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

Abstract

Heart failure is a widespread cardiac pathology with high mortality rates in humans. The therapy of heart failure offers treatment by β-receptor blockers, inhibitors of angiotensin-converting enzymes, and aldosterone antagonists, which affect systolic function.However, the use of these compounds has at least two side effects: an increased Ca 2+ concentration in the cytosol of cardiomyocytes and increased demand for oxygen. 1,2 To overcome these problems, the novel therapy is based on a selective activation of myosin. [3][4][5][6][7][8] The activator is a low-molecular substance omecamtiv mecarbil (OM) which is currently under clinical trial phase 3. 9 It specifically binds to the heavy chain of cardiac β-myosin and enhances cardiac contractility by prolongation of actomyosin interaction. [10][11][12][13] The therapeutic

Effects of omecamtiv mecarbil and mavacamten in isolated human atrium

“…The present data on OME in mouse left atrial preparations concur with previous data in rat papillary (Lookin et al 2022 ). Lookin et al ( 2022 ) also did not detect a positive inotropic effect of OME in rat papillary muscle, but OME prolonged the duration of the muscle contraction. Their data were in contrast to early data in rat cardiomyocytes.…”

“…This interpretation is hardly convincing: in rat and mouse, the alpha myosin isoform of myosin is predominant. Moreover, in rat heart itself based on experimental conditions, a positive inotropic (Malik et al 2011 ) or a negative inotropic effect of OME (Lookin et al 2022 ) has been reported. Thus, experimental conditions seem to be important.…”

“…In the original description of OME (Malik et al 2011 ), a reduction in contractility in isolated electrically stimulated rat ventricular cardiomyocytes was reported. One might be able to reconcile these opposing findings in the rat heart by noticing that auxotonic contractions in single cells were studied (Malik et al 2011 , Fülöp et al 2021 ), whereas later isometric contractions in rat muscle strips were investigated (Lookin et al 2022 ). Adding to the complexity of the literature are other apparent species differences: in canine ventricular cardiomyocytes under auxotonic conditions, an increase in cell shortening reminiscent of a positive inotropic effect was reported by several groups (Butler et al 2015 , Gao et al 2020 ).…”

“…OME has been reported to raise contractility under auxotonic conditions (beating without pre-load or after-load in isolated electrically driven rat ventricular cardiomyocytes: Malik et al 2011 , Nagy et al 2015 ) and isolated electrically driven canine ventricular cardiomyocytes (Shen et al 2010 ). In sharp contrast, others found omecamtiv to reduce force of contraction in isolated rat papillary muscle under isometric conditions (Lookin et al 2022 ) or to leave force of contraction unaltered in isolated muscle preparations from human atrium or failing (heart transplant recipients) human ventricle (Dashwood et al 2021 ). As far as we know, OME has not yet been studied in isolated mouse electrically driven left atrial preparations or spontaneously beating mouse right atrial preparations, which was investigated in the present study.…”

Safety and efficacy of omecamtiv mecarbil for heart failure: A systematic review and meta-analysis

“…Therefore, the Ca 2+ content levels in cardiac cells might be necessary for omecamtiv mecarbil effectiveness. 19 …”