Original ArticleOmecamtiv Mecarbil, a Cardiac Myosin Activator, Increases Ca2+ Sensitivity in Myofilaments With a Dilated Cardiomyopathy Mutant Tropomyosin E54KUtter, Megan S. BS*; Ryba, David M. BS*; Li, Betty H. BA*; Wolska, Beata M. PhD*,†; Solaro, R. John PhD*Author Information *Department of Physiology and Biophysics, Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, Chicago, IL; and †Division of Cardiology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL. Reprints: R. John Solaro, PhD, Department of Physiology and Biophysics, College of Medicine, University of Illinois, 835 S. Wolcott Avenue M/C 901, Chicago, IL 60612-7342 (e-mail: [email protected]). Supported by NIH Grant PO1 HL 62426 (Project 1, Core C); AHA Grant 15PRE22180010 (to D.M.R.). R. J. Solaro is a member of the Scientific Advisory Board of Cytokinetics, Inc. The other authors report no conflicts of interest. Received March 24, 2015 Accepted May 14, 2015 Journal of Cardiovascular Pharmacology: October 2015 - Volume 66 - Issue 4 - p 347-353 doi: 10.1097/FJC.0000000000000286 Buy Metrics Abstract Apart from transplant, there are no satisfactory therapies for the severe depression in contractility in familial dilated cardiomyopathy (DCM). Current heart failure treatments that act by increasing contractility involve signaling cascades that alter calcium homeostasis and induce arrhythmias. Omecamtiv mecarbil is a promising new inotropic agent developed for heart failure that may circumvent such limitations. Omecamtiv is a direct cardiac myosin activator that promotes and prolongs the strong myosin–actin binding conformation to increase the duration of systolic elastance. We tested the effect of omecamtiv on Ca2+ sensitivity of myofilaments of a DCM mouse model containing a tropomyosin E54K mutation. We compared tension and ATPase activity of detergent-extracted myofilaments with and without treatment with 316 nM omecamtiv at varying pCa values. When transgenic myofilaments were treated with omecamtiv, the pCa50 for activation of tension increased from 5.70 ± 0.02 to 5.82 ± 0.02 and ATPase activity increased from 5.73 ± 0.06 to 6.07 ± 0.04. This significant leftward shift restored Ca2+ sensitivity to levels no longer significantly different from controls. Proteomic studies lacked changes in sarcomeric protein phosphorylation. Our data demonstrate that omecamtiv can potentially augment cardiac contractility in DCM by increasing Ca2+ sensitivity. The use of direct myosin activators addresses functional defects without incurring the adverse side effects of Ca2+-dependent treatments. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.