Dose-Dependent Arrhythmia and Cardiac Dysfunction in Restrictive Cardiomyopathy Mice Due to Troponin Mutations

Abstract

Restrictive cardiomyopathy (RCM) is associated with a cardiac troponin I (cTnI) C-terminal mutation (R192H) in human patients. The transgenic mice expressing this mutation have confirmed a phenotype of a diastolic dysfunction and sudden cardiac death (SCD) (Du et al, 2006, 2008). In the present study, we generated transgenic mice (cTnI193His) expressing different levels of mutant cTnI R193H (mouse cTnI sequence) to investigate the dose-dependent cardiac dysfunction and to reveal the cause of the death in RCM mice. Our results indicated that the mice (cTnI193His/KO expressing only the mutant cTnI R193H at a wild type cTnI-null background had a dramatic early death at one-month old after birth. Telemetric ECG recording from these mice showed a significant bradycardia starting on day 22 or 23 after birth and a significant ischemia and arrhythmia 1-2 days before death. The diastolic function was deteriorated in these mice determined by echocardiography compared to wild type and the transgenic cTnI193His mice expressing 25% cTnI R193H and 75% wild type cTnI. Cell-based experiments indicated that myocardial contractility decreased significantly corresponding to the content of the mutant cTnI levels in cardiac myocytes and the alteration of Ca2+ dynamics in the mutant cTnI cardiac myocytes also showed a dose-dependent manner. Our study has demonstrated that cTnI R193H mutation-caused cardiac dysfunction is dose dependent. Bradycardia is likely an adaptive mechanism of RCM mice to compensate for the prolonged relaxation. The main cause of the death in RCM mice is associated with fatal arrhythmia and ventricular ischemia due to the restricted ventricles and enlarged atria. The transgenic mouse model provides us with a good tool to study the mechanisms and the cause of the death of RCM, which will be useful for the prevention and treatment of the disease.