Calcium-dependent arrhythmias in transgenic mice with heart failure.
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 Ca(2+) 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 [Ca(2+)], and prolonged Ca(2+) 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 [Ca(2+)] normalizes conduction and prevents inducible arrhythmias. Thus both action potential prolongation and abnormal Ca(2+) 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.
London
Barry
B
Cardiovascular Institute, University of Pittsburgh, Pennsylvania 15213, USA. londonb@msx.upmc.edu
Baker
Linda C
LC
Lee
Joon S
JS
Shusterman
Vladimir
V
Choi
Bum-Rak
BR
Kubota
Toru
T
McTiernan
Charles F
CF
Feldman
Arthur M
AM
Salama
Guy
G
D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D002303:Cardiac Output, Low / Q000150:complications* / Q000235:genetics; D005456:Fluorescent Dyes; D006575:Heterocyclic Compounds, 3-Ring; D051379:Mice; D008822:Mice, Transgenic; D008991:Monitoring, Physiologic; D009206:Myocardium / Q000378:metabolism; D011726:Pyridinium Compounds; D012016:Reference Values; D013686:Telemetry; D016211:Transforming Growth Factor alpha / Q000235:genetics
D005456:Fluorescent Dyes; D006575:Heterocyclic Compounds, 3-Ring; D011726:Pyridinium Compounds; D016211:Transforming Growth Factor alpha; C068483:rhod-2; C050019:1-(3-sulfonatopropyl)-4-(beta)(2-(di-n-butylamino)-6-naphthylvinyl)pyridinium betaine; D002118:Calcium