Calcium-dependent arrhythmias in transgenic mice with heart failure
Calcium-dependent arrhythmias in transgenic mice with heart failure
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DOI：
10.1152/ajpheart.00431.2002
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发表时间：
2003-02-01
影响因子：
4.8
通讯作者：
Salama, G
中科院分区：
文献类型：
--
作者：
London, B;Baker, LC;Salama, G
在心脏中过度表达炎性细胞因子肿瘤坏死因子（TNF）-α的转基因小鼠（TNF-α小鼠）发生进行性心力衰竭综合征，其特征为双心室扩张、射血分数降低、动态遥测监测的房性和室性心律失常，以及与非转基因同窝小鼠相比生存率降低。体外程序刺激单次额外心跳可诱发TNF-α（n = 13个心脏中的12个）的折返性室性心律失常，但在对照组心脏中没有。我们在TNF-α小鼠的离体灌注心室中进行了电压和Ca 2+的光学映射，以研究导致心律失常的启动和维持的机制。与对照组相比，TNF-α小鼠的心脏动作电位时程延长，（90%复极化时的动作电位时程：23 +/- 2 ms，n = 7，vs. 18 +/- 1 ms，n = 5; P < 0.05），心尖部与基底部不应期离散度无增加，舒张期[Ca 2 +]升高，收缩期[Ca 2 +]降低，Ca 2+瞬变延长（72 +/- 6 ms，n = 10，vs.54 +/- 5 ms，n = 8; P < 0.01）。早搏具有减小的动作电位振幅，并且以缓慢、异质的方式传导。降低细胞外[Ca 2 +]使传导正常化并防止诱导性心律失常。因此，动作电位延长和异常Ca 2+处理可能通过与增强不应性分散或触发活动不同的机制导致该心力衰竭模型中折返性心律失常的发生。
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.