Anders Benjamin Kildal

Myosin Activator Omecamtiv Mecarbil Increases Myocardial Oxygen Consumption and Impairs Cardiac Efficiency Mediated by Resting Myosin ATPase Activity

Background—Omecamtiv mecarbil (OM) is a novel inotropic agent that prolongs systolic ejection time and increases ejection fraction through myosin ATPase activation. We hypothesized that a potentially favorable energetic effect of unloading the left ventricle, and thus reduction of wall stress, could be counteracted by the prolonged contraction time and ATP-consumption. Methods and Results—Postischemic left ventricular dysfunction was created by repetitive left coronary occlusions in 7 pigs (7 healthy pigs also included). In both groups, systolic ejection time and ejection fraction increased after OM (0.75 mg/kg loading for 10 minutes, followed by 0.5 mg/kg/min continuous infusion). Cardiac efficiency was assessed by relating myocardial oxygen consumption to the cardiac work indices, stroke work, and pressure–volume area. To circumvent potential neurohumoral reflexes, cardiac efficiency was additionally assessed in ex vivo mouse hearts and isolated myocardial mitochondria. OM impaired cardiac efficiency; there was a 31% and 23% increase in unloaded myocardial oxygen consumption in healthy and postischemic pigs, respectively. Also, the oxygen cost of the contractile function was increased by 63% and 46% in healthy and postischemic pigs, respectively. The increased unloaded myocardial oxygen consumption was confirmed in OM-treated mouse hearts and explained by an increased basal metabolic rate. Adding the myosin ATPase inhibitor, 2,3-butanedione monoxide abolished all surplus myocardial oxygen consumption in the OM-treated hearts. Conclusions—Omecamtiv mecarbil, in a clinically relevant model, led to a significant myocardial oxygen wastage related to both the contractile and noncontractile function. This was mediated by that OM induces a continuous activation in resting myosin ATPase.

Dobutamine-norepinephrine, but not vasopressin, restores the ventriculoarterial matching in experimental cardiogenic shock.

We assessed the hemodynamic effects of guideline therapy in experimental cardiogenic shock and compared this treatment with a combination containing an alternative vasopressor (arginine vasopressin, AVP). Our hypothesis was that combined dobutamine-norepinephrine still is the superior inopressor therapy assessed by ventriculoarterial matching in both systole and diastole. Cardiogenic shock (CS) was induced by coronary microembolization in 16 pigs. Dobutamine (Dobu, 2ug/kg/min) alone and combined with either norepinephrine (NE, 100 ng/kg/min) or the pure vasopressor AVP (0.001 u/kg/min) were infused. In CS, Dobu increased cardiac output (CO) and central venous oxygen saturation (SVO₂) from 74 ± 3 mL/kg and 37 ± 2% to 103 ± 8 mL/kg and 49 ± 3%. Adding NE resulted in a further improvement of CO (125 ± 9 mL/kg) and SVO₂ (59 ± 4%) because of an increased heart rate and contractility with minimal change in systemic vascular resistance. Also, energy transfer from the ventricle to the arterial system was restored partly by Dobu and was normalized by supplementing NE. In contrast, supplemental AVP further worsened the shock state by decreasing CO (70 ± 6 mL/kg) and SVO₂ (45 ± 5%) compared with Dobu alone. Combined Dobu-NE has an efficient hemodynamic profile in CS. A pure afterload increasing substance used in acute ischemic CS aggravates the shock state by causing a ventriculoarterial mismatch despite its use in combination with an inotropic compound.

Reversing dobutamine-induced tachycardia using ivabradine increases stroke volume with neutral effect on cardiac energetics in left ventricular post-ischaemia dysfunction.

Compensatory tachycardia can potentially be deleterious in acute heart failure. In this study, we tested a therapeutic strategy of combined inotropic support (dobutamine) and selective heart rate (HR) reduction through administration of ivabradine.

The Acute Phase of Experimental Cardiogenic Shock Is Counteracted by Microcirculatory and Mitochondrial Adaptations

The mechanisms contributing to multiorgan dysfunction during cardiogenic shock are poorly understood. Our goal was to characterize the microcirculatory and mitochondrial responses following ≥10 hours of severe left ventricular failure and cardiogenic shock. We employed a closed-chest porcine model of cardiogenic shock induced by left coronary microembolization (n = 12) and a time-matched control group (n = 6). Hemodynamics and metabolism were measured hourly by intravascular pressure catheters, thermodilution, arterial and organ specific blood gases. Echocardiography and assessment of the sublingual microcirculation by sidestream darkfield imaging were performed at baseline, 2±1 and 13±3 (mean±SD) hours after coronary microembolization. Upon hemodynamic decompensation, cardiac, renal and hepatic mitochondria were isolated and evaluated by high-resolution respirometry. Low cardiac output, hypotension, oliguria and severe reductions in mixed-venous and hepatic O2 saturations were evident in cardiogenic shock. The sublingual total and perfused vessel densities were fully preserved throughout the experiments. Cardiac mitochondrial respiration was unaltered, whereas state 2, 3 and 4 respiration of renal and hepatic mitochondria were increased in cardiogenic shock. Mitochondrial viability (RCR; state 3/state 4) and efficiency (ADP/O ratio) were unaffected. Our study demonstrates that the microcirculation is preserved in a porcine model of untreated cardiogenic shock despite vital organ hypoperfusion. Renal and hepatic mitochondrial respiration is upregulated, possibly through demand-related adaptations, and the endogenous shock response is thus compensatory and protective, even after several hours of global hypoperfusion.

Prolonged observation time reveals temporal fluctuations in the sublingual microcirculation in pigs given arginine vasopressin

Intravital videomicroscopy of sublingual microcirculation is used to monitor critically ill patients. Existing guidelines suggest averaging handheld video recordings of ∼20 s in duration from five areas. We assessed whether an extended observation time may provide additional information on the microcirculation. Pigs (n = 8) under general anesthesia were divided between two groups, one with manually held camera, in which microcirculation was assessed continuously for 1 min in five areas, and one with a fixed camera, in which the observation time was extended to 10 min in a single area. The microcirculation was challenged by infusing arginine vasopressin (AVP). In the fixed group, ischemic acute heart failure was induced by left coronary microembolization, and the AVP infusion was repeated. All recordings were divided into 20-s sequences, and the small-vessel microvascular flow index (MFI) was scored and averaged for each measurement point. When administering 0.003, 0.006, and 0.012 IU·kg(-1)·min(-1) of AVP, we observed that the small-vessel MFI in the fixed 10-min group was significantly reduced (2.03 ± 0.38, 0.98 ± 0.18, and 0.48 ± 0.11) compared with both the initial 20 s (2.77 ± 0.04, 2.06 ± 0.04, and 1.74 ± 0.06; P < 0.05) and the 1-min total (2.63 ± 0.09, 1.70 ± 0.07, and 1.33 ± 0.16; P < 0.05) in the handheld group. In acute heart failure, the cardiac output decreased to half of the preischemic values. Interestingly, the small-vessel MFI was more affected by the administration of 0.001 and 0.003 IU·kg(-1)·min(-1) of AVP in acute heart failure (1.62 ± 0.60 and 1.16 ± 0.38) compared with preischemic values (2.86 ± 0.09 and 2.03 ± 0.38; P < 0.05). In conclusion, a prolonged recording time reveals temporal heterogeneity that may impact the assessment of microcirculatory function.

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

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.

Response to Letter Regarding Article, “Myosin Activator Omecamtiv Mecarbil Increases Myocardial Oxygen Consumption and Impairs Cardiac Efficiency Mediated by Resting Myosin ATPase Activity”

We certainly appreciate the swift response1 from the group of scientists who have put so much work into the development of omecamtiv mecarbil. Their joint effort is remarkable. However, as Malik and Morgan have stated previously “…omecamtiv mecarbil might increase ATP turnover at the level of the sarcomere…,”2 and this is clearly demonstrated in Figure 4D of their article. Thus, the main aim in our study3 was assessing this aspect’s impact on cardiac efficiency. A study in conscious dogs4 has the advantage of minimizing surgical and pharmacological interventions, but it precludes the ability to decipher the relation between contractile work and energy consumption. In our view, the Suga-model we have used …

Reassessment of a suggested pharmacological approach to heart failure: L-arginine is only a marginal NO donor in pigs.

Objectives: L-Arginine has been tested in various cardiovascular diseases, mainly to improve endothelial function through NO production. However, as the results have been partly unpredictable, we assessed the hemodynamic, energetic and metabolic effects of L-arginine to clarify any potential benefits in postischemic left ventricular (LV) dysfunction. Methods: LV dysfunction was induced by repetitive brief coronary occlusions in 12 anesthetized, open chest pigs. L-Arginine was subsequently infused (bolus 400 mg·kg−1 and continuously for 1 hour, 250 mg·kg−1·h−1). Hemodynamic parameters, metabolites of L-arginine and myocardial energetics were assessed sequentially. Results: L-Arginine infusions caused a substantial rise in plasma L-arginine (3474 ± 358 &mgr;mole·L−1) accompanied by a 2-fold increase in plasma L-citrulline. No significant alterations in vascular resistance or LV contractility were observed from L-arginine. Mean arterial pressure dropped from 78 ± 11 to 72 ± 10 mm Hg (P = 0.019) and 70 ± 8 mm Hg (P = 0.003) after bolus and infusions, respectively. Myocardial oxygen consumption was unaltered, and myocardial creatine content was not increased after 90 minutes of L-arginine infusion. Conclusion: L-Arginine infusion did not influence the energetic cost of myocardial contractility, and only minor hemodynamic changes were observed despite a demonstrable turnover of L-arginine. These findings question the use of L-arginine to promote therapeutic NO formation in the acute setting.

Adrenomedullin-epinephrine cotreatment enhances cardiac output and left ventricular function by energetically neutral mechanisms

Adrenomedullin (AM) used therapeutically reduces mortality in the acute phase of experimental myocardial infarction. However, AM is potentially deleterious in acute heart failure as it is vasodilative and inotropically neutral. AM and epinephrine (EPI) are cosecreted from chromaffin cells, indicating a physiological interaction. We assessed the hemodynamic and energetic profile of AM-EPI cotreatment, exploring whether drug interaction improves cardiac function. Left ventricular (LV) mechanoenergetics were evaluated in 14 open-chest pigs using pressure-volume analysis and the pressure-volume area-myocardial O(2) consumption (PVA-MVo(2)) framework. AM (15 ng·kg(-1)·min(-1), n = 8) or saline (controls, n = 6) was infused for 120 min. Subsequently, a concurrent infusion of EPI (50 ng·kg(-1)·min(-1)) was added in both groups (AM-EPI vs. EPI). AM increased cardiac output (CO) and coronary blood flow by 20 ± 10% and 39 ± 14% (means ± SD, P < 0.05 vs. baseline), whereas controls were unaffected. AM-EPI increased CO and coronary blood flow by 55 ± 17% and 75 ± 16% (P < 0.05, AM-EPI interaction) compared with 13 ± 12% (P < 0.05 vs. baseline) and 18 ± 31% (P = not significant) with EPI. LV systolic capacitance decreased by -37 ± 22% and peak positive derivative of LV pressure (dP/dt(max)) increased by 32 ± 7% with AM-EPI (P < 0.05, AM-EPI interaction), whereas no significant effects were observed with EPI. Mean arterial pressure was maintained by AM-EPI and tended to decrease with EPI (+2 ± 13% vs. -11 ± 10%, P = not significant). PVA-MVo(2) relationships were unaffected by all treatments. In conclusion, AM-EPI cotreatment has an inodilator profile with CO and LV function augmented beyond individual drug effects and is not associated with relative increases in energetic cost. This can possibly take the inodilator treatment strategy beyond hemodynamic goals and exploit the cardioprotective effects of AM in acute heart failure.