title: Myosin Activator Omecamtiv Mecarbil Increases Myocardial Oxygen Consumption and Impairs Cardiac Efficiency Mediated by Resting Myosin ATPase Activity.
abstract: BACKGROUND
  Omecamtiv mecarbil (OM) is a novel inotropic agent that prolongs systolic ejection time and increases ejection fraction through myosin ATPase activation. We hypothesized that a potentially favorable energetic effect of unloading the left ventricle, and thus reduction of wall stress, could be counteracted by the prolonged contraction time and ATP-consumption.
  
  
  RESULTS
  Postischemic left ventricular dysfunction was created by repetitive left coronary occlusions in 7 pigs (7 healthy pigs also included). In both groups, systolic ejection time and ejection fraction increased after OM (0.75 mg/kg loading for 10 minutes, followed by 0.5 mg/kg/min continuous infusion). Cardiac efficiency was assessed by relating myocardial oxygen consumption to the cardiac work indices, stroke work, and pressure-volume area. To circumvent potential neurohumoral reflexes, cardiac efficiency was additionally assessed in ex vivo mouse hearts and isolated myocardial mitochondria. OM impaired cardiac efficiency; there was a 31% and 23% increase in unloaded myocardial oxygen consumption in healthy and postischemic pigs, respectively. Also, the oxygen cost of the contractile function was increased by 63% and 46% in healthy and postischemic pigs, respectively. The increased unloaded myocardial oxygen consumption was confirmed in OM-treated mouse hearts and explained by an increased basal metabolic rate. Adding the myosin ATPase inhibitor, 2,3-butanedione monoxide abolished all surplus myocardial oxygen consumption in the OM-treated hearts.
  
  
  CONCLUSIONS
  Omecamtiv mecarbil, in a clinically relevant model, led to a significant myocardial oxygen wastage related to both the contractile and noncontractile function. This was mediated by that OM induces a continuous activation in resting myosin ATPase.
authors.affiliation: From the Cardiovascular Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (J.P.B., A.B.K., E.T.E., N.B., L.R., E.A., T.S.L., O.-J.H.); Cardiovascular Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (T.N., T.M.); Department of Cardiothoracic and Vascular Surgery, Heart and Lung Clinic, University Hospital of North Norway, Tromsø, Norway (A.B.K., T.M.).
authors.forename: Jens Petter
authors.initials: JP
authors.lastname: Bakkehaug
authors.affiliation: From the Cardiovascular Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (J.P.B., A.B.K., E.T.E., N.B., L.R., E.A., T.S.L., O.-J.H.); Cardiovascular Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (T.N., T.M.); Department of Cardiothoracic and Vascular Surgery, Heart and Lung Clinic, University Hospital of North Norway, Tromsø, Norway (A.B.K., T.M.).
authors.forename: Anders Benjamin
authors.initials: AB
authors.lastname: Kildal
authors.affiliation: From the Cardiovascular Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (J.P.B., A.B.K., E.T.E., N.B., L.R., E.A., T.S.L., O.-J.H.); Cardiovascular Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (T.N., T.M.); Department of Cardiothoracic and Vascular Surgery, Heart and Lung Clinic, University Hospital of North Norway, Tromsø, Norway (A.B.K., T.M.).
authors.forename: Erik Torgersen
authors.initials: ET
authors.lastname: Engstad
authors.affiliation: From the Cardiovascular Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (J.P.B., A.B.K., E.T.E., N.B., L.R., E.A., T.S.L., O.-J.H.); Cardiovascular Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (T.N., T.M.); Department of Cardiothoracic and Vascular Surgery, Heart and Lung Clinic, University Hospital of North Norway, Tromsø, Norway (A.B.K., T.M.).
authors.forename: Neoma
authors.initials: N
authors.lastname: Boardman
authors.affiliation: From the Cardiovascular Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (J.P.B., A.B.K., E.T.E., N.B., L.R., E.A., T.S.L., O.-J.H.); Cardiovascular Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (T.N., T.M.); Department of Cardiothoracic and Vascular Surgery, Heart and Lung Clinic, University Hospital of North Norway, Tromsø, Norway (A.B.K., T.M.).
authors.forename: Torvind
authors.initials: T
authors.lastname: Næsheim
authors.affiliation: From the Cardiovascular Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (J.P.B., A.B.K., E.T.E., N.B., L.R., E.A., T.S.L., O.-J.H.); Cardiovascular Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (T.N., T.M.); Department of Cardiothoracic and Vascular Surgery, Heart and Lung Clinic, University Hospital of North Norway, Tromsø, Norway (A.B.K., T.M.).
authors.forename: Leif
authors.initials: L
authors.lastname: Rønning
authors.affiliation: From the Cardiovascular Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (J.P.B., A.B.K., E.T.E., N.B., L.R., E.A., T.S.L., O.-J.H.); Cardiovascular Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (T.N., T.M.); Department of Cardiothoracic and Vascular Surgery, Heart and Lung Clinic, University Hospital of North Norway, Tromsø, Norway (A.B.K., T.M.).
authors.forename: Ellen
authors.initials: E
authors.lastname: Aasum
authors.affiliation: From the Cardiovascular Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (J.P.B., A.B.K., E.T.E., N.B., L.R., E.A., T.S.L., O.-J.H.); Cardiovascular Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (T.N., T.M.); Department of Cardiothoracic and Vascular Surgery, Heart and Lung Clinic, University Hospital of North Norway, Tromsø, Norway (A.B.K., T.M.).
authors.forename: Terje Steinar
authors.initials: TS
authors.lastname: Larsen
authors.affiliation: From the Cardiovascular Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (J.P.B., A.B.K., E.T.E., N.B., L.R., E.A., T.S.L., O.-J.H.); Cardiovascular Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (T.N., T.M.); Department of Cardiothoracic and Vascular Surgery, Heart and Lung Clinic, University Hospital of North Norway, Tromsø, Norway (A.B.K., T.M.).
authors.forename: Truls
authors.initials: T
authors.lastname: Myrmel
authors.affiliation: From the Cardiovascular Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (J.P.B., A.B.K., E.T.E., N.B., L.R., E.A., T.S.L., O.-J.H.); Cardiovascular Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway (T.N., T.M.); Department of Cardiothoracic and Vascular Surgery, Heart and Lung Clinic, University Hospital of North Norway, Tromsø, Norway (A.B.K., T.M.). ole-jakob.how@uit.no.
authors.forename: Ole-Jakob
authors.initials: OJ
authors.lastname: How
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D005260:Female; D006333:Heart Failure / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000150:complications*; D009206:Myocardium / Q000201:enzymology*; D009218:Myosins / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects*; D013318:Stroke Volume / Q000187:drug effects; D034421:Sus scrofa; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D002316:Cardiotonic Agents; D020536:Enzyme Activators; C547293:omecamtiv mecarbil; D014508:Urea; D009218:Myosins
keywords: contractility; heart failure; inotropic agent; myocardial metabolism; omecamtiv mecarbil; oxygen consumption