Citation:

Cardiovascular Research Supplements ( 2016 ) 111 ( S1 ), S73

Introduction: Repolarization reserve is a fundamental cardiac protective mechanism, which compensates excessive prolongations of the repolarization, thus reducing the risk of arrhythmias. Such mechanism rests on a complex interplay of cellular mechanisms, which (partly) counteract dangerous Action Potential (AP) prolongations.

Purpose: We aim to quantify, at the cellular level, the mechanisms underlying the repolarization reserve when the rapid delayed rectifying current (IKr) is blocked.

Methods: We compared three in silico models of the ventricular action potential (AP) (TenTusscher 2006 (TT2006), Grandi 2010 (G2010) and O'Hara-Rudy 2011 (ORd2011), paced at 1 Hz) at three levels of IKr block (IC50, 2xIC50 and 4xIC50). We isolated and quantified the current contributions to repolarization by means of a piecewise-linear approximation of the AP repolarization. The AP repolarization is split into uniform membrane potential decrements ΔV: within each ΔV repolarization is approximated by a linear decreasing time course of the membrane potential and each current by its average values in the corresponding time interval. Therefore, the local contribution of each current to the repolarization reserve is computed based on the variation of its mean value after IKr block. The current contributions to repolarization reserve were evaluated at steady state and at different simulation steps (1, 10, 25, 50, 100 and 400 s after IKr block) to show how the cellular mechanisms dynamically evolve after the perturbation.

Results: The currents that compensate the most IKr block are the L-type Ca2+ current (ICaL) and the slow delayed rectifying current (IKs), to a lesser extent. The IC50 IKr block would induce at steady state, by itself, AP prolongations of 218, 61 and 171 ms in ORd2011, G2010 and TT2006, respectively. ICaL compensates such prolongations with shortening contributions of -79, -20 and -41 ms; IKs-related shortenings are -18, 0 and -48 ms. We also observed a smaller and smaller shortening induced by ICaL for increasing block levels in ORd2011, unlike in G2010 and TT2006. The dynamic test shows a stable trend in the three models for ICaL and IKs, while the Na+/Ca2+ exchanger, the Na+/K+ pump and the transient outward K+ current need at least 100 s to reach a steady contribution, especially in ORd2011.

Conclusions: We suggest that the main contribution to repolarization reserve upon IKr block in human ventricular myocytes is due to a reduction in inward currents (mainly ICaL), rather than to an increment in outward currents (IKs, IK1). We also suggest that the instability for high levels of IKr block observed in the ORd2011 model depends on the reduced compensatory ICaL contribution with respect to other models.

Comparison of the repolarization reserve in three state-of-the-art models of the human ventricular action potential

Abstract

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Assistant Professor Stefano Severi

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Poster session 2 - Computer modelling, bioinformatics and big data

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Frontiers in CardioVascular Biology 2016