Omecamtiv mecarbil evokes diastolic dysfunction and leads to periodic electromechanical alternans

Abstract

Omecamtiv mecarbil (OM) is a promising novel drug for improving cardiac contractility. We tested the therapeutic range of OM and identified previously unrecognized side effects. The Ca2+ sensitivity of isometric force production (pCa50) and force at low Ca2+ levels increased with OM concentration in human permeabilized cardiomyocytes. OM (1 µM) slowed the kinetics of contractions and relaxations and evoked an oscillation between normal and reduced intracellular Ca2+ transients, action potential lengths and contractions in isolated canine cardiomyocytes. Echocardiographic studies and left ventricular pressure–volume analyses demonstrated concentration-dependent improvements in cardiac systolic function at OM concentrations of 600–1200 µg/kg in rats. Administration of OM at a concentration of 1200 µg/kg was associated with hypotension, while doses of 600–1200 µg/kg were associated with the following aspects of diastolic dysfunction: decreases in E/A ratio and the maximal rate of diastolic pressure decrement (dP/dtmin) and increases in isovolumic relaxation time, left atrial diameter, the isovolumic relaxation constant Tau, left ventricular end-diastolic pressure and the slope of the end-diastolic pressure–volume relationship. Moreover, OM 1200 µg/kg frequently evoked transient electromechanical alternans in the rat in vivo in which normal systoles were followed by smaller contractions (and T-wave amplitudes) without major differences on the QRS complexes. Besides improving systolic function, OM evoked diastolic dysfunction and pulsus alternans. The narrow therapeutic window for OM may necessitate the monitoring of additional clinical safety parameters in clinical application.

Omecamtiv mecarbil attenuates length–tension relationship in healthy rat myocardium and preserves it in monocrotaline‐induced pulmonary heart failure

“…For example, a recent study revealed that application of a high dose of OM in rats can induce alternating Ca-transients in the beating cardiomyocytes in parallel to the diastolic dysfunction in the whole heart. 24 In addition, OM affects electrophysiological processes, such as action potential which indirectly regulates intracellular calcium kinetics. 25…”

“…21,[26][27][28][29] However, it was demonstrated that OM substantially prolongs contraction and relaxation. 18,24 Its use, therefore, may result in unexpected consequences in the species with the physiologically high beat rate (rodents).…”

A Novel In Silico Electromechanical Model of Human Ventricular Cardiomyocyte

“…Finally, the glycation of myofilaments in diabetes, a major risk factor in heart failure, correlates with significant reduction in calcium sensitivity of the sarcomere ( Papadaki et al, 2022 ) that cannot be captured in electrophysiology-only models. The same applies to new drugs directly targeting sarcomere dynamics, e.g., blebbistatin, omecamtiv mecarbil and mavacamten ( Rahman et al, 2018 ; Awinda et al, 2020 ; Fülöp et al, 2021 ): with no in silico contractility description, it is not possible to properly simulate them.…”

Új lehetőség a szisztolés szívelégtelenség (HFrEF) kezelésében: omecamtiv-mecarbil

“…Az OM HF-rEF-betegek funkcionális kapacitására kifejtett hatását a jelenleg folyó METEORIC-HF-vizsgálat fogja tisztázni (26). A plazmakoncentráció rendszeres mérésének szükségessége (technikai és szervezési nehézségek, terápiás céltartomány elérése) és az esetleges, jelenleg még nem ismert mellékhatások korlátozhatják a szer klinikai alkalmazását (27). alapból finanszírozott szakmai támogatásával készült.…”