Electrical remodeling in the failing heart

Abstract

Purpose of review: 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.

Recent findings: 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.

Summary: 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.

Figure 1

Schematic of inward and outward ionic currents, pumps, and exchangers, which inscribe the mammalian ventricular action potential. A schematic of the time course of each current is shown (left), and the gene product that underlies the current is indicated (right).

Figure 2

Regional heterogeneity of action potential (AP) and Ca transient (CaT) in DHF and its restoration by CRT. CRT abbreviates DHF-induced prolongation of APD and restores amplitude and decay of CaT in the lateral cells, thus reduced regional heterogeneity of repolarization and Ca handling.