Excitation contraction coupling (ECC) is of central importance to enable the contraction of the cardiac myocyte via calcium influx. The electrical signal of a neighbouring cell causes the membrane depolarization of the sarcolemma and L-type Ca2+ channels (LCCs) open. The amplification process is initiated. This process is known as calcium-induced calcium release (CICR). The calcium influx through the LCCs activates the ryanodine receptors (RyRs) of the sarcoplasmic reticulum (SR). The Ca2+ release of the SR accumulates calcium in the cytoplasm. For many decades models for these processes were developed. However, previous models have not combined the spatially resolved concentration dynamics of the dyadic cleft including the stochastic simulation of individual calcium channels and the whole cell calcium dynamics with a whole cardiac myocyte electrophysiology model.
In this study, we developed a novel approach to resolve concentration gradients from single channel to whole cell level by using quasistatic approximation and finite element method for integrating partial differential equations. We ran a series of simulations with different RyR Markov chain models, different parameters for the SR components, sodium-calcium exchanger conditions, and included mitochondria to approximate physiological behaviour of a rabbit ventricular cardiac myocyte. The new multi-scale simulation tool which we developed makes use of high performance computing to reveal detailed information about the distribution, regulation, and importance of components involved in ECC. This tool will find application in investigation of heart contraction and heart failure.
|Advisor:||Klipp , Edda , Falcke , Martin , Holzhütter , Hermann-Georg|
|School:||Humboldt Universitaet zu Berlin (Germany)|
|Source:||DAI-C 81/7(E), Dissertation Abstracts International|
|Keywords:||Markov chain, Mitochondria, Sodium-calcium exchanger, Cardiac myocytes, Calcium cycling, Spatially resolved model, finite elements, Sarcoplasmic reticulum|
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