The myofilament Ca2+ sensitizer levosimendan maintains systolic function in volume overload heart failure in rats

Abstract

This study investigated whether early intervention with a Ca2+‐ sensitizer levosimendan (Levo) stabilized cardiac function and delayed progression to volume‐overload HF. Aortocaval fistula (ACF) or sham surgery was performed in male SD rats (200–240g) 4 week prior to reversing (REV, closing) the shunt in a subset of animals in order to reduce hemodynamic load. At the time of reversal, ACF and REV rats were given either vehicle (Veh) or Levo (1 mg/kg) in drinking water for 4 weeks. Left ventricular end diastolic diameter (LVEDd) progressively increased through the 8 week study in ACF‐Veh and ACF‐Levo, while LVEDd progressively increased through week 4 followed by return to sham levels by week 8 in REV‐Veh and REV‐Levo. Fractional shortening, preload recruitable stroke work, and end systolic elastance were increased in ACF‐Levo vs. ACF‐Veh (41.4 vs. 32.6 (p<0.0001), 129.3 vs. 73.4 (p<0.05), 0.613 vs. 0.381 (p>;0.05), respectively) and REV‐Levo vs. REV‐Veh (41.7 vs. 32.1 (p<0.0001), 100.8 vs. 56.1 (p<0.05), 0.843 vs. 0.516 (p<0.01), respectively). These results suggest that levo treatment maintains systolic function with and without surgical intervention. In association with functional improvement, analysis of left ventricular myocardial mRNA shows a shift from beta myosin heavy chain (MHC) to alpha‐MHC in ACF‐Levo and REV‐Levo vs. ACF‐Veh and REV‐Veh, respectively. Support: ACVP/STP(KL); NCH(PAL)