Transmural electrophysiological heterogeneities underlying arrhythmogenesis in heart failure
Transmural electrophysiological heterogeneities underlying arrhythmogenesis in heart failure
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DOI：
10.1161/01.res.0000092248.59479.ae
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发表时间：
2003-10-03
影响因子：
20.1
通讯作者：
Rosenbaum, DS
中科院分区：
文献类型：
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作者：
Akar, FG;Rosenbaum, DS
虽然许多离子通道的表达在心力衰竭（HF）中发生改变，但离子和分子水平的功能障碍导致HF室性快速性心律失常的机制尚不清楚。以前，我们发现，跨壁复极不均一性在LQT 2时QT间期延长时多态性室性心动过速（PVT）的发生中起关键作用。由于HF患者的QT间期也延长，我们假设透壁异质性是HF患者PVT的一种机制。光学动作电位测量同时从细胞跨越整个透壁动脉灌注犬楔形制剂。从无（对照，n = 5）和有快速心室起搏产生的HF（n = 8）的犬中分离楔形物。在HF中，动作电位时程（APD）延长在透壁壁中明显不均匀，其特征在于中层心肌（M）细胞的APD延长不成比例。M细胞的APD延长解释了QT间期延长，并导致心室壁复极的空间梯度从4.3 +/- 2.1（对照组）显著增加（P < 0.01）至12.4 +/- 3.5 ms/mm（HF组）。功能性传导阻滞的发生与梯度增强直接相关，63%的HF楔形块患者发生PVT，而对照组无此现象（P < 0.03）。此外，壁内递减的传导和过早冲动的阻滞，之前的每一个情节的PVT，总是发生在M细胞和心外膜下区之间的边界，复极梯度最高。M细胞内APD的选择性延长是HF表型的几个关键特征的基础，包括QT间期延长、跨壁复极异质性以及对传导阻滞和折返性PVT的易感性。
Although expression of numerous ion channels is altered in heart failure (HF), mechanisms by which dysfunction at the ionic and molecular levels lead to ventricular tachyarrhythmias in HF are unknown. Previously, we found that transmural heterogeneities of repolarization play a critical role in the genesis of polymorphic ventricular tachycardia (PVT) when QT interval was prolonged in LQT2. Because QT interval is also prolonged in HF, we hypothesized that transmural heterogeneities are a mechanism of PVT in HF. Optical action potentials were measured simultaneously from cells spanning the entire transmural wall of arterially perfused canine wedge preparations. Wedges were isolated from dogs without ( control, n = 5) and with HF ( n = 8) produced by rapid ventricular pacing. In HF, action potential duration (APD) prolongation was markedly heterogeneous across the transmural wall, and was characterized by disproportionate APD prolongation of midmyocardial (M) cells. APD prolongation of M cells accounted for QT-interval prolongation, and caused significant increases (P < 0.01) in spatial gradients of repolarization across the ventricular wall from 4.3 +/- 2.1 (control) to 12.4 +/- 3.5 ms/mm (HF). Enhanced gradients were directly responsible for development of functional conduction block, leading to PVT in 63% of HF wedges but in no controls ( P < 0.03). Moreover, intramural decremental conduction and block of the premature impulse, preceded each episode of PVT, and always occurred at the border between M-cell and subepicardial zones, where repolarization gradients were highest. Selective prolongation of APD within M cells underlies several key features of the HF phenotype, including QT-interval prolongation, transmural heterogeneity of repolarization, and susceptibility to conduction block and reentrant PVT.