Omecamtiv mecarbil augments cardiomyocyte contractile activity both at resting and systolic Ca²⁺ levels

Abstract

Aims Heart failure with reduced ejection fraction (HFrEF) is a disease with high mortality and morbidity. Recent positive inotropic drug developments focused on cardiac myofilaments, that is, direct activators of the myosin molecule and Ca 2+ sensitizers for patients with advanced HFrEF. Omecamtiv mecarbil (OM) is the first direct myosin activator with promising results in clinical studies. Here, we aimed to elucidate the cellular mechanisms of the positive inotropic effect of OM in a comparative in vitro investigation where Ca 2+ ‐sensitizing positive inotropic agents with distinct mechanisms of action [EMD 53998 (EMD), which also docks on the myosin molecule, and levosimendan (Levo), which binds to troponin C] were included. Methods Enzymatically isolated canine cardiomyocytes with intact cell membranes were loaded with Fura‐2AM, a Ca 2+ ‐sensitive, ratiometric, fluorescent dye. Changes in sarcomere length (SL) and intracellular Ca 2+ concentration were recorded in parallel at room temperature, whereas cardiomyocyte contractions were evoked by field stimulation at 0.1 Hz in the presence of different OM, EMD, or Levo concentrations. Results SL was reduced by about 23% or 9% in the presence of 1 μM OM or 1 μM EMD in the absence of electrical stimulation, whereas 1 μM Levo had no effect on resting SL. Fractional sarcomere shortening was increased by 1 μM EMD or 1 μM Levo to about 152%, but only to about 128% in the presence of 0.03 μM OM. At higher OM concentrations, no significant increase in fractional sarcomere shortening could be recorded. Contraction durations largely increased, whereas the kinetics of contractions and relaxations decreased with increasing OM concentrations. One‐micromole EMD or 1 μM Levo had no effects on contraction durations. One‐micromole Levo, but not 1 μM EMD, accelerated the kinetics of cardiomyocyte contractions and relaxations. Ca 2+ transient amplitudes were unaffected by all treatments. Conclusions Our data revealed major distinctions between the cellular effects of myofilament targeted agents (OM, EMD, or Levo) depending on their target proteins and binding sites, although they were compatible with the involvement of Ca 2+ ‐sensitizing mechanisms for all three drugs. Significant part of the cardiotonic effect of OM relates to the prolongation of systolic contraction in combination with its Ca 2+ ‐sensitizing effect.

Characterization of Stimulatory Action on Voltage-Gated Na+ Currents Caused by Omecamtiv Mecarbil, Known to Be a Myosin Activator

“…These findings are consistent with previous studies that showed little or no effect of OM on cytosolic Ca 2+ transients [3,33]. However, other studies have reported that OM is capable of prolonging the duration of the contractile force or Ca 2+ transients in isolated human atrium or heart cells, despite no change in the contractile force [34,35]. Therefore, further investigation is necessary to determine the extent to which OM-induced prolongation of the contractile duration of cardiac muscle is due to its preferential stimulation of I Na(L) [15][16][17][18][19].…”

Omecamtiv Mecarbil in the treatment of heart failure: the past, the present, and the future

“…From this aspect, OM is indeed much superior to these drugs for its Ca2+ level-independent effects in cardiac contractile enhancement. This was proven in in-vitro experiments by Ráduly et al in cardiomyocytes isolated from dogs with entire cell membranes ( 27 ). Upon their experiments, regardless of the distinct difference in intracellular Ca2+ concentrations at systolic and resting states, OM remained intensively functional in strengthening cardiac contractility.…”

Current Approaches to Worsening Heart Failure: Pathophysiological and Molecular Insights

“…The binding pocket is available only when the lever arm is primed. Fundamentally, OM augments the myosin heads primed to bind to the actin filament, thus producing an increased contraction force soon after the binding between Ca 2+ and troponin-tropomyosin complex [30][31][32]. Moreover, OM is responsible for the slowing of the non-productive turnover of ATP, thus reducing the use of ATP not associated with mechanical work [30].…”

“…The latter occurs early on and is itself potentially able to perpetuate myocardial injury and loss of cardiomyocytes. OM could block this negative feedback cycle by acting directly on the systolic function, thus preventing cardiac remodelling and activation of the neurohormonal system [30][31][32]. Importantly, no relevant adverse effects regarding increase in heart rate, blood pressure or myocardial oxygen consumption have been highlighted [30][31][32] (Figure 4).…”

“…OM could block this negative feedback cycle by acting directly on the systolic function, thus preventing cardiac remodelling and activation of the neurohormonal system [30][31][32]. Importantly, no relevant adverse effects regarding increase in heart rate, blood pressure or myocardial oxygen consumption have been highlighted [30][31][32] (Figure 4). The dose and the effects of OM administration were studied in various trials, such as the COSMIC-HF trial [33], the GALACTIC-HF trial [34] and the METEORIC-HF trial [35].…”