Key result
Omecamtiv mecarbil increases contractility by prolonging contraction duration without altering intracellular calcium transients.
Why the study?
This study aimed to characterize the mechanism of action of omecamtiv mecarbil by evaluating its simultaneous effect on myocyte contractility and calcium-transients in healthy canine ventricular myocytes.
Does omecamtiv mecarbil alter calcium-transients and contractility in healthy canine ventricular myocytes?
Does omecamtiv mecarbil alter calcium-transients and contractility in healthy canine ventricular myocytes?
Omecamtiv mecarbil increases cardiac contractility by prolonging contraction duration without altering intracellular calcium transients, confirming a mechanism of action distinct from traditional calcitropes.
Supports distinct mechanism in canine myocytes; leaves open clinical translation to human heart failure.
Omecamtiv mecarbil (OM) is a selective cardiac myosin activator (myotrope), currently in Phase 3 clinical investigation as a novel treatment for heart failure with reduced ejection fraction. OM increases cardiac contractility by enhancing interaction between myosin and actin in a calcium-independent fashion. This study aims to characterize the mechanism of action by evaluating its simultaneous effect on myocyte contractility and calcium-transients (CTs) in healthy canine ventricular myocytes. Left ventricular myocytes were isolated from canines and loaded with Fura-2 AM. With an IonOptix system, contractility parameters including amplitude and duration of sarcomere shortening, contraction and relaxation velocity, and resting sarcomere length were measured. CT parameters including amplitude at systole and diastole, velocity at systole and diastole, and duration at 50% from peak were simultaneously measured. OM was tested at 0.03, 0.1, 0.3, 1, and 3 µmol concentrations to simulate therapeutic human plasma exposure levels. OM and isoproterenol (ISO) demonstrated differential effects on CTs and myocyte contractility. OM increased contractility mainly by prolonging duration of contraction while ISO increased contractility mainly by augmenting the amplitude of contraction. ISO increased the amplitude and velocity of CT, shortened duration of CT concurrent with increasing myocyte contraction, while OM did not change the amplitude, velocity, and duration of CT up to 1 µmol. Decreases in relaxation velocity and increases in duration were present only at 3 µmol. In this translational myocyte model study, therapeutically relevant concentrations of OM increased contractility but did not alter intracellular CTs, a mechanism of action distinct from traditional calcitropes.
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Gao et al. (2020) studied Healthy canine ventricular myocytes. Omecamtiv mecarbil vs. Isoproterenol was evaluated on Myocyte contractility and calcium-transients. Omecamtiv mecarbil increased contractility by prolonging contraction duration without altering intracellular calcium-transients up to 1 µmol/L, a mechanism distinct from isoproterenol.
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