title: Atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model of cardiomyopathy secondary to cardiac-specific overexpression of tumor necrosis factor-{alpha}.
abstract: Transgenic mice overexpressing the inflammatory cytokine TNF-alpha in the heart develop a progressive heart failure syndrome characterized by biventricular dilatation, decreased ejection fraction, decreased survival compared with non-transgenic littermates, and earlier pathology in males. TNF-alpha mice (TNF1.6) develop atrial arrhythmias on ambulatory telemetry monitoring that worsen with age and are more severe in males. We performed in vivo electrophysiological testing in transgenic and control mice, ex vivo optical mapping of voltage in the atria of isolated perfused TNF1.6 hearts, and in vitro studies on isolated atrial muscle and cells to study the mechanisms that lead to the spontaneous arrhythmias. Programmed stimulation induces atrial arrhythmias (n = 8/32) in TNF1.6 but not in control mice (n = 0/37), with a higher inducibility in males. In the isolated perfused hearts, programmed stimulation with single extra beats elicits reentrant atrial arrhythmias (n = 6/6) in TNF1.6 but not control hearts due to slow heterogeneous conduction of the premature beats. Lowering extracellular Ca(2+) normalizes conduction and prevents the arrhythmias. Atrial muscle and cells from TNF1.6 compared with control mice exhibit increased collagen deposition, decreased contractile function, and abnormal systolic and diastolic Ca(2+) handling. Thus abnormalities in action potential propagation and Ca(2+) handling contribute to the initiation of atrial arrhythmias in this mouse model of heart failure.
authors.affiliation: Cardiovascular Institute, University of Pittsburgh, 200 Lothrop St., Scaife S572, Pittsburgh, PA 15213, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Saba
authors.forename: Andrzej M
authors.initials: AM
authors.lastname: Janczewski
authors.forename: Linda C
authors.initials: LC
authors.lastname: Baker
authors.forename: Vladimir
authors.initials: V
authors.lastname: Shusterman
authors.forename: Erdal C
authors.initials: EC
authors.lastname: Gursoy
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Feldman
authors.forename: Guy
authors.initials: G
authors.lastname: Salama
authors.forename: Charles F
authors.initials: CF
authors.lastname: McTiernan
authors.forename: Barry
authors.initials: B
authors.lastname: London
mesh_terms: D000200:Action Potentials; D000367:Age Factors; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography; D005260:Female; D005355:Fibrosis; D015870:Gene Expression; D006325:Heart Atria / Q000473:pathology / Q000503:physiopathology; D006333:Heart Failure / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006339:Heart Rate; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D012727:Sex Characteristics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D002118:Calcium