Session P83.4

Combined Effects of Acquired LQT Syndrome by Dofetilide and Reduced Repolarization Reserve on Human Ventricular Action Potential: A Simulation Study

R Gonzalez*, L Romero, J Gomis-Tena, B Trenor,
JM Ferrero, FJ Sáiz-Rodríguez

Universidad Politecnica de Valencia
Valencia, Spain

Background: One of the major regulatory concerns on the development of new drugs is acquired long QT syndrome caused by drugs that block hERG channels, delay cardiac repolarization and increase the risk of arrhythmias. Although a drug can prolong QT interval, it is not necessarily proarrhythmic suggesting that prolongation of repolarization itself is insufficient to produce arrhythmias. Cardiac repolarization is a complex and redundant physiological process terminating the cardiac action potential and it results from the activities of multiple membrane ion channels and transporters, which interact through membrane potential and ionic concentrations. Repolarization reserve is the intrinsic aspect of a cell to maintain normal repolarization despite impairments in the ability of a cell to repolarize. One way of framing the concept of reduced repolarization reserve is with defective slow component of delayed rectifier potassium current (IKs).
Aim: The aim of this study was to investigate interactions between acquired long QT syndrome by dofetilide and reduced repolarization reserve in simulated human ventricular cells.
Model: A Markovian model of hERG capable of reproducing a wild type as well an acquired long QT syndrome by dofetilide was developed and was included into the Ten Tusscher ventricular cell model for action potential simulation. Dofetilide concentrations used were 7.5, 30 and 100 nM (IC50 was 7.5 nM). The endocardial and mid-myocardial cells were paced with different basic cycle lengths (750, 1000 and 1250 ms). The reduced repolarization reserve was reproduced decreasing the IKs current by 50 and 25%. The triangulation of APD was calculated as the difference between APD90 and APD40.
Results: Dofetilide was found to produce a marked concentration dependent triangulation of the action potential such that 7.5, 30 and 100 nM produced an increase of 12, 23 and 31 ms in mid-myocardial cells, whereas in endocardial cells the increase was 6, 13 and 16 ms respectively. Reduced repolarization reserve alone produced a slight triangulation increase of 1 or 2 ms in both endocardial and mid-myocardial cells. The combination of drug effects with reduced repolarization reserve produced a maximal APD prolongation of 234 ms and a triangulation increase of 62 ms in mid-myocardial cells, whilst in endocardial cells was 213 and 35 ms respectively.
Conclusion: This study had shown the combined effects of acquired LQT and reduced repolarization reserve on APD and triangulation and pointed out that triangulation offers an additional more sensitive and accurate indicator of the proarrhythmic potential of a drug than APD prolongation alone.

(Abstract Control Number: 98)