Opposite diastolic effects of omecamtiv mecarbil versus dobutamine and ivabradine co-treatment in pigs with acute ischemic heart failure

Abstract

Acute ischemic cardiogenic shock is associated with poor prognosis, and the impact of inotropic support on diastolic function in this context is unclear. We assessed two suggested new inotropic strategies in a clinically relevant pig model of ischemic acute heart failure (AHF): treatment with the myosin activator omecamtiv mecarbil (OM) or dobutamine and ivabradine (D+I). Left ventricular (LV) ischemia was induced in anesthetized pigs by coronary microembolization (n = 12). The animals then received OM (bolus 0.75 mg/kg, followed by 0.5 mg/kg per h) (n = 6) or D+I (5 μg/kg per min + 0.29 ± 0.16 mg/kg) (n = 6), respectively. Ischemia reduced the stroke volume (SV), despite the increased left atrial pressure associated with impaired LV early relaxation, systolic dilatation, and LV late diastolic stiffness. Both treatments improved systolic ejection, but only D+I increased the SV from 26 ± 5 to 33 ± 5 mL. D+I enhanced LV early relaxation (Tau; from 45 ± 11 to 29 ± 4 msec) and prolonged the diastolic time (DT) from 338 ± 60 to 352 ± 40 msec. In contrast, OM prolonged Tau (42 ± 5 to 62 ± 10 msec) and shortened the DT (from 326 ± 68 to 248 ± 84 msec). Our data suggest that enhanced early relaxation by D+I improves LV pump function in postischemic acute heart failure. In contrast, OM worsened lusitropy in this model.

Keywords: Acute heart failure; cardiogenic shock; contractility; diastolic function; inotropic agents.

Figure 1

General hemodynamics at intrinsic heart rates and during right atrial pacing at 120 and 160 beats/min. The left panels show the pre‐ischemia (white bars; n = 12) and ischemia values (black bars; n = 12). The right panels show the effects of the inotropic treatments as delta changes from the ischemia values. The blue bars indicate the omecamtiv mecarbil (OM) treatment group (n = 6), and the yellow bars indicate the dobutamine plus ivabradine (D+I) treatment group (n = 6). *P < 0.05 pre‐ versus post‐ischemia (paired t test). ^† P < 0.05 ischemia versus treatment groups (two‐way mixed ANOVA). ^‡ P < 0.05 between treatment groups (two‐way mixed ANOVA).

Figure 2

Systolic indices at intrinsic heart rates and during right atrial pacing at 120 and 160 beats/min. The left panels show the pre‐ischemia (white bars; n = 12) and ischemia values (black bars; n = 12). The right panels show the effects of the inotropic treatments as delta changes from the ischemia values. The blue bars indicate the omecamtiv mecarbil (OM) treatment group (n = 6), and the yellow bars indicate the dobutamine plus ivabradine (D+I) treatment group (n = 6). ESV, end‐systolic volume; ESP, end‐systolic pressure; SET, systolic ejection time; ESPVR, slope of steady state end‐systolic pressure–volume relationship; s′, peak LV long‐axis wall deformation velocity; and dP/dt _max, maximum rate of LV pressure change. *P < 0.05 pre‐ versus post‐ischemia (paired t test). ^† P < 0.05 ischemia versus treatment groups (two‐way mixed ANOVA). ^‡ P < 0.05 between treatment groups (two‐way mixed ANOVA).

Figure 3

Diastolic indices at intrinsic heart rates and during right atrial pacing at 120 and 160 beats/min. The left panels show the pre‐ischemia (white bars) and ischemia values (black bars) (n = 12). The right panels show the effects of the inotropic treatments as delta changes from the ischemia values. The blue bars indicate the omecamtiv mecarbil (OM) treatment group (n = 6), and the yellow bars indicate the dobutamine plus ivabradine (D+I) treatment group (n = 6). EDV, end‐diastolic volume; EDP, end‐diastolic pressure; EDPVR, slope of steady state end‐diastolic pressure–volume relationship; e′, peak LV long‐axis elongation velocity; L _{A‐V MAX}, peak L atrial‐ventricular pressure difference; L _{A‐V INTG}, L atrial‐ventricular pressure–time integral during diastole; Tau, isovolumetric relaxation constant; P_min, minimum LVP; dP/dt _min, maximum rate of pressure decline; SV/L _{A‐V INTG}, SV related to the L atrial‐ventricular pressure–time integral. *P < 0.05 pre‐ versus post‐ischemia (paired t test). ^† P < 0.05 ischemia versus treatment groups (two‐way mixed ANOVA). ^‡ P < 0.05 between treatment groups (two‐way mixed ANOVA).

Figure 4

Modified Wiggers’ diagram showing examples of actual tracings from two pigs. Left column: pre‐ischemia, ischemia, and dobutamine‐ivabradine (D+I) treatment. Right column: pre‐ischemia, ischemia, and omecamtiv mecarbil (OM) treatment. LVP, left ventricular pressure; LAP, left atrial pressure; dP/dt _max and dP/dt _min, maximum and minimum derivatives of the LV pressure, respectively; Tau, isovolumetric relaxation constant; P_min, minimum LV pressure during the cardiac cycle; L _{A‐V MAX}, peak L atrial‐ventricular pressure difference; L _{A‐V INTG}, L atrial‐ventricular pressure–time integral during diastole; DT, diastolic time; SET, systolic ejection time.

Figure 5

Illustration of typical pressure–volume loops at intrinsic heart rates calibrated against the mean values of ESV, EDV, EDP, P_min, and ESP, as shown in Table 1. The left panel shows pre‐ (dotted line) and post‐ischemia (solid line). The middle panel shows treatment with dobutamine plus ivabradine (D+I, yellow line) compared with untreated ischemia. The right panel shows treatment with omecamtiv mecarbil (OM, blue line) compared with untreated ischemia.