This study represents the largest cohort of DMD patients analyzed for the effect of medical therapy on the natural history of DMD-associated cardiac disease. Albeit retrospective, these results suggest that treatment with either an ACEI or ARB does not arrest the decline in DMD-associated cardiac function in patients receiving corticosteroids. In fact, we found a statistically significant worsening in εcc in patients taking both corticosteroids and ACEI or ARB, suggesting that current approaches are inadequate in arresting decline in cardiac function.
Clinical assessment of DMD-associated cardiac disease is particularly challenging, as overt decompensation typically occurs only in the terminal stages of disease at a time when clinical assessment of cardiac function is limited. A sensitive and specific parameter such as εcc
could thus assume great importance in management of these patients. Previous studies have shown that changes in εcc
precede decline in LVEF in DMD-associated cardiac disease as well as in both hypertrophic and hypertensive cardiomyopathy [24
]. Using such an early marker of subclinical disease in a cohort with preserved LVEF, we were unable to detect an improvement with standard therapies.
Assessment of cardiac effects of corticosteroid therapy in animal models and patients has historically yielded mixed results. For example, corticosteroids have been shown to improve systolic function in children with myocarditis but not with dilated cardiomyopathy [39
]. Markham et al demonstrated that freedom from ventricular dysfunction at approximately 50 months between retrospectively-reviewed echocardiograms was 93% for steroid treated versus 53% for untreated DMD cases [6
]. However, in a mouse model of dystrophin deficiency, Bauer et al demonstrated acceleration of cardiac dysfunction in steroid treated animals [40
]. Recently, Pereira et al [41
] observed normalization of multidirectional (radial, longitudinal and circumferential) strain assessed by 2D echo speckle tracking in Cushing syndrome patients following normalization of corticosteroid excess; they concluded that corticosteroid excess not only induced LV hypertrophy and diastolic dysfunction but also subclinical systolic dysfunction, which reverses upon normalization of corticosteroid excess. While there is universal agreement that steroids prolong ambulation in the DMD patient population (reviewed in [21
]), the current study failed to identify a cardioprotective effect of steroids.
Several studies have suggested beneficial effects of ACEI on LV function in small cohorts [17
]. In a murine DMD model, Bauer et al showed hemodynamic benefit to dystrophin-deficient mice treated with ACEI alone [40
]. Jefferies et al suggested that this effect may be linked to specific mutations [19
] in humans, but Ramaciotti et al [42
] did not confirm this finding. In addition to εcc
, we found no difference in EF between baseline and 15 months, which is at odds with the findings of Duboc et al [17
] who found that treatment with perindopril delayed the onset and progression of LV dysfunction in children. There are several possible explanations for the differences in findings. First, in our cohort, the time between the serial CMR studies might be insufficient to develop detectable LV EF decline. However, one would expect to detect more subclinical changes using the more sensitive measure LV εcc
. Furthermore, without an untreated control group, the fact that εcc
magnitude declined only slightly may represent a "good" outcome, as LV function of untreated patients may decline more precipitously. Despite smaller studies reporting benefit of ACEI and BB, there is no published data demonstrating longer life expectancy in DMD boys undergoing "adult-like" CHF therapy.
A long-standing hypothesis regarding DMD-associated cardiac disease pathogenesis is that loss of membrane integrity is a primary event leading to myocyte degeneration. Intermittent tears in the cell membrane permit influx of calcium that then functions as a primary inducer of a destructive cascade culminating in myocyte necrosis and replacement fibrosis [43
]. Although there has been intense interest in treating DMD-associated cardiac disease, successful therapies remain elusive [22
]. Findings in the current study underscore the need for randomized studies in DMD population. As in cases of heart failure in adult population, development of heart failure with normal EF starts early (HFNEF) and proceeds to systolic dysfunction. Of interest, studies in adult HFNEF patients treated with ACEI or BB have not demonstrated improvement in mortality compared to placebo [47
]. In boys with DMD, dystrophin mutation dictates eventual LV dysfunction and once systolic dysfunction and myocardial fibrosis develop, clinical disease typically progresses very rapidly and long-term survival (as seen in adult patients with LV systolic dysfunction) is poor. As such, the window of opportunity to treat DMD-associated cardiac disease needs to be advanced to when εcc
is abnormal but EF has not yet begun its inexorable declined.
Study design based on physician preference is a major limitation of the study and includes retrospective, mostly cross-sectional data with no control group and with strong confounding of group allocation by age of boys being prescribed therapy. Older boys tended to be on combination treatment while younger boys were often treated with steroids alone. Further, longitudinal data is limited. Other confounding factors are very difficult to control for but are beyond the scope of this manuscript. As such, no firm conclusions can be drawn regarding the response rates to steroid or ACEI/ARB use. Further, findings are limited to patients >5 years since in our experience patients < 5 years of age cannot undergo CMR without sedation. While it is possible, that 15 months follow-up was too short to detect therapeutic benefits, studies in other populations with preserved EF but measurable diastolic dysfunction have shown improvement in circumferential and longitudinal strain 12 months after ARB initiation [50