Department of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Curr Opin Cardiol. 2010 Jan;25(1):29-36. doi: 10.1097/HCO.0b013e328333d3d6.
We focus on the molecular and cellular basis of excitability, conduction and electrical remodeling in heart failure with dyssynchronous left ventricular contraction (DHF) and its restoration by cardiac resynchronization therapy (CRT) using a canine tachy-pacing heart failure model.
The electrophysiological hallmark of cells and tissues isolated from failing hearts is prolongation of action potential duration (APD) and conduction slowing. In human studies and a number of animal models of heart failure, functional downregulation of K currents and alterations in depolarizing Na and Ca currents and transporters are demonstrated. Alterations in intercellular ion channels and extracellular matrix contribute to heterogeneity of APD and conduction slowing. The changes in cellular and tissue function are regionally heterogeneous, particularly in the DHF. Furthermore, beta-adrenergic signaling and modulation of ionic currents is blunted in heart failure. CRT partially reverses the DHF-induced downregulation of K current and improves Na channel gating. CRT significantly improves Ca homeostasis, especially in lateral myocytes, and restores the DHF-induced blunted beta-adrenergic receptor responsiveness. CRT abbreviates DHF-induced prolongation of APD in the lateral myocytes, reduces the left ventricular regional gradient of APD and suppresses development of early afterdepolarizations.
CRT partially restores DHF-induced electrophysiological remodeling, abnormal Ca homeostasis, blunted beta-adrenergic responsiveness, and regional heterogeneity of APD, and thus may suppress ventricular arrhythmias and contribute to the mortality benefit of CRT as well as improving mechanical performance of the heart.
我们专注于心力衰竭伴左心室收缩不同步（DHF）的兴奋性、传导和电重构的分子和细胞基础，以及心脏再同步治疗（CRT）对此的恢复作用，采用犬心动过速起搏心力衰竭模型。
从衰竭心脏中分离出的细胞和组织的电生理标志是动作电位时程（APD）延长和传导减慢。在人类研究和许多心力衰竭动物模型中，证明了 K 电流的功能下调以及去极化 Na 和 Ca 电流和转运体的改变。细胞间离子通道和细胞外基质的改变导致 APD 和传导减慢的异质性。细胞和组织功能的改变在区域上是不均匀的，特别是在 DHF 中。此外，心力衰竭时β肾上腺素能信号和离子电流的调节被削弱。CRT 部分逆转 DHF 诱导的 K 电流下调，并改善 Na 通道门控。CRT 显著改善钙稳态，特别是在外侧心肌细胞中，并恢复 DHF 诱导的β肾上腺素能受体反应迟钝。CRT 缩短 DHF 诱导的外侧心肌细胞 APD 延长，降低左心室 APD 的区域梯度，并抑制早期后除极的发展。
CRT 部分恢复了 DHF 诱导的电重构、异常钙稳态、β肾上腺素能反应迟钝和 APD 的区域异质性，因此可能抑制室性心律失常，并有助于 CRT 的死亡率益处以及改善心脏的机械性能。
