A TRUNCATED CARDIAC TROPONIN-T MOLECULE IN TRANSGENIC MICE SUGGESTS MULTIPLE CELLULAR MECHANISMS FOR FAMILIAL HYPERTROPHIC CARDIOMYOPATHY

Mutations in multiple cardiac sarcomeric proteins including myosin hea vy chain (MyHC) and cardiac troponin T (cTnT) cause a dominant genetic heart disease, familial hypertrophic cardiomyopathy (FHC). Patients w ith mutations in these two genes have quite distinct clinical characte ristics. Those with MyHC mutations demonstrate more significant and un iform cardiac hypertrophy and a variable frequency of sudden death. Pa tients with cTnT mutations generally exhibit mild or no hypertrophy, b ut a high frequency of sudden death at an early age. To understand the basis for these distinctions and to study the pathogenesis of the dis ease, we have created transgenic mice expressing a truncated mouse cTn T allele analogous to one found in FHC patients. Mice expressing trunc ated cTnT at low (< 5%) levels develop cardiomyopathy and their hearts are significantly smaller (18-27%) than wild type. These animals also exhibit significant diastolic dysfunction and milder systolic dysfunc tion, Animals that express higher levels of transgene protein die with in 24 h of birth. Transgenic mouse hearts demonstrate myocellular disa rray and have a reduced number of cardiac myocytes that are smaller in size. These studies suggest that multiple cellular mechanisms result in the human disease, which is generally characterized by mild hypertr ophy, but, also, frequent sudden death.