A Heterogeneous Formulation of the Himeno et al. Human Ventricular Myocyte Model for Simulation of Body Surface ECGs

Abstract

Current multi-scale electrophysiology models capture the processes underlying ECG genesis under physiological and many disease conditions with high fidelity. However, proper representation of the extracellular milieu remains challenging. The human ventricular myocyte model by Himeno et al. is one of the first which faithfully represents the dependence of the action potential (AP) duration on the extracellular calcium concentration ([Ca 2+ ]o). Here, we present a heterogeneous formulation of the Himeno et al. cellular model and integrate it into a multi-scale framework to compute body surface ECGs. We propose 3 variants to account for transmural heterogeneity informed by experimental data and tuned to match AP level features such as repolarization stability. As shown before, an apico-basal gradient of IKs conductance is a likely mechanism causing concordant T-waves. Therefore, we increased IKs in the Himeno et al. model at the apex by a factor of 3.5 compared to the base to obtain an APD shortening of 12.5%. The setup comprising transmural and apico-basal heterogeneity yielded a physiological ventricular ECG. Our novel setup allows to study, for the first time, how realistic changes of the AP under hypo-and hypercalcaemic conditions translate to changes in the ECG. Resulting QT prolongation under hypocalcaemic conditions matched human experimental data.

Characterization of T Wave Amplitude, Duration and Morphology Changes During Hemodialysis: Relationship With Serum Electrolyte Levels and Heart Rate

“…In [15],[52], a simulated increase in [K + ] has been shown to lead to QT shortening, which would be in line with our results. Our results on T w reduction with increasing [Ca 2+ ] are concordant with the shortening of the repolarization time reported by others[16],[50],[52]. Also, our results at the cellular level are aligned with those obtained with the human ventricular AP model recently proposed by Bartolucci et al[53], which, in contrast to mostAP models, is able to reproduce a physiological APD-[Ca 2+ ] relationship.…”

“…Both the general trend of such relationships and the high inter-individual variability were well reproduced by our simulated ventricular fibers for most of the markers. This can be explained by the fact that we simulated 22 different transmural fibers accounting for proportions of endocardial, midmyocardial and epicardial cells varying within plausible limits, as reported in previous studies [29], [34], [50], [51]. We are not aware of other in silico studies investigating morphological variability in the T wave of the ECG in relation to electrolyte variations such as those occurring during HD, but there are different in silico studies characterizing T wave duration and amplitude as a function of electrolyte concentrations [15], [16].…”

Computer Modeling of the Heart for ECG Interpretation—A Review

“…It contains a chapter on modeling electrolyte disorders and the characteristic features in the ECG that can be derived from modeling [55]. It also points out that classical ventricular cell models are not prepared to show reasonable results for electrolyte concentrations that are far away from homeostasisthey have to be adapted [100]. This group also presented a method to estimate blood calcium concentration [58] and they suggested an optimized selection of features of the Twave and a polynomial regression method to reconstruct the potassium concentration from the ECG [60].…”