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

C Antzelevitch, G X Yan, W Shimizu
Journal of Electrocardiology 1999, 32: 158-65
Recent studies have shown that ventricular myocardium is composed of at least 3 electrophysiologically distinct cell types: epicardial, endocardial, and M cells. Action potentials recorded from epicardial and M cells, unlike those recorded from endocardium, display a 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 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 well as to the development of a variety of cardiac arrhythmias. The transmural dispersion of repolarization is in large part responsible for the inscription of the J wave and T wave of the electrocardiogram. Because full repolarization of epicardium defines the peak of the T wave and that of the M cells, the end of the T wave, the interval between the peak and the end of the T wave provides a valuable index of transmural dispersion of repolarization. Differences in the response of the 3 cell types to pharmacologic agents and/or pathophysiological states often results in amplification of intrinsic electrical heterogeneities, thus providing a substrate as well as a trigger for the development of reentrant arrhythmias, including torsade de pointes (TdP) commonly associated with the long QT syndrome (LQTS) and the polymorphic ventricular tachycardia/fibrillation encountered in patients with the Brugada syndrome. Early repolarization of the epicardial action potential results in abnormal abbreviation of action potential duration due to an all-or-none repolarization at the end of phase 1 of the epicardial action potential. The loss of the action potential dome in 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 electrocardiogram as an ST segment elevation (or idiopathic J wave). Under these conditions, heterogeneous repolarization of the epicardial action potential gives rise to phase 2 reentry, which provides an extrasystole capable of precipitating ventricular tachycardia/fibrillation (or rapid TdP). Experimental models displaying these phenomena show electrocardiographic characteristics similar to those of the Brugada syndrome as well as those encountered during acute ischemia. Transmural dispersion of repolarization is also greatly 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 a polymorphic ventricular tachycardia closely resembling torsade de pointes. An early afterdepolarization-induced triggered beat is thought to provide the extrasystole that 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 genetic syndromes. In LQTS, as in the Brugada syndrome, a mutation in an ion channel gene (in some cases the same gene--SCN5A) is responsible for the development of a large transmural dispersion of repolarization, which serves to provide the arrhythmogenic substrate tha can lead to sudden death.

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