Quantification of the Ionic Current Contributions to Cardiac Repolarization Reserve Based on a Novel Piecewise-Linear Approximation Approach

Abstract

Cardiac repolarization reserve is an important protective physiological mechanism. The assessment of single current contributions to action potential (AP) duration (APD) changes allows investigating the complex interplay of ionic mechanisms underlying such mechanism. We present a new method to quantify the contributions of each membrane current to APD changes due to a perturbation from the basal to a different condition.The method is based on a piecewise-linear approximation of the AP repolarization, which is dissected into uniform “discrete decreases” deltaV (e.g. −1 mV), splitting the repolarization timecourses into unevenly long time intervals. For each deltaV, APs are approximated by a linear decreasing trend and each current by its mean value; under this assumption the local contributions of each current to the prolongation/shortening can be computed.We tested our method on the O’Hara-Rudy (ORd) computational model of human ventricular AP in case of 50% block of the IKr current, which prolongs APD by 118 ms.Our analysis revealed that when the contribution of IKr only is considered APD results extremely prolonged (+329 ms), but other currents tend to compensate, mostly ICaL (−183 ms) and IKs to a lesser extent (−35 ms). Time-independent currents, like IK1, do not contribute to APD change. The dynamic adaptation to IKr block from the perturbation until the steady state was also quantified.Our method enables the quantification of the adaptive and compensatory mechanisms implemented by the (in silico model of) cardiac cells in response to a perturbation, such as the block of a repolarizing current.According to the ORd model, and surprisingly enough, the cardiac repolarization reserve in case of IKr block is largely attributable to a decrease in ICaL rather than to an increase in other potassium currents.