Duchenne muscular dystrophy is an X-linked neuromuscular disorder that affects 1 in 5,000 boys [6]. Although these children present initially with skeletal muscle weakness, development of cardiomyopathy is inevitable and typically occurs in the second to third decade of life with more than 90% of adolescent males over 18 years of age demonstrating cardiac dysfunction [7]. With improvements in respiratory support for these patients, end-stage heart failure has become an increasing cause of death in this population. Thus, early and pre-emptive treatment of the cardiomyopathy is thought to be important, and identification of pre-clinical changes can allow for initiation of cardioprotective measures to slow the progression of adverse cardiomyopathic remodeling.
In recent years, cardiac MRI with late gadolinium enhancement (LGE) has been demonstrated to be a valuable tool in cardiac assessment of DMD patients. Because of comorbidities including body habitus, contractures, ventilatory disease, and scoliosis, echocardiography in this population is often limited with more severe disease. In addition to providing more detail regarding cardiac dimensions, systolic function, and diastolic function, studies have found that presence of LGE is a poor prognostic indicator for adverse cardiac events in adult patients with DMD [8, 9]. While LGE is a known poor prognostic indicator in older DMD patients with overt cardiomyopathy, this study explores the significance of LGE detected in the preadolescent age range.
Our findings suggest that cardiac functional decline occurs much more rapidly in patients who demonstrate LGE at an early age, which can be observed in roughly one-third of preadolescents with DMD. Historically, symptomatic cardiomyopathy in these DMD patients has been identified later in the second decade of life or by age 20. This study shows there are preclinical changes detectable by cardiac MRI even if systolic function and cardiac dimensions measured by echocardiogram appear within normal range. This implies benefit to performing cardiac MRI on patients with DMD at least once as pre-adolescents as part of thorough risk stratification.
ACE inhibitors, beta blockers, and MRAs are thought to delay progression of DMD cardiomyopathy by affecting neurohormonal regulation and attenuating myocardial fibrosis [10, 11, 12]. Research has demonstrated that early ACEi use is associated with delay in cardiac dysfunction and prolongation of life [13, 14]. ACE inhibitors have now become standard of care for most patients with DMD, even prior to the onset of overt cardiomyopathy [15]. In our cohort, MRI findings likely led to earlier initiation of ACEi, MRA, and beta blockade in the group of patients who developed LGE prior to age 14. Although it will take considerably more time to delineate whether programmatic personalization of medical therapy in response to early teen MRI data will prove important to patient longevity, this approach seems prudent compared with waiting for cardiac dysfunction to occur by echocardiogram before obtaining MRI data for the first time.
Early LGE patients trended toward earlier age of loss of ambulation, but this observation did not meet statistical significance. Larger studies have reported that loss of ambulation and heart function do not occur concomitantly, consistent with the observation that skeletal myocyte function and cardiac myocyte function are distinct [16].
Heart rate, however, has been previously reported to correlate with cardiac severity in DMD, including a case-control study where cardiomyopathy developed in 42% of patients with heart rate in the upper quartile but only in 14% of lower heart rate quartile boys (p < 0.05) [17]. Our study did not detect such a pattern, possibly due to the limited time-points of which heart rate was captured in this study. Our study did not find a correlation between severity of obesity and earlier development of symptomatic cardiomyopathy, consistent with existing literature [18].
Frame shift mutations, as a group, have been shown to demonstrate more severe phenotypes of DMD [19, 20]. Even large deletions of the region corresponding to the central triple helical repeats in the protein that don’t alter the reading frame can correspond with surprisingly mild phenotype [21]. Allelic X-linked dilated cardiomyopathy seems to particularly affect the heart, sparing the skeletal muscle which produces dystrophin by exon skipping or alternative splicing that the heart is not able to replicate [22, 23]. This was not captured in our data, possibly due to small sample size.
Importantly, if timing of loss of ambulation, heart rate trends, genetic mutation, and development of obesity do not clinically correlate with development of cardiac dysfunction, this lends credence to use of cardiac MRI as a standard tool for early detection of myocardial fibrosis in patients before development of clinically symptomatic cardiomyopathy. As 35% of our cohort was found with early-onset fibrosis, utilizing cardiac MRI during this pre-adolescent period is clinically informative in a significant proportion of patients. Prognostic information is not only important for strategizing guideline-directed medical therapy for heart failure, but also for counseling patients with DMD and their caregivers. Giving our patients knowledge about timeline of their hearts’ functional decline is vital in a disease management that is ultimately palliative.
Our study is inherently limited by its retrospective nature and by it representing a single institution, whose patient population and clinician practices may vary from other institutions. We restricted our study to those with adequate follow-up after age 14, further curtailing our sample size. Additionally, this study era pre-dated protocolized age at first MRI at our institution. Finally, the age cutoff of 14 for determining early LGE was a clinically subjective decision, intended to optimize statistical analysis for this study.
One-third of pre-adolescent DMD patients exhibit cardiac myocardial fibrosis as indicated by LGE on cardiac MRI. This early finding is strongly associated with faster progression to cardiac systolic dysfunction. Aggressive augmentation of cardioprotective drugs in these patients who demonstrate early LGE does not prevent development of cardiac dysfunction but may potentially slow the course of cardiomyopathy. Early assessment by cMRI provides valuable prognostic information to help counsel families and guide medical decisions for young patients with DMD.