Abstract 125: Cardiac Myosin Binding Protein-C Phosphorylation Is Critical for Normal Diastolic Function

Abstract

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of all cases of heart failure, but there is no effective treatment of this disease. Cardiac myosin binding protein-C (MyBPC3) is a thick filament protein that is thought to slow cross-bridge cycling by inhibiting acto-myosin interaction. When phosphorylated, MyBPC3 releases its inhibition thereby accelerating cross-bridge cycling. Thus, we hypothesize that MyBPC3 phosphorylation enhances heart’s ability to relax (lusitropy). To test this idea, we expressed wild type MyBPC3(tWT), non-phosphorylatable MyBPC3(t3SA), and constitutively phosphorylated mimetic MyBPC3(t3SD) onto MyBPC3(-/-) mouse background. We used echocardiography, voluntary running, and measurements of brain natriuretic peptide (BNP) for comparison. MyBPC3(t3SA) and MyBPC3(t3SD) hearts had similar ejection fraction as MyBPC3(tWT) hearts. MyBPC3(t3SA) hearts show depressed diastolic function revealed by slower myocardial tissue Doppler relaxation velocity at the mitral valve annulus (Ea) and an increased mitral blood flow/myocardium relaxation ratio (E/Ea). In contrast, MyBPC3(t3SD) hearts exhibited enhanced lusitropy with increased Ea and smaller E/Ea. Moreover, the findings of shorter 7-day average voluntary running distances, increased lung/body weight ratios, and increased BNP levels indicated heart failure in MyBPC3(t3SA) mice. Conversely, MyBPC3(t3SD) mice did not show signs of heart failure. Since cardiac function in MyBPC3(t3SA) mice resembles HFpEF and MyBPC3(t3SD) mice exhibit enhanced lusitropy, we conclude that phosphorylation of MyBPC3 is crucial for normal diastolic function.