Atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model of cardiomyopathy secondary to cardiac-specific overexpression of tumor necrosis factor-α
Atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model of cardiomyopathy secondary to cardiac-specific overexpression of tumor necrosis factor-α
复制标题
DOI：
10.1152/ajpheart.00733.2004
复制
发表时间：
2005-10-01
影响因子：
4.8
通讯作者：
London, B
中科院分区：
文献类型：
--
作者：
Saba, S;Janczewski, AM;London, B
在心脏中过度表达炎性细胞因子TNF-α的转基因小鼠发展为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、与非转基因同窝出生小鼠相比存活率降低以及雄性中的早期病理学。TNF-α小鼠（TNF 1.6）在动态遥测监测下发生房性心律失常，随着年龄的增长而恶化，在雄性中更为严重。我们在转基因小鼠和对照小鼠中进行了体内电生理测试，离体灌注TNF 1.6心脏的心房电压的光学标测，以及对离体心房肌和细胞的体外研究，以研究导致自发性心律失常的机制。程序刺激在TNF 1.6中诱导房性心律失常（n=8/32），但在对照小鼠中未诱导（n=0/37），雄性小鼠的诱导率较高。在离体灌流心脏中，程序性单次额外心搏刺激可诱发TNF 1.6组的折返性房性心律失常（n=6/6），而对照组由于早搏的缓慢异质传导而无此反应。降低细胞外Ca 2+使传导正常化并防止心律失常。与对照小鼠相比，TNF 1.6的心房肌和细胞表现出胶原沉积增加、收缩功能降低以及收缩期和舒张期Ca 2+处理异常。因此，动作电位传播和Ca 2+处理的异常有助于在该心力衰竭小鼠模型中引发房性心律失常。
Transgenic mice overexpressing the inflammatory cytokine TNF-alpha in the heart develop a progressive heart failure syndrome characterized by biventricular dilatation, decreased ejection fraction, decreased survival compared with non-transgenic littermates, and earlier pathology in males. TNF-alpha mice (TNF1.6) develop atrial arrhythmias on ambulatory telemetry monitoring that worsen with age and are more severe in males. We performed in vivo electrophysiological testing in transgenic and control mice, ex vivo optical mapping of voltage in the atria of isolated perfused TNF1.6 hearts, and in vitro studies on isolated atrial muscle and cells to study the mechanisms that lead to the spontaneous arrhythmias. Programmed stimulation induces atrial arrhythmias (n=8/32) in TNF1.6 but not in control mice (n=0/37), with a higher inducibility in males. In the isolated perfused hearts, programmed stimulation with single extra beats elicits reentrant atrial arrhythmias (n=6/6) in TNF1.6 but not control hearts due to slow heterogeneous conduction of the premature beats. Lowering extracellular Ca2+ normalizes conduction and prevents the arrhythmias. Atrial muscle and cells from TNF1.6 compared with control mice exhibit increased collagen deposition, decreased contractile function, and abnormal systolic and diastolic Ca2+ handling. Thus abnormalities in action potential propagation and Ca2+ handling contribute to the initiation of atrial arrhythmias in this mouse model of heart failure.