SPARC: Found in translation: quantitative predictors of cardiac myocyte responses to β‐adrenergic stimulation across species
Authors: Grandi Eleonora , Ni Haibo , Iseppe Alex Fogli , Ghayoumi Bardia , Wang Lianguo , Jiang Yanyan , Chen Yi-Je , Bers Donald M. , Sato Daisuke , Edwards Andrew G. , Ripplinger Crystal M. , Morotti Stefano 
Published: April 2020

Background

Despite strong evidence of the fundamental connection between the brain and the heart, there is still a poor quantitative and functional understanding of the role of autonomic regulation in normal cardiac excitation‐contraction coupling and pathophysiology, including arrhythmias or contractile dysfunction. The intrinsic electrophysiologic differences across various animal models and species upon which our knowledge is based might be a contributing factor to this limited understanding. Indeed, by simulating our multi‐species computational framework for simulation of excitation‐contraction coupling and β‐adrenergic signaling in mouse, rabbit and human ventricular myocytes, we have shown that the well‐conserved fight‐or‐flight response is mediated by different sub‐cellular processes in rodents vs. larger mammals.

Aim

We sought to construct a suite of tools, based on statistical regression, for “translating” findings from animal models into human physiologic responses. To this aim, we also extended our multi‐species framework by developing a new porcine model, informed by ad‐hoc experimental recordings.

Methods & Results

Optical maps of transmembrane potentials and intracellular calcium transients (CaTs) from pig right and left ventricular wedge preparations were utilized for model parameter identification via an optimization algorithm that minimizes the error between simulated and experimental outputs, both with and without β‐adrenergic stimulation. By randomly varying parameters in our baseline multi‐species models, we generated populations of mouse, rabbit, pig and human virtual cells, and then applied multivariable linear regression to the population data to quantify inter‐species differences in the sensitivity of action potential (AP) and CaT properties (at both baseline and upon β‐adrenergic activation) to changes in model parameters. A regression model was used to develop quantitative predictors of human response from different subsets of simulated AP and CaT data (mimicking variable composition of experimental datasets). We found that predictors built upon calibrated AP and CaT signals can well reconstruct human response from mouse, rabbit or pig 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 data from two of the other species.

Conclusion

We developed a robust and predictive framework that is well grounded and validated with a broad experimental data set and that will help to (1) understand inter‐species difference in the response to sympathetic stimulation, and (2) map experimental or simulated data in one species onto another species, most importantly human. We expect our model to provide a powerful tool to study the interaction between β‐adrenergic activation and the functional cardiac substrate and translate these findings across multiple species.

Support or Funding Information

This work is supported by the National Institutes of Health (NIH) Stimulating Peripheral Activity to Relieve Conditions grant OT2OD026580.