Calcium-dependent arrhythmias in transgenic mice with heart failure

被引:104
作者
London, B
Baker, LC
Lee, JS
Shusterman, V
Choi, BR
Kubota, T
McTiernan, CF
Feldman, AM
Salama, G
机构
[1] Univ Pittsburgh, Cardiovasc Inst, Med Ctr, Pittsburgh, PA 15213 USA
[2] Univ Pittsburgh, Dept Cell Biol, Pittsburgh, PA 15213 USA
[3] Thomas Jefferson Univ, Dept Med, Jefferson Med Coll, Philadelphia, PA 19107 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 2003年 / 284卷 / 02期
关键词
optical mapping; genetically engineered mice;
D O I
10.1152/ajpheart.00431.2002
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:H431 / H441
页数:11
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