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

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

Rafik Tadros  1   2 , Hanno L Tan  1 ; ESCAPE-NET Investigators; Sulayman El Mathari  1 , Jan A Kors  3 , Pieter G Postema  1 , Najim Lahrouchi  1 , Leander Beekman  1 , Milena Radivojkov-Blagojevic  4 , Ahmad S Amin  1 , Thomas Meitinger  4   5 , Michael W Tanck  6 , Arthur A Wilde  1   7 , Connie R Bezzina  1
Affiliations

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

Rafik Tadros et al. Eur Heart J. .

Abstract

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.

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Figures

Figure 1
Figure 1
Variability in ajmaline response and linear mixed modelling. (A) Electrocardiograms (leads V1 and V4) at baseline (top) and peak ajmaline infusion (bottom) of two representative cases. Automatic waveform markers are overlaid on the electrocardiograms. Electrocardiogram scale (0.5 mV/200 ms) on the left. (B) Schematic representation of linear mixed modelling of ajmaline dose–response on PR and QRS, illustrating the fixed and random effects on intercept and slope, where fixed effects are average responses, while random effects are individual differences from the average. (C) Automatic measurements (points) and linear mixed model fit (line) of QRS vs. weight-adjusted ajmaline dose for the two cases shown in (A).
Figure 2
Figure 2
Correlation plots of baseline PR and QRS vs. PRSPR (A) and PRSQRS (B), respectively and PR and QRS slopes vs. PRSPR (C) and PRSQRS (D), respectively. Red and blue markers represent SCN5A mutation carriers and those without a known SCN5A mutation, respectively. The line represents the linear regression between correlated variables in cases without a known SCN5A mutation, with the correlation coefficient (r) and Pearson’s correlation test P-value (P) on the top left corner. Legend applies to all panels. Arrows in panels B and D highlight the two cases shown in Figure 1.
Figure 3
Figure 3
(A) Bar plot representing number of individuals per PRSBrS quintile in the cohort without a known SCN5A mutation, with (red bars) and without (blue bars) ajmaline-induced Type I Brugada syndrome electrocardiogram. (B) Correlation plot of ajmaline dose required to induce a Type I Brugada syndrome electrocardiogram and PRSBrS for SCN5A mutation carriers (red markers) and non-carriers (blue markers). Line represents the linear regression in cases without a known SCN5A mutation, with the correlation coefficient (r) and test P-value (P) at the top left corner.
Figure 4
Figure 4
Probability estimate of ajmaline-induced Type I Brugada syndrome electrocardiogram in patients with suspected Brugada syndrome, depending on QRS duration and presence of Type II or III Brugada syndrome electrocardiogram at baseline, family history of Brugada syndrome, as well as PRSBrS. Shaded area represent the 95% confidence interval. PRSBrS = 0.55 × #rs11708996_C − 0.94 × #rs10428132_G + 0.46 × #rs9388451_C, where #rs11708996_C, #rs10428132_G, and #rs9388451_C indicate the number of respective alleles an individual carries.
Take home figure
Take home figure
Figure summarizing the proof of concept that polygenic scores may be used to predict response to sodium-channel blockers in the context of suspected Brugada syndrome and conduction slowing.
None
See this image and copyright information in PMC

Comment in

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