Session P83.1

Ionic Basis of Arrhythmic Risk Biomarkers on Simulated Rabbit Ventricular Myocytes

L Romero, B Carbonell*, B Trénor, JM Ferrero

Universidad Politécnica de Valencia
Valencia, Spain

Cardiac arrhythmias are the main cause of mortality in developed countries. To predict proarrhythmic risk, several biomarkers based on cellular electrophysiological properties have been proposed in the literature.
The aim of the present work was to identify the key ionic mechanisms predicting arrhythmia generation in rabbit hearts at the cellular level.
For this purpose, the electrical activity of an isolated rabbit myocyte was simulated using the Shannon et al. ventricular action potential (AP) model. Cellular electrophysiological biomarkers of arrhythmic risk were characterized through four different protocols. Firstly, steady-state AP duration (APD) and AP triangulation were obtained after delivering a train of 1000 pulses at a cycle length (CL) of 400 ms. Secondly, the S1-S2 and the dynamic restitution protocol were applied to obtain both maximal restitution slopes. Thirdly, the time constant of APD adaptation to abrupt changes in the CL was characterized. Finally, rate dependence of steady-state intracellular Na+ and Ca2+ concentrations was studied at increasingly fast pacing frequencies. Computer simulations were conducted for the control parameter set and after introducing ±15 and ±30% variations in the maximum conductances of the main transmembrane currents involved in AP repolarization. Sensitivities of these biomarkers to changes in maximum conductances were computed.
Simulations show that, in rabbits, APD is moderately sensitive to changes in all repolarization current conductances, highlighting INAK (S=35%), ICaL (S=33%) and IKr (S=-26%). AP triangulation, however, is basically determined by the conductances of IK1 (S=-70%) and IKr (S=-24%). In addition, AP rate dependence was especially sensitive to INaK (S=179%), INaCa (S=157%), IKr (S=-182%) and ICaL (S=-110%) conductances. Furthermore, intracellular Ca2+ and Na+ levels are highly determined by ICaL (S=163%), INaK (S=-59%) and INaCa (S=-38%) conductances. Most of these ionic mechanisms were qualitatively similar to humans, although some differences were found.
This study provides quantitative insights into the sensitivity of preclinical biomarkers of arrhythmic risk to variations in ionic current properties in rabbit hearts.

(Abstract Control Number: 93)