The myosin activator omecamtiv mecarbil: a promising new inotropic agent

Abstract

Heart failure became a leading cause of mortality in the past few decades with a progressively increasing prevalence. Its current therapy is restricted largely to the suppression of the sympathetic activity and the renin–angiotensin system in combination with diuretics. This restrictive strategy is due to the potential long-term adverse effects of inotropic agents despite their effective influence on cardiac function when employed for short durations. Positive inotropes include inhibitors of the Na+/K+ pump, β-receptor agonists, and phosphodiesterase inhibitors. Theoretically, Ca2+ sensitizers may also increase cardiac contractility without resulting in Ca2+ overload; nevertheless, their mechanism of action is frequently complicated by other pleiotropic effects. Recently, a new positive inotropic agent, the myosin activator omecamtiv mecarbil, has been developed. Omecamtiv mecarbil binds directly to β-myosin heavy chain and enhances cardiac contractility by increasing the number of the active force-generating cross-bridges, presumably without major off-target effects. This review focuses on recent in vivo and in vitro results obtained with omecamtiv mecarbil, and discusses its mechanism of action at a molecular level. Based on clinical data, omecamtiv mecarbil is a promising new tool in the treatment of systolic heart failure.

Comprehensive in vitro pro‐arrhythmic assays demonstrate that omecamtiv mecarbil has low pro‐arrhythmic risk

“…Two exploratory electrophysiological studies showed that OM (10 µM) can cause depression of the AP plateau, reduce early repolarization, and shorten ventricular APs in canine myocytes. 23,24 These observations suggest that supratherapeutic concentrations of OM do not prolong canine ventricular APs, a biomarker for delayed repolarization risk. 2 To fully characterize the pro-arrhythmic potential of OM, a battery of in vitro and in silico models were used to evaluate the cardiac safety profile of OM at clinically relevant concentrations.…”

“…The clinical efficacy and safety profile of OM have been demonstrated, 20,22 however, a CiPA‐based assessment for OM has not been performed. Two exploratory electrophysiological studies showed that OM (10 µM) can cause depression of the AP plateau, reduce early repolarization, and shorten ventricular APs in canine myocytes 23,24 . These observations suggest that supratherapeutic concentrations of OM do not prolong canine ventricular APs, a biomarker for delayed repolarization risk 2 .…”

Myocardial Contractility: Historical and Contemporary Considerations

“…Myosin head detachment rate (i.e., k det ) has been identified as a key parameter influencing contractility because it determines the time myosin is bound to actin in a force producing state (Janssen, 2010;Greenberg et al, 2014;Sung et al, 2015;Liu et al, 2018). The discovery of a host of cardiomyopathy mutations and a new generation of chemical compounds that modify myosin "motor" kinetics and chemomechanical processes (Malik et al, 2011;Spudich, 2014;Tardiff et al, 2015;Nanasi et al, 2016Nanasi et al, , 2018Swenson et al, 2017;Kampourakis et al, 2018;Mamidi et al, 2018), which produce divergent effects on force and velocity suggest that revival of the term clinotropy (i.e., velocity) should be considered in order to more holistically define the term contractility as force (i.e., intoropy) and velocity (i.e., clinitropy) (MacLeod, 2016). Myocardial contractility should be defined as the load and length-independent, kinetically controlled, chemo-mechanical processes responsible for the development of force (inotropy) and velocity (clinotropy).…”

A szív pozitív inotróp támogatása a miozin-aktivátor hatású omecamtiv mecarbil segítségével

“…A fenti feltétele-zést részben in vivo tanulmányok is megerősítették (25,28). Terápiás OM-koncentrációk mellett a szívizomsej-tek intracelluláris Ca 2+ -anyagcseréje és ingerlékenysé-gi folyamatai várhatóan nem fognak jelentősen módo-sulni (39,40). Az újabb adatok és saját eredményeink alapján az OM hatásmechanizmusa azonban némileg újragondolásra szorul.…”