Exploring anodal and cathodal make and break cardiac excitation mechanisms in a 3D anisotropic bidomain model

Published studies have investigated the relevance of cardiac virtual electrode responses to unipolar cathodal and anodal stimulations for explaining the make and break excitation mechanisms. Most of these studies have considered 2D bidomain models or cylindrical domains that by symmetry reduce to the 2D case, so the triggering mechanisms and onset of excitation have not yet been fully elucidated in 3D anisotropic models. The goal of this work is to revisit these excitation mechanisms with 3D bidomain simulations considering two tissue types with unequal anisotropy ratio, including transmural fiber rotation and augmenting the Luo\u2013Rudy I membrane model with the so-called funny and the electroporation currents. In addition to usual snapshots of transmembrane potential patterns, we compute from the action potential waveforms the activation time and associated isochrone sequences, yielding a detailed 3D description of the instant and location of excitation origin, shape and propagation of activation wavefronts. A specific aim of this work is to detect the location of the excitation onset and whether its trigger mechanism is (a) electrotonic, i.e. originating from discharge diffusion of currents flowing between virtual cathodes and anods and/or (b) membrane-based, i.e. arising only from intrinsic depolarizing membrane currents. Our results show that the electrotonic mechanism is observed independently of the degree of unequal anisotropy in diastolic anode make and systolic cathode break. The membrane-based mechanism is observed in diastolic cathode make, diastolic anode break, only for a relative weak anisotropy, and systolic anode break. The excitation trigger mechanism, the location of the excitation origin and the pattern of the isochrone sequence are independent of the degree of anisotropy for diastolic cathode make, systolic cathode and anode break, while they might depend on the degree of anisotropy for diastolic anode make and break. Moreover, the tissue anisotropy has a strong influence on the threshold amplitude of the stimulation pulse triggering these mechanisms