Effects of early afterdepolarizations on excitation patterns in an accurate model of the human ventricles

Abstract

Early Afterdepolarizations, EADs, are defined as the reversal of the action potential before completion of the repolarization phase, which can result in ectopic beats. However, the series of mechanisms of EADs leading to these ectopic beats and related cardiac arrhythmias are not well understood. Therefore, we aimed to investigate the influence of this single cell behavior on the whole heart level. For this study we used a modified version of the Ten Tusscher-Panfilov model of human ventricular cells (TP06) which we implemented in a 3D ventricle model including realistic fiber orientations. To increase the likelihood of EAD formation at the single cell level, we reduced the repolarization reserve (RR) by reducing the rapid delayed rectifier Potassium current and raising the L-type Calcium current. Varying these parameters defined a 2D parametric space where different excitation patterns could be classified. Depending on the initial conditions, by either exciting the ventricles with a spiral formation or burst pacing protocol, we found multiple different spatio-temporal excitation patterns. The spiral formation protocol resulted in the categorization of a stable spiral (S), a meandering spiral (MS), a spiral break-up regime (SB), spiral fibrillation type B (B), spiral fibrillation type A (A) and an oscillatory excitation type (O). The last three patterns are a 3D generalization of previously found patterns in 2D. First, the spiral fibrillation type B showed waves determined by a chaotic bi-excitable regime, i.e. mediated by both Sodium and Calcium waves at the same time and in same tissue settings. In the parameter region governed by the B pattern, single cells were able to repolarize completely and different (spiral) waves chaotically burst into each other without finishing a 360 degree rotation. Second, spiral fibrillation type A patterns consisted of multiple small rotating spirals. Single cells failed to repolarize to the resting membrane potential hence prohibiting the Sodium channel gates to recover. Accordingly, we found that Calcium waves mediated these patterns. Third, a further reduction of the RR resulted in a more exotic parameter regime whereby the individual cells behaved independently as oscillators. The patterns arose due to a phase-shift of different oscillators as disconnection of the cells resulted in continuation of the patterns. For all patterns, we computed realistic 9 lead ECGs by including a torso model. The B and A type pattern exposed the behavior of Ventricular Tachycardia (VT). We conclude that EADs at the single cell level can result in different types of cardiac fibrillation at the tissue and 3D ventricle level.

Blinded In Silico Drug Trial Reveals the Minimum Set of Ion Channels for Torsades de Pointes Risk Assessment

“…In clinical settings, patients with structural heart disease and electrophysiological remodeling are at highest risk for drug induced arrhythmia. Experimental work showed that cardiomyocytes isolated from structural heart disease patients with a history of ventricular tachycardia were significantly more prone to the development of EADs (Coppini et al, 2013), and EADs were frequently observed in whole heart experimental recordings of aged or diseased animals, as well as in human whole ventricle simulations Milberg et al, 2012;Dutta et al, 2016;Van Nieuwenhuyse et al, 2017). In this study we considered an optimized population of models with low repolarization reserve, including weak I Kr , I Ks , and I NaK , together with strong I NaL , I CaL , and I NaCa , which are observed in multiple diseases, such as long QT syndrome (Schwartz Peter et al, 2012), hypertrophic cardiomyopathy (Coppini et al, 2013), and heart failure (Shamraj et al, 1993;Ambrosi et al, 2013).…”

“…EADs have been frequently observed in single cells as well as in whole-heart and tissue experimental recordings and simulations in human and animal hearts (Sato et al, 1993;Morita et al, 2009;Sato et al, 2009;Milberg et al, 2012;Coppini et al, 2013;Dutta et al, 2016;Van Nieuwenhuyse et al, 2017). Additional pro-arrhythmic mechanisms such as increased dispersion of repolarization can also provide the substrate for the development of reentrant arrhythmia, and drugs with hERG blockage effects can amplify the intrinsic spatial dispersion of repolarization (Antzelevitch, 2005;Dutta et al, 2016).…”

Directed networks as a novel way to describe and analyze cardiac excitation: Directed Graph mapping

“…In 3D, the heart was sliced in 3 orthogonal directions and the protocol was applied on each slice. However, as the shape of the ventricle model is complex, only grid points with complete circumference in the heart were taken into account, so convolution did not result in false positives on the edges (33). However, this did not result in detection of the filament of the rotor as the density (500 intramural points) was too sparse.…”

Bifurcation Analysis of a Certain Hodgkin-Huxley Model Depending on Multiple Bifurcation Parameters

“…The presence of EADs strongly correlates with the onset of dangerous cardiac arrhythmias, including torsades de pointes (TdP), which is a specific type of abnormal heart rhythm that can lead to sudden cardiac death, see [2][3][4]. Please see for more (biological/physiological) details [5][6][7][8][9][10][11]. In this paper, we will use the bifurcation analysis similar to [12][13][14] to study the system introduced in [1].…”