Myosin Activator Omecamtiv Mecarbil Differentially Impacts the Contractile Properties of Skinned Myocardium from Failing and Donor Human Hearts

Abstract

Omecamtiv mecarbil (OM) is a compound that selectively targets the cardiac sarcomere and enhances myosin crossbridge (XB) activation and force generation. Because of these properties OM has been proposed as a treatment for systolic heart failure in humans, however, there are no studies that have directly examined the functional effects of OM, at XB level, in remodeled human failing myocardium. Thus, we tested whether OM differentially impacts contractile properties in failing and donor human myocardium. Isometric force, myofilament Ca2+-sensitivity (pCa50), rates of XB detachment (krel), recruitment (kdf), and magnitude of XB recruitment (Pdf) were measured both before and after OM incubation in chemically-skinned myocardial preparations isolated from failing and donor hearts. Because the failing myocardium exhibited an enhanced pCa50, dynamic XB parameters were measured at pCa's 6.6 and 6.3, respectively for failing and donor groups in order to achieve equivalent levels of activation (∼22% and ∼35% of maximal force, respectively for pre- and post-OM incubations). OM incubation did not alter the pCa50 but significantly enhanced the sub-maximal force production at forces lower than 50%, an affect that was less pronounced as Ca2+ levels increased. Furthermore, OM differentially impacted the contractile properties of failing and donor myocardium. Specifically, OM-induced force increases were more pronounced in the failing myocardium (∼79% increase vs. ∼28% in donor myocardium). Additionally, the OM-induced slowing of krel and kdf, and increase in Pdf were also more pronounced in the failing myocardium. Our results suggest that OM is effective in increasing force generation in myocardium isolated from failing hearts by increasing XB on-time and enhancing cooperative XB recruitment.