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Am J Physiol Heart Circ Physiol 289: H1456-H1467, 2005. First published May 27, 2005; doi:10.1152/ajpheart.00733.2004
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Atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model of cardiomyopathy secondary to cardiac-specific overexpression of tumor necrosis factor-{alpha}

Samir Saba,1,* Andrzej M. Janczewski,1,* Linda C. Baker,2 Vladimir Shusterman,1 Erdal C. Gursoy,1 Arthur M. Feldman,3 Guy Salama,2 Charles F. McTiernan,1 and Barry London1

Cardiovascular Institute1 and Department of Cell Biology and Physiology,2 University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Medicine,3 Thomas Jefferson University, Philadelphia, Pennsylvania

Submitted 21 July 2004 ; accepted in final form 16 May 2005

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 Ca2+ 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 Ca2+ handling. Thus abnormalities in action potential propagation and Ca2+ handling contribute to the initiation of atrial arrhythmias in this mouse model of heart failure.

heart failure; atrium; atrial fibrillation; cytokines


Address for reprint requests and other correspondence: B. London, Cardiovascular Institute, Univ. of Pittsburgh, 200 Lothrop St., Scaife S572, Pittsburgh, PA 15213 (e-mail: londonb{at}upmc.edu)




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