Dose-Dependent Effects of the Myosin Activator Omecamtiv Mecarbil on Cross-Bridge Behavior and Force Generation in Failing Human Myocardium

作者：Mamidi Ranganath; Li Jiayang; Gresham Kenneth S; Verma Sujeet; Doh Chang Yoon; Li Amy; Lal Sean; dos Remedios Cristobal G; Stelzer Julian E^*

来源：Circulation-Heart Failure, 2017, 10(10): e004257.

DOI：10.1161/CIRCHEARTFAILURE.117.004257

• heart failure
• myocardium
• omecamtiv mecarbil
• sacromere
• systolic function

BACKGROUND: Omecamtiv mecarbil (OM) enhances systolic function in vivo by directly binding the myosin cross-bridges (XBs) in the sarcomere. However, the mechanistic details governing OM-induced modulation of XB behavior in failing human myocardium are unclear.
METHODS AND RESULTS: The effects of OM on steady state and dynamic XB behavior were measured in chemically skinned myocardial preparations isolated from human donor and heart failure (HF) left ventricle. HF myocardium exhibited impaired contractile function as evidenced by reduced maximal force, magnitude of XB recruitment (P-df), and a slowed rate of XB detachment (k(rel)) at submaximal Ca2+ activations. Ca2+ sensitivity of force generation (pCa(50)) was higher in HF myocardium when compared with donor myocardium, both prior to and after OM incubations. OM incubation (0.5 and 1.0 mu mol/L) enhanced force generation at submaximal Ca2+ activations in a dose-dependent manner. Notably, OM induced a slowing in k(rel) with 1.0 mu mol/L OM but not with 0.5 ae mol/L OM in HF myocardium. Additionally, OM exerted other differential effects on XB behavior in HF myocardium as evidenced by a greater enhancement in P-df and slowing in the time course of cooperative XB recruitment (T-rec), which collectively prolonged achievement of peak force development (T-pk), compared with donor myocardium.
CONCLUSIONS: Our findings demonstrate that OM augments force generation but also prolongs the time course of XB transitions to force-bearing states in remodeled HF myocardium, which may extend the systolic ejection time in vivo. Optimal OM dosing is critical for eliciting enhanced systolic function without excessive prolongation of systolic ejection time, which may compromise diastolic filling.

• 出版日期2017-10