Levosimendan preserves systolic and diastolic function in rats with volume overload heart failure through myofilament Ca2+ sensitization and regulatory protein phosphorylation (1081.4)

Abstract

Objectives. This study investigated whether early intervention with the myofilament Ca2+ sensitizer levosimendan (Levo) could preserve cardiac function in aortocaval fistula (ACF)‐induced volume overload (VO). Methods and Results. ACF or sham surgery was performed in male Sprague‐Dawley rats (200‐240g) 4 weeks prior to initiating treatment with Levo (1 mg/kg/day in drinking water) or vehicle (Veh; water) for 4 weeks. Even with continued VO and compared with ACF‐Veh, Levo improved systolic (%FS, Ees, PRSW; 41.3 vs 32.2%, p<0.0001; 0.654 vs 0.392 mmHg/µL, p<0.05; 113.6 vs 60.2 mmHg, p<0.05, respectively) and diastolic (tau, dP/dtmin; 8.9 vs 10.8 msec, p<0.05; ‐7626 vs ‐5739 mmHg/sec, p<0.001, respectively) function without significant LV remodeling. Additionally, Levo treatment resulted in 1) improved myofilament Ca2+ sensitivity without significantly affecting the amplitude and kinetics of the myocyte intracellular Ca2+ transient; 2) preserved in vivo β‐adrenergic responsiveness; and 3) increased phosphorylation of cMyBP‐C Ser‐273 and Ser‐302 and cTnI Ser‐23/24 that was associated with the improved diastolic function. Levo did not increase α‐MHC/β‐MHC mRNA compared with Veh. Conclusion. These results demonstrate that myofilament regulation in VO HF preserves systolic and diastolic function and may provide a new therapeutic target in patients with volume overload heart failure.Grant Funding Source: Supported by: R01 HL‐056046 (to PAL), R01 HL‐62426 (to PDT), R01 HL105826 and K02 HL 114749 (to SS)