Published online before print August 21, 2003, doi: 10.1161/01.RES.0000092248.59479.AE
© 2003 American Heart Association, Inc.
Integrative Physiology |
Transmural Electrophysiological Heterogeneities Underlying Arrhythmogenesis in Heart Failure
From the Heart and Vascular Research Center and the Departments of Medicine and Biomedical Engineering, MetroHealth Campus of Case Western Reserve University, Cleveland, Ohio. Present address for F.G.A. is Division of Cardiology, Johns Hopkins University, Baltimore, Md.
Correspondence to David S. Rosenbaum, MD, Director, Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Dr, Hamman 322, Cleveland, OH 44109-1998. E-mail drosenbaum{at}metrohealth.org
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.
Key Words: heart failure • long-QT syndrome • repolarization • action potentials • arrhythmias
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