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

Abstract

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.

In vitro and in vivo single myosin step-sizes in striated muscle

“…A selective pharmaceutical βmys activator, omecamtive mecarbil (OM), up-regulates cardiac contractility in vivo and is undergoing testing for heart failure therapy (Bakkehaug et al 2015). In vitro βmys actin-activated ATPase, motility velocity, step-size, and step-frequency were measured to explore OM’s effect on the single myosin characteristics of the motor operating in an ensemble.…”

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

“…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.…”

“…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.…”

“…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.…”

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

“…Az OM in vivo hatékonyan javította infarktusos, valamint az aorta leszorításával szívelég-telenné tett kutyák bal kamrájának szisztolés funkcióit, ugyanakkor nem befolyásolta a diasztolés funkciót és nem növelte a szív oxigénfogyasztását sem (28). Egy másik, hasonló tanulmányban azonban az OM szignifikáns mértékben növelte az infarktuson átesett sertések bal kamrájának oxigénfogyasztását, amelynek hátteré-ben a bazális ATPáz-aktivitás fokozódását vélték felismerni (29). Patkány eredetű izolált és permeabilizált szívizomsejteken végzett saját vizsgálatainkban az OM miokardiális kontraktilitásra gyakorolt hatásait és a vá-zizmokra kifejtett feltételezett hatásait tanulmányoztuk.…”