Document Detail


Improvement of cardiac function by a cardiac Myosin activator in conscious dogs with systolic heart failure.
MedLine Citation:
PMID:  20498236     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
METHODS AND 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.
Authors:
You-Tang Shen; Fady I Malik; Xin Zhao; Christophe Depre; Sunil K Dhar; Patricio Abarzúa; David J Morgans; Stephen F Vatner
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-24
Journal Detail:
Title:  Circulation. Heart failure     Volume:  3     ISSN:  1941-3297     ISO Abbreviation:  Circ Heart Fail     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-21     Completed Date:  2010-08-10     Revised Date:  2011-10-27    
Medline Journal Info:
Nlm Unique ID:  101479941     Medline TA:  Circ Heart Fail     Country:  United States    
Other Details:
Languages:  eng     Pagination:  522-7     Citation Subset:  IM    
Affiliation:
CV Dynamics, Inc, North Brunswick, NJ, USA.
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MeSH Terms
Descriptor/Qualifier:
Analysis of Variance
Animals
Cardiac Myosins / drug effects*,  metabolism
Consciousness
Disease Models, Animal
Dobutamine / pharmacology
Dogs
Drug Administration Schedule
Female
Heart Failure, Systolic / drug therapy*,  physiopathology
Heart Function Tests
Infusions, Intravenous
Male
Myocardial Contraction / drug effects*
Myocardial Infarction / drug therapy,  physiopathology
Oxygen Consumption / drug effects
Probability
Random Allocation
Stroke Volume / drug effects
Treatment Outcome
Urea / analogs & derivatives,  pharmacology
Ventricular Function, Left / drug effects*
Ventricular Remodeling / drug effects
Chemical
Reg. No./Substance:
0/omecamtiv mecarbil; 34368-04-2/Dobutamine; 57-13-6/Urea; EC 3.6.1.-/Cardiac Myosins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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