title: A dilated cardiomyopathy mutation blunts adrenergic response and induces contractile dysfunction under chronic angiotensin II stress.
abstract: We investigated cardiac contractility in the ACTC E361G transgenic mouse model of dilated cardiomyopathy (DCM). No differences in cardiac dimensions or systolic function were observed in young mice, whereas young adult mice exhibited only mild diastolic abnormalities. Dobutamine had an inotropic and lusitropic effect on the mouse heart. In papillary muscle at 37°C, dobutamine increased relaxation rates [∼50% increase of peak rate of force decline normalized to force (dF/dtmin/F), 25% reduction of time to 90% relaxation (t90) in nontransgenic (NTG) mice], but in the ACTC E361G mouse, dF/dtmin/F was increased 20-30%, and t90 was only reduced 10% at 10 Hz. Pressure-volume measurements showed increases in maximum rate of pressure decline and decreases in time constant of left ventricular pressure decay in the ACTC E361G mouse that were 25-30% of the changes in the NTG mouse, consistent with blunting of the lusitropic response. The inotropic effect of dobutamine was also blunted in ACTC E361G mice, and the dobutamine-stimulated increase in cardiac output (CO) was reduced from 2,100 to 900 μl/min. Mice were treated with high doses of ANG II for 4 wk. The chronic stress treatment evoked systolic dysfunction in ACTC E361G mice but not in NTG. There was a significant reduction in rates of pressure increase and decrease, as well as reduced end-systolic pressure and increased volume. Ejection fraction and CO were reduced in the ACTC E361G mouse, indicating DCM. In vitro DCM-causing mutations uncouple the relationship between Ca(2+) sensitivity and troponin I phosphorylation. We conclude that this leads to the observed, reduced response to β1 agonists and reduced cardiac reserve that predisposes the heart to DCM under conditions of chronic stress.
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Ross
authors.initials: R
authors.lastname: Wilkinson
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Weihua
authors.initials: W
authors.lastname: Song
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Natalia
authors.initials: N
authors.lastname: Smoktunowicz
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom s.marston@imperial.ac.uk.
authors.forename: Steven
authors.initials: S
authors.lastname: Marston
mesh_terms: D000199:Actins / Q000235:genetics*; D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology*; D000367:Age Factors; D000804:Angiotensin II; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004280:Dobutamine / Q000494:pharmacology*; D056966:Excitation Contraction Coupling / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009154:Mutation; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D010641:Phenotype; D010766:Phosphorylation; D019210:Troponin I / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: C526913:ACTC1 protein, human; D000199:Actins; D058665:Adrenergic beta-1 Receptor Agonists; D002316:Cardiotonic Agents; D019210:Troponin I; D000804:Angiotensin II; D004280:Dobutamine; D002118:Calcium
keywords: angiotensin II stress; dilated cardiomyopathy; dobutamine; heart muscle contractility