The purpose of this proposal is to investigate the molecular mechanisms underlying cardiac conduction disturbances in hypertrophic cardiomyopathy. In order to assess directly the role of specific gene products in cardiac conduction in vivo using transgenic models, the applicants recently developed a mouse model of a complete cardiac electrophysiology (EP) study based on human clinical protocols, including responses to programmed stimulation and pharmacologic agents. The studies in this proposal seek to apply this mouse EP model to characterize the molecular defects that lead to abnormal cardiac conduction and arrhythmias in hypertrophic cardiomyopathy (HCM). Two lines of HCM mice and their littermate controls will be evaluated. The first bears a point mutation in the murine a-myosin heavy chain (Arg4O3Gln), which leads to histological and hemodynamic abnormalities characteristic of HCM, and a propensity to sudden death. The second mouse line will have a disruption in the gene encoding the cardiac troponin T protein, which in humans produces HCM characterized by minimal hypertrophy but a high frequency of sudden death. In preliminary EP studies we have performed, the heterozygous Arg4O3Gln HCM mice have inducible ventricular tachycardia, a distinctly abnormal finding that has not been observed in normal mice at any time. Preliminary data with the Arg4O3Gln HCM mice suggest a difference in the rate of disease progression between the sexes, and also suggest a developmental (age-related) increase in the risk of sudden death in these mice, with no mortality in the first 15 weeks of age. Therefore, both male and female mice, and mice at several different ages will be examined to investigate in detail the electro-physiological characteristics of several different populations of control and HCM mice. Data from a full EP study, including isoproterenol infusion, will be collected from each animal and correlated with surface 6-lead ECG data, including dispersion of repolarization, as well as with longer-term ECG monitoring with wireless microtelemetry and histological evaluation of the underlying myocardial tissue. Taken together, these studies will allow a comparative analysis of electrophysiological abnormalities produced by two distinct and specific mutations that cause HCM, and thus will contribute to our understanding of the molecular mechanisms underlying cardiac conduction and a common cardiovascular disorder.
