Early ACE Inhibitors Can Slow Myocardial Fibrosis Progression in Muscular-Dystrophy Patients

Larry Hand

December 08, 2016

SÃO PAULO, BRAZIL — Early administration of ACE inhibitors can slow progression of myocardial fibrosis (MF) in youth males with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD), according to results of a clinical trial[1].

Dr Carlos Eduardo Rochitte (University of São Paulo Medical School, Brazil) and colleagues conducted a randomized trial in two centers involving 76 male patients (mean age at baseline 13.1 years) between June 2009 to June 2012. All patients underwent cardiovascular magnetic resonance (CMR) imaging at baseline and at 2-year follow-up.

"The early initiation of ACE-inhibitor therapy, before overt myocardial fibrosis by CMR, is beneficial for Duchenne and Becker patients," Rochitte told heartwire from Medscape.

"I think this data also put CMR studies in a central role for managing these patients, which has been and continues to be in part an echocardiography role. But now, only echo seems to be not enough, and we need the myocardial fibrosis data from CMR," he said.

The researchers classified patients into three groups: patients with left ventricular ejection fraction (LVEF) <50% (group D for dysfunction), patients with LVEF of  ≥50% and without MF (group ND-NF for no dysfunction, no fibrosis), and patients with LVEF of ≥50% and with MF who constituted the non-intention-to-treat population of the trial.

Patients in group D received conventional DMD or BMD care and medications for systolic dysfunction at the cardiologists' discretion. They received ACE inhibitors, beta-blockers, and, in patients with LVEF <35%, an aldosterone inhibitor. The ND-NF group received conventional DMD or BMD care but no treatment for cardiomyopathy or heart failure.

Patients with LVEF of ≥50% and MF were randomized into one of two groups: no dysfunction, no treatment (ND-NT), who received treatments according to clinical condition based on guidelines but no cardiomyopathy or heart-failure treatment, and no dysfunction, treatment (ND-T), who received basic treatment plus the ACE inhibitor enalapril.

The dose of enalapril ranged from 2.5 mg every 12 hours to 10 to 20 mg every 12 hours depending on patient age.

Clinicians at a specialized DMD/BMD outpatient clinic followed the patients every 6 months or at any time new symptoms occurred for the primary outcome of degree of MF accumulation.

The researchers observed a significant increase in MF mass in group D, a significant positive correlation between age and the amount of MF at baseline and follow-up, and a significant negative correlation between age and creatine kinase level.

Four patients who died during the study had significantly higher MF than survivors and significantly lower LVEF. The deaths were related to heart failure associated with pneumonia, thromboembolic events, and severe cardiac arrhythmia.

The 42 patients (mean age 12.1 years) included in the randomized trial had their diagnoses confirmed by muscle biopsy or DNA mutation.

At 2-year follow-up, the nontreated group had significantly higher MF compared with the treated group (10.0% vs 3.1%; P=0.001). Although the increase in MF was not statistically significant in the ND-T group (32.8 to 35.9 percentage of LV mass; P=0.07), it was in the ND-NT group (23.8 to 33.8 percentage of LV mass; P<0.001).

"To our knowledge, this is the first study to demonstrate the benefit of ACE-inhibitor therapy specifically in patients with MF identified on CMR and preserved LV function," the researchers wrote.

"I believe our data have the potential to impact guidelines on Duchenne and Becker therapy, indicating an earlier initiation of ACE-inhibitor therapy than current practice, with ACE inhibitors starting only when LV ejection fraction is below normal," Rochitte told heartwire .

"I think now we should investigate how early medication for heart failure should start on these kids. We know that should be before myocardial fibrosis appears on a CMR study, but should it be started in the early infancy? That we still do not know, and it would be very important to access," he said.

In an accompanying editor's note[2], Dr Elizabeth M McNally (Northwestern University Feinberg School of Medicine, Chicago, IL) writes that the new study and previous research together "provide sound evidence for early intervention to prevent or slow cardiomyopathy progression with medical management.

"As we move closer to using genetic signatures to identify individuals at risk and applying tailored therapy, we realize a goal of personalized medicine," she wrote.

The research was funded in part by the Zerbini Foundation, Sao Paulo Research Foundation, and the National Council for Scientific and Technological Development. The researchers and McNally report no relevant financial relationships.

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