Dias Patrícia, Meng Xiaolei, Selimi Zoja, Struckman Heather, Veeraraghavan Rengasayee, Radwański Przemysław B
Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Division of Pharmaceutics and Pharmacology, College of Pharmacy, Ohio State University, Columbus, Ohio, USA.
Epilepsia. 2025 May;66(5):1691-1702. doi: 10.1111/epi.18295. Epub 2025 Jan 30.
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.
Murine hearts were perfused with clinically relevant concentrations of lamotrigine 3.8 μg/mL (15 μmol·L) or flecainide .4 μg/mL (1 μmol·L).
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).
Our findings provide mechanistic insight into the proarrhythmic impact of lamotrigine.
2021年，美国食品药品监督管理局发布了一项关于在有潜在心脏疾病的患者中使用拉莫三嗪的安全警告。该警告基于体外数据，这些数据预测拉莫三嗪具有Ib类抗心律失常活性。因此，我们研究了拉莫三嗪在小鼠心脏中的促心律失常潜力，并将其与氟卡尼的作用进行比较。
用临床相关浓度的拉莫三嗪3.8μg/mL（15μmol·L）或氟卡尼0.4μg/mL（1μmol·L）灌注小鼠心脏。
离体心电图显示，灌注拉莫三嗪的心脏中室性心动过速（VT）的发生率很高（9个心脏中有7个），而仅两个暴露于氟卡尼的心脏出现VT。光学电压标测显示，在所有测试的起搏频率下，拉莫三嗪优先降低纵向的心室传导速度（CV）（200毫秒、180毫秒和150毫秒心动周期长度的起搏频率下分别为-22%±8.6%、-30%±15.4%和-33%±13.3%，p≤0.05），与之相比，横向仅在最快起搏频率下减慢CV（150毫秒心动周期长度的起搏频率下为-15%±16%，p≤0.01）。值得注意的是，纵向优先的CV减慢改变了各向异性比率，产生了折返性VT的功能性基质。相比之下，氟卡尼在纵向和横向均均匀减慢CV（200毫秒、180毫秒和150毫秒心动周期长度的起搏频率下分别为-30%±8.5%对-27%±5.3%、-32%±9.4%对-29%±6.9%以及-29%±8.3%对-27%±10%，p≤0.05）。
我们的研究结果为拉莫三嗪的促心律失常影响提供了机制性见解。
