Mechanisms of Atrial Arrhythmias: Insights from the Development of a Biophysically Detailed Model of the Human Atria PDF
Preview Mechanisms of Atrial Arrhythmias: Insights from the Development of a Biophysically Detailed Model of the Human Atria
Springer Theses Recognizing Outstanding Ph.D. Research Michael A. Colman Mechanisms of Atrial Arrhythmias Insights from the Development of a Biophysically Detailed Model of the Human Atria Springer Theses Recognizing Outstanding Ph.D. Research For furthervolumes: http://www.springer.com/series/8790 Aims and Scope The series ‘‘Springer Theses’’ brings together a selection of the very best Ph.D. theses from around the world and across the physical sciences. Nominated and endorsed by two recognized specialists, each published volume has been selected for its scientific excellence and the high impact of its contents for the pertinent fieldofresearch.Forgreateraccessibilitytonon-specialists,thepublishedversions includeanextendedintroduction,aswellasaforewordbythestudent’ssupervisor explaining the special relevance of the work for the field. As a whole, the series will provide a valuable resource both for newcomers to the research fields described, and for other scientists seeking detailed background information on specialquestions.Finally,itprovidesanaccrediteddocumentationofthevaluable contributions made by today’s younger generation of scientists. Theses are accepted into the series by invited nomination only and must fulfill all of the following criteria • They must be written in good English. • ThetopicshouldfallwithintheconfinesofChemistry,Physics,EarthSciences, Engineering andrelatedinterdisciplinaryfieldssuchasMaterials, Nanoscience, Chemical Engineering, Complex Systems and Biophysics. • The work reported in the thesis must represent a significant scientific advance. • Ifthethesisincludespreviouslypublishedmaterial,permissiontoreproducethis must be gained from the respective copyright holder. • They must have been examined and passed during the 12 months prior to nomination. • Each thesis should include a foreword by the supervisor outlining the signifi- cance of its content. • The theses should have a clearly defined structure including an introduction accessible to scientists not expert in that particular field. Michael A. Colman Mechanisms of Atrial Arrhythmias Insights from the Development of a Biophysically Detailed Model of the Human Atria Doctoral Thesis accepted by the University of Manchester, UK 123 Author Supervisor Dr. Michael A.Colman Prof.Henggui Zhang School ofPhysicsand Astronomy School ofPhysicsand Astronomy Universityof Manchester Universityof Manchester Manchester Manchester UK UK ISSN 2190-5053 ISSN 2190-5061 (electronic) ISBN 978-3-319-01642-9 ISBN 978-3-319-01643-6 (eBook) DOI 10.1007/978-3-319-01643-6 SpringerChamHeidelbergNewYorkDordrechtLondon LibraryofCongressControlNumber:2013946222 (cid:2)SpringerInternationalPublishingSwitzerland2014 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartof the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionor informationstorageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purposeofbeingenteredandexecutedonacomputersystem,forexclusiveusebythepurchaserofthe work. Duplication of this publication or parts thereof is permitted only under the provisions of theCopyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the CopyrightClearanceCenter.ViolationsareliabletoprosecutionundertherespectiveCopyrightLaw. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publicationdoesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexempt fromtherelevantprotectivelawsandregulationsandthereforefreeforgeneraluse. While the advice and information in this book are believed to be true and accurate at the date of publication,neithertheauthorsnortheeditorsnorthepublishercanacceptanylegalresponsibilityfor anyerrorsoromissionsthatmaybemade.Thepublishermakesnowarranty,expressorimplied,with respecttothematerialcontainedherein. Printedonacid-freepaper SpringerispartofSpringerScience+BusinessMedia(www.springer.com) To my grandfather, Edward Schaffer, who passed away January 2010. His passion for science and life has greatly inspired this work Supervisor’s Foreword Atrial arrhythmias (including atrial flutter and fibrillation) are the most common cardiac diseases affecting millions of people in Europe alone. Atrial arrhythmias occur in many forms, including both rapid (e.g., atrial tachycardia and atrial fibrillation) and slow (e.g., sinus bradycardia) atrial electrical activities. These arrhythmiasmayoccurduetothepresenceofectopicpacingactivityintheatrium, impaired cardiac pacemaking activity or dysfunction of autonomic control. However, the underlying mechanisms by which atrial arrhythmias may develop andsustainareunclearinmanycases.Forthisreason,comprehensivestudyofthe humanatriainhealthyanddiseasedstatescanprovideinvaluableinsightstowards understandings of atrial arrhythmogenesis and therefore leads to better diagnosis and treatment of these potentially life-threatening conditions. Experimental approaches can be limited by the inability to investigate the functional impact of observedelectrophysiologicalormolecularchangesatthewholeorganscale.Itis forthisreasonthatcomputationalmodellingoftheheart,orcardiacmodelling,has become an important tool in the investigation of heart disease. Advances in computational techniques and access to detailed electrophysiological and molec- ular data have driven significant progress in the complexity and usefulness of cardiac models within the last two decades. This has allowed multi-scale inte- grative approaches to be employed, in which single cell models can be incorpo- rated into 3D anatomically accurate models, and thus investigation offunctional effects at these scales and any scale in between may be performed. Theworkdescribed inthisthesisrepresentsasignificant advance inmodelling of the human atria, resulting in a cutting-edge model describing the human atria andtorso.Primarily,theworkinthisthesishasfurtheredourunderstandingofthe mechanisms underlying atrial arrhythmias (specifically, atrial fibrillation, pace- maker site shifts andthe potentially pro-arrhythmic effects of autonomic control). In addition, it also provides insight into the improvement of methods for diag- nosing ectopic activity in the atria and possible treatments of atrial fibrillation. Thedevelopmentofanextendedfamilyofregionalatrialcellmodels,including those of the primary and secondary pacemaker regions, with pathophysiological remodellingand autonomic control included,allowsdetailedinvestigationsof the behaviour of excitation waves in the human atria in many different conditions. Withthesemodels,thisthesisdemonstratesthatautonomiccontrolmaybelinked vii viii Supervisor’sForeword to shifts in the leading pacemaker site, and that these shifts may be detected through analysis of the morphology of the P-wave ECG. The thesis also demon- strates the important role of regional heterogeneity in the development and long- termbehaviourofatrialfibrillation,inbothhealthyanddiseasedstates,aswellas insight into the potential efficacy of targeting I for the treatment of atrial Kur fibrillation. Beyond these advances in understanding (and those not mentioned in this foreword) the model developed in this thesis provides a powerful tool for further investigationofatrialarrhythmias.Thistoolmaybeupdatedforspecificpurposes and also may be incorporated into a whole heart model allowing detailed inves- tigations of cardiac disease at the whole organ scale, as is currently being done withinourgroup.Inparticular,therangeofregionalcellmodelsandthepresence of anatomically accurate pacemaker structures allows for many other detailed investigations to be performed in the human atria, which could not have been performed using previously developed models. Manchester, May 2013 Prof. Henggui Zhang Abstract Atrial arrhythmias are the most prevalent sustained cardiac arrhythmias. Rates of hospitalisation and costs incurred to healthcare organisations are increasing in epidemic proportions. Despite this, the mechanisms of the transition from sinus rhythm to arrhythmic states are not well understood. The high level of regional electrical heterogeneity observed in the atria is thought to contribute towards the high prevalence of atrial arrhythmias. However, current computer models of the intact human atria only account for a small degree of this regional electrical heterogeneity, and do not include descriptions of the pacemaker regions of the sinoatrial node and the atrioventricular node. In this project, a new computational model of the intact 3D human atria is developed.First,anewsinglecellmodeltosimulatetheelectricalactionpotential of the human atrial myocyte is developed. This model more accurately simulated the experimentally observed properties of human atrial action potentials than previous models. A family of electrically heterogeneous models describing the major regions within theatriais thendeveloped,includingthoseofthesinoatrial- and atrioventricular-nodes. This set of regional cell models represents the most expansive and complete set currently available. It is demonstrated that the large range of different electrical properties results in a large range of action potential morphologyanddurationwithintheatria.Modelsoftheeffectofsympatheticand parasympatheticregulationontheelectricalAPofthemodelsoftheatrialworking myocardiumandthepacemakerregionswerealsoincorporated.Thisdemonstrated thatsympatheticregulationcanincreasethepacingrateofthesinoatrialnodeand the atrio-ventricular node, and has a complex dose-dependent effect on the atrial working myocardium. Four distinct models of the effects of atrial fibrillation induced remodelling on the atrial working myocardium are developed. These characterised the effect of remodelling of I on the overall changes in action Kur potential morphology and duration observed. It is shown that the presence or absence of remodelling of this channel accounts for two distinct observed morphologies. Aprevious3Danatomicalmodelofthehumanatriaisimproved.First,detailed anatomical models for the sinoatrial node and the atrioventricular node are ix x Abstract incorporatedintothemodel.Second,itisfurthersegmentedtoincluderegionsfor thepulmonaryveins,atrio-ventricularring,atrialseptumandsinoatrialnodeblock zone. This model is used to investigate the effects of sympathetic and parasym- pathetic regulation in the 3D atria. Finally, a detailed investigation of the under- lying mechanisms of atrial fibrillation in the 3D atria, and the effect of electrical remodelling on the behaviour of atrial fibrillation, is performed using the detailed 3D model. This work represents a significant advance in 3D human atrial modelling. The anatomicalmodelincorporatesagreaterlevelofcomplexitythanpreviousmodels, and for the first time allowed investigation of the pacemaking mechanisms in the 3D intact human atria. The atrial fibrillation protocols are more physiologically relevant than previous models and have elucidated the roles that electrophysio- logical remodelling, electrical heterogeneity and structural anisotropy play in the development and maintenance of atrial fibrillation.
Description:The list of books you might like
