Influence of transmural repolarization gradients on the electrophysiology and pharmacology of ventricular myocardium. Cellular basis for the Brugada and long–QT syndromes

Abstract
Ventricular myocardium comprises at least three electrophysiologically distinct cell types: epicardial, endocardial and M cells. Epicardial and M cells, but not endocardial cells, display action potentials with a notched or spike–and–dome morphology: the result of a prominent, transient, outward current–mediated phase 1. M cells are distinguished from endocardial and epicardial cells by the ability of their action potential to disproportionately prolong in response to a slowing down of rate and/or in response to agents with class III actions. This intrinsic electrical heterogeneity contributes to the inscription of the electrocardiogram (ECG) as well as to the development of a variety of cardiac arrhythmias. Heterogeneous response of the three cell types to pharmacological agents and/or pathophysiological states results in amplification of intrinsic electrical heterogeneities, thus providing a substrate as well as a trigger for the development of re–entrant arrhythmias, including Torsade de Pointes, commonly associated with the long–QT syndrome (LQTS), and the polymorphic ventricular tachycardia/ventricular fibrillation (VT/VF) encountered in the Brugada syndrome. Despite an abundance of experimental data describing the heterogeneity of cellular electrophysiology that exists across the ventricular wall, relatively few computer models have been developed to investigate the physiological and pathophysiological consequences of such electrical heterogeneity. As computer power increases and numerical algorithms improve, three–dimensional computer models of ventricular conduction that combine physiological membrane kinetics with realistic descriptions of myocardial structure and geometry will become more feasible. With sufficient detail and accuracy, these models should illuminate the complex mechanisms underlying the initiation and maintenance of Torsade de Pointes and other arrhythmias.