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      Cardiac myosin activation: a potential therapeutic approach for systolic heart failure.

      Science (New York, N.Y.)

      Actin Cytoskeleton, metabolism, Actins, Adenosine Triphosphatases, Adenosine Triphosphate, Adrenergic beta-Agonists, pharmacology, Allosteric Regulation, Animals, Binding Sites, Calcium, Cardiac Myosins, chemistry, Cardiac Output, drug effects, Dogs, Female, Heart Failure, Systolic, drug therapy, physiopathology, Isoproterenol, Male, Myocardial Contraction, Myocytes, Cardiac, physiology, Phosphates, Protein Binding, Protein Conformation, Protein Isoforms, Rats, Rats, Sprague-Dawley, Urea, analogs & derivatives, Ventricular Function, Left

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          Abstract

          Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show that it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5'-triphosphate turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.

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          Author and article information

          Journal
          21415352
          4090309
          10.1126/science.1200113

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