Impaired Function in Rats Following Delayed Reversal of Volume Overload Heart Failure is Rescued by Levosimendan

Abstract

ObjectivesThis study investigated if delayed surgical intervention in rats with aortocaval fistula (ACF)‐induced volume overload HF adversely impacts LV functional recovery and if pre or post‐surgical treatment with levosimendan (Levo, myofilament Ca2+ sensitizer) alters LV recovery.Methods and ResultsACF or Sham surgery was performed in male Sprague‐Dawley rats (200‐240 g) 4 or 8 weeks prior to reversing (REV) the shunt in a subset of rats. REV during established HF at 8 wks resulted in impaired LV systolic (%FS, Ees, PRSW: 31.7%, 0.428 mmHg/µL, 57.4 mmHg, respectively; p<0.05 vs Sham) and diastolic function (tau, dP/dtmin; 12.2 msec, ‐6294 mmHg/sec, respectively; p<0.05 vs Sham), while REV during pre‐HF at 4 wks resulted in delayed, but improved LV systolic (%FS, Ees, PRSW: 39.7%; 0.813 mmHg/µL; 87.4 mmHg, p<0.05 vs ACF) and diastolic function (tau, dP/dtmin; 10.8 msec; ‐7128 mmHg/sec, p<0.5). A subset of ACF rats reversed at 8 wks received Levo (1 mg/kg) for 4 wks prior to REV (Levo‐P) or for 11 wks following REV (Levo‐R). Levo‐P improved LV function prior to and after REV (%FS = 42% and 31.8% at Wks 8 & 19, respectively), while Levo‐R improved LV function through the end of the study (%FS, Ees, PRSW, tau, dP/dtmin: 42.4%, 0.859 mmHg/µL, 98.7 mmHg, 8.7 msec, ‐9583 mmHg/sec, respectively; p<0.05 vs Sham). Improved LV function in Levo‐R correlated with normalized α‐to‐β‐myosin heavy chain and increased cTnI Ser‐23/24 phosphorylation (2‐fold vs REV).ConclusionThese results demonstrate that LV dysfunction persisted when volume overload was reversed during established HF but was rescued if Levo was given continuously post‐REV.