Dose-Dependent Effects of the Myosin Activator Omecamtiv Mecarbil on Cross-Bridge Behavior and Force Generation in Failing Human Myocardium
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- Ranganath Mamidi
- 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...
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- Jiayang Li
- 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...
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- Kenneth S. Gresham
- 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...
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- Sujeet Verma
- 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...
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- Chang Yoon Doh
- 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...
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- Amy Li
- 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...
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- Sean Lal
- 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...
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- Cristobal G. dos Remedios
- 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...
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- Julian E. Stelzer
- 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...
説明
<jats:sec> <jats:title>Background:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results:</jats:title> <jats:p> 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 ( <jats:italic>P</jats:italic> <jats:sub>df</jats:sub> ), and a slowed rate of XB detachment ( <jats:italic>k</jats:italic> <jats:sub>rel</jats:sub> ) at submaximal Ca <jats:sup>2+</jats:sup> activations. Ca <jats:sup>2+</jats:sup> sensitivity of force generation (pCa <jats:sub>50</jats:sub> ) 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 <jats:sup>2+</jats:sup> activations in a dose-dependent manner. Notably, OM induced a slowing in <jats:italic>k</jats:italic> <jats:sub>rel</jats:sub> 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 <jats:italic>P</jats:italic> <jats:sub>df</jats:sub> and slowing in the time course of cooperative XB recruitment ( <jats:italic>T</jats:italic> <jats:sub>rec</jats:sub> ), which collectively prolonged achievement of peak force development ( <jats:italic>T</jats:italic> <jats:sub>pk</jats:sub> ), compared with donor myocardium. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>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.</jats:p> </jats:sec>
収録刊行物
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- Circulation: Heart Failure
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Circulation: Heart Failure 10 (10), e00425-, 2017-10
Ovid Technologies (Wolters Kluwer Health)
