Morita, Hiroshi, Douglas P. Zipes, John Lopshire, Shiho T. Morita, and Jiashin Wu. T wave alternans in an in vitro canine tissue model of Brugada syndrome. Am J Physiol Heart Circ Physiol 291: H421-H428, 2006. First published April 28, 2006 doi:10.1152/ajpheart.01259.2005.-Macroscopic T wave alternans (TWA) associated with increased occurrence of ventricular arrhythmias has been reported in patients with Brugada syndrome. However, the mechanisms in this syndrome are still unclear. We evaluated the hypothesis that TWA in Brugada syndrome was caused by the dynamic instability and heterogeneity of action potentials (APs) in the right ventricle. Using an optical mapping system, we mapped APs on the epicardium or transmural surfaces of 28 isolated and arterially perfused canine right ventricular preparations having drug-induced Brugada syndrome (in mol/l: 2.5-15 pinacidil, 5.0 terfenadine, and 5.0 -13 pilsicainide). Bradycardia at cycle length (CL) of 2,632 Ϯ 496 ms (n ϭ 19) induced alternating deep and shallow T waves in the transmural electrocardiogram. Compared with the shallow T waves, deep T waves were associated with epicardial APs having longer durations and larger domes. Adjacent regions having APs with alternating domes, with constant domes, and without domes coexisted simultaneously in the epicardium and caused TWA. In contrast to the alternating epicardial APs, midmyocardial and endocardial APs did not change during TWA. Alternans could be terminated by rapid (CL: 529 Ϯ 168 ms, n ϭ 7) or very slow (CL: 3,000 ms, n ϭ 7) pacing. The heterogeneic APs during TWA augmented the dispersion of repolarization both within the epicardium and from the epicardium to the endocardium and caused phase 2 reentry. In this drug-induced model of Brugada syndrome, heterogeneic AP contours and dynamic alternans in the dome of right ventricular epicardial, but not midmyocardial or endocardial, APs caused TWA and heightened arrhythmogenicity in part by increasing the dispersion of repolarization. mapping; repolarization; ventricular arrhythmias; phase 2 reentry MACROSCOPIC T WAVE ALTERNANS (macro-TWA), characterized by gross beat-to-beat changes in the polarity, amplitude, and morphology of the T wave in the right precordial leads of the electrocardiogram (ECG), has been reported recently in patients with Brugada syndrome after administration of sodium channel blockers (9,19,21,24,27,28), -adrenergic blocker (27), vasospasm (9), febrile illness (20), glucose loading, and spontaneously (21). Macro-TWA is an indicator of repolarization instability and predicts the occurrence of serious ventricular arrhythmias that can lead to torsades de pointes and sudden cardiac death (23,26,34,40). Macro-TWA can be produced by sequential temporal alternations in the shape of ventricular action potentials (APs) in long QT syndrome (7,25) or by alternating successful and blocked reentrant conduction of the phase 2 dome of AP (12). However, the dynamic interactions between temporal alternans and spatial heterogeneity of AP and their contributions...
