Electrophysiological Basis of Arrhythmogenicity of QT/T Alternans in the Long-QT Syndrome

Abstract

Tachycardia-dependent QT/T alternans occurs in patients with the congenital or idiopathic form of long-QT syndrome (LQTS) and may presage the onset of polymorphic ventricular tachyarrhythmias. To examine the electrophysiological basis of arrhythmogenicity of QT/T alternans in LQTS, the tridimensional repolarization pattern of QT/T alternans was studied in the anthopleurin-A model of LQTS, a surrogate for LQT3. In 11 anesthetized mongrel puppies, tridimensional repolarization and activation patterns were analyzed from 256 to 384 unipolar electrograms. Cardiac repolarization was evaluated as the activation-recovery interval (ARI) of local electrograms. To induce QT/T alternans, the pacing cycle length (CL) was abruptly shortened in steps of 50 ms from a basic drive of 1000 ms. ARIs were calculated at epicardial (Epi), midmyocardial (Mid), and endocardial (End) sites. ARI restitution at each site was assessed by using a single premature stimulation delivered after the basic drive. ARI alternans occurred at longer CLs at Mid sites compared with End and Epi sites, and the magnitude of alternans at Mid sites was greater. Two factors contributed to the modulation of ARI during QT/T alternans: (1) differences in restitution kinetics at Mid sites, characterized by larger DeltaARI and a slower time constant (tau), and (2) differences in diastolic intervals resulting in different input to restitution at the same constant CL. These 2 factors could explain not only the onset of alternans at Mid sites at longer CLs but also the critical observation that ARI dispersion between Epi and Mid sites during alternans was greater than during the slower basic CL. Marked ARI alternans could be present in local electrograms without manifest alternation of the QT/T segment in the surface ECG. The latter was seen at critically short CLs associated with reversal of the gradient of ARI between Epi and Mid sites, with a consequent reversal of polarity of the intramyocardial QT wave in alternate cycles. The arrhythmogenicity of QT/T alternans was primarily due to the greater degree of spatial dispersion of repolarization during alternans than during slower rates not associated with alternans. This could result in functional conduction block and reentrant ventricular tachyarrhythmias during the fixed drive associated with alternans.

T wave alternans in an in vitro canine tissue model of Brugada syndrome

“…TWA has been reported previously in isolated ventricular models of long QT syndrome during rapid pacing (7,25). Excessive midmyocardial prolongation of APD increased the transmural dispersion of repolarization and generated alternans in APD, in intracellular Ca 2ϩ , and in T waves when new activations were initiated before the full recovery from prior activations in left ventricles having long QT syndrome (25).…”

“…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 to the Brugada-type macro-TWA in ECG are not known.…”

Effects of Selective Autonomic Blockade on T-Wave Alternans in Humans

“…[5][6][7][8][9][10][11][12] The autonomic nervous system is also an important determinant of arrhythmia vulnerability among patients with coronary artery disease. 13 Since ␤-blockers reduce total mortality rates and sudden cardiac death among patients with ischemic heart disease 14 and congestive heart failure 15 and there is strong evidence that TWA is mechanistically related to the pathogenesis of ventricular arrhythmias, 16,17 we hypothesized that ␤-blockade would reduce TWA. Accordingly, we prospectively evaluated patients with ischemic heart disease, left ventricular dysfunction, and inducible sustained monomorphic ventricular tachycardia during electrophysiological studies to determine if selective autonomic blockade alters the sensitivity of TWA for life-threatening ventricular arrhythmias.…”

Transmural Dispersion of Repolarization Determines Scroll Wave Behavior During Ventricular Tachyarrhythmias - A Simulation Study -

“…2 T-wave alternans is known as a predictor of arrhythmic events 26,27 and discordant T-wave alternans is associated with a greater propensity to develop ventricular tachyarrhythmias. 28 Chinushi et al showed that the discordant T-wave alternans derived from both the heterogeneous distribution of the diastolic interval and the regional differences in the restitution properties. 29 The majority of clinical and experimental studies have suggested that arrhythmogenesis is primarily caused by a large degree of electrophysiological heterogeneity or TDR that activates the TdP/VF mechanism.…”