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Cardiac troponin T Arg92Trp mutation and progression from hypertrophic to dilated cardiomyopathy
1The Second Department of Internal Medicine, School of Medicine, Kanazawa University, Japan.
Insights
Mutations in the cardiac troponin T gene can cause familial hypertrophic cardiomyopathy (HCM) with mild hypertrophy but poor prognosis. This study found the Arg92Trp mutation leads to diverse cardiac changes, including dilated cardiomyopathy.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Cardiology
Background:
- Familial hypertrophic cardiomyopathy (HCM) linked to cardiac troponin T gene mutations often presents with a poor prognosis despite mild hypertrophy.
- Serial morphologic changes in HCM patients with cardiac troponin T gene mutations have not been well-documented.
Purpose of the Study:
- To investigate the long-term clinical and morphological course of patients with familial HCM caused by the cardiac troponin T gene mutation Arg92Trp.
- To characterize the spectrum of cardiac phenotypes associated with the Arg92Trp mutation.
Main Methods:
- Screening of 140 probands with familial HCM for mutations in the cardiac troponin T gene.
- Clinical and echocardiographic assessment of individuals carrying the Arg92Trp mutation.
- Histopathological analysis of endomyocardial biopsies from affected individuals.
Main Results:
- The Arg92Trp mutation was identified in 10 individuals from two pedigrees, exhibiting varied cardiac morphologies including dilated cardiomyopathy-like features, asymmetric septal hypertrophy, and electrocardiographic abnormalities.
- Three patients with dilated cardiomyopathy-like features showed progressive left ventricular dilation.
- Myocardial biopsies revealed modest hypertrophy, minimal disarray, and mild fibrosis.
Conclusions:
- The Arg92Trp substitution in the cardiac troponin T gene demonstrates high penetrance, moderate hypertrophy, and a propensity for early progression to dilated cardiomyopathy in Japanese patients.
- Early identification of individuals with this mutation is crucial for assessing the potential efficacy of early therapeutic interventions.
Background:
Mutations in the cardiac troponin T gene causing familial hypertrophic cardiomyopathy (HCM) are associated with a very poor prognosis but only mild hypertrophy. To date, the serial morphologic changes in patients with HCM linked to cardiac troponin T gene mutations have not been reported.
Hypothesis:
The aim of this study was to determine the long-term course of patients with familial HCM caused by the cardiac troponin T gene mutation, Arg92Trp.
Methods:
In all, 140 probands with familial HCM were screened for mutations in the cardiac troponin T gene.
Results:
The Arg92Trp missense mutation was present in 10 individuals from two unrelated pedigrees. They exhibited different cardiac morphologies: three had dilated cardiomyopathy-like features, five had asymmetric septal hypertrophy with normal left ventricular systolic function, one had electrocardiographic abnormalities without hypertrophy, and one had the disease-causing mutation but did not fulfill the clinical criteria for the disease. The mean maximum wall thickness was 14.1 +/- 6.0 mm. The three patients with dilated cardiomyopathy-like features had progressive left ventricular dilation. Three individuals underwent right ventricular endomyocardial biopsy. There was a modest degree of myocardial hypertrophy (myocyte diameter: 18.9 +/- 5.2 microm), and minimal myocardial disarray and mild fibrosis were noted.
Conclusion:
The Arg92Trp substitution in the cardiac troponin T gene shows a high degree of penetrance, moderate hypertrophy, and early progression to dilated cardiomyopathy in Japanese patients. Early identification of individuals with this mutation may provide the opportunity to evaluate the efficacy of early therapeutic interventions.