Stochastic Simulation Of Excitation-contraction Coupling

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SUMMARY OF WORK We have begun devoting more attention to so-called spontaneous calcium release events, which vary morphologically from single sparks to localized wavelets to global calcium waves. These events have been shown to play a critical "clock" role in controlling rate in pacemaker cells, as well as triggering arhythmias under pathological condition. A simplified two dimensional model of CICR in the sub-membrane space of sino-atrial node cells demonstrated that there is a robust regime of localized wavelets that are created, move randomly and die out, similar to what we have observed using non-confocal 2D intensified imaging experimentally. These events vary in periodicity from random sparks to periodic waves, with gradually increasing periodicity as event size and frequency increase. This variable periodicity is qualitatively accounted for by a theory of "stochastic filtering" in which the interaction of truly random event initiation with the fixed refractory period of release units leads to a random process with inter-event periods clustered near the refractory time. In order to study this process quantitatively, we will need to extend our previous stochastic EC coupling model to 3 dimensions and cell scale. This will require (in addition to extensive redevelopment the software, which is underway) the creation of a full-scale state-of-the-art computational cluster. Planning for the architecture of this cluster is underway.