Direct Myosin Activation by Omecamtiv Mecarbil for Heart Failure with Reduced Ejection Fraction.
Myosin is the indispensable molecular motor that utilizes chemical energy to produce force for contraction within the cardiac myocyte. Myosin activity is gated by intracellular calcium levels which are regulated by multiple upstream signaling cascades that can be altered for clinical utility using inotropic medications. In contrast to clinically available cardiac inotropes, omecamtiv mecarbil is a novel direct myosin activator developed to augment left ventricular systolic function without the undesirable secondary effects of altered calcium homeostasis. Its identification and synthesis followed high-throughput screening of a reconstituted sarcomere, deliberate optimization, exquisite biochemical evaluation, and subsequently promising effects in animal models were demonstrated. Physiologically, it prolonged the duration of left ventricular systole in animal models, healthy adults, and patients with heart failure with reduced ejection fraction (HFrEF) without changing the velocity of pressure development, as assessed in animal models. It has been formulated for both intravenous and oral administration, and in both acute and chronic settings produced similar alterations in the duration of systole associated with beneficial increases in cardiac output, improvements in left ventricular volumes, and reductions in heart rate and often of natriuretic peptides. Small, asymptomatic increases in troponin were also observed in the absence of clinically evident ischemia. Clinically, the question remains as to whether the possible harm of this minimal troponin release is outweighed by the potential benefits of reduced neurohormonal activation, increased stroke volume and cardiac output, and improved ventricular remodeling in patients treated with omecamtiv mecarbil. The resolution of this question is being addressed by a phase III outcomes trial of this potential novel therapy for heart failure.
School of Medicine, University of California San Francisco, San Francisco, CA, USA.
Mitchell A
MA
Psotka
School of Medicine, University of California San Francisco, San Francisco, CA, USA. john.teerlink@ucsf.edu.|Section of Cardiology, 111C, San Francisco Veterans Affairs Medical Center, 4150 Clement St, San Francisco, CA, 94121-1545, USA. john.teerlink@ucsf.edu.
John R
JR
Teerlink
D000818:Animals; D024722:Cardiac Myosins / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D009200:Myocardial Contraction; D013318:Stroke Volume; D014508:Urea / Q000031:analogs & derivatives* / Q000627:therapeutic use
D002316:Cardiotonic Agents; C547293:omecamtiv mecarbil; D014508:Urea; D024722:Cardiac Myosins
Cardiac output; Heart failure; Myosin activator; Omecamtiv mecarbil; Systolic ejection time