Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores

Eur Heart J. 2019 Oct 1;40(37):3097-3107. doi: 10.1093/eurheartj/ehz435.


Aims: Sodium-channel blockers (SCBs) are associated with arrhythmia, but variability of cardiac electrical response remains unexplained. We sought to identify predictors of ajmaline-induced PR and QRS changes and Type I Brugada syndrome (BrS) electrocardiogram (ECG).

Methods and results: In 1368 patients that underwent ajmaline infusion for suspected BrS, we performed measurements of 26 721 ECGs, dose-response mixed modelling and genotyping. We calculated polygenic risk scores (PRS) for PR interval (PRSPR), QRS duration (PRSQRS), and Brugada syndrome (PRSBrS) derived from published genome-wide association studies and used regression analysis to identify predictors of ajmaline dose related PR change (slope) and QRS slope. We derived and validated using bootstrapping a predictive model for ajmaline-induced Type I BrS ECG. Higher PRSPR, baseline PR, and female sex are associated with more pronounced PR slope, while PRSQRS and age are positively associated with QRS slope (P < 0.01 for all). PRSBrS, baseline QRS duration, presence of Type II or III BrS ECG at baseline, and family history of BrS are independently associated with the occurrence of a Type I BrS ECG, with good predictive accuracy (optimism-corrected C-statistic 0.74).

Conclusion: We show for the first time that genetic factors underlie the variability of cardiac electrical response to SCB. PRSBrS, family history, and a baseline ECG can predict the development of a diagnostic drug-induced Type I BrS ECG with clinically relevant accuracy. These findings could lead to the use of PRS in the diagnosis of BrS and, if confirmed in population studies, to identify patients at risk for toxicity when given SCB.

Keywords: Ajmaline; Brugada syndrome; PR; Polygenic risk score; QRS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ajmaline / adverse effects*
  • Ajmaline / therapeutic use
  • Anti-Arrhythmia Agents / adverse effects
  • Anti-Arrhythmia Agents / therapeutic use
  • Brugada Syndrome / diagnosis
  • Brugada Syndrome / drug therapy*
  • Brugada Syndrome / genetics
  • Brugada Syndrome / physiopathology
  • Clinical Decision Rules*
  • Dose-Response Relationship, Drug
  • Electrocardiography
  • Female
  • Genetic Markers
  • Genome-Wide Association Study*
  • Genotyping Techniques
  • Heart Rate / drug effects*
  • Heart Rate / genetics
  • Humans
  • Infusions, Intravenous
  • Male
  • Polymorphism, Single Nucleotide*
  • Risk Assessment
  • Sodium Channel Blockers / adverse effects*
  • Sodium Channel Blockers / therapeutic use


  • Anti-Arrhythmia Agents
  • Genetic Markers
  • Sodium Channel Blockers
  • Ajmaline