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Am J Physiol Heart Circ Physiol 284: H431-H441, 2003. First published October 17, 2002; doi:10.1152/ajpheart.00431.2002
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Vol. 284, Issue 2, H431-H441, February 2003

Calcium-dependent arrhythmias in transgenic mice with heart failure

Barry London1, Linda C. Baker2, Joon S. Lee1, Vladimir Shusterman1, Bum-Rak Choi2, Toru Kubota1, Charles F. McTiernan1, Arthur M. Feldman3, and Guy Salama2

1 Cardiovascular Institute and 2 Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh 15213; and 3 Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Transgenic mice overexpressing the inflammatory cytokine tumor necrosis factor (TNF)-alpha (TNF-alpha mice) in the heart develop a progressive heart failure syndrome characterized by biventricular dilatation, decreased ejection fraction, atrial and ventricular arrhythmias on ambulatory telemetry monitoring, and decreased survival compared with nontransgenic littermates. Programmed stimulation in vitro with single extra beats elicits reentrant ventricular arrhythmias in TNF-alpha (n = 12 of 13 hearts) but not in control hearts. We performed optical mapping of voltage and Ca2+ in isolated perfused ventricles of TNF-alpha mice to study the mechanisms that lead to the initiation and maintenance of the arrhythmias. When compared with controls, hearts from TNF-alpha mice have prolonged of action potential durations (action potential duration at 90% repolarization: 23 ± 2 ms, n = 7, vs. 18 ± 1 ms, n = 5; P < 0.05), no increased dispersion of refractoriness between apex and base, elevated diastolic and depressed systolic [Ca2+], and prolonged Ca2+ transients (72 ± 6 ms, n = 10, vs. 54 ± 5 ms, n = 8; P < 0.01). Premature beats have diminished action potential amplitudes and conduct in a slow, heterogeneous manner. Lowering extracellular [Ca2+] normalizes conduction and prevents inducible arrhythmias. Thus both action potential prolongation and abnormal Ca2+ handling may contribute to the initiation of reentrant arrhythmias in this heart failure model by mechanisms distinct from enhanced dispersion of refractoriness or triggered activity.

optical mapping; genetically engineered mice


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