Abstract
Aims. Human action potentials in the Brugada syndrome have been characterized by delayed or even complete loss of dome formation, especially in the right ventricular epicardial layers. Such a repolarization pattern is believed to trigger phase-2 reentry (P2R); however, little is known about the conditions necessary for its initiation. This study aims to determine the specific mechanisms that facilitate P2R induction in Brugada-affected cardiac tissue in humans. Methods. Ionic models for Brugada syndrome in human epicardial cells were developed and used to study the induction of P2R in cables, sheets, and a three-dimensional model of the right ventricular free wall. Results. In one-dimensional cables, P2R can be induced by adjoining lost-dome and delayed-dome regions, as mediated by tissue excitability and transmembrane voltage profiles, and reduced coupling facilitates its induction. In two and three dimensions, sustained reentry can arise when three regions (delayed-dome, lost-dome, and normal epicardium) are present. Conclusions. Not only does P2R induction by Brugada syndrome require regions of action potential with delayed-dome and lost-dome, but in order to generate a sustained reentry from a triggered waveback multiple factors are necessary, including heterogeneity in action potential distribution, tissue coupling, direction of stimulation, the shape of the late plateau, the duration of lost-dome action potentials, and recovery of tissue excitability, which is predominantly modulated by tissue coupling.
Highlights
The Brugada syndrome (BrS), first described as a new clinical entity in 1992 [1], constitutes a distinct subtype of idiopathic ventricular fibrillation with unique electrocardiographic (ECG) manifestations characterized by right bundle branch block, ST-segment elevation of coved or saddle-back type, and T-wave inversion in the right precordial ECG leads V1 to V3, together with a high incidence of sudden death from ventricular tachyarrhythmia [1,2,3]
Beyond a marked dispersion of repolarization due to adjacent regions of lost-dome and delayed-dome Brugadaaffected action potential (AP), our findings highlight that the successful achievement of phase-2 reentry (P2R) in BrS requires a specific balance of multiple additional factors
Our results show for the first time the crucial role of cell-tocell coupling strength in the triggering of P2R, through the modulation by diffusive currents of the recovery of tissue excitability
Summary
The Brugada syndrome (BrS), first described as a new clinical entity in 1992 [1], constitutes a distinct subtype of idiopathic ventricular fibrillation with unique electrocardiographic (ECG) manifestations characterized by right bundle branch block, ST-segment elevation of coved or saddle-back type, and T-wave inversion in the right precordial ECG leads V1 to V3, together with a high incidence of sudden death from ventricular tachyarrhythmia [1,2,3]. A landmark in the characterization of the disease was the identification in 1998 by Chen and coworkers [5] of the first mutation in BrS patients in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel.
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