Role of spatial dispersion of repolarization in inherited and acquired sudden cardiac death syndromes

Abstract

Antzelevitch C. Role of spatial dispersion of repolarization in inherited and acquired sudden cardiac death syndromes. Am J Physiol Heart Circ Physiol 293: H2024-H2038, 2007. First published June 22, 2007; doi:10.1152/ajpheart.00355.2007.-This review examines the role of spatial electrical heterogeneity within the ventricular myocardium on the function of the heart in health and disease. The cellular basis for transmural dispersion of repolarization (TDR) is reviewed, and the hypothesis that amplification of spatial dispersion of repolarization underlies the development of life-threatening ventricular arrhythmias associated with inherited ion channelopathies is evaluated. The role of TDR in long QT, short QT, and Brugada syndromes, as well as catecholaminergic polymorphic ventricular tachycardia (VT), is critically examined. In long QT syndrome, amplification of TDR is often secondary to preferential prolongation of the action potential duration (APD) of M cells; in Brugada syndrome, however, it is thought to be due to selective abbreviation of the APD of the right ventricular epicardium. Preferential abbreviation of APD of the endocardium or epicardium appears to be responsible for the amplification of TDR in short QT syndrome. In catecholaminergic polymorphic VT, reversal of the direction of activation of the ventricular wall is responsible for the increase in TDR. In conclusion, long QT, short QT, Brugada, and catecholaminergic polymorphic VT syndromes are pathologies with very different phenotypes and etiologies, but they share a common final pathway in causing sudden cardiac death. Among Wiggers' many seminal contributions to physiology and medicine was his elucidation of the mechanisms responsible for ventricular fibrillation (VF). He described approaches to the prevention and treatment of conditions associated with VF (149). I am pleased to have the opportunity to present some of the work we have done to further his important contributions to our field.My principal focus will be on the heterogeneity within the ventricular myocardium with respect to electrical activity: how this heterogeneity contributes to spatial dispersion of repolarization and the degree to which amplification of this spatial dispersion contributes to the development of life-threatening ventricular arrhythmias associated with inherited ion channelopathies (Table 1), such as long QT, short QT, and Brugada syndromes, as well as catecholaminergic polymorphic ventricular tachycardia (CPVT). Preferential prolongation of the action potential duration (APD) of M cells is responsible for amplification of transmural dispersion of repolarization (TDR) in most cases of long QT syndrome, whereas preferential abbreviation of the APD of the right ventricular (RV) epicardium is believed to responsible for amplification of spatial dispersion of repolarization in Brugada syndrome. Recent reports suggest that preferential abbreviation of APD of the endocardium or epicardium is responsible for amplification of TDR in different forms of short QT syndrome....

Cellular basis for arrhythmogenesis in an experimental model of the SQT1 form of the short QT syndrome

“…The arrhythmogenic effect of reversing the direction of activation of the LV wall by pacing from epicardium instead of endocardium, has been demonstrated previously under a variety of conditions. 14, 16,18,19 Quinidine (10 µmol/L) completely reversed the effect of PD-118057 on QT interval and ERP. In the presence of quinidine, the increase in TDR persisted but pVT could no longer be induced.…”

Isoproterenol disperses distribution of NADPH oxidase, MMP-9, and pPKCε in the heart, which are mitigated by endothelin receptor antagonist CPU0213

“…Interestingly, with intervention of CPU0213 and aminoguanidine of 3 days, these changes were significantly subsided. An increase in QTcd is rough evidence indicating an increased heterogeneity of biological substances relating to repolaryzation in the heart, with an increased QTcd the affected heart manifests cardiac electrophysiological instability and an increased risk of life threatening cardiac arrhyth- [25] . To date, spatial dispersion of repolarization has been considered as an amplification of transmural dispersion of repolarization (TDR) which facilitates commencement of lifethreatening ventricular arrhythmias.…”

Nonlinear physics of electrical wave propagation in the heart: a review

“…This has been linked to an increased risk of cardiac death [151] and, in particular, to a higher risk of arrhythmogenicity in short QT, long QT and Brugada syndromes [152][153][154][155]. In Brugada syndrome, for instance, dispersion of repolarization is thought to be caused by an abbreviation of the APD of the right ventricular epicardium due to loss of the action potential dome [156].…”