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Published on: May 2, 2016
Dose-dependent diastolic dysfunction and early death in a mouse model with cardiac troponin mutations
Yuejin Li1, Lei Zhang, Pierre-Yves Jean-Charles
1Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA.
Abstract:
Our aim was to explore the dose-dependent diastolic dysfunction and the mechanisms of heart failure and early death in transgenic (TG) mice modeling human restrictive cardiomyopathy (RCM). The first RCM mouse model (cTnI(193His) mice) carrying cardiac troponin I (cTnI) R193H mutation (mouse cTnI R193H equals to human cTnI R192H) was generated several years ago in our laboratory. The RCM mice manifested a phenotype similar to that observed in RCM patients carrying the same cTnI mutation, i.e. enlarged atria and restricted ventricles. However, the causes of heart failure and early death observed in RCM mice remain unclear. In this study, we have produced RCM TG mice (cTnI(193His)-L, cTnI(193His)-M and cTnI(193His)-H) that express various levels of mutant cTnI in the heart. Histological examination and echocardiography were performed on these mice to monitor the time course of the disease development and heart failure. Our data demonstrate that cTnI mutation-caused diastolic dysfunction is dose-dependent. The key mechanism is myofibril hypersensitivity to Ca(2+) resulting in an impaired relaxation in the mutant cardiac myocytes. Prolonged relaxation time and delay of Ca(2+) decay observed in the mutant cardiac myocytes are correlated with the level of the mutant protein in the heart. Markedly enlarged atria due to the elevated end-diastolic pressure and myocardial ischemia are observed in the heart of the transgenic mice. In the mice with the highest level of the mutant protein, restricted ventricles and systolic dysfunction occur followed immediately by heart failure and early death. Diastolic dysfunction caused by R193H troponin I mutation is specific, showing a dose-dependent pattern. These mouse models are useful tools for the study of diastolic dysfunction. Impaired diastole can cause myocardial ischemia and fibrosis formation, resulting in the development of systolic dysfunction and heart failure with early death in the RCM mice with a high level of the mutant protein in the heart.
Insights
This study reveals that cardiac troponin I mutations cause dose-dependent diastolic dysfunction in mice, leading to heart failure and early death. The mechanism involves impaired myocyte relaxation and calcium handling, crucial for understanding restrictive cardiomyopathy.
Area of Science:
- Cardiology
- Molecular Biology
- Genetics
Background:
- Restrictive cardiomyopathy (RCM) is characterized by diastolic dysfunction, but the underlying mechanisms and causes of early mortality in mouse models remain unclear.
- Previous RCM mouse models carrying cardiac troponin I (cTnI) R193H mutations exhibited enlarged atria and restricted ventricles, mimicking human RCM phenotypes.
Purpose of the Study:
- To investigate the dose-dependent effects of mutant cTnI on diastolic dysfunction and heart failure mechanisms in a novel RCM transgenic mouse model.
- To elucidate the molecular mechanisms driving heart failure and early death in RCM mice with varying levels of mutant cTnI expression.
Main Methods:
- Generation of RCM transgenic mice (cTnI(193His)-L, -M, -H) expressing different levels of mutant cTnI.
- Histological examination and echocardiography to monitor disease progression and heart failure development over time.
- Analysis of cardiac myocyte function, including calcium sensitivity and relaxation properties.
Main Results:
- Mutant cTnI-induced diastolic dysfunction demonstrated a clear dose-dependent relationship with the level of mutant protein expression.
- The primary mechanism identified was myofibril hypersensitivity to calcium (Ca2+), leading to impaired cardiac myocyte relaxation and delayed Ca2+ decay.
- High levels of mutant cTnI resulted in restricted ventricles, systolic dysfunction, myocardial ischemia, atrial enlargement, heart failure, and early death.
Conclusions:
- The R193H troponin I mutation specifically causes dose-dependent diastolic dysfunction, a key factor in RCM pathogenesis.
- Impaired diastolic function can precipitate myocardial ischemia and fibrosis, ultimately leading to systolic dysfunction, heart failure, and premature mortality.
- These RCM mouse models are valuable tools for studying diastolic dysfunction and developing therapeutic strategies for restrictive cardiomyopathy.
