Multiscale Modeling of Dyadic Structure-Function Relation in Ventricular Cardiac Myocytes.

Cardiovascular disease is often related to defects of subcellular 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 multiscale model to create dyadic structure-function relationships to explore the impact of molecular changes on whole cell electrophysiology and calcium cycling. This multiscale model incorporates stochastic simulation of individual L-type calcium channels and ryanodine receptor channels, 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 sensitively to changes in L-type calcium channel current. The ryanodine receptor channel cluster structure inside dyadic clefts was found to affect all biomarkers investigated. The shape of clusters observed in experiments by Jayasinghe et al. and channel density within the cluster (characterized by mean occupancy) showed the strongest correlation to the effects on biomarkers.

PDE constrained optimization of electrical defibrillation in a 3D ventricular slice geometry.

A computational study of an optimal control approach for cardiac defibrillation in a 3D geometry is presented. The cardiac bioelectric activity at the tissue and bath volumes is modeled by the bidomain model equations. The model includes intramural fiber rotation, axially symmetric around the fiber direction, and anisotropic conductivity coefficients, which are extracted from a histological image. The dynamics of the ionic currents are based on the regularized Mitchell-Schaeffer model. The controls enter in the form of electrodes, which are placed at the boundary of the bath volume with the goal of dampening undesired arrhythmias. The numerical optimization is based on Newton techniques. We demonstrated the parallel architecture environment for the computation of potentials on multidomains and for the higher order optimization techniques.

A multiscale computational model of spatially resolved calcium cycling in cardiac myocytes: from detailed cleft dynamics to the whole cell concentration profiles.

Mathematical modeling of excitation-contraction coupling (ECC) in ventricular cardiac myocytes is a multiscale problem, and it is therefore difficult to develop spatially detailed simulation tools. ECC involves gradients on the length scale of 100 nm in dyadic spaces and concentration profiles along the 100 µm of the whole cell, as well as the sub-millisecond time scale of local concentration changes and the change of lumenal Ca(2+) content within tens of seconds. Our concept for a multiscale mathematical model of Ca(2+) -induced Ca(2+) release (CICR) and whole cardiomyocyte electrophysiology incorporates stochastic simulation of individual LC- and RyR-channels, 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 developed a novel computational approach to resolve the concentration gradients from dyadic space to cell level by using a quasistatic approximation within the dyad and finite element methods for integrating the partial differential equations. We show whole cell Ca(2+)-concentration profiles using three previously published RyR-channel Markov schemes.

On boundary stimulation and optimal boundary control of the bidomain equations.

The bidomain equations with Neumann boundary stimulation and optimal control of these stimuli are investigated. First an analytical framework for boundary control is provided. Then a parallel finite element based algorithm is devised and its efficiency is demonstrated not only for the direct problem but also for the optimal control problem. The computations realize a model configuration corresponding to optimal boundary defibrillation of a reentry phenomenon by applying current density stimuli.