Dynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure
Dynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure
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DOI：
10.1152/ajpheart.00079.2007
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发表时间：
2007-08-01
影响因子：
4.8
通讯作者：
Tomaselli, Gordon F.
中科院分区：
文献类型：
--
作者：
Akar, Fadi G.;Nass, Robert D.;Tomaselli, Gordon F.
终末期心力衰竭（HF）的特征是传导速度（CV）的改变，易导致心律失常。在这里，我们研究了传导变化的时间过程，以及在HF发展过程中连接蛋白43 （Cx43）性质和机械功能的改变。我们对接受0、3、7、14和21天快速起搏的狗进行动脉灌注心肌制备，以产生不同程度的重构，并对其进行高分辨率光学成像。将CV与机械功能指标[左室舒张末压（LVEDP）]以及Cx43的表达、分布和磷酸化的动态变化进行比较。与复极化相反，CV在重构早期（3天和7天）保持不变，并在后期显著降低，这与LVEDP显着增加有关。差异磷酸化的Cx43异构体的测量显示，在CV和LVEDP变化之前，泛Cx43的早期持续下调，在终末期HF中，去磷酸化的Cx43异构体逐渐上升到基线水平的两倍以上，泛Cx43的侧化晚期突然增加，但没有去磷酸化的Cx43。这些数据表明，1)CV减慢仅发生在重构的晚期，2)泛Cx43的总减少是机械功能障碍和CV减慢之前的早期事件，3)Cx43磷酸化的变化与HF的发病更密切相关，4)Cx43侧化是晚期事件，与显著的CV降低相一致。这些数据揭示了一种新的重塑模式，该模式基于与Cx43亚型变化和机械功能障碍相关的传导异常时间。
End-stage heart failure ( HF) is characterized by changes in conduction velocity ( CV) that predispose to arrhythmias. Here, we investigate the time course of conduction changes with respect to alterations in connexin 43 ( Cx43) properties and mechanical function during the development of HF. We perform high-resolution optical mapping in arterially perfused myocardial preparations from dogs subjected to 0, 3, 7, 14, and 21 days of rapid pacing to produce variable degrees of remodeling. CV is compared with an index of mechanical function [ left ventricular end-diastolic pressure ( LVEDP)] and with dynamic changes in the expression, distribution, and phosphorylation of Cx43. In contrast to repolarization, CV was preserved during early stages of remodeling ( 3 and 7 days) and significantly reduced at later stages, which were associated with marked increases in LVEDP. Measurements of differentially phosphorylated Cx43 isoforms revealed early, sustained downregulation of pan-Cx43 that preceded changes in CV and LVEDP, a gradual rise in a dephosphorylated Cx43 isoform to over twofold baseline levels in end-stage HF, and a late abrupt increase in pan-Cx43, but not dephosphorylated Cx43, lateralization. These data demonstrate that 1) CV slowing occurs only at advanced stages of remodeling, 2) total reduction of pan-Cx43 is an early event that precedes mechanical dysfunction and CV slowing, 3) changes in Cx43 phosphorylation are more closely associated with the onset of HF, and 4) Cx43 lateralization is a late event that coincides with marked CV reduction. These data reveal a novel paradigm of remodeling based on the timing of conduction abnormalities relative to changes in Cx43 isoforms and mechanical dysfunction.