There and back again: Iterating between population-based modeling and experiments reveals surprising regulation of calcium transients in rat cardiac myocytes

Abstract

While many ion channels and transporters involved in cardiac cellular physiology have been identified and described, the relative importance of each in determining emergent cellular behaviors remains unclear. Here we address this issue with a novel approach that combines population-based mathematical modeling with experimental tests to systematically quantify the relative contributions of different ion channels and transporters to the amplitude of the cellular Ca2+ transient. Sensitivity analysis of a mathematical model of the rat ventricular cardiomyocyte quantified the response of cell behaviors to changes in the level of each ion channel and transporter, and experimental tests of these predictions were performed to validate or invalidate the predictions. The model analysis found that partial inhibition of transient outward current in rat ventricular epicardial myocytes was predicted to have a greater impact on Ca2+ transient amplitude than either: (1) inhibition of the same current in endocardial myocytes, or (2) comparable inhibition of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA). Experimental tests confirmed the model predictions qualitatively but showed some quantitative disagreement. This guided us to recalibrate the model by adjusting the relative importance of several Ca2+ fluxes, thereby improving the consistency with experimental data and producing a more predictive model. Analysis of human cardiomyocyte models suggests that the relative importance of outward currents to Ca2+ transporters is generalizable to human atrial cardiomyocytes, but not ventricular cardiomyocytes. Overall, our novel approach of combining population-based mathematical modeling with experimental tests has yielded new insight into the relative importance of different determinants of cell behavior.

Differential roles of two delayed rectifier potassium currents in regulation of ventricular action potential duration and arrhythmia susceptibility

“…), only a few studies in cardiomyocytes have directly experimentally tested the key predictions of parameter sensitivity analysis (Lee et al . ; Devenyi & Sobie, ). Experimentally testing a large number of predictions using traditional methods, such as pharmacological inhibition, is difficult and labour intensive.…”

“…These techniques have been used to quantify the determinants of a variety of crucial aspects of cardiomyocyte physiology, such as Ca 2+ handling (Lee et al . ; Devenyi & Sobie, ), AP morphology (Tondel et al . ; Mann et al .…”

Logistic regression analysis of populations of electrophysiological models to assess proarrythmic risk

“…Because of the relatively small σ chosen here for simplicity, APs and Ca 2+ transients in our population fall within the normal range of experimental variability (Fig. 2), and sensitivity coefficients converge upon stable values with population sizes as small as 100 variants (not shown, see also [4]). …”

“…Population-based approaches have been widely adopted in the recent years in the field of computational cardiac electrophysiology [1], [2], [3], [4], [5], [6], [7], [8]. The classical analysis performed with a single action potential (AP) model has been extended to the study of the properties emerging in a broad group of models (called “population”).…”

Population-Based Mechanistic Modeling Allows for Quantitative Predictions of Drug Responses across Cell Types

“…Although many alternative mathematical models of animal myocytes 35,36 and human adult ventricular myocytes 37,38 have been published, the Paci et al model 14 remains, at the present time, the only model of the iPSC-CM. The preferred approach to modeling iPSC-CM physiology will certainly be modified as additional data become available, and as iPSC-CMs developed under particular conditions become more completely characterized.…”