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

Ventricular myocardium comprises at least three electrophysiologically dist inct cell types: epicardial, endocardial and M cells. Epicardial and M cell s, but not endocardial cells, display action potentials with a notched or s pike-and-dome morphology: the result of a prominent, transient, outward cur rent-mediated phase 1. M cells are distinguished from endocardial and epica rdial 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 develo pment of a variety of cardiac arrhythmias. Heterogeneous response of the th ree cell types to pharmacological agents and/or pathophysiological states r esults in amplification of intrinsic electrical heterogeneities, thus provi ding a substrate as well as a trigger for the development of re-entrant arr hythmias, including Torsade de Pointes, commonly associated with the long-Q T syndrome (LQTS), and the polymorphic ventricular tachycardia/ventricular fibrillation (VT/VF) encountered in the Brugada syndrome. Despite an abunda nce of experimental data describing the heterogeneity of cellular electroph ysiology that: exists across the ventricular wall; relatively few computer models have been developed to investigate the physiological and pathophysio logical consequences of such electrical heterogeneity. As computer power in creases and numerical algorithms improve, three-dimensional computer models of ventricular conduction that combine physiological membrane kinetics wit h realistic descriptions of myocardial structure and geometry will become m ore feasible. With. sufficient detail and accuracy, these models should ill uminate the complex mechanisms underlying the initiation and maintenance of Torsade de Pointes and other arrhythmias.