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.