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

• DOI: 10.1161/res.117.suppl_1.62
• Publication Date: 2021-07-03T09:14:18Z
• Authors: Melissa Lynn; Lauren Tal-Grinspan; J.-P. Jin; Jil Tardiff
• Keywords: Troponin complex; Dilated Cardiomyopathy; Troponin T; Tropomyosin

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