PT  - JOURNAL ARTICLE
AU  - Rees, Colin
AU  - Yang, Jun-Hai
AU  - Santolini, Marc
AU  - Lusis, Aldons J.
AU  - Weiss, James N.
AU  - Karma, Alain
TI  - Variability and compensation of cardiomycoyte ionic conductances at the population level
AID  - 10.1101/283275
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 283275
4099  - http://biorxiv.org/content/early/2018/03/15/283275.short
4100  - http://biorxiv.org/content/early/2018/03/15/283275.full
AB  - 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 Ca2+ 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 Ca2+ and outward K+ currents compensate each other to generate a normal Ca2+ 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 Ca2+ transient of the heart suffices to regulate ionic conductances.