Trigger versus Substrate: Multi-Scale Considerations for Arrhythmia Modulation by Pharmacological Action

Abstract

Background: Cardiac arrhythmias such as ventricular fibrillation are intrinsically tissue-scale phenomena, wherein single-cell triggers (e.g. Ca2+-induced spontaneous depolarisation) must interact with tissue-level substrate (e.g. heterogeneous repolarisation) to result in complex and irregular organ excitation (e.g. self-perpetuating re-entrant excitation). Prolongation of the QT interval of the electrocardiogram (pQT), associated with conditions such as heart failure and long-QT syndromes, is linked to increased vulnerability to arrhythmia. Pharmacological management of arrhythmia associated with pQT has been demonstrated to have limited effectiveness; Understanding the impact of pharmacological modulation on the complex interaction between trigger and substrate remains a significant yet important challenge in order to improve intervention efficacy. Methods: We examined the efficacy of a hERG activator (MC-II-157c) to reduce the manifestation of cell- and tissue-scale triggers and its concomitant effects on the tissue substrate using a multi-scale modelling approach: a model of the human ventricular action potential was integrated with a model of stochastic 3D spatiotemporal Ca2+ dynamics, which was then coarse-grained for suitability for 1D-3D tissue simulations. Parameters were modified to mimic pQT and MC-II-157c conditions. Results: pQT conditions promoted the development of spontaneous release events underlying afterdepolarisations during rapid pacing. MC-II-157c applied to pQT conditions shortened the action potential duration, inhibited the development of afterdepolarisations and reduced the probability of afterdepolarisations manifesting as triggered activity in single cells and ectopic activity in tissue. However, it could also increase transmural dispersion of repolarisation, which manifested as an increased vulnerable window for unidirectional conduction block. Conclusions: The combination of stochastic release event modulation and transmural dispersion of repolarisation modulation by MC-II-157c resulted in an integrative behaviour wherein the arrhythmia trigger is reduced but the substrate is increased. Such variable overall vulnerability to arrhythmia cannot be predicted from single-cell studies alone.