A New Approach to Inotropic Therapy in the Treatment of Heart Failure

Abstract

Systolic heart failure remains a leading cause of death and disability, and available pharmacologic treatments for heart failure are limited in both safety and effectiveness. Existing drugs focus on diverse mechanisms related to the pathophysiology of heart failure, yet none directly target the central feature of systolic heart failure, decreased cardiac contractility. Cardiac myosin activators, specifically omecamtiv mecarbil (formerly CK-1827452), directly activate the enzymatic pathway within the cardiac myocyte leading to ventricular contraction. This unique inotropic agent has been shown in preclinical and clinical studies to be effective in improving cardiac contractility by increasing systolic ejection time without the unwanted effects of the currently available indirect inotropic drugs. Cardiac myosin activators show great promise and may prove to be a safer and more effective therapeutic approach for the treatment of systolic heart failure.

Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure

“…VO HF therapeutic options generally target neurohormonal pathways by disrupting receptor-ligand interactions or modulating downstream signaling pathways (e.g., Ca 2ϩ -cAMP). Although these therapies successfully manage LV hypertrophy, their inotropic actions do not directly target impaired LV contractility, the central feature of systolic HF (14). This can result in increased myocardial oxygen consumption and myocardial Ca 2ϩ overload (30).…”

Molecular targets of current and prospective heart failure therapies

“…Omecamtiv mecarbil enhances the interaction between actin and myosin after ATP hydrolysis 33 62. It selectively prolongs systolic ejection time without change in oxygen consumption or even in maximal dP/dt62 and has shown promising results on preliminary clinical evaluation 33.…”

“…It selectively prolongs systolic ejection time without change in oxygen consumption or even in maximal dP/dt62 and has shown promising results on preliminary clinical evaluation 33. In a recent phase II cross-over design clinical trial in HF patients, stroke volume was increased and LV volumes reduced by an infusion of omecamtiv mecarbil, in addition to increased systolic ejection time 63.…”

Inotropes and vasopressors

“…Its effect is increase in contractile force due to more cross-bridges entering the force-producing state and more cross-bridges being activated per unit of time (14,35). Myosin activators stimulate myosin ATPase and increase myocyte shortening without increasing intracellular calcium transients (14,35). Improvements in cardiac function were not associated with increased myocardial oxygen consumption when tested on dogs (36).…”

“…Omecamtivmecarbil is a compound that acts as a cardiac myosin activator. Its effect is increase in contractile force due to more cross-bridges entering the force-producing state and more cross-bridges being activated per unit of time (14,35). Myosin activators stimulate myosin ATPase and increase myocyte shortening without increasing intracellular calcium transients (14,35).…”