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Am J Physiol Heart Circ Physiol (October 17, 2002). doi:10.1152/ajpheart.00431.2002
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Articles in PresS, published online ahead of print October 17, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00431.2002
Submitted on May 21, 2002
Accepted on October 8, 2002

Calcium-Dependent Arrhythmias in Transgenic Mice with Heart Failure

Barry London1*, Linda C Baker2, Joon S Lee3, Vladimir Shusterman3, Bum-Rak Choi2, Toru Kubota3, Charles F McTiernan3, Arthur M Feldman4, and Guy Salama2

1 Department of Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA, USA; Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA, USA
2 Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA, USA
3 Department of Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA, USA
4 Department of Medicine, Thomas Jefferson University, Jefferson Medical College, Philadelphia, PA, USA

* To whom correspondence should be addressed. E-mail: londonb{at}msx.upmc.edu.

Transgenic mice overexpressing the inflammatory cytokine TNF-{alpha} in the heart (TNF-{alpha} mice) 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 to non-transgenic littermates. Programmed stimulation in-vitro with single extra beats elicits reentrant ventricular arrhythmias in TNF-{alpha} (n=12/13) but not 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. Compared to controls, hearts from TNF-{alpha}mice have prolonged of action potential durations (APD90 23±2 ms, n=7, vs 18±1 ms, n=5; p<0.05), no increased dispersion of refractoriness between the 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.




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