection fraction (LVEF) is rarely detected in the first decade of life but circumferential strain abnormalities and late gadolinium enhancement (LGE) can occur much earlier 32, 36-39. DMD patients do not present with classic HF symptoms evident in traditional adult HF patients. Consequently, DMD-CM frequently goes unrecognized until the very advanced stage and cardiac specific therapy has been reserved until abnormal LVEF is evident21, 26, 27. At end stage DMD cardiac pathology shows alternating areas of myocyte hypertrophy, atrophy and fibrosis17, 40. The pathogenesis of which is thought to result from micro-tears in the sarcolemma leading to altered calcium homeostasis, initiating myocyte necrosis and fibrosis41-43. Although there is no method to image cellular damage directly in humans, studies have shown that cardiac magnetic resonance imaging (CMR) can detect subtle changes in contractility and development of myocardial fibrosis before abnormal LVEF is present33, 44-56. The rationale for aggressive cardiac surveillance with non-invasive imaging at a young age is the belief that early therapy to preserve myocardium will yield better outcomes than rescue therapy with DMD-CM is in advance stage. The purpose of this article is to review the role of cardiac imaging in characterizing the cardiac natural history of DMD-CM, highlighting the prognostic implications and an outlook on how this field might evolve in the future.