Altered regulation of cardiac muscle contraction by troponin T mutations that cause familial hypertrophic cardiomyopathy.

Mutations in cardiac Troponin T (TnT) are responsible for approximately 15% of all cases of familial hypertrophic cardiomyopathy (FHC). This review summarizes recent data from in vitro assays, transgenic models and clinical studies on how TnT mutations alter the regulation of cardiac muscle contraction. Each TnT mutation has somewhat different effects on myofilament properties (increased myofilament Ca(2)+ sensitivity, decreased maximal force, decreased binding affinity to the thin filament, impaired pH-regulation). But when the in vitro data are correlated with the results from the transgenic models, essentially all mutations can be predicted to result in: (1) impaired relaxation, (2) reduced diastolic compliance, (3) reduced contractile reserve, (4) preserved systolic function under baseline conditions, and (5) cardiac dysfunction under inotropic stimulation. Thus, the alterations of myofilament function caused by TnT mutations likely play an important role in the pathogenesis of FHC.