Author + information
Background: Cardiac myosin binding protein-C (cMyBP-C) is a thick filament protein. Phosphorylated cMyBP-C increases rate of cross-bridge detachment to enhance diastolic function. cMyBP-C phosphorylation levels are decreased in heart failure (HF). We hypothesize that cMyBP-C de-phosphorylation worsens HF.
Methods: We challenged phosphorylation deficient cMyBP-C(t3SA) with S273A/S282A/S302 mutations, phosphorylation mimetic cMyBP-C(t3SD) with S273D/S282D/S302D mutations, and wild-type equivalent cMyBP-C(tWT) mouse models with trans-aortic constriction (TAC) to induce HF over 5-weeks.
Results: 5-week survival improved with increasing cMyBP-C phosphorylation levels (t3SA 40/69 58%, tWT 35/46 76%, t3SD 39/44 89%, p=0.001). Ejection fraction decreased and left ventricle dilated for all three mouse models. As indicated by E/e’, cMyBP-C phosphorylation mimetic provided the best preservation of diastolic function (5th week E/e’: t3SA n=11, 41.1±3.2*#; tWT n=14, 35.4±2.2#; t3SD n=10, 25.5±2.2*; *p<0.05 vs. tWT and #p<0.05 vs. t3SD). Pacing extracted intact papillary muscles from TAC hearts at 2.5 Hz produced pulsus alternans most frequently in t3SA (t3SA 8/11, t3SD&tWT 5/17, p=0.034). Simultaneous intracellular calcium and force measurements showed that incomplete relaxation (Pearson r= −0.569, p= 0.043, n=13) not attributable to calcium transients correlated with the alternans.
Conclusions: cMyBP-C de-phosphorylation slowing of cross-bridge detachment worsens HF.
Room 144 A
Saturday, March 18, 2017, 9:17 a.m.-9:27 a.m.
Session Title: Highlighted Original Research: Heart Failure and Cardiomyopathies and the Year in Review
Abstract Category: 12. Heart Failure and Cardiomyopathies: Basic
Presentation Number: 902-14
- 2017 American College of Cardiology Foundation