ACE Inhibitors May Help Slow Myocardial Fibrosis In Muscular Dystrophy
Myocardial complications are a leading cause of death in patients with Duchenne or Becker muscular dystrophy.
Treatment with angiotensin-converting enzyme (ACE) inhibitors may help slow the progression of myocardial fibrosis in patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD), according to results from a 2-year randomized trial (ClinicalTrials.gov identifier: NCT02432885) published in JAMA Cardiology.1
Characterized by a progressive degeneration of skeletal muscle, myocardial complications are frequently implicated in the deaths of these patients2,3; however, the effect of interventions on prognosis and progression of myocardial fibrosis in patients with DMD or BMD has not been previously explored.
After first identifying the presence of myocardial fibrosis in patients with DMD or BMD,4 investigators led by Marly Conceição Silva, MD, PhD, of the University of São Paulo Medical School, São Paulo, Brazil enrolled 76 male patients (70 with DMD, 6 with BMD; mean age= 13.1 years) with confirmed DMD or BMD to examine the effects of early intervention with ACE inhibitors on the development and progression of myocardial fibrosis.
Once enrolled, all patients underwent a cardiac evaluation, including a clinical exam, electrocardiogram, chest radiography, serum creatine kinase (CK) level test, Doppler echocardiography, and cardiovascular magnetic resonance (CMR). CMR studies were performed once at baseline and again at 2-year follow-up, in addition to cine MRI for assessment of left ventricular (LV) contractile function and late gadolinium-enhancement imaging (LGE) to detect myocardial fibrosis.
Following assessments, patients were divided into 3 groups: group D (dysfunction; n= 11) consisted of patients with LV ejection fraction (LVEF) <50%; group ND-NF (no dysfunction-no fibrosis; n= 21) consisted of patients with LVEF ≥50% without myocardial fibrosis; and the third group, no-intent-to-treat, consisted of patients with LVEF ≥50% with myocardial fibrosis.
Patients in group D received standard care for DMD or BMD plus therapy for systolic dysfunction as determined by a cardiologist, including treatment with ACE inhibitors (enalapril 10-20 mg/12 hrs) and beta-blockers (total carvedilol dose of 1 mg/kg, starting at 3.125 mg/ 12 hrs to reach maximum dose of 25 mg/12 hrs). Patients with LVEF of ˂35% were also given an aldosterone inhibitor (spironolactone 25 mg/d).
Patients in group ND-NF received standard care for DMD and BMD and no treatment for cardiomyopathy or heart failure. The no-intent-to-treat group was randomized into 2 subgroups: group ND-NT (no dysfunction-no treatment), in which patients received all necessary, guideline-based treatment for their condition but no treatment for cardiomyopathy or heart failure; and group ND-T (no dysfunction-treatment), who, in addition to standard therapy received by patients in the ND-NT group, received treatment with an ACE inhibitor.
Overall, myocardial fibrosis significantly increased in group D but not in group ND-NF. A significant positive correlation was observed between age and the amount of myocardial fibrosis at baseline and follow-up (correlation coefficients, r = 0.52 at baseline and r = 0.50 at follow-up; P <.001 for both), while a negative correlation was observed between age and CK levels (r = −0.693; P <.001). Notably, CK levels decreased with age as myocardial fibrosis increased with age. A similar inverse association was observed between LVEF and myocardial fibrosis. Corticosteroids appeared to have no affect on myocardial fibrosis progression.
During follow-up, 4 patients died, all of whom had worse myocardial fibrosis than the 72 survivors (36.4 [16.2] vs 11.0 [12.1] g; P <.001). These patients also had significantly lower LVEF than survivors (35.9% [16.3%] vs 55.5% [9.0%]; P <.001). Overall, patients with myocardial fibrosis had a greater probability of experiencing a cardiovascular event than those who did not (event rate: 10 of 55 [18.2%] vs 0 of 21 [0%]; log-rank P =.04).
Among the 2 subgroups included in the randomized trial, patients in the ND-NT group showed a significant increase in myocardial fibrosis compared with patients in the ND-T group (10.0% [6.2%] vs 3.1% [7.4%]; P =.001). Similarly, patients taking corticosteroids showed no significant difference in baseline or progression of myocardial fibrosis compared with patients not taking corticosteroids. Notably, treatment with ACE inhibitors was an independent indicator of less myocardial fibrosis at follow-up, and the only indicator of improved LVEF function at follow-up.
“In the present study, 55 patients (72%) presented with MF at baseline and, of those, only 13 individuals (24%) had abnormal LVEF shown on echocardiogram, highlighting the critical role of early detection of MF, particularly considering that the slower progression of MF over 2 years occurred only in patients with MF and no LV dysfunction at baseline,” the authors pointed out. “Our data suggest that ACE inhibitor therapy should start before the onset of LV dysfunction and when MF becomes detectable by CMR.”
- Silva MC, Magalhães TA, Meira ZMA, et al. Myocardial fibrosis progression in Duchenne and Becker muscular dystrophy: A randomized clinical trial. JAMA Cardiol. 2016 Dec 6; doi:10.1001/jamacardio.2016.4801 [Epub ahead of print]
- Muntoni F. Cardiac complications of childhood myopathies. J Child Neurol. 2003;18(3):191-202.
- Eagle M, Bourke J, Bullock R, et al. Managing Duchenne muscular dystrophy—the additive effect of spinal surgery and home nocturnal ventilation in improving survival. Neuromuscul Disord. 2007;17(6):470-475.
- Silva MC, Meira ZM, Gurgel Giannetti J, et al. Myocardial delayed enhancement by magnetic resonance imaging in patients with muscular dystrophy. J Am Coll Cardiol. 2007;49(18):1874-1879.