Author + information
- ↵*Reprint requests and correspondence:
Dr. Jeffrey A. Towbin, Pediatric Cardiology, Texas Children’s Hospital, Feigin Center, F430.09, 6621 Fannin Street, Houston, Texas 77030, USA.
Dystrophin is a key linker protein between the sarcolemma of the myocyte and the contractile apparatus, the sarcomere (1,2). When dystrophin is deficient, various clinical phenotypes may develop, the most devastating of which is Duchenne muscular dystrophy (DMD) (3). This disorder is characterized predominantly by skeletal muscle disease that presents early in life and rapidly progresses to require a wheelchair before age 11 years (4). The disorder affects 1:3,500 male births, having X-linked recessive inheritance, and female carriers may also develop milder disease later in life (3,4). In addition to severe progressive skeletal myopathy, nearly all affected boys will eventually develop a dilated cardiomyopathy (DCM) and congestive heart failure (CHF), usually during or after puberty (5). Dystrophin mutations that cause DMD are typically deletion mutations that are “out of frame” (i.e., the deletion disrupts the 3-nucleotide codon, which encodes an amino acid, causing the deoxyribonucleic acid reading frame to encode the wrong amino acids after the deleted region), resulting in a dysfunctional protein (6). Other forms of disease caused by dystrophin deficiency include the milder muscular dystrophy called Becker muscular dystrophy (BMD), with later onset, slower progression (wheelchair-bound after age 16 years) of skeletal myopathy, and DCM, which may be severe (6). Deletion mutations are also common but typically are “in-frame” (6). Other forms of dystrophinopathies include X-linked dilated cardiomyopathy (XLCM), (7–9)with severe, progressive DCM and elevated muscle creatine kinase (CK-MM) but without clinically evident myopathy, as well as myalgia and CK-emia.
The onset of DCM in DMD most typically occurs during or after puberty, most commonly between 14 to 16 years of age (5,8). The DCM may be severe and progressive, with life-threatening heart failure and/or arrhythmias, or may be asymptomatic for many years without clinical features. The standard diagnostic evaluation of cardiac involvement, the echocardiogram, is a noninvasive method of evaluating left ventricular (LV) size and systolic function, with the ability to analyze a variety of more subtle parameters. In most centers, individuals affected with DMD obtain echocardiograms after symptoms of heart failure begin. Unfortunately, this approach may lead to irreversibly progressive disease, ending in death. Hence, the concept of early referral and a noninvasive imaging approach that identifies early disease could be a more useful methodology with better long-term outcomes. Clearly, new approaches that enable early, presymptomatic diagnostic capability would be useful.
In this issue of the Journal,Giglio et al. (10)report on the use of noninvasive ultrasonic tissue characterization (UTC) analysis (11, 12)of the myocardium of children with DMD under 10 years of age. Previously, Mori et al. (13)used the same methodology to study older patients with DMD (17.6 ± 2.7 years) with overt DCM and demonstrated consistent abnormalities compared to normal controls, suggesting this method was useful in the diagnostic cardiovascular evaluation of these patients. Giglio et al. (10)took this one step further, seeking early detection of myocardial physical property changes in children with no signs or symptoms of cardiac involvement, including normal electrocardiograms and normal LV size and systolic function indexes. Patients and controls displayed significantly different UTC parameters, and interindividual differences were larger in DMD patients than in controls as well. Based on their results, the investigators (10)suggest that this method demonstrates subtle involvement of the myocardium early in DMD and could be potentially useful and reliable in assessing myocardial changes over time.
The work described has several potential important features that should be highlighted. First, essentially all patients with dystrophin deficiency are at risk for the development of DCM (5)and should be screened by noninvasive methods. The earlier that individuals are screened, the better, allowing early diagnosis and therapeutic intervention. Female carriers are also at risk and should be screened (5). The method outlined by Mori et al. (13)and Giglio et al. (10)should be considered in children and adults, including female carriers, in order to follow individuals with dystrophin deficiency before symptoms develop. Another important use of the method could include longitudinal studies assessing drug therapy response in these patients that might help answer the question of whether institution of therapy should be considered before abnormal echocardiograms develop.
We have been studying children through the use of echocardiography and cardiac magnetic resonance imaging; the children are evaluated starting at 10 years of age and are evaluated longitudinally on a yearly basis, with therapeutic intervention using angiotensin-converting enzyme inhibitors and beta-blockers at the earliest signs of myocardial disease. In a high percentage of cases, both reverse remodeling and normalization of LV size and systolic function rapidly occur using this approach. It is possible that earlier use of these agents would be beneficial as these patients are “destined” to develop cardiac disease. Perhaps UTC analysis will answer this question.
The potential improvement in the care of DMD patients attributable to the development of UTC analysis is exciting. Perhaps more exciting, however, is the possibility that this method could be used more globally for other skeletal myopathies and cardiomyopathies. We have suggested previously that a “final common pathway” for myocardial disorders exist, with the cytoskeletal links between sarcolemma and sarcomere being critical (14,15). In addition, we have raised the possibility that “muscle is muscle” because the majority of the genes identified as DCM-causing have a parallel skeletal myopathy phenotype and the majority of skeletal myopathies have associated DCM (16). Thus, it is possible that UTC can also be useful in determining at-risk myocardium in these disorders. It is hoped that the answer to the question of whether UTC is “a noninvasive means of detecting preclinical cardiomyopathy in DMD” will be shown to be true and extended to these other disorders, improving the care and outcomes of these difficult diseases.
☆ Dr. Towbin is funded by the National Institutes of Health; the National Heart, Lung, and Blood Institute (NIH-NHLBI); the Muscular Dystrophy Association; the John Patrick Albright Foundation; and the Texas Children’s Hospital Foundation Chair in Pediatric Cardiac Research.
↵* Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
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