Abstract 62: Cardiac Troponin T Isoform Switching in Early Childhood Tropomyosin-linked Dilated Cardiomyopathy

An oft-noted component of sarcomeric DCM is the observation that patients within families carrying the same primary mutation exhibit significant phenotypic variability. This lack of a distinct link between genotype and phenotype has complicated clinical management. In a recent study of two unrelated multigenerational families with the tropomyosin (Tm) mutation Asp230Asn (D230N), a striking “bimodal” distribution of severity was observed. In these families, many children (<1 year) with the mutation presented with a severe form of DCM that led to sudden, often fatal CHF while adults developed a mild to moderate DCM in mid-life. Of note, children who survived the initial presentation often recovered significant systolic function into young adulthood. A potential hypothesis to explain this improvement despite the continued presence of the mutant Tm, is that the phenotype is modified by other thin filament isoforms. Thus we propose that the age-dependent remodeling seen in children with D230N Tm is a result of temporal isoform switches involving a closely linked Tm binding partner cardiac Troponin T (cTnT). Our initial biophysical studies (Regulated-IVM) revealed a decreased Ca2+ sensitivity in filaments containing D230N Tm that is more severe in the presence of fetal TnT (cTnT1), suggesting a modulatory role for cTnT1. Cardiac performance, assessed via 2D echo, in our novel D230N Tm x cTnT1 double transgenic (DTg) mouse model found a significantly reduced % FS for DTg (17%) mice as compared to D230N Tm (21%) littermates. This reduction in %FS was seen at 4 months but not 2 suggesting a progressive cardiomyopathy. Current efforts aim to model the early phase of this “bimodal” phenotype and assess the potential for disease reversibility using a cardiac specific inducible cTnT1 transgenic mouse model. Furthermore, we propose that modulation by cTnT1 could represent a more general mechanism for the progressive remodeling seen in human heart failure. Preliminary in vitro studies with human tissue found that RNA levels of cTnT1 are significantly higher in failing hearts as compared to non-failing. Thus these data suggest an isoform dependent mechanism for the “bimodal” phenotype in patients carrying D230N Tm that could translate to other sarcomeric cardiomyopathies.