Cardiomyopathy is a consequence of Duchenne muscular dystrophy (DMD). Suggested treatments include angiotensin-converting enzyme (ACE) inhibitors and/or β blockers (BBs), but few large series have been reported. We present 42 patients with DMD and cardiomyopathy treated with an ACE inhibitor or an ACE inhibitor plus a BB. Serial echocardiograms were recorded. Adequate ejection fractions (EFs) were obtained at initiation of therapy (EF <55%). ACE inhibitor dosage adjustments were made if a continued decrease in EF was noted. BB therapy was initiated when average heart rate on Holter monitoring exceeded 100 beats/min. Data were analyzed using paired t test and linear regression. Before ACE inhibition, patients (n = 22) demonstrated decreased EF over time (r 2 = 0.23). At ACE inhibitor therapy initiation, mean age was 14.1 ± 4.6 years and mean EF was 44.2 ± 6.8%. BB therapy was used in 24 of 42 patients. Mean age for the ACE inhibitor + BB group was 15.7 ± 3.9 years. The 2 groups showed significant improvement (p <0.0001 for ACE inhibitor and ACE inhibitor plus BB) compared to the pretherapy group. No significant differences were noted between treatment groups. Patients with DMD demonstrated a gradual decrease in myocardial function. Treatment with ACE inhibitor or ACE inhibitor plus BB resulted in significant improvement compared to pretherapy. No significant difference occurred in EF improvement between treatment groups. In conclusion, treatment with ACE inhibitor or ACE inhibitor plus BB can delay progression of cardiomyopathy.
No consensus exists regarding the proper pharmacologic intervention and timing of treatment for cardiomyopathy in patients with Duchenne muscular dystrophy (DMD). Corticosteroids have been reported to retard the development of left ventricular dysfunction in patients with DMD as measured by echocardiography and by cardiac magnetic resonance imaging. This is in contrast to findings in the mdx mouse model, where treatment with steroids resulted in hemodynamic deterioration, increased cardiac fibrosis, and increased sarcolemmal injury associated with tumor necrosis factor-α expression. Others have hypothesized that interventions that benefit skeletal muscle may accelerate the development of cardiomyopathy because skeletal myopathy may limit cardiac demand secondary to decreased exercise capacity. Studies have also demonstrated that use of angiotensin-converting enzyme (ACE) inhibitors and β blockers (BBs) in patients with DMD reverse congestive heart failure signs and symptoms, delay progression of left ventricular dysfunction, and improve systolic function. However, debate continues regarding the optimal timing of initiation of such treatments. The purpose of this study was to examine the natural course of ventricular function and cardiomyopathy in patients with DMD before initiation of an ACE inhibitor and to assess their responses to treatment using an ACE inhibitor with or without concomitant BB therapy.
Methods
Patients were identified from a prospectively maintained database from the cardiology neuromuscular referral program at Nationwide Children’s Hospital, Columbus, Ohio. Their charts were reviewed after institutional review board approval. In each patient, the clinical diagnosis of DMD was confirmed by mutational analysis from genomic DNA of the DMD gene or by muscle biopsy that demonstrated an absence of dystrophin by immunofluorescence or western blot (<5% dystrophin). All patients were serially evaluated by a pediatric cardiologist (H.D.A.) including history, physical examination, blood pressure monitoring, electrocardiogram, and echocardiogram. Holter monitoring was added at 12 years of age or if they were noted to have tachycardia at rest. Echocardiographic data are maintained in a central database.
Cardiomyopathy was arbitrarily diagnosed by ejection fraction (EF) <55% measured on echocardiographic Doppler studies. All echocardiograms were interpreted by the same cardiologist (H.D.A.). Therapy was provided according to the clinic’s standard clinical care, defined as treatment with an ACE inhibitor (lisinopril) for EF <55%. Typical initial doses were 2.5 mg/day if a patient’s weight was <40 kg and 5 mg/day if a patient’s weight was ≥40 kg (as close to 0.07 mg/kg as possible). Patients were scheduled for follow-up every 3 to 4 months after initiation of therapy, and the ACE inhibitor dose was increased if a >5% downward trend was seen in EF. BB therapy (metoprolol) was initiated at 1 to 2 mg/kg when patients demonstrated disordered automaticity, defined as an average heart rate >100 beats/min on Holter monitoring.
Patients were excluded from analysis if (1) therapy with an ACE inhibitor exceeded 6 months’ duration before initial evaluation at this institution, (2) poor echocardiographic images precluded accurate evaluation of ejection fraction, or (3) there were no pretherapy data and <6 months’ follow-up data after starting an ACE inhibitor. Natural progression of left ventricular function before ACE inhibitor initiation was assessed using linear regression. Pretherapy data for the 12 months before ACE inhibitor initiation were arbitrarily chosen as baseline to compare responses to therapy. For analysis, patients were divided into 2 groups: (1) patients receiving an ACE inhibitor only and (2) those patients receiving an ACE inhibitor and a BB. Of note, the latter group consisted of 3 subgroups including (1) those patients in whom treatment was initiated simultaneously with an ACE inhibitor and a BB, (2) those patients treated with an ACE inhibitor with subsequent addition of a BB, and (3) those initially treated with a BB for disordered automaticity or arrhythmia without cardiomyopathy with subsequent addition of an ACE inhibitor after EF decreased to <55%. Those patients who subsequently had a BB added to ACE inhibitor therapy were included in data analysis of the ACE inhibitor only group until the addition of the BB. Then, they were analyzed in the ACE inhibitor and BB treatment group after BB was added. For each treatment group, mean EF was calculated for each period (0 months to 6 months, 6 to 12 months 12 to 18 months, 18 to 24 months 24 to 36 months, and 36 to 48 months). SEMs were determined. Paired t tests were used to compare mean EFs between time points for all groups, slopes of the 2 treatment groups, and therapeutic responses to the baseline group. Treatment groups were also analyzed for changes in EF from start of therapy.
Results
We identified 65 patients with DMD from July 2005 through January 2011 who were treated with an ACE inhibitor (lisinopril) for cardiomyopathy. Twenty-two patients had sufficient pretreatment data, defined as ≥1 echocardiogram ≥6 months before therapy, to be included for analysis in the pretherapy group. Two were not included in treatment analysis because of inadequate follow-up. Twenty-three of the 65 patients were excluded from treatment analysis owing to >6 months of previous treatment with an ACE inhibitor (n = 11), <6 months of follow-up data (n = 8), initiation of ACE inhibitor when EF was ≥55% (n = 3), or inadequate echocardiographic imaging precluding accurate measurement of EF (n = 1; Figure 1 ) . Age at diagnosis of cardiomyopathy ranged from 7.0 to 27.3 years (mean 14.8 ± 4.6). Of the 42 remaining patients, patients were grouped into those treated with an ACE inhibitor alone or an ACE inhibitor in combination with a BB ( Figure 1 and Table 1 ). Two patients did not start ACE inhibitor therapy after initially prescribed and subsequently showed a decrease in their EF. At the time of ACE inhibitor initiation, 13 of 42 patients had been treated with corticosteroids. The mean age this group was 13.8 ± 3.9 versus 15.4 ± 4.9 years for those not receiving steroids.
| Control (natural history) | ACE Inhibitor ⁎ Only | ACE Inhibitor ⁎ + BB | |
|---|---|---|---|
| (n = 22) | (n = 30) | (n = 24) | |
| Ages (years) | |||
| Range | — | 7–27.3 | 9.8–23.7 |
| Mean ± SD | — | 14.1 ± 4.6 | 15.7 ± 3.9 |
| Number of patients/follow-up group | |||
| Period (months) | |||
| 0–6 | — | 30 | 24 |
| 6–12 | — | 25 | 20 |
| 12–18 | — | 23 | 17 |
| 18–24 | — | 15 | 17 |
| 24–36 | — | 11 | 12 |
| 36–48 | — | 8 | 7 |
| Ejection fraction (%), mean ± SD | |||
| Period (months) | |||
| −12 to −6 | 54 ± 8.1 | — | — |
| 6–0 | 47 ± 7.4 | — | — |
| 0–6 | — | 47 ± 6.1 | 46 ± 10 |
| 6–12 | — | 52 ± 8.4 | 50 ± 11 |
| p Value | 0.006 | 0.011 | 0.001 |
BBs were used in 24 patients. Seventeen patients were treated initially for disordered automaticity. Of these, 2 subsequently developed supraventricular tachycardia and 1 developed ventricular tachycardia. Two patients started BB therapy because of disordered automaticity and concurrent ventricular tachycardia, and 1 patient started therapy for isolated ventricular tachycardia. One patient started therapy for supraventricular tachycardia and subsequently developed ventricular tachycardia. Two patients started BB therapy because of ventricular dysfunction. One patient started therapy for significant multifocal ventricular ectopy. Of those receiving BBs, 17 of 24 were started on a BB after initiation of an ACE inhibitor, 4 of 24 were started concomitantly, and 3 of 24 were started on a BB before initiation of an ACE inhibitor. These patients were treated for 7 to 18.7 months (median 18.7). No statistical comparison to treatment groups was performed because of insufficient numbers. The initial metoprolol dose was 1 to 2 mg/kg/day. Mean dose achieved at the end of the study period was 1.1 ± 0.6 mg/kg/day (range 0.3 to 3.2). One patient was treated with atenolol instead of metoprolol.
Echocardiographic information was obtainable for 22 patients before initiation of an ACE inhibitor. Only 1 patient was excluded because of inadequate echocardiographic information. This confirms that such testing is possible in most patients with DMD. Duration of surveillance before initiation of therapy was 6 to 52 months. Before initiation of an ACE inhibitor, patients with DMD demonstrated a gradual decrease in EF ( Figure 2 ) . Onset of cardiomyopathy is displayed in Figure 3 .
