Mechanisms of Atrial Arrhythmias: Insights from the Development of a Biophysically Detailed Model of the Human Atria

267 Pages·2014·8.23 MB·English

by  Michael A. Colman (auth.)

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
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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
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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.