Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy

John L. Jefferies, Benjamin W. Eidem, John W. Belmont, William J. Craigen, Stephanie Ware, Susan D. Fernbach, Steven R. Neish, E. O Brian Smith, Jeffrey A. Towbin

Research output: Contribution to journalArticle

182 Citations (Scopus)

Abstract

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 β-blocker therapy was started. β-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.

Original languageEnglish (US)
Pages (from-to)2799-2804
Number of pages6
JournalCirculation
Volume112
Issue number18
DOIs
StatePublished - Nov 1 2005
Externally publishedYes

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Duchenne Muscular Dystrophy
Muscular Dystrophies
Dilated Cardiomyopathy
Mutation
Dystrophin
Ventricular Remodeling
Exons
Left Ventricular Function
Angiotensin-Converting Enzyme Inhibitors
Echocardiography
Early Diagnosis
Genes
Premature Mortality
DNA
Therapeutics
Age of Onset

Keywords

  • Cardiomyopathy
  • Genetics
  • Muscular dystrophy
  • Remodeling
  • Risk factors

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Jefferies, J. L., Eidem, B. W., Belmont, J. W., Craigen, W. J., Ware, S., Fernbach, S. D., ... Towbin, J. A. (2005). Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy. Circulation, 112(18), 2799-2804. https://doi.org/10.1161/CIRCULATIONAHA.104.528281

Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy. / Jefferies, John L.; Eidem, Benjamin W.; Belmont, John W.; Craigen, William J.; Ware, Stephanie; Fernbach, Susan D.; Neish, Steven R.; Smith, E. O Brian; Towbin, Jeffrey A.

In: Circulation, Vol. 112, No. 18, 01.11.2005, p. 2799-2804.

Research output: Contribution to journalArticle

Jefferies, JL, Eidem, BW, Belmont, JW, Craigen, WJ, Ware, S, Fernbach, SD, Neish, SR, Smith, EOB & Towbin, JA 2005, 'Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy', Circulation, vol. 112, no. 18, pp. 2799-2804. https://doi.org/10.1161/CIRCULATIONAHA.104.528281
Jefferies JL, Eidem BW, Belmont JW, Craigen WJ, Ware S, Fernbach SD et al. Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy. Circulation. 2005 Nov 1;112(18):2799-2804. https://doi.org/10.1161/CIRCULATIONAHA.104.528281
Jefferies, John L. ; Eidem, Benjamin W. ; Belmont, John W. ; Craigen, William J. ; Ware, Stephanie ; Fernbach, Susan D. ; Neish, Steven R. ; Smith, E. O Brian ; Towbin, Jeffrey A. / Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy. In: Circulation. 2005 ; Vol. 112, No. 18. pp. 2799-2804.
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abstract = "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 β-blocker therapy was started. β-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.",
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AU - Jefferies, John L.

AU - Eidem, Benjamin W.

AU - Belmont, John W.

AU - Craigen, William J.

AU - Ware, Stephanie

AU - Fernbach, Susan D.

AU - Neish, Steven R.

AU - Smith, E. O Brian

AU - Towbin, Jeffrey A.

PY - 2005/11/1

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N2 - 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 β-blocker therapy was started. β-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.

AB - 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 β-blocker therapy was started. β-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.

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KW - Genetics

KW - Muscular dystrophy

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