Improvement of cardiac function by a cardiac Myosin activator in conscious dogs with systolic heart failure.
BACKGROUND
Therapy for chronic systolic heart failure (sHF) has improved over the past 2 decades, but the armamentarium of drugs is limited and consequently sHF remains a leading cause of death and disability. In this investigation, we examined the effects of a novel cardiac myosin activator, omecamtiv mecarbil (formerly CK-1827452) in 2 different models of heart failure.


RESULTS
Two different models of sHF were used: (1) pacing-induced sHF after myocardial infarction (MI-sHF) and (2) pacing-induced sHF after 1 year of chronic pressure overload left ventricular hypertrophy (LVH-sHF). Omecamtiv mecarbil increased systolic function in sHF dogs, chronically instrumented to measure LV pressure, wall thickness, and cardiac output. Omecamtiv mecarbil, infused for 24 hours, induced a sustained increase without desensitization (P<0.05) in wall thickening (25+/-6.2%), stroke volume (44+/-6.5%) and cardiac output (22+/-2.8%), and decreased heart rate (15+/-3.0%). The major differences between the effect of omecamtiv mecarbil on cardiac function and the effect induced by a catecholamine, for example, dobutamine, is that omecamtiv mecarbil did not increase LV dP/dt but rather increased LV systolic ejection time by 26+/-2.9% in sHF. Another key difference is that myocardial O(2) consumption (MVO(2)), which increases with catecholamines, was not significantly affected by omecamtiv mecarbil.


CONCLUSIONS
These results demonstrate that chronic infusion of the cardiac myosin activator, omecamtiv mecarbil, improves LV function in sHF without the limitations of progressive desensitization and increased MVO(2.) This unique profile may provide a new therapeutic approach for patients with sHF.
Shen
You-Tang
YT
CV Dynamics, Inc, North Brunswick, NJ, USA.
Malik
Fady I
FI
Zhao
Xin
X
Depre
Christophe
C
Dhar
Sunil K
SK
Abarzúa
Patricio
P
Morgans
David J
DJ
Vatner
Stephen F
SF
D000704:Analysis of Variance; D000818:Animals; D024722:Cardiac Myosins / Q000187:drug effects* / Q000378:metabolism; D003243:Consciousness; D004195:Disease Models, Animal; D004280:Dobutamine / Q000494:pharmacology; D004285:Dogs; D004334:Drug Administration Schedule; D005260:Female; D054143:Heart Failure, Systolic / Q000188:drug therapy* / Q000503:physiopathology; D006334:Heart Function Tests; D007262:Infusions, Intravenous; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009203:Myocardial Infarction / Q000188:drug therapy / Q000503:physiopathology; D010101:Oxygen Consumption / Q000187:drug effects; D011336:Probability; D011897:Random Allocation; D013318:Stroke Volume / Q000187:drug effects; D016896:Treatment Outcome; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects
C547293:omecamtiv mecarbil; D004280:Dobutamine; D014508:Urea; D024722:Cardiac Myosins