Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43
Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43
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DOI：
10.1161/01.res.88.3.333
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发表时间：
2001-02-16
影响因子：
20.1
通讯作者：
Fishman, GI
中科院分区：
文献类型：
--
作者：
Gutstein, DE;Morley, GE;Fishman, GI
心律失常是多种心脏病的常见且常致死性表现。尽管在体内的致病作用仍在推测中，但间隙连接重构已被认为有助于患病心肌中心律失常发生的倾向增加。通过产生心脏限制性敲除connexin43 （Cx43）的小鼠，我们已经绕过了与该间隙连接通道基因的种系失活相关的围产期致命发育缺陷，并揭示了Cx43在维持电稳定性中的重要作用。心脏特异性Cx43缺失的小鼠具有正常的心脏结构和收缩功能，但它们（观察到28只条件性Cx43基因敲除小鼠中的28只）在2月龄时均发生自发性室性心律失常引起的心源性猝死。Cx43条件敲除小鼠心外膜电激活模式的光学图谱显示，心室传导速度在横向上显著减慢55%，在纵向上显著减慢42%，导致各向异性比与对照组相比增加(2.1+/-0.13比1.66+/-0.06
Cardiac arrhythmia is a common and often lethal manifestation of many forms of heart disease. Gap junction remodeling has been postulated to contribute to the increased propensity for arrhythmogenesis in diseased myocardium, although a causative role in vivo remains speculative. By generating mice with cardiac-restricted knockout of connexin43 (Cx43), we have circumvented the perinatal lethal developmental defect associated with germline inactivation of this gap junction channel gene and uncovered an essential role for Cx43 in the maintenance of electrical stability. Mice with cardiac-specific loss of Cx43 have normal heart structure and contractile function, and yet they uniformly (28 of 28 conditional Cx43 knockout mice observed) develop sudden cardiac death from spontaneous ventricular arrhythmias by 2 months of age. Optical mapping of the epicardial electrical activation pattern in Cx43 conditional knockout mice revealed that ventricular conduction velocity was significantly slowed by up to 55% in the transverse direction and 42% in the longitudinal direction, resulting in an increase in anisotropic ratio compared with control littermates (2.1+/-0.13 versus 1.66+/-0.06; P