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Levosimendan preserves systolic and diastolic function in rats with volume overload heart failure through myofilament Ca2+ sensitization and regulatory protein phosphorylation (1081.4)
Author(s) -
Lewis Kristin,
West T.,
Zhang Xiaojin,
Trask Aaron,
Cismowski Mary,
Tombe Pieter,
Sadayappan Sathivel,
Lucchesi Pamela
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1081.4
Subject(s) - myofilament , levosimendan , heart failure , volume overload , medicine , diastole , cardiology , diastolic heart failure , cardiac function curve , crossbridge , endocrinology , myocyte , ejection fraction , blood pressure , muscle contraction
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)