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.
A combined infusion of dobutamine and ivabradine had a neutral effect on post-ischaemia LV efficiency and increased left ventricular output without an increase in HR.
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.
CorrespondenceWe certainly appreciate the swift response 1 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 study 3 was assessing this aspect's impact on cardiac efficiency. A study in conscious dogs 4 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 in the pig studies, the isolated heart, and mitochondrial model fills in some of the missing aspects. 3 We cannot see that the concerns raised by Teerlink et al 1 would hamper our conclusions. First, a general statement of increased oxygen consumption from our study 3 is supported by the fact that this was measured in the unloaded mouse heart. Also, calculation of unloaded MVO 2 in the pig heart (Y-intercept, Table 2) has few assumptions given the downloading protocol used. All exclusion of pigs (ie, sustainable ventricular arrhythmias causing hemodynamic collapse; 3/19=16%) occurred before inclusion in the protocol. After ischemia and stabilization, this model shows remarkably stable hemodynamics.5 This referred study also has the requested placebo controls, demonstrating a stable myocardial energetics for the extent of the study period. Second, the model tolerates hemodynamic downloading well, as demonstrated, 5 probably because of the anesthetic protocol. No significant alterations in heart rate or dP/dt were observed after infusion of omecamtiv in the postischemic pigs.Third, we can only state that our observation in whole hearts is compatible with a continuous activated myosin ATPase, supported by the 2,3-butanedione monoxime experiment. We appreciate that the authors have split myosin and actin in their in vitro assay, but the integrated effect of omecamtiv seems to be an increased ATPase activity. 2As for the dose used, we did a dose-response study along the lines described by the respondents, aiming at an increased systolic ejection time of 20% that is suggested to be clinically safe.6 Of notice, the drug was used for the first time in pigs. We apologize for the error in the abstract.We will maintain that our study raises concerns about the energetic effects of omecamtiv mecarbil. In fact, we previously only observed such an extensive energy wastage by blocking NO using L-NGnitroarginine methyl ester motivated by the TRIUMPH (Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients With Cardiogenic Shock) investigation of tilarginine.
Intensivavdelingen Aku klinikkenOslo universitetssykehus, Rikshospitalet Forfa erbidrag: design, utarbeiding, utforming og revisjon av manus samt godkjenning av innsendte manusversjon. Alle medforfa erne hadde sentralt behandlingsansvar og var involvert i etiske diskusjoner og diskusjoner om behandlingsutfordringer. Jens Pe er Bakkehaug er spesialist i anestesiologi og overlege. Forfa eren har fylt ut ICMJE-skjemaet og oppgir følgende interessekonflikter: Han er involvert i disse pasientforløpene i egenskap av si kliniske engasjement. Intensivavdelingen Aku klinikkenOslo universitetssykehus, Rikshospitalet Forfa erbidrag: design, utarbeiding, utforming og revisjon av manus samt godkjenning av innsendte manusversjon. Alle medforfa erne hadde sentralt behandlingsansvar og var involvert i etiske diskusjoner og diskusjoner om behandlingsutfordringer. Trine Kåsine er spesialist i anestesiologi og overlege. Forfa eren har fylt ut ICMJE-skjemaet og oppgir følgende interessekonflikter: Hun er involvert i disse pasientforløpene i egenskap av si kliniske engasjement. Intensivavdelingen Aku klinikkenOslo universitetssykehus, Rikshospitalet Forfa erbidrag: design, utarbeiding, utforming og revisjon av manus samt godkjenning av innsendte manusversjon. Alle medforfa erne hadde sentralt behandlingsansvar og var involvert i etiske diskusjoner og diskusjoner om behandlingsutfordringer. Luis Romundstad er spesialist i anestesiologi og overlege. Forfa eren har fylt ut ICMJE-skjemaet og oppgir følgende interessekonflikter: Han er involvert i disse pasientforløpene i egenskap av si kliniske engasjement.Ekstrakorporal membranoksygenering ved aku lungesviktsyndrom hos covid-19-pasienter | Tidsskrift for Den norske legeforening
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.