Multi-scale modeling of dyadic structure-function relation in ventricular cardiac myocytes

Abstract Cardiovascular disease is often related to defects of sub-cellular components in cardiac myocytes, specifically in the dyadic cleft, which include changes in cleft geometry and channel placement. Modeling of these pathological changes requires both spatially resolved cleft as well as whole cell level descriptions. We use a multi-scale model to create dyadic structure-function relationships in order to explore the impact of molecular changes on whole cell electrophysiology and calcium cycling. This multi-scale model incorporates stochastic simulation of individual L-type calcium channels (LCC) and ryanodine receptor channels (RyRs), spatially detailed concentration dynamics in dyadic clefts, rabbit membrane potential dynamics, and a system of partial differential equations for myoplasmic and lumenal free Ca2+ and Ca2+-binding molecules in the bulk of the cell. We found action potential duration, systolic and diastolic [Ca2+] to respond most sensitive to changes in LCC current. The RyR cluster structure inside dyadic clefts was found to affect all biomarkers investigated. The shape of clusters observed in experiments by Jayasinghe et al. (1) and channel density within the cluster (characterised by mean occupancy) showed the strongest correlation to the effects on biomarkers. SIGNIFICANCE Diseases such as myocardial infarction, aortic stenosis, tachycardia, hypertension, chronic ischemia and atrial fibrillation have been related to changes inside the dyadic cleft (2, 3), which is a sub-volume of cardiac myocytes of about 10-17 l (typical cell volume 10-11 l). However, exploration of the relation between sub-dyadic structures and disease is difficult since such microscopic structures in cells are in many cases not amenable to experimental manipulation or experiments addressing them might not allow for simultaneous observation of cellular responses. Multi-scale mathematical models can explore the relation between microscopic structures and cellular response. We show by mathematical modelling that the geometric properties of RyR clusters within dyadic clefts affect cellular responses.