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J Mol Cell Cardiol. 2016 Jul;96:38-48. doi: 10.1016/j.yjmcc.2015.07.016. Epub 2015 Jul 30.

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

Author information

1
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, New York, NY, USA.
2
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, New York, NY, USA. Electronic address: eric.sobie@mssm.edu.

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 Ca(2+) 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 the transient outward current in rat ventricular epicardial myocytes was predicted to have a greater impact on Ca(2+) transient amplitude than either: (1) inhibition of the same current in endocardial myocytes, or (2) comparable inhibition of the sarco/endoplasmic reticulum Ca(2+) 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 Ca(2+) 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 Ca(2+) 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.

KEYWORDS:

Cardiac Ca(2+) transients; Cardiac myocytes; Cardiac potassium channels; Parameter sensitivity analysis; Sarcoplasmic/endoplasmic-reticulum Ca(2+) ATPase

PMID:
26235057
PMCID:
PMC4733425
DOI:
10.1016/j.yjmcc.2015.07.016
[Indexed for MEDLINE]
Free PMC Article

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