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Abstract
Cardiac electrophysiology is a field with a rich history of integrative modeling. A particularly important milestone was the development of the first biophysically-based cell model describing interactions between voltage-gated membrane currents, pumps and exchangers, and intracellular calcium Ca2+ cycling processes in the cardiac Purkinje fiber (DiFrancesco & Noble, Phil. Trans. Roy. Soc. Lond. B 307: 353) and the subsequent elaboration of this model to describe the cardiac ventricular myocyte action potential (Noble et al. Ann. N. Y. Acad. Sci. 639: 334; Luo, C-H and Rudy, Y. Circ. Res. 74: 1071). This talk will review the “state-of-the-art”‚ in integrative modeling of the cardiac myocyte, focusing on modeling of the ventricular myocyte because of its significance to arrhythmia and heart disease. Special emphasis will be placed on the importance of modeling mechanisms of Ca2+-Induced Ca2+-Release (CICR). CICR is the process by which influx of trigger calcium (Ca2+) through L-Type Ca2+ channels (LCCs) leads to opening of ryanodine sensitive Ca2+ release channels (RyRs) in the junctional sarcoplasmic reticulum (JSR) membrane and release of Ca2+ from the JSR. It is of fundamental importance in cardiac muscle function, as it not only underlies the process of muscle contraction, but is also involved in regulation of the cardiac action potential. We will demonstrate that every model of CICR in use today has serious shortcomings, and we will offer insights as to how these shortcomings must be addressed in order to develop reconstructive and predictive models that can be used to investigate myocyte function in both health and disease. (Supported by NIH HL60133, the NIH Specialized Center of Research on Sudden Cardiac Death P50 HL52307, the Whitaker Foundation, the Falk Medical Trust, and IBM Corp)