Published Online
on October 24, 2005

A more recent version of this article appeared on November 1, 2005

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Submitted on December 7, 2004
Revised on July 6, 2005
Accepted on July 11, 2005

Genetic Predictors and Remodeling of Dilated Cardiomyopathy in Muscular Dystrophy

John L. Jefferies MD, MPH, Benjamin W. Eidem MD, John W. Belmont MD, PhD, William J. Craigen MD, PhD, Stephanie M. Ware MD, PhD, Susan D. Fernbach RN, BSN, Steven R. Neish MD, E. O’Brian Smith PhD, and Jeffrey A. Towbin MD^*

From the Department of Cardiology, Texas Heart Institute at St Luke’s Episcopal Hospital (J.L.J.), Houston, and the Divisions of Pediatric Cardiology (J.L.J., B.W.E., S.D.F., S.R.N., J.A.T.), Genetics (J.W.B., W.J.C., S.M.W., S.D.F., J.A.T.), and Nutrition (E.O.S.), Texas Children’s Hospital, Baylor College of Medicine, Houston, Tex.

^* To whom correspondence should be addressed. E-mail: jtowbin{at}bcm.tmc.edu.

Background--Dystrophin gene mutations cause 2 common muscular dystrophies, Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Both are frequently associated with dilated cardiomyopathy (DCM) and premature death. We hypothesized that early diagnosis and treatment of DCM in DMD/BMD patients would lead to ventricular remodeling and that specific dystrophin gene mutations would predict cardiac involvement.

Methods and Results--Sixty-nine boys with DMD (n=62) and BMD (n=7) (mean age, 12.9 and 13.7 years, respectively) were referred to our Cardiovascular Genetics Clinic for evaluation, including echocardiography and DNA analysis. Follow-up evaluations were scheduled yearly until the first abnormal echocardiogram indicative of DCM and quarterly thereafter. After the first abnormal echocardiogram, angiotensin-converting enzyme inhibitor or -blocker therapy was started. -Blockers were added if echocardiography showed no ventricular remodeling in angiotensin-converting enzyme inhibitor-treated patients after 3 months. DCM was diagnosed in 31 subjects (DMD, 27/62, 44%; BMD, 4/7, 57%) (mean age at onset, 15.4±2.8 years; range, 10.4 to 21.2 years). All 31 subjects were begun on pharmacological therapy after diagnosis. On follow-up (n=29), 2 subjects (both DMD) showed stable DCM, 8 subjects (all DMD) showed improvement, and 19 subjects (16 DMD; 3 BMD) showed normalization of left ventricular size and function (total improvement, 27/29 [93%]). DNA analysis in 47 cases (68%) revealed a significant association between DCM and exon 12 and 14 to 17 mutations, possible protection against DCM by exon 51 to 52 mutations, and a trend toward significant association between onset of DCM and exon 31 to 42 mutations. Statistical significance was based on nominal probability values.

Conclusions--Early diagnosis and treatment of DCM may lead to ventricular remodeling in DMD/BMD patients. Specific dystrophin gene mutations appear to be predictive of cardiac involvement, while other mutations may protect against or inhibit development of DCM. Further studies evaluating the impact of early intervention strategies on left ventricular geometry and function in muscular dystrophy patients seem warranted.

Key words: cardiomyopathy • genetics • muscular dystrophy • remodeling • risk factors

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