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.

Ivabradine and endothelium: an update

“…Adding ivabradine to inotropic drug treatment in ischaemic acute HF or cardiogenic shock was shown to optimize the lusitropic effect of dobutamine and was associated with an improved diastolic function (enhanced LV early relaxation and prolonged diastolic time), leading to an increased stroke volume compared with omecamtiv mecarbil. 51…”

Combined Therapy With Dobutamine and Omecamtiv Mecarbil in Pigs With Ischemic Acute Heart Failure Is Attributed to the Effect of Dobutamine

“…Induction of anesthesia, intubation, and general instrumentation for all animals is described elsewhere. 8 Schematic overview of the experimental groups are given in Figure 1.…”

“…After surgical preparation and stabilization in the closed-chest protocol (n ¼ 10), baseline recordings were performed before LV ischemia by coronary microembolization was induced as described previously. 8 Level of ischemic AHF was aimed at reduction in the stroke volume by approximately 30% and the pulmonary capillary wedge pressure rise to 15 to 20 mmHg. An average of 16.1 + 6.3 mL of microspheres was injected to reach this level of heart failure.…”

“…3,12 Hemodynamics Methods for pressure, flow, and CO measurements are described earlier by our research group. 8 All LV volumes were calculated using the bullet formula, 16 where Volume ¼ 5/6  Area  Length. End-diastolic and end-systolic areas were measured with short-axis transthoracic echocardiography, and the long-axis diameter (length) was calculated as 1.37 times the short-axis diameter obtained by echocardiography.…”

“…6 Omecamtiv mecarbil prolongs the systolic ejection time (SET), 7 which shortens diastole. 8 This finding has raised concerns related to ventricular filling 8 and myocardial blood flow 9 that are supported by the elevated troponins in clinical trials. 10,11 In addition, continuous activation of myosin ATPase by OM 7 causes substantial myocardial oxygen wastage when OM is given as a monotherapy for experimental AHF.…”