Session P83.3

Potentiation of Dofetilide LQT-Related Effects by Late Sodium Current Enhancement: A Simulation Study

K Cardona, J Saíz, L Romero, B Carbonell,
JM Ferrero, B Trenor*

Universidad Politecnica de Valencia
Valencia , Spain

Torsades de pointes (TdP) is a life-threatening ventricular tachycardia associated with reduction of IKr and prolongation of ventricular action potential duration (APD) and LQT syndrome. An abnormal increase of the late sodium current (INaL) due to either heritable SCN5A mutations or to organic heart disease, is also associated with a decrease in depolarization reserve and susceptibility to TdP, making this current an appealing pharmacological target.
The aim of the present study was to assess the combined effect of dofetilide, an IKr blocker, and the enhancement of INaL in rabbit ventricular cells through a simulation study, to evaluate the impact on biomarkers of arrhythmic risk.
The AP model by Shannon et al. was used to simulate the electrical activity of rabbit ventricular cells. To evaluate the effects of INaL on APD, triangulation, APD rate-dependency and restitution, we incorporated a novel INaL formulation based on Hund and Rudy equation and adapted to rabbit experimental data. Additionally, the mathematical model of the effects of dofetilide developed previously by our group was included in order to asses the combined effects of IKr block and INaL enhancement. Our results show that the increase in the maximum conductance of INaL prolongs APD, which is in agreement with experimental observations. When the maximum conductance was increased 5 and 10-fold, APD underwent an increase of 15 and 31 % respectively, for a BCL of 1000 ms. APD rate-dependency was observed, as prolongation became higher (22 and 53 %, respectively) for a BCL of 2000 ms. Triangulation was also increased in a rate–dependent manner for 10-fold enhanced INaL (34% for BCL 1000 and 61% for BCL 200). Finally, APD restitution curves also revealed a higher slope and a wider APD range. The concomitant effect of several degrees of INaL enhancement (5-fold and 10-fold) and Dofetilide (30, 100 and 300 nM) yielded dramatical rate-dependent AP prolongation. Furthermore, for doses of 100 and 300 nM of Dofetilide, EADs arose only when INaL was increased 10-fold for a BCL of 2000 ms.
In conclusion, this study provides new insights of the proarrhythmic effects of INaL enhancement combined with Dofetilide administration in the virtual rabbit ventricular cell, quantified in specific biomarkers of arrhythmic risk, revealing the importance to pharmacologically target INaL.

(Abstract Control Number: 97)