Clark, John W., Jr.2013-07-242013-07-242013-07-242013-07-242012-122013-07-24December 2Krishna, Abhilash. "Multiphysics model of a cardiac myocyte: A voltage-clamp study." (2013) Diss., Rice University. <a href="https://hdl.handle.net/1911/71664">https://hdl.handle.net/1911/71664</a>.https://hdl.handle.net/1911/71664We develop a composite multiphysics model of excitation-contraction coupling for a rat ventricular myocyte under voltage clamp (VC) conditions to: (1) probe mechanisms underlying the response to Ca2+-perturbation; (2) investigate the factors influencing its electromechanical response; and (3) examine its rate-dependent behavior (particularly the force-frequency response (FFR)). Motivation for the study was to pinpoint key control variables influencing calcium-induced calcium-release (CICR) and examine its role in the context of a physiological control system regulating cytosolic Ca2+ concentration and hence the cardiac contractile response. Our cell model consists of an electrical-equivalent model for the cell membrane and a fluid-compartment model describing the flux of ionic species between the extracellular and several intracellular compartments. The model incorporates frequency-dependent calmodulin (CaM) mediated spatially heterogenous interaction of calcineurin (CaN) and Ca2+/calmodulin-dependent protein kinase-II (CaMKII) with their principal targets and accounts for rate-dependent, cyclic adenosine monophosphate (cAMP)-mediated up-regulation. We also incorporate a biophysical model for cardiac contractile mechanics to study the factors influencing force response. The model reproduces measured VC data published by several laboratories, and generates graded Ca2+-release with high Ca2+ gain by achieving negative feedback control and Ca2+-homeostasis. We examine the dependence of cellular contractile response on: (1) the amount of activator Ca2+ available; (2) the type of mechanical load applied; (3) temperature (22 to 38ºC); and (4) myofilament Ca2+ sensitivity. We demonstrate contraction-relaxation coupling over a wide range of physiological perturbations. Our model reproduces positive peak FFR observed in rat ventricular myocytes and provides quantitative insight into the underlying rate-dependence of CICR. The role of Ca2+ regulating mechanisms are examined in handling induced Ca2+-perturbations using a rigorous cellular Ca2+ balance. Extensive testing of the composite model elucidates the importance of various direct and indirect modulatory influences on the cellular twitch-response with wide agreement with measured data on all accounts. We identify cAMP-mediated stimulation, and rate-dependent CaMKII-mediated up-regulation of Ca2+-trigger current (ICaL) as the key mechanisms underlying the aforementioned positive FFR. Our model provides biophysically-based explanations of phenomena associated with CICR and provides mechanistic insights into whole-cell responses to a wide variety of testing approaches used in studies of cardiac myofilament contractility.application/pdfengCopyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.Multiphysics modelExcitation-contraction couplingRatsVentricular myocyteVoltage clampElectromechanicsFFRForce-frequency responseCICRCalcium-induced calcium-releaseMyofilament contractionThesis2013-07-24123456789/ETD-2012-12-272