Computational modeling and experimental validation in diverse mouse strains demonstrate that inward Ca2+ and outward K+ currents compensate each other to maintain a normal calcium transient, suggesting a feedback mechanism regulating ionic conductances.
Predicts cardiac conductance variability from Ca2+ transients; leaves open clinical translation of personalized models.
Conductances of ion channels and transporters controlling cardiac excitation may vary in a population of subjects with different cardiac gene expression patterns. However, the amount of variability and its origin are not quantitatively known. We propose a new computational method to predict this variability that consists of finding combinations of conductances generating a normal intracellular Ca 2+ transient without any constraint on the action potential. Furthermore, we validate experimentally its predictions using the Hybrid Mouse Diversity Panel, a model system of genetically diverse mouse strains that allows us to quantify inter-subject versus intra-subject variability. The method predicts that conductances of inward Ca 2+ and outward K + currents compensate each other to generate a normal Ca 2+ transient in good quantitative agreement with current measurements in ventricular myocytes from hearts of different isogenic strains. Our results suggest that a feedback mechanism sensing the aggregate Ca 2+ transient of the heart suffices to regulate ionic conductances.
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Rees et al. (2018) studied this question.
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