Transgenic rat hearts expressing a human cardiac troponin T deletion reveal diastolic dysfunction and ventricular arrhythmias

Objective: Familial hypertrophic cardiomyopathy (FHC) due to mutations of c ardiac troponin T (cTnT) is associated with a high frequency of sudden deat h even in the absence of cardiac hypertrophy. To investigate the causal rel ationship of cTnT mutations and this particular phenotype, we sought to est ablish a transgenic rat model for the disease, Methods: Transgenic rats wer e generated expressing human wild-type cTnT or two truncated cTnT molecules (del ex16, del ex15/16), resulting from an intron 15 splice donor site mut ation previously observed in FHC patients. Transgenic rat hearts were chara cterized by histology, immunohistochemistry and in the 'working heart'. Res ults: Human wild-type and del ex16 cTnT were stably expressed and incorpora ted into the sarcomere of transgenic cardiomyocytes. Del ex16 transgenic ra ts revealed a lower level of expression (4-5%) than human wt cTnT animals ( 25-40%). In the 'working heart' model del ex16 hearts exhibited significant systolic and diastolic dysfunction without cardiac hypertrophy. In contras t, human wt cTnT hearts showed improved contractile performance and moderat e myocardial hypertrophy. After 6 months of daily physical exercise one del ex16 rat died suddenly and three out of five del ex16 hearts revealed vent ricular tachycardia/fibrillation. No arrhythmia was observed in human wt cT nT expressors. Myofibrillar disarray was present in del ex16 hearts after t raining but not in human wild-type cTnT rats or non-transgenic controls. Co nclusion: A human cTnT deletion overexpressed in transgenic rats exerts a d ominant-negative effect and mimics the phenotype of FHC with diastolic dysf unction and arrhythmias. By contrast, human cTnT wild-type animals reveal a gain of function and cardiac hypertrophy without arrhythmias. (C) 2000 Els evier Science B.V. All rights reserved.