Philip T. Thrush

Effects of Angiotensin-Converting Enzyme Inhibitors and/or Beta Blockers on the Cardiomyopathy in Duchenne Muscular Dystrophy

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.

Re-examination of the Electrocardiogram in Boys With Duchenne Muscular Dystrophy and Correlation With Its Dilated Cardiomyopathy

Duchenne muscular dystrophy (DMD) results in dilated cardiomyopathy (DC). Characteristic electrocardiographic (ECG) changes include short PR interval, right ventricular hypertrophy (RVH), prolonged QTc interval, and prominent Q waves in leads I, aVL, V5, and V6 or in leads II, III, aVF, V5, and V6. We re-examined the prevalence and correlation of ECG changes with DC in DMD. Electrograms of 115 patients with DMD were evaluated. DC was defined as an echocardiographic ejection fraction<55%. PR interval and RVH were based on age-based normal values. Abnormal Q waves were >or=4 mm. Abnormal QTc interval was >or=450 ms. ST-segment depression was defined as >0.5 mm. Fishers exact test evaluated significant differences between groups and logistic regression determined whether number of ECG changes predicted DC. Forty had DC. No significant differences existed between the number of ECG changes in DC and non-DC groups (p=0.279). Distribution of findings included short PR interval (43%), RVH (37%), prominent Q waves in leads V5 (34%) and V6 (33%), prominent Q waves in leads I, aVL, V5, and V6 (3, 1 with DC), prominent Q waves in leads II, III, aVF, V5, and V6 (9, 4 with DC), long QTc interval (0), ST depression (2, 1 with DC), and flat/biphasic ST segments (38, 15 with DC). In conclusion, ECG changes are similar in patients with DMD regardless of presence of DC. Previously reported characteristic ECG changes are seen in a minority of DMD cases. The most common findings are short PR interval and RVH. Prominent Q waves in leads II, III, aVF, V5, and V6 are more likely.

A randomized, double-blind trial of lisinopril and losartan for the treatment of cardiomyopathy in duchenne muscular dystrophy.

Objectives: This study sought to compare the effectiveness and safety of an angiotensin converting enzyme inhibitor (ACE-I) (lisinopril) vs. an angiotensin receptor blocker (ARB) (losartan) for the treatment of cardiomyopathy (CM) in boys with Duchenne muscular dystrophy (DMD). Background: Development of CM is universal in boys with DMD. ACE-I and ARB have both been suggested as effective treatment options. ARBs have been associated with skeletal muscle regeneration in a mouse model of DMD. The question of which, if either, is more effective for CM treatment in DMD remains. The purpose of this multicenter double-blind prospective study was to compare efficacy and safety of lisinopril versus losartan in the treatment of newly diagnosed CM in boys with DMD. Methods: Echocardiographic technician inter- and intraobserver variability were tested on 2 separate days on 2 different boys with DMD CM. Results were compared with paired t-testing. Twenty-two boys with newly diagnosed DMD CM (echocardiographic ejection fraction (EF) 10% EF drop. Three boys in the aCE-I group had 3 visits, due to study funding termination. Two were withdrawn because of low EF. All their data are included in the analysis for as long as they remained in the study. Mean EF’s were similar at baseline (47.5%- ACE-I, 48.4%- ARB). After 1 year each group significantly improved to 54.6% and 55.2% respectively (p=.02). There was no difference between the 2 treatment groups at 1 year. Conclusions: Inter-observer and intra-observer reliability studies showed no differences between echocardiographers on serial examinations. EF improved equally in the two groups. There is no therapeutic difference in EF improvement between lisinopril and losartan over the one-year duration for treatment of boys with DMD-related CM. Trial Registration: ClinicalTrials.gov NCT01982695

Pediatric heart transplantation—indications and outcomes in the current era

Pediatric heart transplantation (HTx) remains an important treatment option in the care of children with end-stage heart disease, whether it is secondary to cardiomyopathy or congenital heart disease (CHD). As surgical outcomes for CHD have improved, the indications for pediatric HTx have had to be dynamic, not only for children with CHD but also for the growing population of adults with CHD. As the field of pediatric HTx has evolved, the outcomes for children undergoing HTx have improved. This is undoubtedly due to the continued research efforts of both single-center studies, as well as research collaboratives such as the International Society for Heart and Lung Transplantation (ISHLT) and the Pediatric Heart Transplant Study (PHTS) group. Research collaboratives are increasingly important in pediatric HTx as single center studies for a limited patient population may not elicit strong enough evidence for practice evolution. Similarly, complications that limit the long term graft survival may occur in a minority of patients thus pooled experience is essential. This review focuses on the indications and outcomes for pediatric HTx, with a special emphasis on studies generated by these research collaboratives.

Cardiac Management in Neuromuscular Diseases

This article addresses the pathophysiology, diagnostic approaches, and therapeutic options in the more common forms of muscular dystrophy, especially those seen in pediatric and young adult populations. The major emphasis is on the dystrophinopathies because their treatment options are templates for those used in various other forms of dystrophy. Most patients with cardiomyopathy are treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, with other agents added as the disease progresses. Destination therapies and transplantation options are mentioned where appropriate. Some dystrophies can have significant conduction abnormalities requiring pacemaker treatment. Others with ventricular tachydysrhythmias may necessitate internal cardiac defibrillator placement.

Visual Diagnosis: Chest Pain in a Boy With Duchenne Muscular Dystrophy and Cardiomyopathy

1. Philip T. Thrush, MD* 2. Kevin M. Flanigan, MD†,‡§ 3. Jerry R. Mendell, MD†,‡§ 4. Subha V. Raman, MD|| 5. Curt J. Daniels, MD*,|| 6. Hugh D. Allen, MD¶ 1. *Department of Pediatrics, The Ohio State University, The Heart Center, Nationwide Childrens Hospital, Columbus, OH. 2. †The Center for Gene Therapy, Research Institute, Nationwide Children’s Hospital, Columbus, OH. 3. ‡Muscular Dystrophy Cooperative Research Center, Nationwide Childrens Hospital, Columbus, OH. 4. §Departments of Pediatrics and Neurology, The Ohio State University, Nationwide Childrens Hospital, Columbus, OH. 5. ||Division of Cardiovascular Medicine, The Ohio State University, Columbus, OH. 6. ¶Associate Editor. Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX. * Abbreviations: DMD: : Duchenne muscular dystrophy EF: : ejection fraction ECG: : electrocardiography CMRI: : cardiac magnetic resonance imaging LGE: : late gadolinium enhancement A 17-year-old boy with Duchenne muscular dystrophy (DMD) due to a deletion of exons 18 to 37 in the DMD gene was diagnosed in our clinic as having cardiomyopathy at age 12 years. His current medications include deflazacort (30 mg/d), lisinopril (10 mg once daily for cardiomyopathy), and metoprolol succinate (50 mg twice daily for disordered automaticity). His cardiac function had been stable, with ejection fractions (EFs) ranging from 47% to 55%. After 1 day of headache and emesis, he presents to a local emergency department with acute onset of chest pain and shortness of breath. Electrocardiography (ECG) reveals ST-segment elevation in the inferolateral leads and ST-segment depression in the midprecordial leads, which prompts further testing (Figure 1). His initial troponin I level is elevated. He is transferred to a tertiary care facility for further evaluation. At the time of admission, his chest pain is substantially improved without intervention, but his troponin I level is now 40.27 ng/mL (40.27 μg/L) (reference range, <0.04 ng/mL [<0.04 μg/L]). Further laboratory evaluation reveals a white blood cell count of 12,900 /μL, 72% neutrophils, 20% lymphocytes, a C-reactive protein level of 299.8 mg/L (2855.3 nmol/L) (reference range, <12.0 mg/L [114.3 nmol/L]), and a lactate level of 7.2 mg/dL (0.8 mmol/L) (reference range, 4.5-19.8 mg/dL [0.5-2.2 mmol/L]). Cardiac magnetic resonance imaging (CMRI) with late gadolinium enhancement (LGE) reveals extensive left ventricular lateral wall epicardial enhancement (Figure 2A) and an EF of 50%. Quantitative T2 mapping reveals an increased T2 signal (80 milliseconds compared with 48 milliseconds in the unaffected interventricular septum) in the same region consistent with acute inflammation and injury …

Precordial R wave height does not correlate with echocardiographic findings in boys with Duchenne muscular dystrophy.

OBJECTIVES Cardiomyopathy (CM) is an inevitable consequence of Duchenne muscular dystrophy, and electrocardiographic changes, right ventricular hypertrophy in particular, have been proposed to serve as an early marker for CM. To evaluate this concept, we assessed the correlation between R wave height in lead V1 and echocardiographic findings in boys with Duchenne muscular dystrophy. METHODS Serial echocardiograms and electrocardiograms (n = 800) were performed during each clinic visit in a cohort of 155 boys with Duchenne muscular dystrophy. Precordial R wave height in lead V1 was measured. Echocardiographic parameters included ejection fraction (EF), shortening fraction, and left ventricular end-diastolic dimension. Data were analyzed using Pearson correlation and linear regression. RESULTS Ages ranged from 1.8 to 37.2 years (mean 14.7 ± 5.9 years). Seventy-one patients had CM and 318/800 echocardiograms had an EF < 55%. Older patients tended to have a lower EF, but there was no correlation between age and left ventricular end-diastolic dimension. R wave height in lead V1 correlated poorly with both left ventricular end-diastolic dimension (r = 0.096, P =.0078) and EF (r = 0.096, P =.0088) for the whole cohort as well as those studies demonstrating an EF <55% (left ventricular end-diastolic dimension r = 0.089, P =.12 and EF r = -0.044, P =.94). No individual patient demonstrated significant correlation between R wave height in lead V1 and left ventricular end-diastolic dimension or EF. Left ventricular end-diastolic dimension showed a moderate negative correlation with EF for the whole cohort (r = -0.394, P <.001) as well as those with an EF < 55% (r = -0.376, P <.001). CONCLUSIONS The precordial R wave height in V1 correlates poorly with the presence of depressed left ventricular function and is not prognostic for the development of CM. While not predictive for CM, the electrocardiogram remains vital to cardiac screening for boys with Duchenne muscular dystrophy due to risk for other cardiac manifestations such as arrhythmias.

NATURAL HISTORY OF CARDIOMYOPATHY IN DUCHENNE MUSCULAR DYSTROPHY AND THE EFFECTS OF ANGIOTENSIN-CONVERTING ENZYME INHIBITOR WITH OR WITHOUT BETA-BLOCKER

Cardiomyopathy (CM) is an inevitable consequence of Duchenne muscular dystrophy (DMD). Suggested treatments include angiotensin-converting enzyme inhibitors (ACEI) and/or beta-blockers (BB), but few large series have been reported. We present 65 DMD patients with CM treated with ACEI or ACEIpBB