Abstract 5397: Human Valvular Heart Disease is Associated with a Phosphorylation-Mediated Modulation in Myocardial Thin Filament Performance
Background: Aortic Stenosis (AS) induces concentric left ventricular hypertrophy (LVH) whereas mitral regurgitation (MR) induces an eccentric pattern of LVH. In association with these patterns of hypertrophy, wall stress tends to be normalized in AS and increased in MR. In the present study, we tested the hypothesis that these patterns of hypertrophy are associated with distinct changes in thin filament function in patients with AS and MR.
Methods and Results: Patients with symptomatic MR or AS and normal LV ejection fraction (EF) were identified at time of referral for valvular surgery. Patients undergoing coronary bypass grafting for stable coronary artery disease who had normal LVEF and no evidence of LVH were employed as controls. Epicardial biopsies were obtained from each group at the time of surgery and thin filaments subsequently isolated. Thin filament function was characterized with an in vitro motility assay in which skeletal muscle myosin was used as the motility substrate. Thin filaments isolated from patients with AS generated 34 ± 7% more force at maximally activating Ca++concentrations when compared to controls (p < 0.001). In contrast, thin filaments from MR patients generated 24 ± 4% less force compared with controls (p = 0.002). There were no differences in thin filament calcium sensitivity. Treatment of thin filaments with protein phosphatase 2A resulted in reversal of both the contractile enhancement in AS and the contractile deficit in MR, implicating thin filament phosphorylation in mediating these disease related changes in thin filament function.
Conclusion: Thin filament function is dynamically modulated in human valvular heart disease. The reduction in force observed in the MR thin filaments is similar to that observed in failing human myocardial thin filaments and suggests that the observed changes in thin filament function in MR may be a precursor to the eventual development of LV contractile dysfunction. The alterations in contractile force observed may be the result of differences in wall stress characteristic of these two conditions.