Simulation of the Undiseased Human Cardiac Ventricular Action Potential Model Formulation and Experimental Validation 英文参考文献.docVIP

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Simulation of the Undiseased Human Cardiac Ventricular Action Potential Model Formulation and Experimental Validation 英文参考文献.doc

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Simulation of the Undiseased Human Cardiac Ventricular Action Potential Model Formulation and Experimental Validation 英文参考文献

SimulationoftheUndiseasedHumanCardiacVentricular ActionPotential:ModelFormulationandExperimental Validation ThomasO’Hara1,La′szlo′ Vira′g2,Andra′sVarro′2,3,YoramRudy1* 1CardiacBioelectricityandArrhythmiaCenter,DepartmentofBiomedicalEngineering,WashingtonUniversityinSt.Louis,St.Louis,Missouri,UnitedStatesofAmerica, 2Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary, 3Division of Cardiovascular Pharmacology, Hungarian Academy of Sciences,Szeged,Hungary Abstract Cellularelectrophysiologyexperiments,importantforunderstandingcardiacarrhythmiamechanisms,areusuallyperformed withchannelsexpressedinnonmyocytes,orwithnon-humanmyocytes.Differencesbetweencelltypesandspeciesaffect results.Thus,anaccuratemodelfortheundiseasedhumanventricularactionpotential(AP)whichreproducesabroadrange ofphysiologicalbehaviorsisneeded.Suchamodelrequiresextensiveexperimentaldata,butessentialelementshavebeen versus 2+ unavailable.Here,wedevelopahumanventricularAPmodelusingnewundiseasedhumanventriculardata:Ca voltagedependentinactivationofL-typeCa current(ICaL);kineticsforthetransientoutward,rapiddelayedrectifier(IKr), 2+ + 2+ Na /Ca exchange (INaCa), and inward rectifier currents; AP recordings at all physiological cycle lengths; and rate dependenceandrestitutionofAPduration(APD)withandwithoutavarietyofspecificchannelblockers.SimulatedAPs reproducedtheexperimentalAPmorphology,APDratedependence,andrestitution.UsingundiseasedhumanmRNAand 2+ proteindata,modelsfordifferenttransmuralcelltypesweredeveloped.ExperimentsforratedependenceofCa (including + peakanddecay)andintracellularsodium([Na ]i)inundiseased humanmyocyteswerequantitatively reproduced bythe model.EarlyafterdepolarizationswereinducedbyIKrblockduringslowpacing,andAPandCa alternansappearedatrates .200bpm,asobservedinthenonfailinghumanventricle.Ca /calmodulin-dependentproteinkinaseII(CaMK)modulated ratedependenceofCa cycling.INaCa linkedCa alternationtoAPalternans.CaMKsuppression