A large population of cell-specific action potential models replicating fluorescence recordings of voltage in rabbit ventricular myocytes

TL;DR

This study develops a large, cell-specific action potential model population for rabbit ventricular myocytes, accurately capturing electrophysiological diversity and biomarker distributions from fluorescence data, advancing understanding of cellular variability.

Contribution

It introduces a method to estimate parameters for nearly 1200 cell-specific models from fluorescence recordings, matching both population and individual cell biomarker data, which was not achieved in prior work.

Findings

Model population replicates experimental biomarker ranges and distributions

Parameter correlations are weak, and action potential duration is not strongly dependent on single features

Feasibility of large-scale, accurate action potential waveform fitting demonstrated

Abstract

Recent high-throughput experiments unveil substantial electrophysiological diversity among uncoupled healthy myocytes under identical conditions. To quantify inter-cell variability, the values of a subset of the parameters in a well-regarded mathematical model of the action potential of rabbit ventricular myocytes are estimated from fluorescence voltage measurements of a large number of cells. Statistical inference yields a population of nearly 1200 cell-specific model variants that, on a population-level replicate experimentally measured biomarker ranges and distributions, and in contrast to earlier studies, also match experimental biomarker values on a cell-by-cell basis. This model population may be regarded as a random sample from the phenotype of healthy rabbit ventricular myocytes. Uni-variate and bi-variate joint marginal distributions of the estimated parameters are presented, and the parameter dependencies of several commonly utilised electrophysiological biomarkers are revealed. Parameter values are weakly correlated, while summary metrics such as the action potential duration are not strongly dependent on any single electrophysiological characteristic of the myocyte. Our results demonstrate the feasibility of accurately and efficiently fitting entire action potential waveforms at scale. Keywords: cellular excitability, rabbit ventricular myocytes, fluorescence voltage measurements, action potential waveform, parameter estimation in differential equations, noisy time series