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Talk Abstract
Modeling Cardiac Excitation-Contraction Coupling: New Insights into Interval-Force Relations

Saleet Jafri, Johns Hopkins Univ. Sch. of Medicine

We construct a detailed mathematical model for calcium (Ca) regulation in the ventricular myocyte that includes novel descriptions of subcellular mechanisms based on recent experimental findings: 1) the Keizer-Levine model for the sarcoplasmic reticulum (SR) Ca release channel, the ryanodine receptor (RyR), which displays adaptation at elevated Ca as observed by Gyorke and Fill; 2) a model for the L-type Ca channel that inactivates by mode switching, as suggested by Imredy and Yue; and 3) a restricted subspace into which the RyRs and L-type Ca channels empty and interact via Ca. We add membrane currents from the Luo-Rudy Phase II ventricular cell model and isometric force generation from the Rice-Hunter-Winslow model to our description of Ca handling to formulate a new model for ventricular action potentials, Ca regulation and force generation. The model can simulate Ca transients during an action potential similar to those seen experimentally. The subspace [Ca] rises more rapidly and reaches a higher level (10-30 uM) than the bulk myoplasmic Ca (peak [Cai] 1 uM). Termination of SR Ca release is predominately due to emptying of the SR but is influenced by RyR adaptation. We explore the effects of pacing rate on force generation. The model reproduces transitions seen in force generation due to changes in pacing that cannot be simulated by previous models. Simulation of such complex phenomena requires an interplay of both RyR adaptation and the degree of SR Ca loading. This model, therefore, shows improved behavior over existing models that lack detailed descriptions of subcellular Ca regulatory mechanisms.

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