Authors :
Presenting Author: Xiaolei Meng, BS – The Ohio State University
D. Ryan King, PhD – Post-doc scholar, College of Pharmacy, The Ohio State Univerisy; Przemyslaw Radwanski, PharmD, PhD – Associate professor, College of Pharmacy, The Ohio State University
Rationale:
Lamotrigine is a commonly prescribed antiepileptic. It prevents seizures by blocking voltage-gated sodium channels. Recently, an FDA safety warning on the cardiac effects of lamotrigine was issued; however, the mechanisms of the proarrhythmic effect of lamotrigine remains unknown. We hypothesize that unlike other sodium channel blockers, therapeutic concentrations of lamotrigine will heterogeneously slow electrical impulse propagation (conduction velocity) in the heart as reflected by an increase in anisotropic ratio to promote substrate formation for reentrant arrhythmia.
Methods:
To address this, we used optical mapping technique to assess arrhythmia inducibility and conduction velocity in Langendroff-perfused middle-aged (30 weeks) wild-type male mouse hearts that were perfused with therapeutic concentrations of various sodium channel blockers: lamotrigine (15 µM, therapeutic range 11.7-58.6 µM), flecainide (1µM, therapeutic range 0.5-2.4 µM), or riluzole (3 µM, therapeutic range 0.03-4.1µM).
Results:
Therapeutic concentrations of both riluzole and flecainide slowed cardiac conduction velocity proportionally in both longitudinal and transverse directions compared to control. Furthermore, at these concentrations, no arrhythmias were evidenced during pacing at a basic cycle length of 150 ms. On the other hand, 15 µM lamotrigine slowed conduction velocity in the transverse direction to a greater extent than in the longitudinal, resulting in an enhanced anisotropic ratio. Importantly, all hearts exposed to a therapeutic concentration of lamotrigine evidenced reentrant arrhythmia during pacing at a basic cycle length of 150 ms.
Conclusions:
Unlike flecainide or riluzole, lamotrigine promotes heterogeneous cardiac conduction slowing and enhanced anisotropic ratio in adult wild-type murine hearts. This in turn, serves as a substrate for reentrant cardiac arrhythmias. Our findings provide a mechanistic rationale and an additional impetus for closer monitoring of adult epileptic patients treated with lamotrigine in order to help reduced proarrhythmic adverse effects.
Funding: R01 NS121234