Multiscale studies of delayed afterdepolarizations I: A comparison of two biophysically realistic mathematical models for human ventricular myocytes

TL;DR

This study compares two detailed mathematical models of human ventricular myocytes to understand the mechanisms of delayed afterdepolarizations (DADs) and their role in arrhythmias, using multiscale simulations and stability analysis.

Contribution

It provides a comprehensive multiscale analysis of two biophysically realistic models for DADs, identifying key parameters and mechanisms influencing arrhythmogenic activity.

Findings

SERCA pump rate and RyR leak significantly affect DAD transitions.

DADs can be classified into three types based on frequency and amplitude.

Na+/Ca2+ exchanger can suppress DADs and reduce arrhythmia risk.

Abstract

Focal arrhythmias, which arise from delayed afterdepolarizations (DADs), are observed in various pathophysiological heart conditions; these can lead to sudden cardiac death. A clear understanding of the electrophysiological factors of cardiac myocytes, which lead to DADs, can suggest pharmacological targets that can eliminate DAD-induced arrhythmias. Therefore, we carry out multiscale investigations of two mathematical models for human-ventricular myocytes, namely, the ten Tusscher-Panfilov and the HuVEC15 model, at the levels of single myocytes, one- and two-dimensional (1D and 2D) tissue, and anatomically realistic bi-ventricular domains. By using continuation analysis, we uncover steady- to oscillatory-state transitions in the Ca\textsuperscript{2+} concentrations and show that they lead to DADs. We demonstrate that the Sarco/endoplasmic reticulum Ca\textsuperscript{2+}-ATPase (SERCA) pump uptake rate and the Ca\textsuperscript{2+} leak through the ryanodine-receptor (RyR) channel impact this transition significantly. We show that the frequencies and amplitudes of the DADs are key features that can be used to classify them into three types. By carrying out detailed parameter-sensitivity analyses, we identify the electrophysiological parameters, in the myocyte models, that most affect these key features. We then obtain stability (or phase) diagrams for different types of DADs. We demonstrate that the Na\textsuperscript{+}/Ca\textsuperscript{2+} exchanger plays a protective role by suppressing DADs in the TP06 model. We present tissue simulations to illustrate how arrhythmogenic premature ventricular complexes (PVCs) emerge from patches of DAD cells when we pace the tissue. We discuss the implications of our results for some DAD-induced ventricular arrhythmias, which we examine in detail in the companion Paper II.