The Ca 2 + transient as a feedback 1 sensor controlling cardiomyocyte 2 ionic conductances in mouse 3 populations

Conductances of ion channels and transporters controlling cardiac excitation may vary 14 in a population of subjects with different cardiac gene expression patterns. However, the amount 15 of variability and its origin are not quantitatively known. We propose a new conceptual approach to 16 predict this variability that consists of finding combinations of conductances generating a normal 17 intracellular Ca2+ transient without any constraint on the action potential. Furthermore, we validate 18 experimentally its predictions using the Hybrid Mouse Diversity Panel, a model system of 19 genetically diverse mouse strains that allows us to quantify inter-subject versus intra-subject 20 variability. The method predicts that conductances of inward Ca2+ and outward K+ currents 21 compensate each other to generate a normal Ca2+ transient in good quantitative agreement with 22 current measurements in ventricular myocytes from hearts of different isogenic strains. Our results 23 suggest that a feedback mechanism sensing the aggregate Ca2+ transient of the heart suffices to 24 regulate ionic conductances. 25