Aging increases pulmonary veins arrhythmogenesis and susceptibility to calcium regulation agents
Aging increases pulmonary veins arrhythmogenesis and susceptibility to calcium regulation agents
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DOI：
10.1016/j.hrthm.2007.06.023
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发表时间：
2007-10-01
期刊：
影响因子：
5.5
通讯作者：
Chen, Shih-Ann
中科院分区：
文献类型：
--
作者：
Wongcharoen, Wanwarang;Chen, Yao-Chang;Chen, Shih-Ann
背景老化和肺静脉（pv）在房颤的病理生理中起关键作用。已知异常Ca2+调节和ryanodine受体有助于PV心律失常的发生。目的：研究衰老是否会改变PV电生理、Ca2+调节蛋白以及对雷帕霉素、FK-506、瑞诺定和瓦巴因的反应。方法用常规微电极记录15只幼龄（3月龄）和16只成年（3岁）家兔给药前后离体PV组织的动作电位和收缩力。western blot检测肌浆网Ca2+ atp酶（SERCA2a）、ryanodine受体和Na+/Ca2+交换器的表达。结果老年pv延迟去极化后振幅较大，去极化静息膜电位较大，动作电位持续时间较长，动作电位交替和收缩交替发生率较高，Na+/Ca2+交换器和ryanodine受体表达增加，SERCA2a表达降低。雷帕霉素（1,10,100 nM）， FK-506 (0.01, 0.1, 1 μ M)，瑞诺定（0.1,1 μ M）和瓦阿因（0.1,1 μ M）浓度依赖性地增加了年轻和老年PV的自发率和延迟后去极化发生率。与年轻PV相比，雷帕霉素和FK-506在老年PV中更大程度地增加了PV自发率，并表现出更大的延迟后去极化振幅。在没有自发活性的pv中，雷帕霉素和FK-506仅在老年pv中诱导自发活性，而瑞诺定和瓦巴因在年轻和老年pv中均诱导自发活性。结论衰老通过Ca2+异常调节增加PV心律失常。这些发现支持了ryanodine受体功能障碍可能导致高PV心律失常和衰老相关的心律失常易感性的概念。
BACKGROUND Aging and pulmonary veins (PVs) play a critical role in the pathophysiology of atrial fibrillation. Abnormal Ca2+ regulation and ryanodine receptors are known to contribute to PV arrhythmogenesis.OBJECTIVE The purpose of this study was to investigate whether aging alters PV electrophysiology, Ca2+ regulation proteins, and responses to rapamycin, FK-506, ryanodine, and ouabain.METHODS Conventional microelectrodes were used to record action potential and contractility in isolated PV tissue samples in 15 young (age 3 months) and 16 aged (age 3 years) rabbits before and after drug administration. Expression of sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), ryanodine receptor, and Na+/Ca2+ exchanger was evaluated by western blot.RESULTS Aged PVs had Larger amplitude of delayed afterdepolarizations, greater depolarized resting membrane potential, longer action potential duration, and higher incidence of action potential alternans and contractile alternans with increased expression of Na+/Ca2+ exchanger and ryanodine receptor and decreased expression of SERCA2a. Rapamycin (1,10,100 nM), FK-506 (0.01, 0.1, 1 mu M), ryanodine (0.1, 1 mu M), and ouabain (0.1, 1 mu M concentration-dependendy increased PV spontaneous rates and the incidence of delayed afterdepolarizations in young and aged PVs. Compared with results in young PVs, rapamycin and FK-506 in aged PVs increased PV spontaneous rates to a greater extent and exhibited a larger delayed afterdepolarization amplitude. In PVs without spontaneous activity, rapamycin and FK-506 induced spontaneous activity only in aged PVs, but ryanodine and ouabain induced spontaneous activity in both young and aged PVs.CONCLUSION Aging increases PV arrhythmogenesis via abnormal Ca2+ regulation. These findings support the concept that ryanodine receptor dysfunction may result in high PV arrhythmogenesis and aging-related arrhythmogenic vulnerability.