Mamidi Ranganath, Li Jiayang, Gresham Kenneth S, Verma Sujeet, Doh Chang Yoon, Li Amy, Lal Sean, Dos Remedios Cristobal G, Stelzer Julian E
From the Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH (R.M., J.L., C.Y.D., J.E.S.); Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA (K.S.G); Department of Horticulture Sciences, IFAS, Gulf Coast Research and Education Center, University of Florida, Wimauma (S.V.); Sydney Heart Bank, Discipline of Anatomy & Histology, Bosch Institute, University of Sydney, Australia (A.L., S.L., C.G.d.R.).
Circ Heart Fail. 2017 Oct;10(10). doi: 10.1161/CIRCHEARTFAILURE.117.004257.
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.
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 (), and a slowed rate of XB detachment () at submaximal Ca activations. Ca sensitivity of force generation (pCa) was higher in HF myocardium when compared with donor myocardium, both prior to and after OM incubations. OM incubation (0.5 and 1.0 μmol/L) enhanced force generation at submaximal Ca activations in a dose-dependent manner. Notably, OM induced a slowing in with 1.0 μmol/L OM but not with 0.5 μmol/L OM in HF myocardium. Additionally, OM exerted other differential effects on XB behavior in HF myocardium as evidenced by a greater enhancement in and slowing in the time course of cooperative XB recruitment (), which collectively prolonged achievement of peak force development (), compared with donor myocardium.
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.
奥米卡替麦卡比（OM）通过直接结合肌节中的肌球蛋白横桥（XB）来增强体内收缩功能。然而，在衰竭的人类心肌中，OM诱导的XB行为调节的机制细节尚不清楚。
在从人类供体和心力衰竭（HF）左心室分离的化学去表皮心肌制剂中测量了OM对稳态和动态XB行为的影响。HF心肌表现出收缩功能受损，这表现为最大力量降低、XB募集幅度（）降低以及在次最大钙激活时XB脱离速率（）减慢。与供体心肌相比，在OM孵育之前和之后，HF心肌中力产生的钙敏感性（pCa）更高。OM孵育（0.5和1.0 μmol/L）以剂量依赖的方式增强了次最大钙激活时的力产生。值得注意的是，在HF心肌中，1.0 μmol/L的OM诱导了 减慢，但0.5 μmol/L的OM没有。此外，与供体心肌相比，OM对HF心肌中的XB行为产生了其他不同的影响，表现为 在 方面有更大的增强以及协同XB募集（）的时间进程减慢，这共同延长了达到峰值力发展（）的时间。
我们的研究结果表明，OM增强了力的产生，但也延长了重塑的HF心肌中XB转变为承载力状态的时间进程，这可能会延长体内的收缩射血时间。最佳的OM给药剂量对于在不过度延长收缩射血时间的情况下引发增强的收缩功能至关重要，过度延长收缩射血时间可能会损害舒张期充盈。
