Heterogeneity of the action potential duration is required for sustained atrial fibrillation
Heterogeneity of the action potential duration is required for sustained atrial fibrillation
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DOI：
10.1172/jci.insight.128765
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发表时间：
2019-06-06
期刊：
影响因子：
8
通讯作者：
Wan, Elaine Y.
中科院分区：
文献类型：
--
作者：
Avula, Uma Mahesh R.;Abrams, Jeffrey;Wan, Elaine Y.
心房颤动（AF）是最常见的心律失常，并占相当大的发病率和死亡率。最近，我们建立了一个自发性和持续性AF的小鼠模型，该模型由Na（v）1.5通道（F1759A）中的突变引起，该突变增强了持续性Na+电流，从而能够研究引起AF的分子机制并识别潜在的新型治疗策略。小鼠有区域异质性的动作电位持续时间的心房相似的AF患者的观察。在这些小鼠中，我们发现，旋转折返性AF心律失常，称为螺旋波或转子的启动和持久性，依赖于动作电位持续时间的异质性。转子的中心被定位到动作电位持续时间的最大异质性的区域。药理学上减弱动作电位时程异质性降低了自发性和起搏诱导的AF。基于计算机的模拟还表明，动作电位时程异质性是产生表现为AF的转子所必需的。这些发现表明，小鼠和人类的动作电位时程异质性是引发房颤的一种机制，降低动作电位时程异质性可以减轻的负担。
Atrial fibrillation (AF) is the most common cardiac arrhythmia and accounts for substantial morbidity and mortality. Recently, we created a mouse model with spontaneous and sustained AF caused by a mutation in the Na(v)1.5 channel (F1759A) that enhances persistent Na+ current, thereby enabling the investigation of molecular mechanisms that cause AF and the identification of potentially novel treatment strategies. The mice have regional heterogeneity of action potential duration of the atria similar to observations in patients with AF. In these mice, we found that the initiation and persistence of the rotational reentrant AF arrhythmias, known as spiral waves or rotors, were dependent upon action potential duration heterogeneity. The centers of the rotors were localized to regions of greatest heterogeneity of the action potential duration. Pharmacologically attenuating the action potential duration heterogeneity reduced both spontaneous and pacing-induced AF. Computer-based simulations also demonstrated that the action potential duration heterogeneity is required to generate rotors that manifest as AF. Taken together, these findings suggest that action potential duration heterogeneity in mice and humans is one mechanism by which AF is initiated and that reducing action potential duration heterogeneity can lessen the burden of AF.