Lamotrigine promotes reentrant ventricular tachycardia in murine hearts

IF 6.6 1区医学 Q1 CLINICAL NEUROLOGY Epilepsia Pub Date : 2025-01-30 DOI:10.1111/epi.18295

Patrícia Dias, Xiaolei Meng, Zoja Selimi, Heather Struckman, Rengasayee Veeraraghavan, Przemysław B. Radwański

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Abstract

Objective

In 2021, the US Food and Drug Administration issued a safety warning concerning lamotrigine use in patients with underlying cardiac disorders. This warning was based on in vitro data that predicted class Ib antiarrhythmic activity for lamotrigine. Therefore, we investigated the proarrhythmic potential of lamotrigine in the murine heart and compared its effect with flecainide.

Methods

Murine hearts were perfused with clinically relevant concentrations of lamotrigine 3.8 μg/mL (15 μmol·L⁻¹) or flecainide .4 μg/mL (1 μmol·L⁻¹).

Results

Ex vivo electrocardiography revealed a high prevalence of ventricular tachycardia (VT) in lamotrigine-perfused hearts (7/9 hearts), whereas only two hearts exposed to flecainide evidenced VT. Optical voltage mapping showed that lamotrigine preferentially decreased ventricular conduction velocity (CV) in the longitudinal direction at all pacing frequencies tested (−22% ± 8.6%, −30% ± 15.4%, and −33% ± 13.3% for pacing frequency of 200-ms, 180-ms, and 150-ms cycle length, respectively, p ≤ .05) compared to the transverse direction, which only slowed CV at the fastest pacing frequency (−15% ± 16% for pacing frequency of 150-ms cycle length, p ≤ .01). Notably, the preferential CV slowing in the longitudinal direction altered the anisotropic ratio, giving rise to a functional substrate for reentrant VT. In contrast, flecainide slowed CV uniformly in both longitudinal and transverse directions (−30% ± 8.5% vs. −27% ± 5.3%, −32% ± 9.4% vs. −29% ± 6.9%, and − 29% ± 8.3% vs. −27% ± 10% for pacing frequency of 200-ms, 180-ms, and 150-ms cycle length, respectively, p ≤ .05).

Significance

Our findings provide mechanistic insight into the proarrhythmic impact of lamotrigine.

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拉莫三嗪促进小鼠心脏重入性室性心动过速。

目的：2021年，美国食品和药物管理局发布了关于拉莫三嗪用于潜在心脏疾病患者的安全警告。这一警告是基于预测拉莫三嗪Ib级抗心律失常活性的体外数据。因此，我们研究了拉莫三嗪在小鼠心脏中的促心律失常电位，并比较了其与氟屈胺的作用。方法：小鼠心脏灌注临床相关浓度的拉莫三嗪3.8 μg/mL （15 μmol·L-1）或氟氯胺0.4 μg/mL （1 μmol·L-1）。结果:体外心电图显示，拉莫三嗪灌注心脏（7/9颗心脏）室性心动过速（VT）的发生率很高，而暴露于氟氯胺的心脏只有2颗存在室性心动过速。光学电压测图显示，在所有测试的起搏频率下，拉莫三嗪在纵向上优先降低心室传导速度（CV），分别为-22%±8.6%、-30%±15.4%和-33%±13.3%，起搏频率分别为200 ms、180 ms和150 ms周期长度。p≤0.05)，而横向仅在最快起搏频率下减慢CV（起搏频率为-15%±16%，周期长度为150 ms， p≤0.01）。值得注意的是，纵向上的优先CV减慢改变了各向异性比，从而产生了可重入性VT的功能底物。相比之下，氟氯胺在纵向和横向上均匀减慢CV（分别为-30%±8.5%对-27%±5.3%,-32%±9.4%对-29%±6.9%,-29%±8.3%对-27%±10%，分别为起搏频率200 ms， 180 ms和150 ms周期长度，p≤0.05）。意义：我们的发现为拉莫三嗪对心律失常的影响提供了机制上的见解。

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来源期刊

Epilepsia 医学-临床神经学

CiteScore

10.90

自引率

10.70%

发文量

319

审稿时长

2-4 weeks

期刊介绍： Epilepsia is the leading, authoritative source for innovative clinical and basic science research for all aspects of epilepsy and seizures. In addition, Epilepsia publishes critical reviews, opinion pieces, and guidelines that foster understanding and aim to improve the diagnosis and treatment of people with seizures and epilepsy.