Drug-induced spatial dispersion of repolarization

Abstract

Spatial dispersion of repolarization in the form of transmural, trans-septal and apico-basal dispersion of repolarization creates voltage gradients that inscribe the J wave and T wave of the ECG. Amplification of this spatial dispersion of repolarization (SDR) underlies the development of life-threatening ventricular arrhythmias associated with inherited or acquired ion channelopathies giving rise to the long QT, short QT and Brugada syndromes (BrS). This review focuses on the role of spatial dispersion of repolarization in drug-induced arrhythmogenesis associated with the long QT and BrS. In the long QT syndrome, drug-induced amplification of SDR is often secondary to preferential prolongation of the action potential duration (APD) of M cells, whereas in the BrS, it is thought to be due to selective abbreviation of the APD of right ventricular epicardium. Among the challenges ahead is the identification of a means to quantitate SDR non-invasively. This review also discusses the value of the interval between the peak and end of the T wave (T(peak)-T(end), T(p)-T(e)) as an index of SDR and transmural dispersion of repolarization, in particular.

Figure 1

Proposed cellular mechanism for the development of torsade de pointes in the long QT syndromes.

Figure 2

Electrocardiographic T_peak–T_end interval as a measure of transmural dispersion of repolarization. The figure shows the correspondence among transmembrane, unipolar, and ECG recordings in the absence (left) and the presence (right) of ATX-II (20 nmol/L). Each panel shows: A. Transmembrane action potentials recorded from M (M2) and epicardial sites of a canine left ventricular wedge preparation together with a transmural ECG recorded across the bath (BCL of 2000 ms); B. Eight intramural unipolar electrograms recorded approximately 1.2 mm apart from endocardial (Endo), M (6 sites; M1–M6) and epicardial (Epi) regions (120 μm silver electrodes insulated except at the tip) inserted midway into the wedge preparation. Dashed vertical lines in the unipolar electrograms denote the time maximum of the first derivative (V_max) of the T wave (ARI, end of activation-recovery interval). Close correspondence between the repolarization time of the cells deep within the wedge and those at the cut surface attest the uniformity of the electrical activity in the respective transmural layers. Modified from [2], with permission.

Figure 3

Brugada syndrome phenotype induced by an overdose of desipramine and clonazepam in a 44 year old man previously medicated with desipramine, clonazepam and trazodone. A. ECG shows sinus bradycardia, first degree atrioventricular block (228 ms), prolonged QRS interval (132 ms) and downsloping ST elevation (Type 1) in leads V1–V2, ST elevation in lead V3, upsloping ST depression in leads II, III, and aVF; B. Baseline ECG recorded one year earlier. Modified from [155] with permission.

Figure 4

Schematic representation of right ventricular epicardial action potential changes proposed to underlie the electrocardiographic manifestation of the Brugada syndrome. Modified from [173], with permission.

Figure 5

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 ventricular tachycardia/ventricular fibrillation (VT/VF) via a circus movement reentry mechanism. Modified from [174], with permission.