Department of Clinical and Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Heart Center, Amsterdam Cardiovascular Sciences, Meibergdreef 9, AZ Amsterdam, The Netherlands.
Department of Medicine, Cardiovascular Genetics Center, Montreal Heart Institute and Faculty of Medicine, Université de Montréal, 5000 Belanger, Montreal, QC, Canada.
Eur Heart J. 2019 Oct 1;40(37):3097-3107. doi: 10.1093/eurheartj/ehz435.
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).
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).
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.
钠通道阻滞剂（SCB）与心律失常有关，但心脏电反应的变异性仍未得到解释。我们试图确定吖啶诱发的 PR 和 QRS 变化以及 I 型 Brugada 综合征（BrS）心电图（ECG）的预测因子。
在 1368 例疑似 BrS 接受吖啶胺输注的患者中，我们进行了 26721 次 ECG 测量、剂量反应混合模型和基因分型。我们计算了来自已发表的全基因组关联研究的 PR 间隔（PRSPR）、QRS 持续时间（PRSQRS）和 Brugada 综合征（PRSBrS）的多基因风险评分（PRS），并使用回归分析确定与吖啶剂量相关的 PR 变化（斜率）和 QRS 斜率的预测因子。我们使用 bootstrap 方法得出并验证了一种用于预测吖啶诱导的 I 型 BrS ECG 的预测模型。较高的 PRSPR、基线 PR 和女性与更明显的 PR 斜率相关，而 PRSQRS 和年龄与 QRS 斜率呈正相关（所有 P<0.01）。PRSBrS、基线 QRS 持续时间、基线存在 II 型或 III 型 BrS ECG 以及 BrS 家族史与 I 型 BrS ECG 的发生独立相关，具有良好的预测准确性（校正后的乐观 C 统计量为 0.74）。
我们首次表明，遗传因素是 SCB 对心脏电反应变异性的基础。PRSBrS、家族史和基线 ECG 可以预测诊断性药物诱导的 I 型 BrS ECG 的发生，具有临床相关的准确性。这些发现可能导致 PRS 在 BrS 的诊断中得到应用，如果在人群研究中得到证实，也可能识别出在给予 SCB 时存在毒性风险的患者。
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