Transmural dispersion of repolarization and arrhythmogenicity - The Brugada syndrome versus the long QT syndrome

Recent studies have shown that ventricular myocardium is composed of at lea st 3 electrophysiologically distinct cell types: epicardial, endocardial, a nd M cells. Action potentials recorded from epicardial and M cells, unlike those recorded from endocardium, display a spike-and-dome morphology, the r esult of a prominent transient outward currrent-mediated phase 1. M cells a re distinguished from endocardial and epicardial cells by the ability of th eir action potential to prolong disproportionately in response to a slowing of rate and/or to agents with class III actions. This intrinsic electrical heterogeneity contributes to the inscription of the electrocardiogram as w ell as to the development of a variety of cardiac arrhythmias. The transmur al dispersion of repolarization is in large parr responsible for the inscri ption of the J wave and T wave of the electrocardiogram. Because full repol arization of epicardium defines the peak of the T wave and that of the M ce lls, the end of the T wave, the interval between the peak and the end of th e T wave provides a valuable index of transmural dispersion of repolarizati on. Differences in the response of the 3 cell types to pharmacologic agents and/or pathophysiological states often results in amplification of intrins ic electrical heterogeneities, thus providing a substrate as well as a trig ger for the development of reentrant arrhythmias, including torsade de poin tes (TdP) commonly associated with the long QT syndrome (LQTS) and the poly morphic ventricular tachycardia/fibrillation encountered in patients with t he Brugada syndrome. Early repolarization of the epicardial action potentia l results in abnormal abbreviation of action potential duration due to an a ll-or-none repolarization at the end of phase 1 of the epicardial action po tential. The loss of the action potential dome in epicardium but not endoca rdium gives rise to a large dispersion of repolarization across the ventric ular wall, resulting in a transmural voltage gradient that manifests in the electrocardiogram as an ST segment elevation (or idiopathic J wave). Under these conditions, heterogeneous repolarization of the epicardial action po tential gives rise to phase 2 reentry, which provides an extrasystole capab le of precipitating ventricular tachycardia/fibrillation (or rapid TdP). Ex perimental models displaying these phenomena show electrocardiographic char acteristics similar to those of the Brugada syndrome as well as those encou ntered during acute ischemia. Transmural dispersion of repolarization is al so greatly amplified in LQTS. Disproportionate prolongation of the M-cell a ction potential contributes to the development of long QT intervals, wide-b ased or notched T waves, and a large transmural dispersion of repolarizatio n, which provides the substrate for the development of a polymorphic ventri cular tachycardia closely resembling torsade de pointes. An early afterdepo larization-induced triggered beat is thought to provide the extrasystole th at precipitates TdP. Pharmacologic models of the LQT1, LQT2 and LQT3 forms of LQTS mimic the distinctive electrocardiographic, electrophysiologic, and pharmacologic responses observed in patients with these 3 different geneti c syndromes. In LQTS, as in the Brugada syndrome, a mutation in an ion chan nel gene (in some cases the same gene-SCN5A) is responsible for the develop ment of a large transmural dispersion of repolarization, which serves to pr ovide the arrhythmogenic substrate tha can lead to sudden death.