Abstract 19346: Cardiac Myosin Binding Protein-C Phosphorylation Preserves Diastolic Function in Aging Hearts
Introduction: Prevalence of heart failure with preserved ejection fraction (HFpEF) increases with age. Cardiac myosin binding protein-C (cMyBP-C), a heart muscle thick filament protein, regulates cross-bridge attach/detachment process by its phosphorylation status.
Hypothesis: Phosphorylated cMyBP-C preserves cardiac relaxation even with aging.
Methods: We aged phosphorylation-deficient cMyBP-C(t3SA):S273A/S282A/S302A, and phosphorylation-mimetic cMyBP-C(t3SD):S273D/S282D/S302D mouse models to 15±1 months.
Results: cMyBP-C(t3SD) hearts demonstrate enhanced diastolic function with faster tissue Doppler of myocardial relaxation velocity during early diastole e’ and smaller blood flow Doppler to e’ ratio (E/e’). Conversely, cMyBP-C(t3SA) hearts show diastolic dysfunction by slower e’ and larger E/e’. Both models show ejection fraction (EF) <50%. Both models show similar blood glucose levels and weight. Blood pressure levels are within normal ranges. We use peak relaxation rate (-dF/dt)min to peak force generation rate (+dF/dt)max ratio (dFR) to compare lusitropy of intact papillary muscles. cMyBP-C(t3SD) muscles show increased dFR, meaning enhanced relaxation. Increasing pacing frequency increases dFR in cMyBP-C(t3SD) but not in cMyBP-C(t3SA) muscles. Single negative exponential was used to calculate [Ca2+]i decay rate constant kCa. Both models show similar kCa; therefore, enhanced relaxation in cMyBP-C(t3SD) is attributable to cross-bridge cycling but not differences in [Ca2+]i handling.
Conclusions: cMyBP-C(t3SD) show enhanced relaxation by echocardiography with aging. Simultaneous force and [Ca2+]i measurements on papillary muscles show that cMyBP-C(t3SD) enhancement of relaxation occurs independently of [Ca2+]i therefore we conclude that phosphorylated cMyBP-C accelerating cross-bridge cycling rate is the mechanism and can be used as a future target treatment for age related cardiac dysfunction.
Author Disclosures: P.C. Rosas: None. G. Dusio: None. P. Chatterjee: None. Y. Liu: None. C.W. Tong: None.
- © 2016 by American Heart Association, Inc.