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.