Phenomenological analysis of simple ion channel block in large populations of uncoupled cardiomyocytes

TL;DR

This study develops a method to quantify individual electrophysiological properties of large populations of uncoupled cardiomyocytes under ion channel block, revealing heterogeneity and enabling predictions of drug effects on action potential duration.

Contribution

A novel methodology using a fast-slow model and asymptotic APD expression to analyze heterogeneity in cardiomyocyte responses to ion channel blocking drugs.

Findings

Quantified electrophysiological parameters for nearly 500 myocytes.

Predicted cell excitability and drug response with high accuracy.

Validated dose-response predictions against experimental data.

Abstract

Current understanding of arrhythmia mechanisms and design of anti-arrhythmic drug therapies hinges on the assumption that myocytes from the same region of a single heart have similar, if not identical, action potential waveforms and drug responses. On the contrary, recent experiments reveal significant heterogeneity in uncoupled healthy myocytes both from different hearts as well as from identical regions within a single heart. In this work, a methodology is developed for quantifying the individual electrophysiological properties of large numbers of uncoupled cardiomyocytes under ion channel block in terms of the parameters values of a conceptual fast-slow model of electrical excitability. The approach is applied to a population of nearly 500 rabbit ventricular myocytes for which action potential duration (APD) before and after the application of the drug nifedipine was experimentally measured (Lachaud et al., 2022, Cardiovasc. Res.). To this end, drug action is represented by a multiplicative factor to an effective ion conductance, a closed form asymptotic expression for APD is derived and inverted to determine model parameters as functions of APD and dAPD (drug-induced change in APD) for each myocyte. Two free protocol-related quantities are calibrated to experiment using an adaptive-domain procedure based on an original assumption of optimal excitability. The explicit APD expression and the resulting set of model parameter values allow (a) direct evaluation of conditions necessary to maintain fixed APD or dAPD, (b) predictions of the proportion of cells remaining excitable after drug application, (c) predictions of stimulus period dependency and (d) predictions of dose-response curves, the latter being in agreement with additional experimental data.