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dc.contributor.advisor Clark, John W., Jr.
dc.creatorKrishna, Abhilash
dc.date.accessioned 2013-07-24T19:33:22Z
dc.date.accessioned 2013-07-24T19:33:26Z
dc.date.available 2013-07-24T19:33:22Z
dc.date.available 2013-07-24T19:33:26Z
dc.date.created 2012-12
dc.date.issued 2013-07-24
dc.date.submitted December 2012
dc.identifier.urihttps://hdl.handle.net/1911/71664
dc.description.abstract We 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.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.subjectMultiphysics model
Excitation-contraction coupling
Rats
Ventricular myocyte
Voltage clamp
Electromechanics
FFR
Force-frequency response
CICR
Calcium-induced calcium-release
Myofilament contraction
dc.title Multiphysics model of a cardiac myocyte: A voltage-clamp study
dc.contributor.committeeMember Cavallaro, Joseph R.
dc.contributor.committeeMember Dick, Andrew J.
dc.date.updated 2013-07-24T19:33:26Z
dc.identifier.slug 123456789/ETD-2012-12-272
dc.type.genre Thesis
dc.type.material Text
thesis.degree.department Electrical and Computer Engineering
thesis.degree.discipline Engineering
thesis.degree.grantor Rice University
thesis.degree.level Doctoral
thesis.degree.name Doctor of Philosophy
dc.identifier.citation Krishna, Abhilash. "Multiphysics model of a cardiac myocyte: A voltage-clamp study." (2013) Diss., Rice University. https://hdl.handle.net/1911/71664.


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