Heterogeneity and cardiac arrhythmias: an overview

Abstract

This lecture examines the hypothesis that amplification of spatial dispersion of repolarization in the form of transmural dispersion of repolarization (TDR) underlies the development of life-threatening ventricular arrhythmias associated with inherited ion channelopathies, including the long QT, short QT, and Brugada syndromes as well as catecholaminergic polymorphic ventricular tachycardia. In the long QT syndrome, amplification of TDR often is secondary to preferential prolongation of the action potential duration of M cells, whereas in Brugada syndrome, it is thought to be due to selective abbreviation of the action potential duration of right ventricular epicardium. In the short QT syndrome, preferential abbreviation of action potential duration of either endocardium or epicardium appears to be responsible for amplification of TDR. In catecholaminergic polymorphic ventricular tachycardia, reversal of the direction of activation of the ventricular wall is responsible for the increase in TDR. Thus, the long QT, short QT, Brugada, and catecholaminergic ventricular tachycardia syndromes are pathologies with very different phenotypes and etiologies. However, these syndromes share a common final pathway in their predisposition to sudden cardiac death.

Figure 1.

Proposed cellular mechanism for the development of Torsade de Pointes in the long QT syndromes.

Figure 2.

Proposed Mechanism for the Brugada syndrome. A shift in the balance of currents serves to amplify existing heterogeneities by causing loss of the action potential dome at some epicardial, but not endocardial sites. A vulnerable window develops as a result of the dispersion of repolarization and refractoriness within epicardium as well as across the wall. Epicardial dispersion leads to the development of phase 2 reentry, which provides the extrasystole that captures the vulnerable window and initiates VT/VF via a circus movement reentry mechanism. Modified from, with permission.

Figure 3.

Proposed mechanism for arrhythmogenesis in the short QT syndrome. An increase in net outward current due to a reduction in late inward current or augmentation of outward repolarizing current serves to abbreviate action potential duration heterogeneously leading to an amplification of transmural dispersion of repolarization and the creation of a vulnerable window for the development of reentry. Reentry is facilitated both by the increase in TDR and abbreviation of refractoriness.

Figure 4.

The role of transmural dispersion of repolarization (TDR) in channelopathy‐induced sudden cardiac death. In the long QT syndrome, QT increases as a function of disease or drug concentration. In the Brugada syndrome it remains largely unchanged and in the short QT syndrome QT interval decreases as a function of disease or drug. The three syndromes have in common the ability to amplify TDR, which results in the development of TdP when dispersion reaches the threshold for reentry. The threshold for reentry decreases as APD and refractoriness are reduced.