Quantitative Cross-Species Prediction Of Beta-Adrenergic Response In Ventricular Myocytes

Despite the large body of research on neural control of the heart, our quantitative understanding of the role of β-adrenergic receptor (β-AR) stimulation in human cardiac electrophysiology and arrhythmogenesis remains poor. One possible reason is in the fact that our knowledge is mostly based on experimental animal models (e.g., mouse and rabbit) characterized by quite different cellular electrophysiology. Indeed, we have shown that well conserved mammalian responses to β-AR stimulation (fight or flight) are mediated by different sub-cellular processes in mouse vs. rabbit. Here, we aim to quantitatively assess these inter-species differences, and to construct a suite of tools for mapping physiological responses across species. We simulated our mathematical models of excitation-contraction coupling in mouse, rabbit and human ventricular myocytes, integrating detailed formulation of β-AR signaling, to generate populations of models by random parameter variations. Population-level analysis of action potential (AP) and calcium transient (CaT) properties, at both baseline and upon β-AR activation, allowed quantifying inter-species differences in the sensitivity of these features to changes in model parameters. We then utilized statistical regression models to develop quantitative predictors of human response from different subsets of simulated AP and CaT data (mimicking variable composition of experimental datasets). Predictors built upon calibrated AP and CaT signals can well reconstruct human response from mouse or rabbit measurements. However, predictors devoid of calibrated (absolute) measures performed more poorly. In the absence of calibrated data, prediction of human response could be improved by combining both mouse and rabbit data. Further refinement and validation of these quantitative models will provide new tools to understand inter-species difference in the response to sympathetic stimulation and might aid future therapeutic strategies based on neuromodulation.