Characterizing parameter sensitivity and uncertainty in dyadic structure-function relationships by using a multiscale model of ventricular cardiac myocytes

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• Wolfgang Giese (Max Delbrück Center for Molecular Medicine )
• Thursday 06 June 2019, 10:00-10:30
• Seminar Room 1, Newton Institute.

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The heart is an electromechanical pump and its functioning is based on the precisely controlled contraction of its cardiac myocytes in a process that is called excitation-contraction-coupling (ECC). The heart rhythm is set by waves of electrical action potentials emanating from the sinoatrial node. Mathematical models of cardiac myocytes are valuable research tools as they express quantitatively the knowledge of the biophysical processes that generate the cardiac action potential.

Cardiovascular disease is often related to defects in molecular and sub-cellular components in cardiac myocytes, specifically in the dyadic cleft. We use a multiscale model to create dyadic structure-function relationships in order to explore the impact of molecular changes on whole cell electrophysiology. This multiscale model incorporates stochastic simulation of individual L-type calcium channels (LCC) and ryanodine receptor (RyRs), spatially detailed concentration dynamics in dyadic clefts, rabbit membrane potential dynamics, and a system of partial differential equations for myoplasmic and lumenal free Ca(2+) and Ca(2+)-binding molecules in the bulk of the cell.

We created a population of models with changes of crucial dyadic cleft properties, such as RyR and LCC clustering properties, stochastic opening and closing rates as well as changes in LCC   and RyR calcium currents. We investigated commonly used biomarkers describing action potential, Ca(2+) transient and Ca(2+) spark dynamics. By using surrogate models we are able to quantify sensitivity and parameter uncertainty in order to derive functional implications from molecular level properties.

This talk is part of the Isaac Newton Institute Seminar Series series.

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