Electrophysiological distinctions among the three predominant cell types that comprise the ventricular myocardium are responsible for the transmural voltage gradients that inscribe the J and T waves of the ECG. Differences in the response of epicardial, endocardial and M cells to pharmacological agents and/or pathophysiological states result in amplification of these intrinsic electrical heterogeneities, thus providing a substrate and trigger for the development of re-entrant arrhythmias, including Torsade de Pointes (TdP) commonly associated with the long QT syndrome (LQTS) and the rapid polymorphic ventricular tachycardia and ventricular fibrillation (VT/VF) encountered in patients with the Brugada syndrome.

Early repolarization of the epicardium results in abnormal abbreviation of action potential duration (APD) due to an all-or-none repolarization at the end of phase 1 of the epicardial action potential. Loss of the action potential dome in the epicardium but not endocardium gives rise to a large dispersion of repolarization across the ventricular wall, resulting in a transmural voltage gradient that manifests in the ECG as an ST segment elevation (or idiopathic J wave). Under these conditions, heterogeneous repolarization of the epicardial action potential gives rise to phase 2 re-entry, which provides an extrasystole capable of precipitating VT/VF (or rapid TdP). Experimental models displaying these phenomena show ECG characteristics similar to those of the Brugada syndrome as well as those encountered during acute ischaemia.

Transmural dispersion of repolarization is also amplified in LQTS. Disproportionate prolongation of the M cell action potential contributes to the development of long QT intervals, wide-based or notched T waves, and a large transmural dispersion of repolarization, which provides the substrate for the development of re-entrant polymorphic VT closely resembling Torsade de Pointes. An early afterdepolarization (EAD)-induced triggered beat is thought to provide the extrasystole that precipitates TdP. Experimental models of LQT1, LQT2 and LQT3 forms of LQTS suggest a protective effect of mexiletine, an agent that blocks the late sodium current, in all three genotypes. Similar studies provide the basis for the actions of β-adrenergic agonists and antagonists, showing that β-blockers are protective in LQT1 and LQT2, but may promote TdP in LQT3.

In conclusion, recent studies from a number of laboratories have demonstrated important electrical heterogeneities in ventricular myocardium. Amplification of the intrinsic heterogeneities in final repolarization give rise to the long QT syndrome, whereas amplification of those in the early phases of the action potential are thought to give rise to the Brugada syndrome. In both cases we see the development of a vulnerable window in the form of a transmural dispersion of repolarization. In the case of LQTS, re-entry is probably precipitated by an EAD-induced extrasystole, whereas in the Brugada syndrome the extrasystole is due to phase 2 re-entry. Polymorphic ventricular tachycardia develops in both. It is more rapid in the Brugada syndrome because of the reduced refractoriness and relatively slower in LQTS because of the prolonged refractoriness that attends this syndrome. These two syndromes depict paradigms of arrhythmogenesis representing a wide spectrum of mechanisms responsible for arrhythmias in structurally normal hearts. Appreciation of these mechanisms should provide us with an important stepping stone for understanding more complex mechanisms of arrhythmogenesis in structurally abnormal hearts.