Modelling the Short QT Syndrome Gene Mutations: And Their Role in Cardiac Arrhythmogenesis

228 Pages·2014·7.22 MB·English

by  Ismail Adeniran (auth.)

Springer Theses
Recognizing Outstanding Ph.D. Research
Ismail Adeniran

Modelling the Short
QT Syndrome Gene
Mutations
And Their Role in Cardiac
Arrhythmogenesis
Springer Theses
Recognizing Outstanding Ph.D. Research
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Ismail Adeniran
Modelling the Short QT
Syndrome Gene Mutations
And Their Role in Cardiac Arrhythmogenesis
Doctoral Thesis accepted by
the University of Manchester, UK
123
Author Supervisor
Dr. IsmailAdeniran Prof.Henggui Zhang
Biological PhysicsGroup Biological PhysicsGroup
SchoolofPhysics andAstronomy SchoolofPhysics andAstronomy
Universityof Manchester Universityof Manchester
Manchester Manchester
UK UK
ISSN 2190-5053 ISSN 2190-5061 (electronic)
ISBN 978-3-319-07199-2 ISBN 978-3-319-07200-5 (eBook)
DOI 10.1007/978-3-319-07200-5
Springer ChamHeidelberg New YorkDordrecht London
LibraryofCongressControlNumber:2014940518
(cid:2)SpringerInternationalPublishingSwitzerland2014
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To my mother, for her continued patience
and support and my father, Lateef Ajani
Adeniran, who passed away from heart
disease in 1996
Supervisor’s Foreword
The QT interval of the electrocardiogram (ECG) corresponds to the period from
the initiation of ventricular depolarisation to the completion of ventricular repo-
larisation.Undernormalconditions,theQTintervalisinarangebetween360and
440ms.Toolongortooshort,aQTintervalisassociatedwithanincreasedriskof
abnormal cardiac electrical activity, predisposing to sudden cardiac death.
Recently, a distinct, genetic syndrome involving abnormally short QT intervals
(SQTS)hasbeenidentified.PatientswithSQTStypicallyexhibitQTintervals\320ms
andhavehighincidenceofventricularandatrialarrhythmiasandsuddendeath.
Themechanismsbywhich theSQTSresultsinanincreasedriskofarrhythmia
and sudden death are not yet fully understood. In the absence of phenotypically
accurate experimental models of SQTS variants, computer modelling offers the
only available way of investigating how genetic forms of the SQTS lead to ini-
tiation andmaintenanceofatrial andventricular arrhythmias atthe tissue level. It
provides the best available means of bridging understanding between molecular
and clinical electrophysiology.
In this thesis, Dr. Adeniran presented details of the development of multi-
physicsmodelsofthehumanventriclesaswellassimulationresultsofhowsome
oftheSQTSgeneticvariantsaffectingpotassiumchannelscauseimpairedcardiac
electrical activity, leading to increased susceptibility to cardiac arrhythmias. The
thesis presented an excellent exemplar of systems biology by which a causative
link between molecular mutations and changes to heart functions can be estab-
lished. The presented results provide mechanistic insight into how the SQTS
influences ventricular risk. This is of value in helping optimise treatments for
SQTS patients or those with disorders involving ventricular repolarisation.
The multiscale ventricular models developed and used in this thesis provide a
powerfulfoundationforfurtherinvestigationofthecellularandmolecularbasisof
cardiac functions.
Manchester, April 2014 Prof. Henggui Zhang
vii
Abstract
TherecentlyidentifiedgeneticshortQTsyndromeischaracterisedbyabbreviated
QT intervals on the electrocardiogram, an increased risk of atrial and ventricular
arrhythmias, and an increased risk of sudden death. Although the short QT
syndrome has been suggested to provide a paradigm for increasing understanding
of the role of potassium channels in ventricular fibrillation, the basis for
arrhythmogenesisintheshortQTsyndromeisincompletelyunderstood.Thereare
no animal models that accurately reproduce a short QT phenotype, and whilst
invitroelectrophysiologyofshortQTmutantchannelsprovidesaroutetogreater
understandingoftheeffectsofshortQTmutantsonactionpotentialrepolarisation,
on its own, this approach is insufficient to explain how arrhythmias arise and are
maintained at the tissue level. Consequently, this thesis is concerned with the use
of the viable alternative; in silico (computational) modelling to elucidate how the
short QT syndrome facilitates the genesis and maintenance of ventricular
arrhythmias and its effects on ventricular contraction. Using extant biophysical
data on changes induced by the short QT mutations and data from BHF-funded
in vitro electrophysiology, three novel mathematical models of the first three
variants of the short QT syndrome were developed; a Markov chain model for
shortQTvariant1,aMarkovchainmodelforshortQTvariant2andaHodgkin-
HuxleymodelforshortQTvariant3.Thesemodelswereincorporatedintosingle
cellandanatomicallydetailedtissueandorgancomputermodelstoelucidatehow
these variants lead to ventricular arrhythmias. The developed short QT models
were then incorporated into electromechanically coupled single cell and tissue
models to investigate the effects of the short QT mutants on ventricular
contraction. It was found that each short QT variant uniquely increased the
transmural dispersion of action potential duration across the ventricular wall,
increased the temporal window of tissue vulnerability to premature excitation
stimulus, leading to increased susceptibility to re-entrant arrhythmia.
ix
Acknowledgments
Iwouldliketothankmysupervisors,Prof.HengguiZhangandProf.JulesHancox
for their supervision and support, without which this thesis would not have been
possible. I am grateful for all the time and enthusiasm they have invested in this
project, and the guidance and education they have imparted to me in cardiac
electrophysiology.
Finally, I would also like to thank all the members of the Biological Physics
group at the University of Manchester for providing a stimulating and inspiring
environment.
xi
Contents
1 IntroductiontoIonChannelsandtheCardiacActionPotential. . . 1
1.1 The Cardiac Action Potential. . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Morphology of the Action Potential in Different Parts
of the Heart. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.2.1 Sinoatrial Node . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.2.2 Atria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.2.3 Atrioventricular Node. . . . . . . . . . . . . . . . . . . . . . . 5
1.2.4 His Bundle Purkinje System . . . . . . . . . . . . . . . . . . 5
1.2.5 Ventricle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.3 Ionic Basis of Resting and Action Potential. . . . . . . . . . . . . . 7
1.3.1 The Uniformly Polarised Cell . . . . . . . . . . . . . . . . . 7
1.3.2 Electrical Equivalent Circuit of a Cell. . . . . . . . . . . . 9
1.3.3 Equilibrium Potential . . . . . . . . . . . . . . . . . . . . . . . 9
1.4 Properties of Ion Channels. . . . . . . . . . . . . . . . . . . . . . . . . . 10
1.4.1 Ion Permeation. . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
1.4.2 Gating. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
1.5 Sodium Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
1.6 Calcium Channels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
1.6.1 L-Type Calcium Channel . . . . . . . . . . . . . . . . . . . . 13
1.6.2 T-Type Calcium Channel . . . . . . . . . . . . . . . . . . . . 14
1.7 Potassium Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
1.7.1 Voltage-Dependent K+ Channels . . . . . . . . . . . . . . . 14
1.7.2 Inward Rectifier Potassium Channels . . . . . . . . . . . . 16
1.8 Stretch-Activated Channels . . . . . . . . . . . . . . . . . . . . . . . . . 17
1.9 Cardiac Muscle Contraction. . . . . . . . . . . . . . . . . . . . . . . . . 17
1.9.1 Cardiac Muscle Fibre . . . . . . . . . . . . . . . . . . . . . . . 17
1.9.2 Molecular Mechanism of Contraction. . . . . . . . . . . . 22
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2 Potassium Channels Implicated in the Short QT Syndrome. . . . . 33
2.1 Rectification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
2.2 The hERG/I Potassium Channel . . . . . . . . . . . . . . . . . . . . 34
Kr
2.2.1 hERG/I Potassium Channel Gating . . . . . . . . . . . . 35
Kr
2.2.2 hERG/I Channel Structure . . . . . . . . . . . . . . . . . . 36
Kr
xiii