Mechanism of the effects of sodium channel blockade on the arrhythmogenic substrate of Brugada syndrome

Heart Rhythm. 2022 Mar;19(3):407-416. doi: 10.1016/j.hrthm.2021.10.031. Epub 2021 Nov 4.

Abstract

Background: The mechanisms by which sodium channel blockade and high-rate pacing modify electrogram (EGM) substrates of Brugada syndrome (BrS) have not been elucidated.

Objective: The purpose of this study was to determine the effect of ajmaline and high pacing rate on the BrS substrates.

Methods: Thirty-two patients with BrS (mean age 40 ± 12 years) and frequent ventricular fibrillation episodes underwent right ventricular outflow tract substrate electroanatomical and electrocardiographic imaging (ECGI) mapping before and after ajmaline administration and during high-rate atrial pacing. In 4 patients, epicardial mapping was performed using open thoracotomy with targeted biopsies.

Results: Ajmaline increased the activation time delay in the substrate (33%; P = .002), ST-segment elevation in the right precordial leads (74%; P < .0001), and the area of delayed activation (170%; P < .0001), coinciding with the increased substrate size (75%; P < .0001). High atrial pacing rate increased the abnormal EGM duration at the right ventricular outflow tract areas from 112 ± 48 to 143 ± 66 ms (P = .003) and produced intermittent conduction block and/or excitation failure at the substrate sites, especially after ajmaline administration. Biopsies from the 4 patients with thoracotomy showed epicardial fibrosis where EGMs were normal at baseline but became fractionated after ajmaline administration. In some areas, local activation was absent and unipolar EGMs had a monophasic morphology resembling the shape of the action potential.

Conclusion: Sodium current reduction with ajmaline severely compromises impulse conduction at the BrS fibrotic substrates by producing fractionated EGMs, conduction block, or excitation failure, leading to the Brugada ECG pattern and favoring ventricular fibrillation genesis.

Keywords: Brugada syndrome; Catheter ablation; Fibrosis; Sodium channel blocker; Ventricular fibrillation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Ajmaline / pharmacology
  • Arrhythmias, Cardiac
  • Brugada Syndrome* / diagnosis
  • Electrocardiography / methods
  • Humans
  • Middle Aged
  • Sodium Channel Blockers* / therapeutic use
  • Ventricular Fibrillation / diagnosis
  • Ventricular Fibrillation / drug therapy
  • Ventricular Fibrillation / etiology

Substances

  • Sodium Channel Blockers
  • Ajmaline