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OULU 2013
UNIV ER S IT Y OF OULU P. O. B R[ 00 FI-90014 UNIVERSITY OF OULU FINLAND
U N I V E R S I TAT I S
S E R I E S
SCIENTIAE RERUM NATURALIUM
Professor Esa Hohtola
HUMANIORA
University Lecturer Santeri Palviainen
TECHNICA
Postdoctoral research fellow Sanna Taskila
MEDICA
Professor Olli Vuolteenaho
ACTA
EARLY REPOLARIZATION
IN THE INFEROLATERAL
LEADS OF THE ELECTROCARDIOGRAM
PREVALENCE, PROGNOSIS AND CHARACTERISTICS
SCIENTIAE RERUM SOCIALIUM
University Lecturer Hannu Heikkinen
SCRIPTA ACADEMICA
Director Sinikka Eskelinen
OECONOMICA
Professor Jari Juga
EDITOR IN CHIEF
Professor Olli Vuolteenaho
PUBLICATIONS EDITOR
Publications Editor Kirsti Nurkkala
ISBN 978-952-62-0230-3 (Paperback)
ISBN 978-952-62-0231-0 (PDF)
ISSN 0355-3221 (Print)
ISSN 1796-2234 (Online)
U N I V E R S I T AT I S O U L U E N S I S
Jani Tikkanen
E D I T O R S
Jani Tikkanen
A
B
C
D
E
F
G
O U L U E N S I S
ACTA
A C TA
D 1212
UNIVERSITY OF OULU GRADUATE SCHOOL;
UNIVERSITY OF OULU,
FACULTY OF MEDICINE,
INSTITUTE OF CLINICAL MEDICINE,
DEPARTMENT OF INTERNAL MEDICINE;
OULU UNIVERSITY HOSPITAL
D
MEDICA
ACTA UNIVERSITATIS OULUENSIS
D Medica 1212
JANI TIKKANEN
EARLY REPOLARIZATION IN
THE INFEROLATERAL LEADS OF
THE ELECTROCARDIOGRAM
Prevalence, prognosis and characteristics
Academic dissertation to be presented with the assent
of the Doctoral Training Committee of Health and
Biosciences of the University of Oulu for public defence
in Auditorium 10 of Oulu University Hospital, on 19
October 2013, at 12 noon
U N I VE R S I T Y O F O U L U , O U L U 2 0 1 3
Copyright © 2013
Acta Univ. Oul. D 1212, 2013
Supervised by
Professor Heikki Huikuri
Docent Juhani Junttila
Docent Olli Anttonen
Reviewed by
Docent Vesa Virtanen
Docent Antti Ylitalo
Opponent
Doctor Sami Viskin
ISBN 978-952-62-0230-3 (Paperback)
ISBN 978-952-62-0231-0 (PDF)
ISSN 0355-3221 (Printed)
ISSN 1796-2234 (Online)
Cover Design
Raimo Ahonen
JUVENES PRINT
TAMPERE 2013
Tikkanen, Jani, Early repolarization in the inferolateral leads of the electrocardiogram : Prevalence, prognosis and characteristics
University of Oulu Graduate School; University of Oulu, Faculty of Medicine, Institute of
Clinical Medicine, Department of Internal Medicine; Oulu University Hospital
Acta Univ. Oul. D 1212, 2013
University of Oulu, P.O. Box 8000, FI-90014 University of Oulu, Finland
Abstract
“Early repolarization” (ER), consisting of J waves and ST-segment elevation in the standard 12lead electrocardiogram (ECG), has been considered a benign finding for over 60 years until 2008
an over-presentation of ER ECG pattern in infero-lateral leads was described in patients with
idiopathic ventricular fibrillation. The purpose of this thesis was to assess the prevalence and
prognostic significance, and to characterize the clinical features of this ECG pattern primarily in
the general population.
This thesis investigated the electrocardiographic features of a total of 20,308 general
population individuals, 565 athletes, 432 victims of sudden cardiac death and 532 survivors of an
acute coronary event. The overall prevalence of infero-lateral ER ECG pattern in the general
population samples was in range between 3.3 and 6.1 percent. ER seemed to have a heritable basis
as siblings of individuals displaying the ER pattern had significantly increased odds for presenting
this ECG pattern. Several strong associations between ER pattern and clinical factors were
observed in all populations. The ER patterns with horizontal or descending ST-segments were
associated with significantly increased arrhythmic mortality during a follow-up of 30±11 years,
and high amplitude (>0.2mV) J waves in the inferior leads were associated with a high risk of
arrhythmic death (multivariate adjusted hazard ratio 3.13 (95% confidence interval 1.55 to 6.32).
The ER ECG pattern was also independently associated with sudden cardiac death during an acute
coronary event, with an odds ratio of 2.02 (95% CI 1.04 to 3.61) for suffering sudden death. The
ER patterns with rapidly ascending ST-segments, the dominant type of ER ECG in young, healthy
individuals, were not associated with any adverse outcomes. A multicentre meta-analysis of
genome wide association study of ER ECG pattern performed in a total of 14,633 individuals
pointed to an associated locus in KCND3 (Kv4.3) gene, which encodes a subunit of the Ito
channel, but the association did not reach genome-wide significance and could not be replicated
in all study populations.
In conclusion, the results of these studies demonstrated that the ER ECG pattern with
horizontal or descending ST-segments, especially in the inferior leads, is associated with an
increased risk of sudden arrhythmic death in the general population, and that individuals carrying
this ECG pattern are at increased risk of suffering fatal arrhythmia during an acute coronary event.
The ER pattern with rapidly ascending ST-segments is common in young healthy athletes and is
not associated with any increased risk of fatal events. Although the ER ECG pattern increases the
relative risk of arrhythmic events, the absolute risk in an individual is low and therefore this ECG
pattern should not be interpreted as a high-risk marker of mortality. The genetic background of
this ECG pattern remains to be clarified.
Keywords: arrhythmia, early repolarization, electrocardiography, mortality, sudden
cardiac death
Tikkanen, Jani, Varhainen repolarisaatio sydänfilmissä.
Oulun yliopiston tutkijakoulu; Oulun yliopisto, Lääketieteellinen tiedekunta, Kliinisen
lääketieteen laitos, Sisätaudit; Oulun yliopistollinen sairaala
Acta Univ. Oul. D 1212, 2013
Oulun yliopisto, PL 8000, 90014 Oulun yliopisto
Tiivistelmä
Normaalissa 12-kytkentäisessä sydänfilmissä (EKG) J-aalloista ja ST-segmentin noususta koostuvaa varhaista repolarisaatiota (ER) pidettiin yli 60 vuotta hyvänlaatuisena muutoksena, kunnes vuonna 2008 ER esiintyminen alaseinä-lateraalikytkennöissä liitettiin idiopaattiseen kammiovärinään. Tämän väitöstutkimuksen tarkoitus oli selvittää EKG-muutoksen esiintyvyys ja
ennustearvo normaaliväestössä, sekä selvittää sen kliinisiä erityispiirteitä.
Väitöstutkimusta varten tutkittiin 20,308 normaaliväestön henkilöä, 565 urheilijaa, 432 äkillisesti (sydänperäisesti) menehtynyttä henkilöä ja 532 akuutista sepelvaltimotautikohtauksesta
selviytynyttä potilasta. ER-EKG:n kokonaisesiintyvyys alaseinä-lateraalikytkennöissä normaaliväestön otoksissa vaihteli 3.3 % ja 6.1 % välillä. ER-EKG:n esiintyessä merkittävästi muita useammin sisaruksilla ER-EKG vaikutti periytyvältä muutokselta, ja lisäksi kaikissa otoksissa EREKG liittyi useisiin muihin tunnettuihin kliinisiin muuttujiin. ER-EKG, ts. J-aallot, joita seurasivat horisontaalinen tai laskeva ST-segmentti, liittyivät merkittävästi lisääntyneeseen rytmihäiriökuolleisuuteen pitkän seuranta-ajan (30±11 vuotta) aikana, ja korkea-amplitudiset (>0.2mV) Jaallot alaseinäkytkennöissä liittyivät korkeaan riskiin kuolla äkillisesti rytmihäiriöön (monimuuttuja-vakioitu riskisuhde 3.13, 95 % luottamusväli 1.55–6.32). ER-EKG lisäsi lisäksi itsenäisesti sydänperäisen äkkikuoleman riskiä akuutin sepelvaltimotautikohtauksen aikana (vetosuhde 2.02, 95 % luottamusväli 1.04–3.61). Etenkin nuorilla ja terveillä urheilijoilla esiintynyt
EKG tyyppi, J-aallot ST-segmentin nousujen yhteydessä, ei liittynyt huonoon ennusteeseen.
Monikeskusmeta-analyysi perimänlaajuisista assosiaatiotutkimuksista (GWAS) 14,633 henkilöllä antoi viitteitä geenimuutoksesta KCND3, joka koodittaa osaa Ito kanavasta, mutta löydöstä ei
kyetty toistamaan kaikissa tutkituissa aineistoissa.
Väitöstutkimuksen osatöiden perusteella ER-EKG muutos ilman ST-segmentin nousua, erityisesti alaseinäkytkennöissä esiintyessään, liittyy normaaliväestössä lisääntyneeseen riskiin
sydänperäiselle rytmihäiriökuolemalle, ja että henkilöillä, joilla muutos esiintyy, on lisääntynyt
riski menehtyä äkillisesti sepelvaltimotautikohtauksen aikana. ER-EKG ST-segmentin nousuihin liittyen on yleinen löydös nuorilla terveillä urheilijoilla ja se ei näytä liittyvän lisääntyneeseen riskiin rytmihöiriöille. Vaikka ER-EKG lisääkin suhteellista riskiä rytmihäiriöille ja ennenaikaiselle kuolemalle väestötasolla, absoluuttinen riski on pieni, eikä muutosta tulisi luokitella
suureksi riskitekijäksi. Löydöksen geneettinen tausta on vielä avoin kysymys.
Asiasanat: EKG, kuolleisuus, rytmihäiriö, sydänperäinen äkkikuolema, varhainen
repolarisaatio
To my family
8
Acknowledgements
This thesis was carried out in the Department of Internal Medicine, University of
Oulu, Finland during the years 2008-2012. In part, the studies were carried out in the
following collaborative institutions: National Institute for Health and Welfare,
Helsinki, Finland; Broad Institute of Harvard and MIT, Cambridge, Massachusetts,
USA; Massachusetts General Hospital, Boston, Massachusetts USA.
My deepest and most sincere thanks go to my supervisor and mentor Professor
Heikki Huikuri, whose outstanding clinical knowledge and vision in cardiac
electrophysiology and sudden cardiac death research are internationally highly
recognized. Heikki has delivered an exceptionally inspiring athmosphere for his
research group, and without his optimism and innovativeness but also criticism
throughout this project, the outcome of this thesis could not have been as good as it
was. Even as a novise medical student I always felt as a member of a larger family,
and never had any issues in expressing my ideas and questions. I was privileged to
have a supervisor who was actively engaged in this work and gave me excellent
support throughout the project.
I am also very grateful to my co-supervisors and dear colleagues Docent Juhani
Junttila and Docent Olli Anttonen, whose never-ending enthusiasm and optimism
towards our research projects encouraged me to pursue even higher and more
descriptive results, not to ignore all their support and understanding of personal life in
general. I’m very thankful for my friendship with Juhani and his family.
I want to thank all the members of my follow-up group, Professor Timo
Mäkikallio, Docent Juha Perkiömäki and Mirja Peltola. Particularly I’d like to thank
Timo for his warm personal appearance and his guidance in both science and life in
general.
I want to express my warmest thanks to all my co-authors, who all cannot be
listed here, but who certainly all are acknowledged. I’ve been privilidged to have such
wonderful people to work with. Special thanks go to Tuomas Kenttä for both all his
help in technology but also friendship outside work. I’d also like to thank Harri
Rissanen for never rejecting my continuous suggestions for new statistical analyses
and for his supportive thoughts on the results. I owe my thanks also to Aapo Aro for
his input in data gathering and our fluent collaboration. I warmly thank Kimmo
Porthan not only for his efforts towards this thesis but also for our friendship and
fluent cooperation throughout the past few years. I also wish to acknowledge my debt
to my colleagues in Boston, especially Peter Noseworthy and Christopher NewtonCheh, for their expertise and sincerity. I also highly acknowledge and appreciate the
9
input of Antti Reunanen and Veikko Salomaa from Institute of Health and Welfare in
gathering and organizing our unique population cohorts.
I appreciate and thank the official pre-examiners of this dissertation, Antti Ylitalo
and Vesa Kivinen, for detailed commentary and constructive criticism.
I greatly acknowledge the financial support of this thesis provided by the Finnish
Foundation for Cardiovascular Research, the Finnish Medical Foundation, the Aarne
Koskelo Foundation, the Emil Aaltonen Foundation, the Finnish Culural Foundation,
the Paavo Nurmi Foundation, the Orion-Farmos Foundation, the Ida Montin
Foundation, the Aarne and Aili Turunen Foundation, and the Maud Kuistila Memorial
Foundation. Without these grants, the research work this magnitude and all the
congresses around the globe would never have been possible.
I wish to thank all my colleagues and also friends outside medicine for all the
great memorable moments and support.
I also want to express my gratitude to my family in law for all the support during
the past few years. They've always had the patience to listen to the latest turns in my
work and encouraged to keep on going, not to mention all their essential help in
everyday life.
I wish to express my deepest appreciation to my parents Pertti and Mirja, and my
sister Tiia, for their enormous care and support throughout my life. My dad, a nuclear
physicist and scientist himself, and my mom, a teacher of natural science, have
always been exceptional role models for me, and with my sister we’ve experienced a
lot of happiness in our childhood. You all have provided me with a solid foundation
with your trust and unconditional love. I owe you everything I've ever achieved in my
life.
Above all, my warmest thoughts and gratitude go to my lovely wife Johanna and
our wonderful sons Väinö and Veikko. I know I've spent too much time struggling
with scientific work or practising medicine during late hours. Johanna, you have taken
care of our children and home so incredibly well, and words cannot describe how
grateful I am for your patience and all the emotional support. I would be nothing
without you. I love you.
Oulu, May 2013
10
Jani Tikkanen
Abbrevations
ARVD
BMI
BrS
CAD
CVD
CI
CPVT
ECG
ER
ERP
ERS
EU
fQRS
GWA(S)
HR
ICD
IVF
LBBB
LQTS
LVEF
N/A
QRSd
QTc
OR
RBBB
RR
SAECG
SCD
SNP(s)
SQTS
STEMI
VF
arrhythmogenic right ventricular dysplasia
body mass index
Brugada syndrome
coronary artery disease
cardiovascular disease
confidence interval
catecholaminergic polymorphic ventricular tachycardia
electrocardiogra/m, -hic –phy
early repolarization
early repolarization ECG pattern
early repolarization syndrome
European Union
fragmented QRS complex
genome wide association (stud/y, -ies)
hazard ratio
implatable cardioverter defibrillator
idiopathic ventricular fibrillation
left bundle branch block
long QT syndrome
left ventricular ejection fraction
not applicable
Nonspecific QRS complex prolongation
QT interval corrected for heart rate
odds ratio
right bundle branch block
relative risk
signal averaged electrocardiogram
sudden cardiac death
single nucleotide polymorphism(s)
short QT syndrome
ST-elevation myocardial infarction
ventricular fibrillation
11
12
List of original articles
This thesis is based on the following original articles, which are referred to in the
text by their Roman numerals.
I
Tikkanen JT, Anttonen O, Junttila MJ, Aro AL, Kerola T, Rissanen HA, Reunanen A
& Huikuri HV (2009) Long-term outcome associated with early repolarization on
electrocardiography. N Engl J Med 361: 2529–2537
II Noseworthy PA*, Tikkanen JT*, Porthan K*, Oikarinen L, Pietilä A, Harald K,
Peloso GM, Merchant FM, Jula A, Väänänen H, Hwang SJ, O’Donnel CJ, Salomaa V,
Newton-Cheh C & Huikuri HV (2011) The early repolarization pattern in the general
population: clinical correlates and heritability. J Am Coll Cardiol 57: 2284–2289
III Tikkanen JT, Junttila MJ, Anttonen O, Aro AL, Luttinen S, Kerola T, Sager SJ,
Rissanen HA, Myerburg RJ, Reunanen A & Huikuri HV (2011) Early repolarization:
electrocardiographic phenotypes associated with favorable long-term outcome.
Circulation 123: 2666–2673
IV Tikkanen JT, Wichmann V, Junttila MJ, Rainio M, Hookana E, Lappi O, Kortelainen
ML, Anttonen O & Huikuri HV (2012) Association of early repolarization and sudden
cardiac death during an acute coronary event. Circ Arrh Electrophysiol 5: 714–718.
V Sinner MF*, Porthan K*, Noseworthy PA*, Havulinna AS*, Tikkanen JT*, MüllerNurasyid M, Peloso G, Ulivi S, Beckmann BM, Brockhaus AC, Cooper RR, Gasparini
P, Hengstenberg C, Hwang SJ, Iorio A, Junttila MJ, Klopp N, Kähönen M, Laaksonen
MA, Lehtimäki T, Lichtner P, Lyytikäinen LP, Martens E, Meisinger C, Meitinger T,
Merchant FM, Nieminen MS, Peters A, Pietilä A, Perz S, Oikarinen L, Raitakari O,
Reinhard W, Silander K, Thorand B, Wichmann HE, Sinagra G, Viikari J, O'Donnell
CJ, Ellinor PT, Huikuri HV, Kääb S, Newton-Cheh C & Salomaa V (2012) A metaanalysis of genome-wide association studies of the electrocardiographic early
repolarization pattern. Heart Rhythm 9: 1627–1634.
*Equal authorship
13
14
Contents
Acknowledgements
9
Abbrevations
11
List of original articles
13
Contents
15
1 Introduction
19
2 Review of the literature
21
2.1 Basic electrophysiology and electrocardiography................................... 21
2.1.1 Cardiac action potential ................................................................ 21
2.1.2 Normal electric cycle in the ECG ................................................. 22
2.1.3 Cellular basis of electrocardiographic J waves ............................. 23
2.1.4 Electrocardiography as an evaluation tool.................................... 27
2.2 Cardiovascular morbidity and mortality ................................................. 27
2.2.1 Sudden unexplained death in the community ............................... 28
2.3 Cardiomyopathies ................................................................................... 31
2.3.1 Hypertrophic cardiomyopathy ...................................................... 31
2.3.2 Dilated cardiomyopathy ............................................................... 32
2.3.3 Arrhythmogenic right ventricular dysplasia ................................. 32
2.3.4 Myocardial fibrosis....................................................................... 33
2.4 Channelopathies ...................................................................................... 34
2.4.1 Long QT syndrome....................................................................... 35
2.4.2 Short QT syndrome ...................................................................... 36
2.4.3 Catecholaminergic polymorphic ventricular tachycardia ............. 37
2.5 J wave associated syndromes .................................................................. 37
2.5.1 Brugada syndrome – anterior J waves .......................................... 37
2.5.2 Early repolarization – inferolateral J waves ................................. 42
2.6 QRS complex abnormalities ................................................................... 48
2.6.1 Prolonged QRS duration and bundle branch blocks ..................... 48
2.6.2 Peri-infarction block ..................................................................... 49
2.6.3 Fragmented QRS complex ........................................................... 49
2.7 Summary of the literature........................................................................ 50
3 Aims of the study
53
4 Study populations
55
4.1 Study population A .................................................................................. 55
4.2 Study populations B and C ...................................................................... 55
4.3 Study population D ................................................................................. 56
15
4.4 Study population E .................................................................................. 57
5 Study methods
59
5.1 Study I. Prevalence and long-term prognosis of early
repolarization pattern in general population ............................................ 59
5.2 Study II. Clinical features and heritability of early repolarization
pattern in the general population ............................................................. 60
5.3 Study III. Long-term prognosis of various early repolarization
patterns and the significance of ST-segment in general
population................................................................................................ 61
5.4 Study IV. The significance of early repolarization pattern in acute
coronary events ....................................................................................... 62
5.5 Study V. Identification of common genetic variants influencing
early repolarization pattern...................................................................... 62
5.6 Statistical analysis ................................................................................... 63
6 Results
65
6.1 Prevalence and prognostic significance of early repolarization
pattern in a large Finnish general population with a long followup (I) ........................................................................................................ 65
6.2 The clinical correlates and heritability assessment of early
repolarization pattern in general population (II) ..................................... 70
6.3 The long-term significance of ER ECG pattern subtypes and STsegment morphology (III) ....................................................................... 75
6.4 Significance of early repolarization pattern during acute coronary
events (IV)............................................................................................... 81
6.5 Meta-analysis of genome wide association studies of early
repolarization pattern (V) ........................................................................ 84
7 Discussion
87
7.1 Key findings ............................................................................................ 87
7.2 Prevalence of early repolarization patterns (I-IV) ................................... 88
7.3 Demographic features, clinical correlates and heritability of early
repolarization pattern (I-III) .................................................................... 90
7.4 Prognosis of early repolarization pattern and the significance of
ST-segment morphology (I, III) .............................................................. 92
7.5 Significance of early repolarization pattern during acute coronary
events (IV)............................................................................................... 94
7.6 Genetics of early repolarization pattern (V) ............................................ 95
16
7.7 Early repolarization – overall evidence ................................................... 97
7.7.1 The overall evidence of ERP among general population in
the literature.................................................................................. 97
7.7.2 Analogies with QT syndromes ..................................................... 99
7.7.3 Association with Brugada syndrome ............................................ 99
7.7.4 Early repolarization or delayed depolarization? ......................... 100
7.7.5 Markers of higher risk of adverse events.................................... 102
7.8 Screening for early repolarization and patient management ................. 107
7.9 Remaining questions and future directions ........................................... 108
8 Strengths and limitations of the thesis
109
9 Conclusions and clinical implications
113
References
115
Original publications
143
17
18
1
Introduction
Sudden cardiac death (SCD) is a major cause of mortality in Western societies. It
mainly comprises of coronary artery disease and its complications, followed by
other cardiomyopathies (Huikuri et al. 2001, Josephson & Wellens 2004, Rubart
& Zipes 2005). However, in up to 20% of SCDs, there are no structural
abnormalities evident (Puranik et al. 2005). In those situations, the underlying
cause is often an electrical disorder, such as Brugada syndrome or long-and-shortQT syndromes. When no specific etiology is known, a term idiopathic ventricular
fibrillation is usually used. All of these cardiac states leading to unexpected death
are a major issue in affected families, the general community and medical
professionals.
The standard 12-lead electrocardiogram (ECG), invented over 100 years ago
by Willem Einthoven (Moukabary 2007), has been an important assistant in
gathering diagnostic and prognostic evidence of electrophysiological disorders of
the heart. Even in the current era of molecular biology and genetics, ECG is, if
not the most important, at least a significant tool in recognizing the arrhythmia
syndromes. Its ease of usage has lead to its spread to all medical professionals and
thus it has had a major impact on health care.
In the absence of a conduction defect or chest pain, ST-segment elevation
often accompanied by J waves, an ECG variant called early repolarization (ER),
has been considered a normal state for over 60 years, ever since its first
description in 1936 (Myers & Klein 1947a, Shipley & Hallaran 1936). After some
case-reports pointing to the arrhythmogenic potential of early repolarization, a
series of case-control studies in 2008 unexpectedly described an apparent overpresentation of J waves in patients with idiopathic ventricular fibrillation (IVF)
(Haissaguerre et al. 2008, Nam et al. 2008, Rosso et al. 2008). These findings
challenged physicians to think again about the belief that this pattern was simply
a normal variant, leading to some confusion among both professionals and
patients. Therefore a thorough investigation of this phenomenon was urgently
warranted.
Since early repolarization is known to affect a large section of the population,
the focus of this thesis was to assess the prevalence and prognostic significance,
and to characterize the clinical features of this ECG pattern primarily in the
general population.
19
20
2
Review of the literature
2.1
Basic electrophysiology and electrocardiography
The report of the first human electrocardiogram was published in 1887 (Waller
1887), and subsequently it has been used in examination of the heart. The father
of the modern ECG is William Einthoven, whose terminology is still being used
and whose original research remains fundamental in understanding the ECG.
Even though the ECG itself is an ancient entity, it still is a routine part of the
patient’s examination. The equipment is widely available, very cost effective and
non-invasive, and thus ECG represents an excellent tool in clinical practice. The
interpretation of changes in surface ECG can be used in diagnosing otherwise
unsuspected cardiac conditions and is indicated in all patients who are being
evaluated for suspected ventricular arrhythmias (European Heart Rhythm
Association et al. 2006). Knowledge of how to evaluate the standard 12-lead ECG
should be familiar to every physician.
2.1.1 Cardiac action potential
The action potential of a cardiac myocyte is of interest of electrophysiologists
since it not only makes possible the muscle contractions, but also has the potential
to induce cardiac arrhythmias. The action potential is a complex event generated
by the transient flow of potassium, sodium, and calcium ions across the cell
membrane thourgh various ion channels, pumps and exchangers.
The cardiac action potential consists of five phases. Phase 0 is the rapid
depolarization, phase 1 the early rapid repolarization, phase 2 is the plateau or
dome, phase 3 is the final rapid repolarization, and phase 4 is the resting
membrane potential. Once the cell has been electrically stimulated, phases from 4
to 0 are generated by the influx or efflux of ions as a consequence of a sequence
of events. The consecutive activation of adjacent cells is the basis of cardiac
depolarization and repolarization. The ventricular myocite action potential with
the currents involved is presented in Figure 1.
In the resting state, interior voltage of the cardiac cell is more negative than
exterior. The inward sodium and the L-type calcium are the main depolarizing
currents. These currents trigger the rapid up-stroke of the action potential, making
the membrane potential more positive, with calcium being also involved in the
21
plateau phase. There are several ionic currents involved in the repolarization
phase, but the two mainly responsible are the rapid and slow components of the
delayed rectifier potassium currents. The repolarizing currents restore the cell’s
resting membrane potential by gradually reducing the potential and making it
more negative.
Fig. 1. Cardiac myocite action potential.
The properties and distribution of the ion channels can differ in various cardiac
tissues, they are regulated by several genes and they can be modulated by several
exogenous factors, such as drugs and electrolyte imbalances.
2.1.2 Normal electric cycle in the ECG
On the basis of biophysical principles, every deflection in the ECG represents a
coincident voltage gradient generated by cellular electrical activity. The normal
surface ECG is the result of temporal changes in the depolarization and
repolarization processes; Action potentials between two random regions of the
heart are similar in duration and the small variations in timing of local
22
depolarization and repolarization produce the electrocardiographic patterns of the
QRS complex and the T-wave. The QRS complex reflects the rapid depolarization
of the cardiac ventricles, whereas the T-wave describes ventricular repolarization.
Often also J and U waves are claimed to represent ventricular repolarization. The
origin of J waves will be discussed in depth in the next chapter. The ST-segment
between the QRS complex and T-wave represents the time period, in which all
cells in the ventricles are normally depolarized. The leads of an ECG collate the
electrical activity from different anatomical areas, for examplethey are important
in the recognition of regional ischemia. Usually four lead categories are used:
inferior, lateral, anterior and septal leads. Often septal and anterior leads are
merged into one category. The inferior lead category includes leads II, III and
aVF of the ECG; the lateral category includes leads I, aVL, and precordial leads
V(3-)4 through V6; and the anterior category includes precordial leads V1 through
V3(-4).
2.1.3 Cellular basis of electrocardiographic J waves
The J-point is the point at which the QRS complex finishes and the ST-segment
starts, i.e. the onset of the ST-segment. J waves are deflections in the terminal
portion of the QRS complex or immediately following it. They are usually
described as an elevation of the J-point (normally isoelectric), appearing as a late
delta wave following the QRS complex, or as a secondary R wave. Several
investigators described prominent J waves during hypothermia in the early 1940s,
but over the years, the hypothermic J wave has generally came to be named after
Joseph Osborn, who examined the physiological effects of hypothermia and
defined the typical electrocardiographic associations in 1953 (Osborn 1953). This
ECG deflection has also been called late delta wave, J-point wave, and epsilon
wave. The typical electrocardiographic patterns and their variations are illustrated
in Figure 2.
Three distinct cell types have been demonstrated to be present in the
ventricular myocardium; endocardial, epicardial and mid-myocardial (M) cells.
The morphology of phase 1 in the action potential in the epicardial and M cells
differs from that in the endocardial cells, due to the presence of prominent
transient outward current (Ito). Differences in the electrophysiological properties
within these cells, leading to transmural differences in the early phases of the
action potential, are the basis for the various deflections, such as presentation of J
waves, in the ECG. Ventricular epicardial and M cell action potentials, unlike
23
endocardial action potentials, display a prominent phase 1 due to the large Ito
current, giving rise to the spike-and-dome configuration of the action potential.
Furthermore, the distribution of Ito and thus also the degree of the action potential
notch differ regionally, especially between right and left ventricles; the highest
density of Ito is present in the right ventricle. The presence of a prominent Ito
mediated action potential notch in ventricular epicardium but not in endocardium,
produces a transmural voltage gradient, and this is believed to lead to the
manifestation of a J wave in the ECG. This transmural voltage gradient is
established as the ventricular activation moves from endocardium to epicardium,
with the epicardium becoming activated last. Increases in repolarizing currents (Ito)
or decreases in depolarizing currents (INa, ICa) accelerate repolarization and
accentuate the action potential notch, thus leading to augmentation of the J wave
or the appearance of ST-segment elevation. A further increase in net repolarizing
current can lead to a partial or even complete loss of the action potential dome,
which increases transmural voltage gradient and this evokes an even greater
accentuation of J waves and ST-elevation. (Antzelevitch et al. 1991, Hlaing et al.
2005, Yan & Antzelevitch 1996a)
In clinical situations, the appearance of prominent J waves is typically
associated with hypothermia or hypercalcemia. (Hlaing et al. 2005, Krantz &
Lowery 2005, Sridharan & Horan 1984) The augmentation of J waves during
hypothermia may be the result of slowing of the kinetics of activation of Ito, as
well as the slowing of conduction, leading to an epicardial notch manifesting
itself as a distinct deflection in the ECG. Prominent J waves can also be observed
during other metabolic alterations, such as acidosis or hypokalemia, and they can
be found in several other clinical conditions and even during normal states, as
described later. Under all of these conditions, an outward shift in the currents
active in phase 1 can lead to augmentation of the action potential notch and thus
unmask or augment the J wave. Furthermore, similarities between early phase
ischemia and J waves in terms of ECG appearance have been reported in
laboratory models. Myocardial ischemia is known to reduce inward currents and
to increase the outward potassium currents particularly by intensifying Ito
especially in the epicardium, thus possibly unmasking J waves (Yan &
Antzelevitch 1999).
In classical early repolarization, with concave upward ST-segment elevations,
a large voltage gradient is present between two regions and the current flow
towards the region still at plateau phase creates a positive ST-segment elevation
24
in the electrocardiographic leads, reflecting the electrical activity in that particular
region. Simply put, the heterogeneity in repolarization evokes a current flow from
the normal myocardium towards the area with a shorter action potential. These
two regions could be two different cardiac regions or different cardiac layers with
regional or transmural voltage gradients. To create J waves with only mild or no
ST-elevation, the voltage gradient needs to be present early in the repolarization
phase, but not later in the action potential, which would create an ST-elevation.
Figure 1 illustrates a theoretical mechanism for the origin of a J wave in which
the two regions are epi- and endocardium within the same electrophysiological
area.
Fig. 2. Theoretical origin of a J wave
25
Fig. 3. Possible consequences of a prominent Ito mediated action potential notch in
epicardium but not endocardium
If one is trying to distinguish a J wave from altered ventricular activation,
manifested as various terminal QRS changes, the heart rate can deliver useful
diagnostics. In a normal ventricular activation from endocardium to epicardium,
acceleration in the heart rate reduces Ito due to its slow recovery from inactivation,
thus resulting in a decrease in the J wave amplitude (Yan et al. 2003). In contrast,
during a variety of alterations of normal activation and conduction, the increase in
heart rate tends to amplify the magnitude of the terminal QRS changes. Similarly
drugs that block sodium channel and inhibit Ito, such as quinidine, reduce the J
wave amplitude, but they have no effect on the conduction abnormalities. Mainly
as a sequence of the known slow recovery of Ito, factors that influence Ito kinetics
or ventricular activation sequence can modify the presence of J waves in an ECG.
The regional control of repolarization is poorly understood and thus also the
basis of regional J waves, i.e. inferior and lateral manifestations, remains also
unknown.
Arrhythmogenic potential of J waves
There are several theories pointing to an arrhythmogenic potential of J waves. If
larger Ito currents underlie J waves than any further outward shift of the currents
during the early phase of the action potential can lead to a loss of the epicardial
action potential dome, and then to a dispersion of repolarization between the
region where the dome is lost and regions at which the plateau phase and action
potential duration are at least relatively maintained. An all-or-none repolarization
due to accelerated Ito could cause a marked shortening of action potential at some
sites but not others, which could initiate arrhythmogenesis, either by initiating
26
extrasystoles (by phase 2 re-entry) or via boundary currents analogous to the
injury currents observed in acute myocardial ischemia. Re-entry is the
propagation of an electrical impulse around two interconnected pathways. The
phase 2 re-entrant beat is capable of initiating polymorphic VT or VF via R-on-T
extrasystoles. (Gussak & Antzelevitch 2000, Yan & Antzelevitch 1996b, Yan &
Antzelevitch 1999)
Hypothermia-related giant J waves without ST segment elevation reflect an
increased dispersion of repolarization, eventually leading to spontaneous
ventricular fibrillation (Fish & Antzelevitch 2004). Hypokalemia has also been
reported to increase the amplitude of J waves and lead to multiple episodes of
ventricular fibrillation (Myojo et al. 2012).
2.1.4 Electrocardiography as an evaluation tool
Over the years, ECG has been used in the diagnostics and risk assessment in the
community, in patients with different heart conditions as well as in competitive
athletes. Resting and exercise ECGs are now widely used for risk stratification as
a supplement to the conventional risk factors. It is believed that the information
gathered from an ECG would lead to better risk-reduction therapies in
asymptomatic patients without any apparent heart disease (O'Malley & Redberg
2010).
2.2
Cardiovascular morbidity and mortality
Cardiovascular diseases (CVDs) are the main cause of death in Europe and other
Western societies. Although the death rates from CVD have declined, CVD still
accounts for 12% to 25% of potential years of life lost due to premature deaths.
The main forms of CVD are coronary artery disease (CAD) and stroke, these
account for 40% of all deaths in the European Union (EU). Coronary artery
disease itself is the single most common cause of death also before the age of 65
in the EU. In addition to being the largest contributor to mortality in Europe,
CVD and CAD are responsible for significant morbidity. The annual rates of
discharges for CAD in Europe are around 600 /100,000. CVD is estimated to cost
the EU economy almost 200 billion euros a year in health care costs, productivity
losses and costs attributable to the informal care of patients with CVD. (European
Cardiovascular Disease Statistics, 2012 edition) There is no doubt about the
magnitude of the problem.
27
The main risk factors for CVD and CAD are smoking, raised cholesterol
levels and blood pressure, and thus control of these conventional risk factors
remains essential in the prevention of the disease and its complications. One of
the most feared consequences of coronary artery disease is sudden cardiac death
(SCD), which is unfortunately also often the first and only manifestation of the
disease. Furthermore, most of these deaths occur in the general population, in
individuals who have been considered to be at a low risk for such an event
(Huikuri et al. 2001, Myerburg 2002). SCD accounts for about 50% of all CAD
related deaths and up to 20% of all deaths, and thus represents an enormous
public health problem. Today, one of the major challenges faced in current
cardiology is to predict who will die suddenly from ventricular arrhythmias and a
large amount of effort is being put into solving this problem.
2.2.1 Sudden unexplained death in the community
To begin with, it is important to distinguish sudden cardiac death from acute
myocardial infarction (AMI) or heart attack. SCD is the manifestation of a fatal
heart rhythm disorder such as ventricular tachycardia, fibrillation or severe
bradycardia, leading to hemodynamic collapse, whereas myocardial infarction
evolves due to an occlusion of a coronary artery leading to an insufficient blood
supply to the myocardium. Acute myocardial infarction might lead to SCD, but
these conditions are not to be considered as uniform events, as SCD can occur
also in the absence of myocardial ischemia. (Zipes & Wellens 1998) The
European Society of Cardiology has proposed the following definition for sudden
cardiac death: death from an unexpected circulatory arrest, usually due to a
cardiac arrhythmia occurring within an hour of the onset of acute symptoms
(European Heart Rhythm Association et al. 2006). Prior cardiac disease may have
been known to be present, but the time and mode of death is unexpected (Priori
et al. 2001).
In Europe and North America, the incidence of sudden cardiac death ranges
from 50 to 100 /100 000/year among general population (Byrne et al. 2008,
Chugh et al. 2004, de Vreede-Swagemakers et al. 1997, Vaillancourt et al. 2004).
In a recent report from Finland, the annual incidence of SCD was 57 /100 000
(Hookana et al. 2011a). In younger populations, the incidence of SCD is lower,
approximately 1-2 /100,000/year (Papadakis et al. 2009). The tradgedy is that in
two thirds of all SCDs in adulthood, the death occurs among previously
28
asymptomatic victims, i.e. it is the first clinical manifestation of the disease or
unexpectedly in individuals in whom the disease had been diagnosed, but who
had been assessed to be at low risk (Huikuri et al. 2001, Myerburg 2001,
Myerburg & Vetter 2007, Wellens et al. 1995). The proportion of death in
asymptomatic individuals is even greater among adolescents and young adults.
Mechanisms of sudden cardiac death
Cardiac arrhythmias represent a major risk factor for cardiac arrest and sudden
death. The accurate identification of the electrophysiological mechanisms
responsible for SCD is difficult, since the pathophysiology is complex and the
underlying mechanisms are likely to be multifactorial. The rhythm most often
recorded at the time of cardiac arrest is ventricular fibrillation, which is believed
to account for approximately three quarters of SCDs, followed by
bradyarrhythmias and electromechanical dissociation (Bayes de Luna et al. 1989,
Luu et al. 1989).
It is still unclear, how a previously asymptomatic, apparently healthy
individual suddenly develops SCD at a certain time. It is believed, that several
dynamic factors interact with a fixed substrate to stimulate arrhythmias,
ultimately leading to hemodynamic collapse. The factors possibly modulating
cardiac conduction have been postulated to include transient ischemia,
inflammation, pharmacologic effects, electrolyte changes and other systemic
metabolic alterations perhaps involving several other dynamic, often transient
events. Of these, the most common factor triggering fatal arrhythmias is severe
myocardial ischemia, which accounts for about 80% of all cases.
Genetics of SCD
SCD is believed to have a strong genetic background. However, coronary artery
disease, the premier contributor to SCD, is known to develop as a result of
complex interactions between genetics, lifestyle habits and the environment.
A familial component to SCD have been demonstrated in several independent
studies (Dekker et al. 2006, Jouven et al. 1999, Kaikkonen et al. 2006), and a
history of sudden deaths within the family can be found in up to 30% of victims
of SCD (Behr et al. 2003, Behr et al. 2008). Therefore the presence of a family
history of unexplained seizures and early sudden death should be systematically
obtained. Nowadays genetic testing is performed more often to confirm the
29
diagnosis in a patient with clinical manifestations of a certain condition. However,
it should be noted that although genetic and heritable factors are evident in
several inherited syndromes, family members with the same genetic mutation
might present with different clinical signs and symptoms ranging from being
completely asymptomatic to suffering sudden death. In other words, the
phenotype does not always match the genotype, i.e. the penetrance of the
syndrome is usually incomplete. A large number of the arrhythmia syndromes,
some of which will be described later in this literature review, are influenced by
not only genetic, but also individual and environmental factors (Priori 2004).
Nevertheless genotyping is increasingly useful in risk stratification as the cost
effectiveness and sequencing technologies are developing. The ultimate goal is to
be able to provide gene-specific therapies.
The genome-wide association (GWA) study is a method of genetic
epidemiology in which many common genetic variants in different individuals are
examined to identify associations between single-nucleotide polymorphisms
(SNPs) and traits such sas SCD. After the first published GWA study in 2005, the
numbers of GWA studies have skyrocketed. GWA studies have the ability to
identify genetic variants with effects on the investigated disease, but they require
large sample sizes in order to reach statistically significant associations. Recently,
a large-scale GWA meta-analysis identified a locus associated with SCD
susceptibility in individuals of European ancestry (Arking et al. 2011). However,
much work is still required to define the functional basis for the observed
associations before any medical interventions can be developed with clinical
significance.
Idiopathic ventricular fibrillation
Idiopathic ventricular fibrillation is a disorder especially affecting young adults,
which presents as syncope or cardiac arrest due to polymorphic ventricular
tachycardia (Belhassen & Viskin 1993, Viskin & Belhassen 1990). The term
idiopathic refers to the absence of any identifiable etiology and therefore
idiopathic VF is a diagnosis made after the exclusion of other known etiologies.
There is no demonstrable structural heart disease or identifiable channelopathy to
account for the arrhythmias. In some contexts, this condition is also referred to as
sudden unexplained death syndrome or sudden arrhythmic death syndrome.
30
A typical patient with idiopathic VF is aged 20 to 40 years, tends to develop
arrhythmic storms unrelated to stress with numerous episodes of ventricular
fibrillation and fails to respond to conventional antiarrhythmic therapy
(Haissaguerre et al. 2008, Haissaguerre et al. 2009b, Martini et al. 1989). In fact,
the initial report hinting at the malignancy of early repolarization and also the
impotus for this thesis, was the observation that one out of three patients with
idiopathic VF had exhibited early repolarization in the inferolateral leads
(Haissaguerre et al. 2008).
2.3
Cardiomyopathies
Cardiomyopathies cause heart failure, ventricular arrhythmias and sudden cardiac
death because of structural changes in the myocardium. They are defined as
disorders in which the myocardium is structurally and functionally abnormal in
the absence of CAD, valvular disease or congenital heart disease (Elliott et al.
2008a). Cardiomyopathies are the most common cause of death in non-ischemic
SCDs, which account for approximately 20% of all sudden cardiac deaths
(Hookana et al. 2011b, Huikuri et al. 2001).
2.3.1 Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) involves myocardial hypertrophy in the
absence of any obvious hemodynamic load that could cause extensive
hypertrophy (Elliott et al. 2008b, Maron & Maron 2012, Richardson et al. 1996).
It is a rare cause of sudden death among middle-aged adults, but in young adults,
particularly in competitive athletes, it is a common cause of SCD (Huikuri et al.
2001, Maron et al. 1998). The prevalence of HCM is estimated to be 0.2%. In
Finnish children, the prevalence has been reported to be 0.03% (Arola et al.
1997). The annual incidence of SCD is <1%, although the prognosis varies widely
from asymptomatic to high risk of SCD (Adabag et al. 2005, Elliott et al. 2006,
Maron et al. 2000).
The electrocardiographic features of HCM primarily reflect voltage patterns
associated with left ventricular hypertrophy and they are often difficult to
distinguish from the secondary hypertrophy seen in other heart illnesses
(Fananapazir et al. 1989, Savage et al. 1978). Typically, there is evidence of left
atrial and ventricular enlargement and marked strain patterns characterized by
prominent ST-T wave changes in the absence of hypertension. However, in a
31
recent study the pre-participation screening ECG was normal in 10% of patients
with hypertrophic cardiomyopathy (Rowin et al. 2012). In the obstructive form
of HCM with asymmetrical septal hypertrophy, prominent inferior Q waves
and/or tall R waves in V1 may be present. In apical HCM, there is a possibility
for the absence of increased voltages, but prominent T wave inversions in the
antero-lateral leads are usually present. Similar ECG changes have been observed
among young healthy male athletes, with so-called athlete’s hearts, but in that
situation usually repolarization changes are less prominent and there are no atrial
enlargement patterns (Corrado et al. 2010).
2.3.2 Dilated cardiomyopathy
Dilated cardiomyopathy (DCM) is a condition in which the left or both ventricles
dilate leading to dysfunction of the heart and the symptoms of heart failure. The
prevalence of DCM is estimated to be under 0.04% (Dec & Fuster 1994, Manolio
et al. 1992). Ventricular arrhythmias are common in the advanced stage of DCM
(Cleland et al. 2002), but in rare cases, SCD can be the first manifestation of the
disease (Adabag et al. 2010). The median survival of patients with DCM has
been reported to be 2 years, and half of the deaths occur suddenly and
unexpectedly (Fuster et al. 1981, Johnson & Palacios 1982a, Johnson & Palacios
1982b).
The electrocardiographic features of DCM are non-specific, but concomitant
with the structural changes related to the condition (atrial enlargement and
ventricular dilatation with thin walls due to loss of myocardium). ST-T wave
abnormalities particularly in the lateral leads and abnormal intraventricular
conduction are common. A rare ECG combination of left bundle branch block and
right axis deviation has been reported to be suggestive for dilated or congestive
cardiomyopathy (Nikolic & Marriott 1985). The presence of symptoms of heart
failure and ultimately echocardiography can distinguish these changes from other
cardiac illnesses.
2.3.3 Arrhythmogenic right ventricular dysplasia
Arrhythmogenic right ventricular dysplasia or cardiomyopathy (ARVD or ARVC)
is an inherited heart disease, which involves cardiomyocyte death and
replacement of the myocardium with fibro-fatty tissue in the right ventricle.
32
(Corrado et al. 1997, Dalal et al. 2005, Marcus et al. 1982) In advanced cases also
the left ventricle might be affected, causing dilated cardiomyopathy. This disorder
is a common cause of SCD in young athletes (Thiene et al. 1988). The fibro-fatty
replacement has been proposed to lead to delayed conduction and abnormal
depolarization in the affected areas, predisposing to re-entry-mediated ventricular
tachycardia. The most common presenting symptoms are palpitations, syncope
and death (Dalal et al. 2005, Fontaine et al. 1999, Marcus & Fontaine 1995). The
prevalence of ARVD is unknown, but has been estimated to be 0.02% (Cox et al.
2009, McKenna et al. 1994, Norman & McKenna 1999). However, the condition
is likely to be under-diagnosed due to the challenging diagnosis. The clinical
presentation varies from an asymptomatic state to SCD. ARVD is a progressive
condition and therefore the risk of SCD might change over time. The annual
incidence of mortality has been estimated to be 1% to 3%, depending on the
treatment provided (Corrado et al. 2000).
The golden standard for diagnosis is the demonstration of the fibro-fatty
infiltration, which can only be observed during cardiac surgery or autopsy, but
fortunately ECG changes are present in up to 90% of patients (Dalal et al. 2005,
McKenna et al. 1994). The most recent major electrocardiographic diagnostic
criteria for ARVD have included epsilon waves, QRS >110 ms, inverted T-waves
in precordial leads V1-V3, and left bundle branch block morphology VT with
superior axis (Jain et al. 2009, Marcus et al. 2010). Minor ECG criteria are Twave inversions in 2-3 consecutive precordial leads, LBBB morphology VT
without superior axis, terminal activation delay, and right bundle branch block
pattern with T-wave inversions in precordial leads. T-wave inversions in left
precordial leads are considered as characteristic although non-specific for ARVD,
but are still mostly ignored in clinical situations. The prevalence of these T-wave
changes has been estimated to be between 1% and 3% (Marcus 2005). In a recent
Finnish study, the prevalence of T-wave inversions in the right precordial leads
was 0.5% among middle-aged general population subjects (Aro et al. 2012). In
this large sample, T-wave changes in V1-V3 did not predict any increased
mortality or sudden death.
2.3.4 Myocardial fibrosis
Usually the formation of fibrosis in the myocardium is triggered by tissue stresses
such as myocardial ischemia, inflammation or hypertensive overload. Infrequent
cases of SCD as the first manifestation of underlying disease have been associated
33
with idiopathic myocardial fibrosis, the presence of fibrosis in the absence of
other cardiac diseases. Recently, fibrotic cardiomyopathy, especially in victims
under 40 years, was associated with non-ischemic SCD in a large Finnish
population (Hookana et al. 2011b). Earlier myocardial fibrosis had been
identified in only 1% to 3% of cases among autopsy series of victims of sudden
cardiac death (Chugh et al. 2000a, Drory et al. 1991, Priori 1997). This condition
involves transmural, interstitial fibrosis and other structural abnormalities, which
can cause electrical heterogeneity and that are recognized as determinants of
ventricular arrhythmogenesis (John et al. 2004).
The electrocardiographic features of the condition are thought to include T
wave inversions throughout the precordial leads, although fibrosis could cause a
wide range of non-specific ECG changes as a result to modification in impulse
conduction. Thus far there is no reliable data available of the variety of ECG
changes present in a fibrotic heart. In the future, improvements in imaging
techniques and biomarkers will probably allow more precise recognition of the
condition.
2.4
Channelopathies
A significant portion of unexplained sudden cardiac deaths are caused by a
spectrum of different arrhythmia syndromes with a structurally normal heart and
no other identifiable aetiology leading to sudden death. These conditions are rare,
but often serious. These so called sudden arrhythmic death syndromes or
channelopathies have been estimated to account for approximately 5% of SCDs
(Chugh et al. 2000b). Most cases occur in young men, who die during sleep or at
rest, usually without any prior cardiac symptoms such as syncope. Although the
absolute number of unexpected SCD among previously healthy persons in the
community is small, the presence of this kind of risk is disstressing and every
death causes unnecessary sorrow within the families of the victims.
The so-called channelopathies are caused by mutations in genes leading to
electrical instability of the heart, and thus predisposing the individual to
malignant arrhythmias. The heterogeneous group of channelopathies include short
and long QT syndromes, Brugada syndrome and catecholaminergic polymorphic
ventricular tachycardia (CPVT). These cardiac abnormalities are believed to have
a structurally normal heart, a genetic basis, and they are known to predispose to
life-threatening arrhythmias.
34
2.4.1 Long QT syndrome
The long QT syndrome (LQTS) is an inherited syndrome characterized by
prolongation of the heart rate corrected QT interval in a standard
electrocardiogram with vulnerability for ventricular tachyarrhythmias potentially
leading to sudden cardiac death (Moss et al. 1991). The QT interval might also
be prolonged due to so-called acquired factors, such as drugs that modify cardiac
repolarization. Both forms, congenital and acquired QT prolongation, have the
potential to develop ventricular arrhythmias (Algra et al. 1991, Chugh et al. 2009,
Moss et al. 1991, Straus et al. 2006). A total of twelve genes have been identified
as being involved in inherited LQTS, but three subtypes account for the vast
majority of cases (Hedley et al. 2009). It is noteworthy that nearly a quarter of
affected patients may not have any identifiable gene mutations (Lehnart et al.
2007, Tester et al. 2006).
The prevalence of long QT syndrome has been estimated to be 4/10,000
(Schwartz et al. 2009), but the disorder remains underdiagnosed as some of the
LQTS gene carriers have a normal QTc duration. Recently, a very high risk of
adverse events was observed in patients with the LQTS gene carries although
presenting with normal resting ECGs (Goldenberg et al. 2011). There is a
considerable overlap between patients with LQTS associated mutations and
individuals in the general population with otherwise prolonged QT interval, as the
prevalence of prolonged QTc has been reported to be as high as 11% (Schwartz
et al. 2009, Straus et al. 2006). Idiopathic abnormal prolongation of the QTc has
been associated with a five-fold risk of SCD among patients with CAD (Chugh et
al. 2009). In the general population, the mortality risk has been reported to be
moderate when QTc is less than 500ms (Priori et al. 2003, Priori et al. 2004).
The electrocardiographic features include QT interval prolongation and
morphological T-wave abnormalities. Heart rate correction is required in order to
obtain reliable values, and Bazett’s formula is the most commonly used correction
method. Leads II and V5 are usually recommended for interval measurements
(Schwartz et al. 1993). The current limits for prolonged QTc (heart rate corrected
QT interval) are 440 or 450 ms for men and 460 ms for women (Rautaharju et al.
2009a), but clinically significant prolongation might be greater. Several
suggestive ECG patterns have been correlated to different genotypes (Schwartz et
al. 2001), but they are not in general clinical usage.
35
2.4.2 Short QT syndrome
The short QT syndrome (SQTS) is a rare arrhythmogenic repolarization
abnormality characterized by a very short QT interval. The possible clinical
consequences related to the condition include atrial fibrillation, syncope, cardiac
arrest and sudden cardiac death. (Gaita et al. 2003a, Gussak et al. 2000, Gussak
& Bjerregaard 2005, Viskin et al. 2004) Similarly to the situation of prolongation,
the QT interval may be shortened due to either congenital or acquired causes
(Maury et al. 2008). SQTS is also genetically similarly heterogeneous as LQTS.
Thus far, five mutations have been identified in SQTS (Antzelevitch et al. 2007a,
Bellocq et al. 2004, Brugada et al. 2004, Priori et al. 2005).
The electrocardiographic features are a QT interval significantly below the
lower limit of normal, and tall and sharp T waves (Gaita et al. 2003b). The lower
limit of normal corrected QT interval in the general population is believed to be
340-360ms according to Gaussian normal distributions of QTc. In SQTS, the
QTC is <320ms, but the exact cutoff values for QTc in SQTS are still a matter of
debate. Currently, diagnostic scores for inherited SQTS include the QTc <370330ms and J-point to T-peak interval <120ms, clinical symptoms, family history
and genotype (Gollob et al. 2011).
A short QT interval in standard resting ECGs in the general population is not
uniformly associated with fatal cardiac events. The prevalence of a short QT
interval (<340 ms) was 0.4% in a Finnish general population sample, and none of
those individuals had died during a very long follow-up of nearly 40 years
(Anttonen et al. 2007). There is a report of a prevalence of 1% in another
European sample with a similar QTc cutoff value (Kobza et al. 2009).
Furthermore, the presence of a short QTc was rare and it was not associated with
any increased risk of SCD in Italian and Japanese populations (Funada et al.
2008, Gallagher et al. 2006, Moriya et al. 2007).
Recently it has been demonstrated that nearly two thirds of SQTS subjects
also present J waves in the inferolateral leads (Miyamoto et al. 2012, Watanabe
et al. 2010), which is consistent with prior case reports (Efremidis et al. 2009). J
waves may also increase the likelihood of arrhythmic events in those with SQTS,
but further studies are required.
36
2.4.3 Catecholaminergic polymorphic ventricular tachycardia
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of the
most malign forms of ventricular arrhythmia in the absence of structural
abnormalities of the heart. It manifests often during early childhood, adolescence,
or young adulthood causing syncope during exercise. Sudden death is commonly
the first manifestation of this disease. (Leenhardt et al. 1995) CPVT causes
symptoms in up to 80% of patients under the age of 40 carrying the condition
which means that the cumulative mortality may be as high as 40% (Sumitomo et
al. 2003).
CPVT is not recognizable in the resting ECG, since it does not display any
typical ECG abnormalities. Polymorphic ventricular extrasystoles are typical
findings during exercise, but syncope during exercise or during sympathetic
activation are the keys to identifying this disease.
2.5
J wave associated syndromes
The cellular basis and arrhythmogenic potential of J waves were presented
previously in this literature review. It is known that the magnitude and location of
J waves can vary and influence the prognostic significance. In this chapter, the
basics of Brugada syndrome and early repolarization, both in which J waves are
present, are briefly described. Due to their similarity in ECG characteristics,
clinical outcomes and shared arrhythmic platform, it has been proposed that
Brugada syndrome and early repolarization syndrome should be collectively
referred to as “J wave syndromes” as a continuous spectrum of phenotypic
expression (Anzelevitch & Yan 2010).
2.5.1 Brugada syndrome – anterior J waves
Historical background
The Brugada syndrome (BrS) is an inherited arrhythmic disorder predisposing to
sudden cardiac death. It was first described in 1992 as a new clinical entity of
right bundle branch block, ST-segment elevation followed by a negative T-wave
and susceptibility to SCD in patients without any obvious structural heart disease
(Brugada & Brugada 1992). Thereafter the syndrome has been defined in a series
of independent studies, and today it is recognized as an important cause of SCD
37
in young men, especially in Southeast Asians. (Antzelevitch et al. 2005a,
Nademanee et al. 1997).
Fig. 4. Theoretical examples of Brugada ECG types in leads V1 to V3.
Electrocardiographic characteristics and diagnostics
The diagnosis of Brugada syndrome can be made by recognizing its distinct ECG
pattern from baseline or drug induced ECG. The electrocardiographic features of
Brugada syndrome include ST-elevation in right precordial leads in combination
with an atypical right bundle branch block pattern and T-wave abnormalities
(Brugada & Brugada 1992). The diagnosis of Brugada syndrome is definite if
there is a positive family history, arrhythmia related symptoms or if documented
arrhythmias are observed in a patient presenting with type I ECG pattern, as
explained below.
Three types of Brugada ECG patterns can be recognized, of which the type 1
is required for the diagnosis of Brugada syndrome. This is described as a coved
ST-elevation over 2 mm 40ms after the J-point followed by a negative T-wave in
at least two right precordial leads at baseline or after drug challenge (class I
antiarrhythmic drugs) (Antzelevitch et al. 2005b, Wilde et al. 2002). Types 2 and
3 are considered as suggestive, but not diagnostic for Brugada syndrome in the
absence of documented arrhythmias, unexplained syncope or druginduced/spontaneous conversion to a typical type 1 pattern. The type 2 ECG
38
pattern differs from type 1 since it exhibits upright T waves in right precordial
leads, and the type 3 pattern otherwise resembles type 2, but there is only minimal
ST-segment elevation. The three different Brugada ECG types are presented in
Figure 3. An interesting article was recently published with results suggesting that
patients carrying the type 1 Brugada pattern in only one precordial lead presented
with similar clinical profile and had a similar arrhythmic risk as those with the
diagnostic two positive precordial leads, and therefore a revision of the concensus
criteria of Brugada syndrome has been proposed (Richter et al. 2010).
Furthermore, one notable observation is the fluctuation between normal ECG and
different types of Brugada ECG patterns, which is common in patients with
Brugada syndrome (Tatsumi et al. 2006, Veltmann et al. 2006). Thus, it is
important to acknowledge that all of the mentioned three Brugada patterns may
coexist in the same patient at different times, and that the patterns might
sometimes be completely absent and present only during some transient
circumstance. Similar to the situation with the QT-prolongation in LQTS,
pharmacological agents can also provoke the typical Brugada ECG pattern, and
therefore drug challenge with class I antiarrhythmics (flecainide, ajmaline,
procainamide, etc.) is sometimes required to unmask the characteristical ECG
changes.
Epidemiology and prognosis
The prevalence of Brugada type 1 ECG pattern among the general population in
European region ranges from 0% to 0.2% (Gallagher et al. 2008, Hermida et al.
2000, Junttila et al. 2004, Sinner et al. 2009), but in individuals of SoutheastAsian origin, it is more common (Matsuo et al. 2001, Miyasaka et al. 2001). The
syndrome predominates in males (approximately 80% of patients are men). The
mean age for diagnosis, and the average age of the first event are around 30-40
years. (Antzelevitch et al. 2005a, Brugada et al. 2002, Brugada et al. 2003, Priori
et al. 2002, Probst et al. 2010a)
Brugada syndrome patients usually remain asymptomatic, but between 17%
to 42% of them have been reported to suffer from syncope or SCD at some time
during their lives (Brugada et al. 2002, Eckardt et al. 2005, Priori et al. 2002),
although this is probably an overestimation of the risk as most of the
asymptomatic patients are never diagnosed with the syndrome. The annual
incidence of malignant arrhythmias among previously asymptomatic subjects has
been estimated to be 0.5%, among patients with prior syncope it is 1.9%, and
39
among patients with aborted cardiac arrest it is as high as 7.7% (Probst et al.
2010b). The long-term risk of malignant arrhythmias has been reported to range
from 0.5% up to 8% among previously asymptomatic patients, and from 6% up to
62% among patients with a previous episode of cardiac arrest or syncope
(Antzelevitch et al. 2005a, Brugada et al. 2002, Brugada et al. 2003, Giustetto et
al. 2009, Priori et al. 2002, Probst et al. 2010a).
The prevalence of types 2 and 3 has been claimed to be as high as 0.5% in
Western populations, but fortunately they do not seem to predispose to sudden
cardiac death in a similar fashion to type 1 (Gallagher et al. 2008, Junttila et al.
2004).
In individuals with the type 1 Brugada ECG pattern, prolonged QRS (>100ms)
and a markedly elevated J-point in precordial leads, are signs of an elevated risk
of SCD. Furthermore, medication, anesthesia, or the fever-induced type 1 pattern,
have been claimed to possess a high risk of ventricular arrhythmias. (Junttila et al.
2008a, Junttila et al. 2008b) A family history of SCD does not seem to reliably
predict a high arrhythmia risk in Brugada syndrome (Brugada et al. 2003, Probst
et al. 2010a).
Genetics and pathophysiology
Brugada syndrome is typically an autosomal-dominantly transmitted inherited
condition with a heterogenous genetic basis, but the disease can be sporadic in a
proportion of patients. During past years, several mutations have been linked with
the syndrome. The most commonly found genotype in Brugada syndrome is a
mutation in SCN5A, which leads to a loss of function of the cardiac sodium
channel, but these mutations account for only between 11 to 28% of BrS cases.
(Antzelevitch et al. 2005a)
Sudden death in Brugada syndrome typically occurs at rest, often at night,
when vagal tone is augmented (Matsuo et al. 1999). SCD is caused by
polymorphic ventricular tachycardia originating in the right ventricular outflow
tract (Morita et al. 2003).
The pathophysiologic mechanisms of Brugada syndrome are still somewhat
indefinite. The syndrome has been considered as a channelopathy since its
recognition, but no single causal factor appears to apply for all patients. The ECG
pattern has been demonstrated to be modulated by genetic mutations and the
kinds of pharmacological agents which can disrupt the function of ion channels,
40
but often also signs of right ventricular structural abnormalities are found.
Basically, there are two theories of depolarization and repolarization to explain
the pathophysiologic mechanisms responsible for the syndrome, and there is
evidence supporting both theories (Hoogendijk et al. 2010).
The repolarization disorder hypothesis is supported by several pieces of
clinical and experimental evidence. First, sodium channel blockers provoke STelevation in BrS (Brugada et al. 2000). Second, there is an association with the
SCN5A mutations, which result in reduced INa current (Chen et al. 1998). Third,
quinidine, an antiarrhythmic drug with Ito blocking properties, normalizes the
ECG pattern and prevents arrhythmias (Belhassen et al. 2004, Hermida et al.
2004). Furthermore, the ECG pattern is dynamic and more prevalent among
males, and ST-elevations are usually facilitated by slow heart rates (Antzelevitch
et al. 2005a, Atarashi et al. 1996, Matsuo et al. 1998).
There is good evidence to support depolarization disorder hypothesis as well.
First, structural changes, such as fibrosis, have been found in BrS patients
(Corrado et al. 1996, Corrado et al. 2001). Second, there is a high prevalence of
late potentials, which also indicate an increased risk of suffering arrhythmic
events (Hisamatsu et al. 2004, Ikeda et al. 2001). There are also other signs of
general conduction abnormalities, such as axis deviation and QRS prolongation
(Atarashi et al. 2001, Brugada & Brugada 1992). Additionally, fragmented QRS
complexes in BrS also are indicative of an increased risk of recurrent VF (Morita
et al. 2008a). Finally, flecainide, a conduction slowing drug, induces a greater
QRS widening in BrS patients than controls (Shimizu et al. 2000).
Based on these observations, it seems reasonable to conclude, that BrS is
likely to be a multifactorial disease and thus further studies will be needed to
clarify this issue.
Patient management in Brugada syndrome
Family screening in first-degree relatives is recommended due to the known
heritability of Brugada syndrome. All patients diagnosed with Brugada syndrome
should be followed-up on a regular basis to identify possible development of
symptoms. If syncope or seizures appear, the patient should be promptly clinically
evaluated. Since fever may trigger arrhythmias in Brugada patients, close
monitoring is recommended during fever episodes. Patients are also advised to
avoid all drugs that are known to have the possibility to trigger ventricular
41
arrhythmias, and to avoid unnecessary usage of other medication. (Antzelevitch
et al. 2005a)
Ultimately the implantation of an ICD is the only proven and effective
treatment for prevention of SCD in Brugada syndrome. An ICD is recommended
in all patients with symptoms and for asymptomatic patients in whom arrhythmias
are inducible. (Antzelevitch et al. 2005a) The rate of inappropriate shocks has
been reported to be considerable (Sarkozy et al. 2007), and therefore efforts have
been made to search for possible drug options for the treatment. Quinidine has
been proposed as an alternative to ICD (Belhassen et al. 2009), but at present,
ICD is the standard treatment.
2.5.2 Early repolarization – inferolateral J waves
Historical background and terminology
Early repolarization, ST-segment elevation in the absence of conduction
abnormalities or chest pain, occurring particularly in young and physically active,
bradycardic individuals, has been considered as a normal state for over half a
century (Fenichel 1962, Gibbons et al. 1977, Goldman 1953a, Grant et al. 1951,
Kambara & Phillips 1976a, Klatsky et al. 2003a, Myers & Klein 1947b,
Wasserburger & Alt 1961). It was first described in 1936 as J deflections
manifested as slurring or notching of the terminal part of QRS complex in healthy
young men and women (Shipley & Hallaran 1936). In fact, since this ECG
pattern predominates among young and fit individuals with slow heart rates, it has
been generally viewed as a marker of good health.
Fig. 5. Theoretical example of classical early repolarization in precordial leads V2 to V5.
During the years, ER was further defined as an elevated take-off of the STsegment at J-point (Wasserburger & Alt 1961). Historically, the hallmark of early
42
repolarization has indeed been an elevation of the ST-segment in the absence of
conduction abnormalities or chest pain, since it could be confused with
myocardial injury, ischemia or pericarditis. Furthermore, most recommendations
for standardization and interpretation of the electrocardiogram include a statement
that the term early repolarization is used to describe a normal QRS-T variant with
ST segment elevation (Rautaharju et al. 2009b). Figure 4 illustrates some
theoretical examples of precordial leads in classical early repolarization.
Since the high impact publication by Haissaguerre and his colleagues in 2008
(Haissaguerre et al. 2008), the term early repolarization pattern has been used to
describe an elevation of the QRS-ST junction (J-point), manifested as terminal
QRS notching or slurring (Figure 5), and also referred to as J waves, with or
without ST segment elevation in the infero-lateral leads. Leads V1 to V3 were
excluded to avoid confusion with BrS and ARVD. This definition is somewhat
inconsistent with the classical viewpoint, in which J waves are nearly inevitably
considered to be accompanied by ST-segment elevation, and the antero-septal
leads are also included. In fact, traditionally early repolarization has been used to
describe ST-elevation in antero-lateral leads. Subsequently inevitably the question
arouse of whether this described abnormality at the end of the QRS complex
reflecting early repolarization or alternatively delayed activation of the
inferolateral wall (Wellens 2008); this will be discussed in more detail in the
Discussion. Throughout this thesis, the term early repolarization (ER) ECG
pattern is used to describe terminal QRS changes (J waves) irrespective of the
following presence or absence of ST segment elevation.
Fig. 6. J waves, manifested as notching and slurring in theoretical limb leads (lead II).
Electrocardiographic characteristics
As stated in the previous section, the classical definition of early repolarization is
more or less equivalent to ST-segment elevation. However, in recent years, the
usage of the term has evolved. Today, early repolarization can be considered as an
elevation at J-point or a distinct J wave manifested as slurring or notching of the
43
terminal part of the QRS complex, and often, but not necessarily, accompanied by
ST-segment elevation (Haissaguerre et al. 2008). These QRS changes are often
described as at least 0.1 mV “hump-like” deflections immediately after a positive
QRS complex; either a well-defined positive deflection inscribed on the S wave
(notching) or a smooth transition from QRS to ST segment (slurring). By
definition, at least two leads positive for these terminal QRS changes within the
same cardiac location are required for the diagnosis of an early repolarization
pattern.
The grading of ERP is not always straightforward due to electrophysiological
issues. Since QRS complex onset and offset usually varies according to which
lead is being inspected, the grading of ERP and measurement of the J-point is
occasionally problematic. In fact, there might be up to 20 ms difference in the end
of the QRS complex between two leads (Lepeschkin & Surawicz 1952).
Therefore, the gradual shifting of QRS into ST-segment as “slurring” is more or
less subjective, and similarly notching of the terminal QRS in one lead might be
considered to be either due to a conduction delay or to a fragmented QRS
(Bastiaenen & Behr 2012). Defining the point for amplitude measurement is not
always accurate due to these issues.
In most cases, an early repolarization pattern is recognizable from resting
baseline ECG, but the knowledge of its instability does exist. Heart rate and
autonomic tone have a major impact on the variability of ERP (Gross 2010).
Adrenergic stimulation suppresses the pattern, and conversely vagal tone
increases the occurrence of J waves and their amplitude (Abe et al. 2010, Kalla et
al. 2000, Shinohara et al. 2006a, Takagi et al. 2000).
Early repolarization pattern and the risk of adverse events
Before 1980, most of the literature concerning early repolarization viewed the
pattern as a sign of good prognosis. However, these reports were small in sample
size, poorly matched with controls, and mainly consisted of early repolarization in
the precordial leads. (Fenichel 1962, Goldman 1953b, Goldman 1960, Grusin
1954, Kambara & Phillips 1976b, Wasserburger & Alt 1961) More recently, in the
1990s and early 2000, numerous cases have been reported describing J waves in
otherwise typical idiopathic ventricular fibrillation (Kalla et al. 2000, Komiya et
al. 2006, Riera et al. 2008a, Sahara et al. 2002, Shinohara et al. 2006a, Tsunoda et
al. 2004). These cases commonly exhibited J waves in the inferior leads, and J
44
waves augmented during slower heart rates and immediately prior to the onset of
VF. Other than the obvious distribution difference in the presence of ER patterns,
the proarrhythmic potential of J waves with cellular mechanistic explanations in
late 1990s probably is the reason why more emphasis was placed on J waves
rather than on plain ST-elevation. However, as late as 2003, Klatsky and
colleagues published a study on ER, highlighting the benign nature of the pattern
in a follow-up of over 12 years (Klatsky et al. 2003b). They defined the ERP as
ST-elevation, but did not describe in detail the number of leads needed for
diagnosis of early repolarization, and actually only 29% of their ERP positives
had J waves present.
A landmark case-control study on ERP was published in 2008 by
Haissaguerre and colleagues (Haissaguerre et al. 2008). They found that the early
repolarization ECG pattern was over six times more frequent in patients with IVF
than controls, and ICD monitoring exhibited higher incidence of recurrent VF in
case patients with ERP than those cases without the pattern. These results were
soon confirmed in two independent case-control studies (Nam et al. 2008, Rosso
et al. 2008). The publication of these high impact studies stimulated the ongoing
revisitation of early repolarization.
Table 1 summarizes the most widely cited publications on the prognosis of
ERP prior to the onset of this thesis in 2008. More recent evidence will be
presented in detail in the Discussion of the thesis.
The syndrome of early repolarization
Since the groundbreaking publications indicating an over-presentation of ERP in
patients with idiopathic VF, the term early repolarization syndrome (ERS) has
been commonly used to describe patients with an early repolarization ECG
pattern and documented idiopathic VT/VF. This term is to be considered only in
those patients with documented malignant arrhythmias, whereas the term early
repolarization pattern refers to the ECG pattern itself, and can be applied also to
asymptomatic individuals.
Patients with the early repolarization syndrome are likely to be young males
with a history of cardiac arrest during sleep (Abe et al. 2010, Haissaguerre et al.
2008, Rosso et al. 2008). The characteristic ECG includes ERP with high
amplitude J waves in the infero-lateral leads, which are augmented prior to an
arrhythmic event (Nam et al. 2008, Tereshchenko et al. 2012).
45
Genetic studies have thus far revealed mutations mainly in the candidate
genes that might influence the phase 2 of the action potential. A gain of function
mutation in KCNJ8, which encodes the KATP-channel, has been found in patients
with ERS in several independent investigations (Barajas-Martinez et al. 2012,
Delaney et al. 2012, Haissaguerre et al. 2009a, Medeiros-Domingo et al. 2010).
Another study found mutations in CACNA1, CACNB2 and CACNA2D1 in 16%
of probands with ERS (Burashnikov et al. 2010). These mutations are postulated
to cause loss of function affecting the L-type calcium current. Loss of function
SCN5A mutations have also been found in 6% of Japanese ERS patients
(Watanabe et al. 2011). The function of SCN5A was briefly discussed in the BrS
chapter above. However, a recent study demonstrating the autosomal dominant
heritance of familial ERS detected no mutations in the above genes. The
phenotype is likely influenced by many independent loci and interactions. A
further discussion on the genetics and heritability of early repolarization will be
presented later in this thesis.
46
47
emphasis on J waves
124 controls, 132
athletes
Inferolateral leads,
emphasis on J waves
1395 controls
45 IVF patients,
N/A
N/A
N/A
N/A
12 years
5-26 years
1-20 years
None
1-3 years
<1 year
Follow-up
<2 years
N/A denotes not applicable (no follow-up in case reports or case-control series)
Rosso (2008)
Inferolateral leads,
emphasis on J waves
19 IVF patients,
412 controls
Nam (2008)
Inferolateral leads,
206 IVF patients,
Haissaguerre (2008)
Inferolateral leads
Mainly precordial leads
8
2081
Klatsky (2003)
Mainly precordial leads
One or more leads
Mainly precordial leads
Precordial leads
Precordial leads
Distribution of ERP
Precordial leads
Various case reports
75
65
48
Wesserburger (1961)
Kambara (1976)
5
Fenichel (1962)
54
Goldman (1960)
No. of subjects
25
Grusin (1954)
Authors (year)
Goldman (1953)
controls
Increased prevalence of ERP among patients with IVF than
leads
ERP more common in IVF patients, especially ERP in multiple
controls
Increased prevalence of ERP among patients with IVF than
bradycardia and immediately prior to the onset of VF
ERP in patients with IVF. Augmentation of J waves during
ERP not associated with hospitalization or arrhythmias
Vast majority with ERP remained free of heart disease
Vast majority with ERP remained free of heart disease
ERP is a normal variant
disease
ERP persisted and none of the subjects developed heart
ERP persisted in majority of subjects in the follow-up
Main findings
2-4mm J point elevation in mid precordial leads a normal variant
Table 1. Summary of the publications of prognosis of ERP prior to this thesis.
2.6
QRS complex abnormalities
Abnormal ventricular conduction, which is manifested as variations in the QRS
complex, is known to have the potential to cause life-threatening brady- and
tachyarrhythmias, such as heart block and ventricular fibrillation. Nonspecific
QRS prolongation, bundle branch blocks, peri-infarction block and fragmentation
of the QRS complex are briefly presented within this literature review, as both of
the proposed J wave syndromes also possess theories of depolarization as the
underlying pathophysiologic mechanism. Figure 7 illustrates theoretical examples
of various QRS complex abnormalities.
2.6.1 Prolonged QRS duration and bundle branch blocks
Nonspecific prolongation of the QRS complex (QRSd) have been shown to
predict adverse outcomes in patients with various cardiac conditions, including
coronary artery disease and congestive heart failure (Bode-Schnurbus et al. 2003,
Bongioanni et al. 2007, Desai et al. 2006, Elhendy et al. 2005, Iuliano et al. 2002,
Kashani & Barold 2005, Oikarinen et al. 2004, Teodorescu et al. 2011a, Wang et
al. 2008, Zimetbaum et al. 2004). Recently, a QRS duration ≥ 110ms, in the
absence of complete or incomplete bundle-branch block was claimed to be a
strong predictor of cardiac and arrhythmic death in a sample of middle-aged
general population subjects (Aro et al. 2011), in which the prevalence of this
nonspecific intraventricular conduction delay was 0.6%. Another recent study
reported similar findings, i.e. QRS >100ms including incomplete branch blocks,
was a strong predictor of SCD among middle aged men, and each 10ms increment
in QRS duration was associated with a 27% higher SCD risk (Kurl et al. 2012).
These observations indicate that QRSd has significant importance in the
prognosis of individuals in the general population. The pathophysiology of QRSd
could be anticipated to include various forms of cardiomyopathies, which have
remained clinically absent but often cause conduction abnormalities. A genetic
predisposition is also possible, since several loci of the genome have been
associated with QRS duration and ventricular conduction (Sotoodehnia et al.
2010).
For some time, right bundle branch block (RBBB) has been considered as a
normal variant or at maximum as a marker of marginal risk if it occurred in the
absence of cardiac disease (Fahy et al. 1996, Fleg et al. 1983, Miller et al. 2008,
48
Rotman & Triebwasser 1975). It presents as a prolonged QRS >120ms and a
typical RSR’ pattern in V1 due to slowed conduction in the right ventricle. In a
recent Finnish study, RBBB was not associated with increased mortality rates
among a general population sample with a long follow-up (Aro et al. 2011).
Conflicting results have been reported on the prognostic significance of left
bundle branch block (LBBB). LBBB manifests itself as prolonged QRS >120ms
and broad monomorphic S wave in V1. The pattern in an asymptomatic state has
been associated with higher mortality rates in several studies (Eriksson et al.
2005, Miller et al. 2005), including the Finnish study previously mentioned (Aro
et al. 2011), while others have reported negative results (Eriksson et al. 1998,
Fleg et al. 1983).
2.6.2 Peri-infarction block
Peri-infarction block is an ECG abnormality, which usually is indicative of latent
coronary artery disease. It develops following myocardial infarction and leads to
delayed activation in the region of the infarction. It is frequently associated with
extensive scarring of the left ventricle and ventricular late potentials in signal
averaged ECG. (Castle & Keane 1965, Flowers et al. 1990, Scherlag et al. 1985a)
The pattern is known to increase the risk of malignant ventricular arrhythmias and
sudden cardiac death (Flowers et al. 1990, Scherlag et al. 1985b). In the ECG, the
peri-infarction block manifests itself as Q waves as a sign of myocardial
infarction and slurring or prolongation of the terminal QRS complex. The QRS
interval is either normal or borderline prolonged. (First et al. 1950)Due to the
terminal QRS changes, peri-infarction block has been proposed to overlap with
the identification of J waves (Littmann 2010).
2.6.3 Fragmented QRS complex
The fragmented QRS complex (fQRS) includes several different morphologies of
the QRS complex, such as the presence of an additional R wave (R’) or notching
in the nadir or the R or the S wave in two contiguous leads corresponding to a
major coronary artery territory (Das et al. 2006). It has been demonstrated to
represent a myocardial scar in patients with coronary artery disease (Das et al.
2008, Homsi et al. 2009), but is also encountered in several other cardiac
conditions, such as ARVD and Brugada syndrome (Morita et al. 2008b, Peters et
al. 2008, Peters et al. 2012). Generally, the mechanism of fragmentation of the
49
QRS complex is explained by inhomogeneous activation of the ventricles
(Flowers et al. 1969, Varriale & Chryssos 1992).
There is no unequivocal data on the prevalence and prognosis of fQRS
among general population, but there is growing evidence to support its relation to
ventricular arrhythmias and SCD in patients with various cardiac conditions. In
CAD patients, the all-cause mortality and cardiac event rate have been shown to
be significantly higher in patients with fQRS than those without this abnormality
(Das et al. 2007). Another study reported a two-fold higher risk of recurrent
cardiac events in patients with fQRS compared to controls among patients with Q
wave myocardial infarction (Pietrasik et al. 2007). Furthermore, patients with
fQRS have been shown to exhibit a significantly decreased time to death in acute
coronary syndrome (Das et al. 2008, Das et al. 2009), and the presence of ≥3
leads with fQRS have been associated with significantly increased rates of cardiac
death and hospitalization due to heart failure in patients with prior myocardial
infarction (Torigoe et al. 2012). In patients with dilated and ischemic
cardiomyopathy, the inferior presentation of fQRS or J waves have predicted
higher risk of sudden cardiac death (Brenyo et al. 2012, Pei et al. 2012). These
results refer to a possibility of overlapping between J waves, manifested as
notching of the terminal QRS, and end-QRS fragmentation (Bastiaenen & Behr
2012).
Fig. 7. Theoretical examples of various QRS-ST junction abnormalities.
2.7
Summary of the literature
In summary, even in the present era, the traditional standard 12-lead
electrocardiogram is an important tool in risk stratification of asymptomatic
individuals. Sudden cardiac death represents a major health issue, and since the
majority of SCDs occur among low risk individuals in the general population, the
50
quest for better risk stratification is clearly warranted. As presented in this concise
literature review, ECG has an important role in the recognition of many cardiac
conditions and syndromes associated with malignant ventricular arrhythmias.
However, there is still much to be clarified, and these gaps in our knowledge can
only be elucidated by further investigation of many electrocardiographic
parameters. Early repolarization in the ECG has been one of these controversial
issues. Several studies investigating early repolarization have pointed to a benign
nature for decades, but the recent emphasis on J waves, especially in inferolateral
leads, has challenged this old belief. The arrhythmogenic potential of J waves had
been recognized earlier in the Brugada syndrome, but the prevalence and
prognostic significance of inferolateral J waves in the general population were
unknown prior to this thesis.
51
52
3
Aims of the study
After the initial case-control studies pointing to the potential arrhythmia risk of
subjects with early repolarization ECG pattern, a study protocol was designed to
investigate the phenomenon of ERP in the general population. The primary aim
was to evaluate the prevalence and prognosis of such ECG pattern, and thereafter
to characterize the features of the ECG pattern in more detail. The specific aims
for the study were set as follows:
I
II
III
IV
V
VI
To assess the prevalence and prognostic significance of the early
repolarization pattern in a large Finnish general population with a long
follow-up (study I).
To identify the clinical features of early repolarization pattern in the general
population (study II).
To assess the heritability of early repolarization pattern in the general
population (study II).
To identify the electrocardiographic features of the early repolarization
patterns that are associated with arrhythmia risk in the general population
(study III).
To assess the significance of the early repolarization pattern during acute
ischemic coronary events in the general population (study IV).
To identify common genetic variants influencing the early repolarization
pattern by performing a meta-analysis of genome-wide association studies
(study V).
53
54
4
Study populations
4.1
Study population A
In the first and third study of the thesis, the study population was composed of a
sample of 10 957 men and women aged 30 to 59 years (52.3% men, mean age
44±8 years) drawn from different geographic areas of Finland, who participated
in the Social Insurance Institution’s Coronary Heart Disease Study (CHD study)
in 1966-72 (participation rate 89% of 12 310 invited subjects). The CHD study
was part of a large, prospective Mobile Clinic Health Survey in which the
participants underwent a thorough clinical examination including a resting 12lead ECG. The cohort was representative of the middle-aged Finnish population,
since the population groups consisted of either the whole population or a random
sample of the population of a certain geographic area. Furthermore the
geographical areas were chosen from regions with varying death rates. The
mortality data was determined when the follow-up was completed in 2007.
It was necessary to exclude 93 subjects who had missing data or whose ECG
traces were unreadable. Thus, the study population of the first study consisted of
10 864 subjects (52% men, mean age 44±8 years).
4.2
Study populations B and C
In the second study, the study population composed of two general population
cohorts: the Framingham Heart Study (FHS, study population B) and the Health
2000 Study (H2K, study population C). These populations were also used in the
GWAS meta-analysis (study V). The Framingham Heart Study (FHS) is a
prospective community-based study initiated in 1948 in the town of Framingham,
Massachusetts, United States, to evaluate potential risk factors for coronary heart
disease, and 4 095 subjects with available ECGs were included. Originally, a
listing of all residents 20 years of age and older, living in Framingham, was used
as the basis of the sampling of subjects.
The Health 2000 (H2K) Study is a cross-sectional, population-based cohort of
8028 Finnish adults aged ≥30 years, sampled by the Finnish Population
Information System in 2000-2001. Full details of the sample procedures have
been described elsewhere (Aromaa & Koskinen 2004, Heistaro 2008). Briefly, it
55
included similar interviews and extensive health examinations as utilized in the
protocol of the Framingham Heart Study.
Both cohorts, the Framingham Heart Study and the Health 2000 Study, were
representative of the general population. The final study population of the second
study of this thesis consisted of 3 955 subjects from FHS and 5 489 from H2K
after exclusions of missing data, poor ECG quality, various unsuitable ECG
features for ERP analysis, age over 80, and non-Caucasian race. For the fifth
study, 3726 participant from FHS and 2082 from H2K with both GWAS and ECG
available were studied.
4.3
Study population D
The study population of the fourth study consisted of cases and controls from the
same regional area in Northern Finland. The cases were subjects from the Finnish
Genetic Study of Arrhythmic Events (FinGesture), which was initiated in 1998,
and by 2009, had gathered data from 2732 consecutive victims of out-of-hospital
sudden unexpected death in the Oulu University Hospital District, with all of
these deaths being autopsy-verified to have been due to an acute coronary event.
The SCD victims consisted of those with a witnessed sudden death within 6 hours
of onset of the forewarning symptoms. For those with unwitnessed SCD, the time
definition was extended to within 24 hours of the time when the victim had been
last seen alive and in a normal state of health. Those with any other cause than
SCD (accidental or suicidal intoxication) during an acute coronary event were
excluded, as well as those subjects with signs of severe heart failure (prior history
of hospitalization due to congestive heart failure or acute pulmonary edema at
autopsy).
The controls consisted of 1565 survivors of an acute coronary event,
confirmed by the current guidelines (positive troponin assay), from the same time
period and the same geographical area from which the SCD victims were
gathered.
As the aim was to investigate the early repolarization pattern, subjects were
included if a prior standard 12-lead ECG unrelated to the event (SCD or acute
coronary event) had been recorded and was available for interpretation. Sixteen
percent of 2732 victims of SCD and thirty four percent of 1565 survivors had
prior ECG traces available. Consequently, the study population of the fourth study
consisted of 432 victims of sudden death and 532 controls.
56
4.4
Study population E
In the fifth study, a meta-analysis of genome wide association studies was
performed and in addition to populations B and C, another general population
sample from Germany was included. This Cooperative Health Research in the
Region of Augsburg (KORA) F4 Study was conducted in 2006 to 2008 and
included men and women aged between 32 and 81 years. After identical
exclusions as applied to populations B and C, 1674 subjects with available GWAS
and ECG data were studied.
4.5
Study population F
In the third study, two separate athlete samples were examined for ERP prior to
the re-evaluation of study population A. ECG tracings were recorded and
analyzed from 62 volunteer Finnish young male athletes, aged 13 to 15 years
(100% men) and from 503 competitive athletes from the University of Miami,
United States. Fifty-one percent of the US athletes were men, with ages ranging
from 17 to 24 years, and 34% were african descent.
57
58
5
Study methods
5.1
Study I. Prevalence and long-term prognosis of early
repolarization pattern in general population
The aim of the first study was to assess the prevalence and long-term prognosis of
early repolarization pattern in leads other than V1-V3. At the baseline
examinations in 1966-72 all of the studied subjects completed a questionnaire
concerning their health habits, risk factors for cardiovascular disease, known
diseases and medications. In addition to resting 12-lead ECG and the health
questionnaire, blood pressure, body-mass index and serum cholesterol were
measured. It should be noted that usage of beta-blockers or other medications
causing potential changes in cardiac repolarization was extremely rare during that
era. The ECGs were recorded at a paper speed of 50 mm per second and a
specially trained nurse measured the basic ECG parameters, such as SokolowLyon index at the time of baseline examinations. The majority of the participants
in the original Mobile Health Clinic Survey also participated in re-examinations
between 1973 and 1976, in which resting ECGs were recorded in similar way to
the baseline evaluation.
All of the participants were automatically followed-up until the end of 2007,
as Finland maintains extensive administrative registers and every death in the
country is recorded. Less than 2% of the studied subjects had moved abroad, but
even then in majority of the cases, the survival status could be determined. The
causes and rates of death were determined by examining death certificates from
Statistics Finland. The mean follow-up was 30±11 years. The primary end point
used in the publications was death from cardiac causes, and the secondary end
points were death from arrhythmia and death from any cause. Another important
feature was the arrhythmic mortality, and all deaths classified as cardiac death
were reviewed to identify the cases of sudden death due to arrhythmia.
Experienced cardiologists, who were unaware of the ECG data, performed this
analysis. After reviewing the data available from death certificates and hospital
records, the cardiac deaths were classified as either or not associated with
arrhythmia. Definite and probable arrhythmic deaths were included according to
the definitions described in Cardiac Arrhythmia Pilot Study (Greene et al. 1989),
in which the arrhythmic death was defined as a spontaneous cessation of
respiration and circulation with loss of consciousness in one of the following
59
situations: witnessed and instantaneous without new or accelerating symptoms,
witnessed and preceded or accompanied by symptoms attributable to myocardial
ischemia in the absence of heart failure, witnessed and preceded by symptoms
attributable to cardiac arrhythmia, and unwitnessed but without evidence of
another cause. If severe congestive heart failure was present, death was not
included in the arrhythmia category if death from heart failure was considered to
be likely within 4 months before the fatal event.
All 10,957 baseline ECGs were re-analyzed. QRS duration and PQ-interval
were measured, as well as the presence of early repolarization ECG pattern and Tinversions were recorded by five physicians blinded to the original measurements
and outcome data. ERP was defined as J-point elevation in at least two
consecutive leads in the inferior (II, III, aVF) or lateral (I, aVL, V4-V6) leads,
with or without ST-segment elevation. Terminal QRS notching (a positive J
deflection inscribed on the S wave) and slurring (a smooth transition from QRS to
ST-segment) of at least 0.1 mV were considered as early repolarization.
Additionally the amplitude of the J wave at its highest point was measured and
categorized as ≥0.1 mV or >0.2 mV. Post-extrasystolic beats were not used. The
ECGs with positive ERP grading were double-checked and the grading was
established by consensus. All of the available 542 re-examination ECGs from
subjects who presented ERP at baseline were also analyzed. In order to estimate
interobserver and intraobserver variations, 556 ECGs were analyzed twice. In the
comparative analyses, prolonged QTc interval was defined as at least 440 ms for
men and at least 460 ms for women, and left ventricular hypertrophy as SokolowLyon index >35 mm.
5.2
Study II. Clinical features and heritability of early repolarization
pattern in the general population
In the second publication, the aim was to identify the clinical correlates and to
assess the heritability of ERP in general population.
At the baseline examinations of the Framingham and Health 2000 survey
participants, extensive studies were performed in each individual, including
standard resting ECG, blood samples, medical history, physical examination, etc.
In the FHS sample, the 25 mm/s paper ECGs were read manually by two
investigators, and in the Health 2000 sample, the measurements were performed
from digital 50 mm/s ECGs (a single median heart beat for each 12 leads
60
separately) by another two physicians. Post-extrasystolic beats were not used. All
interpretations were performed blinded to the clinical data. Within the FHS
reviewers, 100 ECGs were cross-analyzed to assess the interobserver variability.
In order to estimate the interobserver variability there was cross-analyzing of all
available ECGs within the Health 2000 by the reviewers.
5.3
Study III. Long-term prognosis of various early repolarization
patterns and the significance of ST-segment in general
population
The aim of the third publication was to assess the significance of different ERP
variants and the significance of ST-segment associated with the pattern, i.e. to
identify the subjects with the highest risk of arrhythmic death. Three different
cohorts were examined in this publication. The athlete samples were 62 young
and healthy volunteer Finnish ice hockey players from Oulu, Finland, and 503
competitive college athletes from University of Miami, United States. The main
study population used for mortality assessment was the same middle-aged general
population sample as used in study I (study population A).
First, a pilot study was performed with the athletes in Finland and United
States to assess the prevalence and different patterns of ERP. The ECGs of
Finnish athletes were read by two readers independently and the US athletes by a
single reader. Thereafter, all the 630 ECGs of middle-aged subjects with positive
grading for ERP were re-analyzed to assess the prevalence and long-term
prognosis of those patterns and in the general population. Fifty-four subjects from
population I had to be excluded from the analyses, as their ST-segment status
could not be unequivocally determined due to the poor quality of the ECG tracing
or no consensus could be reached.
The different patterns of ERP were defined as follows. The J waves were
categorized into notching or slurring, similar to the notch/slur definition used in
the first publication. Furthermore, the ST-segments following the J waves were
categorized into rapidly ascending or horizontal/descending. The ascending STsegment was defined as >0.1 mV ST-elevation 100 ms after the J-point, and
consistently the ST-segment was defined as horizontal/descending if this criterion
was not met, i.e. ST-elevation was ≤0.1 mV. The Finnish and US ECGs were
recorded at paper speed of 50 mm/s and 25 mm/s, respectively.
61
5.4
Study IV. The significance of early repolarization pattern in
acute coronary events
In the fourth publication, the aim was to investigate the significance of ERP
during an acute ischemic coronary event with a case-control layout. First, the
electrical medical records were retrospectively reviewed to identify those subjects
with a prior ECG available before the event (sudden death or myocardial
infarction). If several ECGs were available, the most recent one was utilized in
the analyses. Simultaneously, basic demographic parameters and medication data
were collected as well as known diseases from those subjects either from digital
medical records, medicolegal autopsy records, or from standardized
questionnaires completed by the victims’ closest relatives. Consequently, the
information in this study represents the known medical history of the subjects,
prior to the acute index coronary event. Medication data could not be reliably
obtained from 209 (22%) subjects.
The ECGs, all recorded at paper speed of 50 mm/s, were analyzed by three
investigators independently and blinded to the clinical data and outcome status,
and consensus readings were performed if necessary. ERP and the following
dominant ST-segment types were defined as in studies I and III.
5.5
Study V. Identification of common genetic variants influencing
early repolarization pattern
The aim of the fifth study was to conduct a meta-analysis of genome-wide
association studies to identify common genetic variants that influence ERP. Three
large community based cohorts (study populations B, C and E) were used.
The ECG analyses in study populations B and C are described above in Study
II. Identical measurements, classifications and exclusion criteria were applied also
for study population E.
GWA studies in participants with and without ERP were analyzed by logistic
regression assuming an additive genetic model and individual cohort results were
meta-analyzed. Those findings that reached p-value 1 x 10-5 in independent
individuals were further investigated by direct genotyping or in-silico analysis of
genome-wide data.
62
5.6
Statistical analysis
In all studies, continuous values are presented as mean ± standard deviation (SD)
and categorical values as number of subjects or percentages. In categorical
variables, groups were compared with Chi-square test. In continuous variables,
the groups were compared with the independent samples t-test (two group
comparison) or analysis of variance (multiple group comparison). P values were
two-tailed, and a P value <0.05 was considered statistically significant.
In studies I and III, hazard ratios and 95% confidence intervals were
computed with Cox proportional hazard models. These models were adjusted
with covariates that had a known association with cardiovascular mortality. The
covariates included age, gender, systolic blood pressure, body mass index, heart
rate, smoking and ECG signs of left ventricular hypertrophy or coronary artery
disease. Kaplan-Meier estimates were used for overall, cardiac and arrhythmic
mortality.
In the second study, a multivariable logistic regression model was constructed
to identify independent determinants of ERP status, forcing in age and sex, using
a forward selection procedure (entry p<0.05 in the initial models, retention
p<0.05). SAS proc logistic (version 9.2) was used for model selection in both
cohorts. Within each of the used stratified samples in the heritability analyses of
the second study, odds ratios were obtained predicting the ERP status of the
sibling of the index individual using logistic regression, with and without
adjustment for age and sex.
In the fourth study, logistic regression analysis was used to assess the
significance of predictors of SCD between groups after adjustments for age,
gender, smoking, body mass index, prior myocardial infarction, history of
coronary artery disease, and medication (beta blocker, statin, angiotensin II
receptor antagonist and nitroglycerin in model 2). The Hosmer and Lemeshow
test was used to assess the goodness-of-fit of the logistic regression models.
In the fifth study, primary analyses were performed separately at each site by
using logistic regression assuming an additive genetic model. Models were
adjusted for age, gender, and RR interval. The meta-analysis of site-specific
association results was performed by using the meta-analysis tool Meta Analysis
Helper (Willer et al. 2010), and finally the GWAS and replication stage were
combined for overall effect estimate.
The statistical analyses were performed with SPSS 16.0 (I, III, IV) (SPSS Inc,
Chicago IL), and SAS software v 9.1.3 (I, III) and 9.2 (II) (SAS, Cary, NC).
63
64
6
Results
6.1
Prevalence and prognostic significance of early repolarization
pattern in a large Finnish general population with a long followup (I)
In the first epidemiological study (I), 630 persons were identified (5.8% out of
10,864 middle-aged subjects) displaying the early repolarization pattern,
including 3.5% in the inferior and 2.4% in the lateral leads. Higher amplitude J
waves (>0.2 mV) were observed in 67 subjects (0.6%). Those with ERP in the
inferior leads were more often male, smokers, had a lower body mass-index,
lower blood pressure, a lower resting heart rate, a shorter QTc interval, a longer
QRS duration, and were more likely to have ECG signs of coronary artery disease
according to Minnesota-codes. In contrast, those with ERP in the lateral leads
were more often male, had a lower resting heart rate, and were more likely to
have ECG signs of left ventricular hypertrophy. Table 2 describes the
characteristics of the groups at baseline.
During a follow-up of 30±11 years, 6133 (56.5%) subjects had died. Of these
deaths, 1969 (32.1%) were due to cardiac causes, and furthermore 795 (40.4%) of
the cardiac deaths were classified as arrhythmic deaths. Before and after
multivariate adjustments, those with ≥0.1 mV ERP in the inferior leads had an
elevated risk of cardiac (adjusted relative risk [RR] 1.28, 95% confidence interval
[CI] 1.04 to 1.59) and arrhythmic death (RR 1.43, 95% CI 1.06 to 1.94), but did
not possess a higher rate of overall mortality. Those with the higher amplitude
ERP (>0.2 mV) had an even higher risk of cardiac (RR 2.98, 95% CI 1.85 to 4.92)
and arrhythmic death (RR 3.94, 95% CI 1.96 to 7.90). Those with ≥0.1 ERP in the
lateral leads had an elevated risk of cardiac (RR 1.34, 95% CI 1.04 to 1.74) and
had a higher rate of overall mortality (RR 1.19, 95% CI 1.02 to 1.39), but did not
suffer an elevated risk for arrhythmic death. Table 3 presents the adjusted relative
risks of prolonged QTc, left ventricular hypertrophy, and ERP.
65
66
Age (years) ‡
87±9
10.2
1.1
2.2
Coronary artery disease (%) §
Prior myocardial infarction (%)
Prior angina pectoris (%)
2.3
1.1
9.7
87±8
408±28
30.8
8.1
4.3
82±12
139±22
0.7*
1.4
14.9*
89±7*
404±26*
35.0
7.7
2.7
80±12*
136±19*
74±14*
25.1±3.3**
6.51±1.23
42.6**
44.2±8.1
44.2**
384
* P value <0.05; ** P value <0.001 compared to group None
1.6
1.1
13.5*
88±7**
406±27
40.1**
7.5
4.0
82±13
137±20
74±14**
25.6±3.4*
6.53±1.26
36.1
44.5±8.3*
44.8**
630
Inferior or lateral leads
§ The criteria for the diagnosis of coronary artery disease corresponded to Minnesota codes 1.1 to 1.3, 5.1 to 5.2, 4.1 to 4.3, 7.1, and 7.4.
3.0
0.6
11.2
87±7
409±27
49.5**
6.9
5.8
84±14*
139±21
74±15*
26.4±3.7
6.58±1.28
26.1*
45.2±8.7*
45.2*
262
Lateral leads
Early repolarization pattern ≥ 0.1mV
Inferior leads
† P values in this category were adjusted for age. ‡ P values in this category were adjusted for sex.
Plus–minus values are means ± SD. QTc denotes QT corrected for heart rate.
408±28
31.2
ECG signs of LVH (%) †‡
QRS duration
8.2
Cardiovascular disease (%) †‡
QTc duration
4.3
82±12
Diastolic blood pressure †‡
Chronotropic medication (%) †‡
138±22
Systolic blood pressure †‡
76±15
25.9±3.9
25.9±3.9
76±15
6.50±1.32
6.50±1.32
33.9
44.0±8.5
34.0
44.0±8.5
Heart rate (beats/min) †‡
Body-mass index †‡
Total cholesterol (mmol/liter) †‡
Current smoker (%) †‡
51.5
10 234
None
52.4
10 864
No. of subjects
Male gender (%)†
All subjects
Characteristics
Table 2. Characteristics of the subjects at baseline (I).
Table 3. Adjusted relative risk of death from cardiac causes (I).
Variable
No.
Relative risk
Prolonged QTc interval
668
1.20 (1.02-1.42)
0.03
3410
1.16 (1.05-1.27)
0.004
Electrocardiographic LVH
P value
ERP ≥ 0.1mV in inferior leads
384
1.28 (1.04-1.59)
0.03
ERP > 0.2mV in inferior leads
36
2.98 (1.85-4.92)
<0.001
Relative risks are presented as RR (95% confidence intervals), and adjusted for age, sex, body mass
index, heart rate, smoking status, systolic blood pressure, presence of left ventricular hypertrophy or
coronary artery disease on electrocardiography. QTc indicates QT interval corrected for heart rate, LVH
left ventricular hypertrophy, and ERP early repolarization pattern.
Furthermore, the cumulative survival plots (Figure 8) showed that the mortality
rates between those with and without ERP started to diverge only after a notably
long follow-up. This study illustrated that ERP was a quite common finding and
that it was associated with adverse cardiovascular outcomes in the general
population. Figure 9 illustrates an example ECG of a middle-aged subject with
ERP in the inferior leads.
67
Fig. 8. Kaplan-meier survival curves (I).
68
Fig. 9. Example ECG of a middle-aged subjects carrying inferior ERP followed by
horizontal ST segments.
69
6.2
The clinical correlates and heritability assessment of early
repolarization pattern in general population (II)
The second study (II) identified a total of 423 persons (4.5% out of 9,444 subjects
from general population samples) displaying ERP. The pattern was present in
243/3,955 (6.1%) of FHS subjects, and 180/5,489 (3.3%) of H2K subjects.
After stepwise selection using all significant covariates from age- and sexadjusted models, male sex, increased RR interval, decreased systolic BP,
decreased Cornell voltage, and increased Sokolow-Lyon voltage were
independently associated with ERP status on multivariable regression in FHS
cohort. Correspondingly, younger age, male sex, shorter RR-corrected QT interval,
shorter QRS duration, lower Cornell voltage, higher Sokolow-Lyon index, and
lower systolic blood pressure were independently associated with ERP status in
the H2K sample. A family history of SCD or syncope was no more commonly
reported in subjects with ERP. The full descriptive data is presented in Table 4,
and the results of the multivariate regression model are shown in Table 5.
In the Health 2000 sample, the prevalence of ERP was decreasing with
increasing age, and there was evidence for a modest age by sex interaction
(p=0.048). The prevalence of ERP by gender in different decades of age in the
Health 2000 sample is presented in Figure 10.
With respect to the heritability assessment in the Framingham sample, there
were 1,111 sibling pairs available for analyses. Siblings of those with ERP had an
ERP prevalence of 11.6% vs 6.1% in those without the pattern (sibling occurrence
risk ratio 1.89), and furthermore, siblings of ERP-positive individuals exhibited
an increased odds of ERP before adjustments (OR 2.20, 95% CI 1.00 to 4.90).
This study showed quite similar prevalence of ERP as in study I, and
demonstrated that ERP has a strong association with clinical factors. ERP also
seemed to have a heritable basis, although other confounders such as age, sex or
exercise habits could partly explain ERP among siblings.
70
71
120 (31.6)
78.8 (9.3)
121 (12.8)
LDL cholesterol, mg/dL
Diastolic BP, mmHg
Systolic BP, mmHg
73 (4.5%)
140 (114)
Triglycerides, mg/dL
Beta blocker medication
46.6 (12.5)
HDL cholesterol, mg/dL
19 (1.2%)
281 (17.2%)
Cardiovascular disease
Current smoker
4 (0.2%)
Coronary heart disease
Hypertension
68 (4.2%)
Sokolow-Lyon, mV
10 (0.6%)
2.15 (0.57)
371 (22.7%)
Cornell voltage, mV
History of AF
1.27 (0.46)
QRS duration, msec
Diabetes mellitus
414 (21.9)
91.0 (9.51)
QTc interval, msec
28.1 (4.7)
155 (22.7)
Weight, kg
PR interval, msec
89.2 (16.1)
Height, m
BMI, kg/m2
1004 (164)
1.78 (0.07)
RR interval, msec
40.7 (8.7)
1 638
No. of subjects
Men
Age, years
ERP-
Characteristic
6 (3.3%)
117 (10.4)
75.2 (8.9)
118 (31.3)
114 (87.2)
48.4 (12.3)
20 (10.9%)
0 (0%)
0 (0%)
3 (1.6%)
4 (2.2%)
22 (12.0%)
2.64 (0.72)
1.07 (0.53)
92.4 (9.6)
406 (21.9)
155 (24.9)
26.8 (4.4)
84.2 (15.2)
1.77 (0.06)
1076 (189)
37.7 (8.8)
184
ERP+
81 (3.9%)
113 (14.5)
72.8 (9.2)
105 (29.9)
97.6 (63.0)
60.9 (16.0)
303 (14.6%)
15 (0.7%)
5 (0.2%)
9 (0.4%)
56 (2.7%)
248 (12.0%)
1.87 (0.51)
0.84 (0.38)
84.2 (8.8)
426 (21.8)
143 (21.3)
26.1 (6.1)
70.4 (16.9)
1.64 (0.06)
966 (153)
40.1 (8.8)
2 074
ERP59
ERP+
1 (1.7%)
109 (10.4)
71.0 (7.3)
101 (29.3)
82.1 (35.7)
63.8 (14.9)
10 (17.0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
1 (1.7%)
2.15 (0.67)
0.66 (0.4)
85.3 (7.4)
422 (20.9)
141 (19.9)
24.7 (6.1)
67.33 (18.1)
1.65 (0.06)
1030 (174)
36.4 (9.2)
Women
Framingham Heart Study
Table 4. Descriptive data of subjects in the Framingham and Health 2000 (II).
336 (14.7%)
136 (18.5)
85.0 (10.6)
149 (40.1)
162 (111)
46.0 (12.5)
809 (35.3)
156 (6.8)
108 (4.7%)
NA
154 (6.7%)
1171 (51.1%)
3.15 (0.78)
1.67 (0.54)
93.2 (9.1)
390 (21.8)
166 (28.5)
27.3 (4.1)
84.8 (14.4)
1.76 (0.07)
987 (170)
50.2 (12.1)
2 291
ERP137
ERP+
11 (8.0%)
126 (13.9)
81.3 (9.6)
147 (40.3)
136 (92.2)
50.7 (14.5)
64 (46.7%)
4 (2.9%)
3 (2.2%)
NA
4 (2.9%)
43 (31.4%)
3.93 (0.87)
1.38 (0.64)
91.7 (8.1)
374 (18.4)
165 (25.9)
25.2 (3.1)
79.4 (11.3)
1.78 (0.06)
1072 (167)
43.2 (10.8)
Men
561 (18.6%)
132 (21.6)
80.0 (10.7)
139 (40.3)
123 (63.7)
55.9 (14.5)
732 (24.3%)
128 (4.3%)
56 (1.9%)
NA
128 (4.2%)
1270 (42.1%)
2.66 (0.64)
1.34 (0.50)
86.4 (8.2)
403 (21.2)
158 (24.8)
26.8 (5.1)
70.7 (13.7)
1.63 (0.07)
961 (149)
50.8 (13.1)
3 018
ERP-
Health 2000 Study
7 (16.3%)
121 (15.9)
74.6 (10.0)
131 (41.2)
104 (41.6)
54.2 (12.7)
16 (37.2%)
4 (9.3%)
1 (2.3%)
NA
2 (4.7%)
10 (23.3%)
3.11 (0.74)
1.02 (0.58)
82.3 (7.1)
393 (20.6)
160 (22.6)
26.0 (4.3)
69.5 (13.4)
1.63 (0.07)
1000 (175)
47.0 (14.2)
43
ERP+
Women
72
41 (2.5%)
208 (12.7%)
21 (11.4%)
4 (2.17%)
1 (0.5%)
ERP+
519 (25.0%)
67 (3.23%)
108 (5.2%)
1 (1.7%)
0 (0%)
ERP+
21 (35.6%)
Women
ERP-
NA
NA
252 (11.0%)
ERP-
ERP+
NA
NA
12 (8.8%)
Men
NA
NA
524 (17.4%)
ERP-
Health 2000 Study
NA
NA
8 (18.6%)
ERP+
Women
for heart rate with Bazett’s formula. NA indicates data not available, and AF atrial fibrillation/flutter
Numbers presented as mean (standard deviation) for continuous variables and number of cases (percentage) for dichotomous variables. QT interval corrected
History of syncope
Family history of SCD
medication
42 (2.6%)
QT prolonging
Men
ERP-
Characteristic
Framingham Heart Study
Table 5. Independent predictors of ERP in multivariate regression model (II).
Variable
Odds ratio
P
Framingham Heart Study
Age, per 10 years
0.84 (0.71-1.00)
0.05
Male, vs. female
4.10 (2.80-5.80)
1.0x10-14
Cornell voltage, per mV
0.41 (0.28-0.61)
1.4x10-5
Sokolow-Lyon, per mV
3.20 (2.50-4.10)
1.3x10-20
Systolic BP, per 10 mmHg
0.82 (0.72-0.92)
0.001
RR interval, per 100 msec
1.20 (1.10-1.30)
4.3x10-5
Health 2000 Study
Age, per 10 years
0.95 (0.80-1.12)
0.51
Male, vs. female
2.74 (1.80-4.20)
5.6x10-6
Cornell voltage, per mV
0.22 (0.15-0.32)
3.9x10-16
Sokolow-Lyon, per mV
4.30 (3.40-5.40)
1.8x10-34
Systolic BP, per 10 mmHg
0.78 (0.69-0.88)
7.8x10-5
QTc interval, per 20 msec
0.61 (0.51-0.72)
1.0x10-8
QRS duration, per 10 msec
0.77 (0.63-0.95)
0.01
Odds ratios are presented as OR (95% confidence intervals)
73
Fig. 10. Prevalence of ERP by gender in the Health 2000 study (II).
74
6.3
The long-term significance of ER ECG pattern subtypes and
ST-segment morphology (III)
The sequel study (III) to the first observational study (I) explored the prognosis of
different ERP subtypes after reviewing a large amount of ECGs from young and
healthy athletes. Among the young Finnish athletes, the prevalence of ERP was
43.5% (27 out of 62 persons), and in the US athletes, the prevalence was 30.0%
(151/503 persons). Both terminal QRS notching and slurring were present, and
ST-segments following the J waves were elevated or rapidly ascending in 96.3%
and 85.0% of Finnish and US athletes, respectively. In contrast, in the general
middle-aged population, this ST-segment subtype was observed in only 28.5% of
subjects with ERP. The dominant form of ST-segment in those middle-aged
subjects with ERP was horizontal or descending (71.5%). ERP in the general
population sample was classified as notched in 39.6%, slurred in 50.7% and
undetermined in 9.7%. Table 6 presents the characteristics of the Finnish athletes.
In the general population sample, those with ERP and horizontal/descending
ST-segment were older, had a higher prevalence of ECG signs of coronary artery
disease, and had a longer QRS duration compared with those without ERP. In
contrast, those with ERP and a rapidly ascending ST-segment were more often
male, were younger, had lower body mass index, lower heart rate, lower blood
pressure, shorter QTc duration, and higher prevalence of ECG signs of left
ventricular hypertrophy. Table 7 presents the baseline data in different groups.
Subjects with ≥0.1 mV ERP and horizontal or descending ST-segments had a
higher risk of sudden arrhythmic death (age- and sex adjusted HR 1.43, 95% CI
1.05 to 1.94) than those without the pattern. Subjects with ERP but rapidly
ascending ST-segment did not display a similar elevated risk for arrhythmic death
(HR 0.89, 95% CI 0.52 to 1.55). The same trends were found in subjects with
inferior ER patterns, as subjects with inferior ERP and horizontal/descending STsegment had a HR of 1.72 (95% CI 1.22 to 2.41) for arrhythmic death after
adjustments for age and sex, but in contrast, the ascending ST-segment type was
not associated with adverse outcomes. Table 8 summarizes the risk of sudden
arrhythmic death. Two example ECGs from subjects displaying ERP with
horizontal ST-segments are presented in Figure 11.
75
Table 6. Characteristics of the subjects in the Finnish athlete population (III).
Characteristic
No ER
No. of subjects
35
27
13.3±0.6
13.4±0.6
Age
Males, %
Heart rate. bpm
QRS duration, ms
ER +
100
100
71±17
68±11
88±8
84±12*
QTc interval,ms
405±17
417±22*
PR-interval, ms
145±25
142±20
Sokolow-Lyon index, mV
3.1±0.7
3.6±0.7*
QRS-angle, degrees
71±21
74±47
J-point amplitude, mV
0
0.13±0.03**
Numbers presented as mean ± standard deviation for continuous variables and percentage for
dichotomous variables. QTc indicates QT interval corrected for heart rate.
* P-value <0.05; ** P-value <0.001
Subjects with notched ≥0.1 mV ERP (terminal QRS notching independent of the
ST-segment patterns) had an age- and sex adjusted HR of 1.58 (95% CI 1.07 to
2.32) for arrhythmic death. Correspondingly subjects with slurred ≥0.1 mV ERP
(terminal QRS slurring independent of the ST-segment patterns) had an adjusted
HR or 1.19 (95% CI 0.81 to 1.76) for arrhythmic death. In subjects with greater
amplitude ERP (>0.2 mV), the notched subtype had an adjusted HR of 2.14 (95%
CI 0.89 to 5.16) and those with the slurred subtype had a very high adjusted HR
of 5.14 (95% CI 1.92 to 13.76). When only inferior location was investigated
(≥0.1 mV), only notched type was significantly associated with arrhythmic death
(HR 1.54, 95% CI 1.00 to 2.38).
76
Table 7. Adjusted characteristics of subjects with ERP and different ST segment
patterns (III).
Characteristic
No ERP
ERP with ascending ERP with horizontal
No. of subjects
10 288
164
412
51.5
88.1**
57.1*
45.5 ± 8.2**
/ upsloping ST
Males (%)1
Age (years)†
/ descending ST
44.0 ± 8.5
42.6 ± 7.9
Current smoker (%) ‡
33.8
38.4
36.4
Cholesterol (mmol/l) ‡
6.50 ± 1.32
6.48 ± 1.32
6.58 ± 1.21
BMI (kg/m2) ‡
25.7 ± 3.6
25.9 ± 3.9
25.0 ± 2.9*
Heart rate (bpm) ‡
76 ± 15
70 ± 12**
75 ± 14
Systolic blood pressure (mmHg) ‡
138 ± 22
134 ± 16*
138 ± 21
Diastolic blood pressure (mmHg) ‡
82 ± 12
79 ± 12**
83 ± 13
Chronotropic medication (%) ‡
4.3
3.2
4.2
Cardiovascular disease (%) ‡
8.1
8.7
7.2
Electrocardiographic LVH (%) ‡
30.8
60.6**
33.2
QTc duration (ms) ‡
408 ± 28
400 ± 22**
409 ± 28
QRS duration (ms) ‡
87 ± 8
87 ± 7
89 ± 7**
ECG signs of CAD (%) ‡
9.6
12.2
14.9**
History of prior MI (%) ‡
1.1
0.3
1.3
History of angina pectoris (%) ‡
2.3
2.5
1.6
1
Adjusted for age; † Adjusted for sex; ‡ Adjusted for age and sex; ± values are means SD
* P-value <0.05; ** P-value <0.001 compared to group No ERP
CAD denotes coronary artery disease, MI myocardial infarction
77
Fig. 11. Example ECGs of two middle-aged subjects with inferior ERP followed by
horizontal/descending ST segments (III).
78
Table 8. Risk of sudden arrhythmic death in different ERP groups according to STsegment morphology (III).
Characteristic
No. of subjects at
No. of arrhythmic
risk
events
10 288
739
1
horizontal / descending ST
412
43
1.39 (1.02-1.89)
ascending ST
164
13
0.87 (0.50-1.52)
horizontal / descending ST
265
35
1.73 (1.22-2.44)
ascending ST
90
8
1.05 (0.52-2.11)
horizontal / descending ST
50
9
2.42 (1.25-4.69)
ascending ST
10
1
0.96 (0.13-6.83)
No ERP
Adjusted HR
Inferior / lateral ERP ≥ 0.1mV
Inferior ERP ≥ 0.1mV
Inferior / lateral ERP > 0.2mV
HR denotes hazard ratio, ERP early repolarization pattern and ST ST-segment. Hazard ratios (95%
confidence intervals) are adjusted for age, gender, body-mass index, heart rate, QTc duration, QRS
duration, ECG signs of left ventricular hypertrophy or ECG signs of coronary artery disease.
79
Fig. 12. Cardiac and arrhythmic death survival plotted for ERP in middle-aged subjects.
80
6.4
Significance of early repolarization pattern during acute
coronary events (IV)
The fourth study revealed a total prevalence of 10.8% for ERP among 432 victims
of sudden cardiac death and 532 survivors of an acute coronary event. The
victims of SCD were more often men and smokers, were significantly younger,
and had lower body mass index than the survivors of an acute event. Overall, the
victims of SCD had a lower prevalence of medical admissions due to a prior
myocardial infarction (23% vs 59%, p<0.001) or diagnosed coronary artery
disease (44% vs 76%, p<0.001), as well as a reduced usage of cardiovascular
medication, as shown in Table 9.
ERP was significantly more common in victims of SCD than survivors
(14.4% vs. 7.9%, p=0.001). Those with ERP had a lower prevalence of diagnosed
diabetes mellitus (p=0.01) and diagnosed coronary artery disease (p=0.04), lower
heart rate (p=0.02) and higher Sokolow-Lyon index (p<0.001) than those without
the pattern. An inferior manifestation of ERP was more common in victims than
survivors (6.7% vs 3.6%, p=0.03). Furthermore, a specific ERP pattern with a
horizontal or descending ST-segment was associated with SCD (10.2% vs 5.3%,
p=0.004), whereas ERP with ascending ST-segment was not (3.0% vs 2.3%,
p=0.46). The electrocardiographic features are presented in Table 10. In a
secondary analysis with a subset of patients without documented coronary artery
disease (n=309), the results remained essentially the same, as ERP was more
common in victims than survivors (16.9% vs 7.2%, p=0.04).
Table 11 presents the odds ratios of sudden cardiac death in the evaluated
variables. Unadjusted predictors of SCD during acute coronary event were male
gender (OR 2.08, 95% CI 1.55 to 2.80), elevated heart rate (OR 1.90, 95% CI
1.46 to 2.47) and ERP (OR 1.85, 95% CI 1.23 to 2.80). In more specific terms,
ERP with horizontal/descending ST-segment was associated with SCD (OR 2.04,
95% CI 1.25 to 3.34). In both multivariate models, ERP with
horizontal/descending ST-segment remained as a significant predictor of SCD.
The group with ERP and ascending ST-segment did not reach statistical
significance either before or after adjustments.
81
Table 9. Demographic and clinical characteristics recorded before the event (IV).
Characteristic
Victims
Survivors
No. of subjects
432
532
Age, y
P-value
66±11
69±12
<0.001
Male, %
79.4
64.9
<0.001
Body mass index
27±6
28±5
0.02
Current/ex smoker, %
43.3
32.3
0.001
<0.001
History of
Prior myocardial infarction, %
23.1
59.1
Diabetes mellitus, %
26.6
26.3
0.93
Coronary artery disease, %
47.6
84.4
<0.001
Hypertension, %
50.0
54.0
0.22
Medication
Beta-blocker, %
35.1
48.9
<0.001
Statin, %
11.3
32.0
<0.001
Acetylsalicylic acid, %
27.8
28.6
0.79
ACE inhibitor, %
16.0
20.9
0.09
ATII antagonist, %
3.6
10.9
<0.001
Nitroglycerin, %
14.9
25.2
<0.001
ACE indicates angiotensin-converting enzyme; ATII angiotensin II receptor.
Table 10. Electrocardiographic variables (IV).
Characteristic
Victims
Survivors
No. of subjects
432
532
P-value
QRS duration, ms
91±15
88±16
0.01
Heart rate, bpm
73±16
70±15
0.002
QTc, ms
421±38
419±35
0.39
27±9
27±8
0.83
0.03
Sokolow-Lyon, mV
PQ-interval, ms
166±30
171±34
Atrial fibrillation, %
5.3
5.8
0.74
Pathologic Q waves, %
5.8
8.3
0.16
ERP in inferior and/or lateral leads, %
14.4
7.9
0.001
0.03
Location specific ERP
ERP in inferior leads, %
6.7
3.6
ERP in lateral leads, %
6.0
3.6
0.07
ERP in inferior and lateral leads, %
1.7
0.7
0.13
ERP + horizontal/descending ST segment, %
10.2
5.3
0.004
ERP + ascending ST segment, %
3.0
2.3
0.46
Morphology specific ERP
ERP indicates early repolarization pattern; bpm beats per minute
82
83
101
Early repolarization pattern
2.04 (1.25-3.34)
1.34 (0.61-2.98)
1.85 (1.23-2.80)
1.05 (0.73-1.52)
1.39 (0.83-2.33)
2.13 (1.29-3.52)
1.03 (0.46-2.32)
1.77 (1.15-2.70)
0.97 (0.67-1.41)
1.28 (0.89-1.84)
1.89 (1.45-2.46)
1.34 (0.79-2.28)
…
Adjusted OR*
2.15 (1.20-3.85)
1.12 (0.44-2.85)
1.73 (1.06-2.83)
0.94 (0.58-1.51)
1.27 (0.84-1.93)
1.65 (1.22-2.23)
1.59 (0.87-2.91)
…
Multivariate model 1†
2.29 (1.16-4.54)
1.67 (0.50-5.49)
2.02 (1.04-3.61)
1.30 (0.76-2.21)
1.17 (0.73-1.89)
1.79 (1.17-2.72)
1.28 (0.68-2.39)
…
Multivariate model 2‡
ATII receptor antagonist, and nitroglycerin medication.
‡Multivariate model 2 adjusted for age, gender, smoking, body mass index, prior myocardial infarction, history of coronary artery disease, beta blocker, statin,
*Adjusted for age and gender; †Multivariate model 1 adjusted for age, gender, smoking, prior myocardial infarction, history of coronary artery disease.
for women.
Prolonged QRS ≥120ms; Elevated heart rate >80bpm; Left ventricular hypertrophy Sokolow-Lyon index >35mm; Prolonged QTc >450ms for men and >470ms
No. indicates number of subjects. Odds ratios presented as OR (95% confidence intervals)
25
135
72
133
Prolonged QTc
Left ventricular hypertrophy
ERP + horizontal ST segment
1.36 (0.96-1.95)
377
Elevated heart rate
ERP + ascending ST segment
1.90 (1.46-2.47)
61
Prolonged QRS duration
2.08 (1.55-2.80)
687
Male gender
Unadjusted OR
No.
Variable
Table 11. Odds ratios (OR) for sudden cardiac death during acute coronary event (IV).
6.5
Meta-analysis of genome wide association studies of early
repolarization pattern (V)
In the fifth study, the GWA study stage combined 7,482 subjects from the three
cohorts, and the total prevalence of ERP was 6.0%.
A total of 2,523,555 single nucleotide polymorphisms (SNPs) were analyzed
for their association with an early repolarization pattern, with 8 loci being
identified with p-values under 1 x 10-5. The most interesting SNP (rs17029069)
was on chromosome 1p13.2 and maps to KCND3, which encodes the voltagegated potassium channel Kv4.3.
Replication of the results of GWA study stage were attempted in independent
samples of 7,151 individuals, but none of the identified eight SNPs could be
replicated, and when meta-analyzed with primary GWAS results, none of the
SNPs reached genome-wide significance (Table 12).
84
85
17
10
1
14
2
1
8
4
rs11653989
rs6585436
rs17029069
rs17097328
rs17012480
rs1541064
rs6988260
rs1382629
Closest gene(s)
KIAA1211
FAM110B
UBE2U
LTBP1
C14orf177
KCND3
PDZD8, EMX2
MGAT5B, SEC14L
OR
2.23
0.69
1.38
0.69
1.51
1.46
0.32
0.47
95% CI
1.56–3.18
0.59–0.81
1.20–1.59
0.58–0.81
1.27–1.78
1.25–1.69
0.21–0.50
0.36–0.61
P-value
9.82 x 10-06
8.92 x 10-06
8.54 x 10-06
6.97 x 10-06
1.71 x 10-06
8.50 x 10-07
4.88 x 10-07
6.87 x 10-09
OR
1.48
0.75
1.20
0.83
1.21
1.29
0.48
0.62
1.17–1.87
0.66–0.86
1.08–1.34
0.73–0.94
1.06–1.38
1.15–1.44
0.35–0.66
0.50–0.76
95% CI
9.12 x 10-04
1.72 x 10-05
6.80 x 10-04
3.45 x 10-03
4.03 x 10-03
8.28 x 10-06
6.11 x 10-06
2.80 x 10-06
P-value
Overall after replication
All results are adjusted for age, sex and RR-interval. Chr indicates chromosome, OR odds ratio, CI confidence interval, and SNP single nucleotide polymorphism.
Chr
SNP
GWAS meta-analysis
Table 12. GWA studies association results for the most significant SNPs (V).
86
7
Discussion
7.1
Key findings
Study purpose 1. The assessment of prevalence and prognostic significance of
early repolarization pattern in general population.
There was a prevalence of 5.8% for ERP in the middle-aged general
population and an association was found between ERP in the inferior leads and
death from cardiac causes. These observations warranted further research on the
topic.
Study purpose 2. The identification of clinical features and the assessment of
the heritability of the early repolarization pattern in general population.
A strong association was observed between ERP and several physiological
and clinical factors, such as gender, age, blood pressure and ECG voltages. There
was also evidence for a heritable basis in general population, as ERP was
significantly more prevalent in siblings of individuals with ERP than those
without the pattern, which warranted further investigation into the genetic
variants predisposing to ERP.
Study purpose 3. The identification of electrocardiographic features of early
repolarization patterns associated with arrhythmia risk in general population.
It was demonstrated that ST-segment morphology variants associated with
ERP separated subjects with and without an increased risk of arrhythmic death in
middle-aged subjects. The arrhythmia risk at the population level was linked to
the presence of ERP and a horizontal or descending ST-segment.
Study purpose 4. The assessment of the significance of early repolarization
pattern during acute ischemic coronary events in general population.
A higher prevalence of ERP was observed in victims of SCD than in
survivors of an acute coronary event in ECGs recorded prior to and unrelated to
the event. The presence of ER ECG patterns, especially with horizontal or
descending ST-segments, seemed to be a marker of increased vulnerability to fatal
arrhythmia during acute myocardial ischemia.
Study purpose 5. The identification of common genetic variants influencing
early repolarization pattern (a meta-analysis of genome-wide association studies).
A multicentre meta-analysis of GWA studies was performed in almost 15,000
individuals from community-based cohorts of European ancestry. It failed to
reliably identify any genetic variants predisposing to ERP. There was presumably
87
insufficient statistical power, but more importantly these results suggested
significant heterogeneity within the ERP phenotype.
7.2
Prevalence of early repolarization patterns (I-IV)
Among the 10 864 middle-aged Finnish subjects (I), the overall prevalence of an
early repolarization ECG pattern was 5.8%, including 3.5% in inferior and 2.4%
in lateral leads. Comparably, in the Health 2000 Finnish general population
sample of 5489 subjects (II), the ERP prevalence was 3.3%, and in the
Framingham –sample of 3955 subjects from United States (II), the prevalence
was 6.1%. Among the examined athlete cohorts (III), the total ERP prevalence
was 43.5% in 62 young Finnish athletes, and 30.0% in 503 US collegiate athletes.
Among the victims of SCD and survivors of acute coronary event (IV), the total
prevalence of ERP was 10.8%. The distributions of ERP in inferior and lateral
territory in different cohorts are presented in Figure 13. These numbers were in
the same range or somewhat lower than in other recent studies, in which the
prevalence of ERP has been reported to lie in a range between 3% and 24%
(Haissaguerre et al. 2008, Haruta et al. 2011, Noseworthy et al. 2011a, Reinhard
et al. 2011, Rosso et al. 2008, Sinner et al. 2010, Tikkanen et al. 2009a). In
athletes, significantly higher prevalences have been reported (Cappato et al. 2010,
Junttila et al. 2010, Noseworthy et al. 2011c).
The prevalence of ERP seems to vary considerably, depending on the
demographic features of the studied population; age, race, gender and physical
activity. For instance, in the present studies the ages ranged from 30 to 60 years in
study population B, in which an obvious age dependency of ERP was also
observed. Interestingly, in the same study, by using uniform methods the
prevalence of ERP was estimated to be twice as high in Americans as in the
Finnish sample (6.1% vs 3.3%, respectively). One plausible explanation could be
that the observation of ERP is dependent on whether the interpretation is done
from paper or digital ECG, and whether the paper speed of the ECG is 25 or 50
mm/s. The higher prevalence of ERP in the fourth study can probably be
explained by a higher prevalence of cardiac disease within this older population,
as structural heart disease might itself increase the presence of ERP
(depolarization hypothesis). Although there is less information available on the
prevalence of ERP in patients with diagnosed structural heart disease, there is one
study claiming that there is a prevalence of 20% for ERP in patients with chronic
88
coronary artery disease (Patel et al. 2010). A recent publication also highlighted
the importance of definition, as the prevalence of ERP varied from 2% up to 30%
in the same cohort sample depending on the kind of definition being used to
categorize ERP (Heng et al. 2012).
Fig. 13. Prevalences of J waves in investigated populations.
One interesting observation from the first study was the finding that in more than
three out of every four subjects, ERP was present in baseline ECG and also in a
tracing recorded several years later. This suggested that ERP was a stable rather
than a transient phenomenon, but was in conflict with the claim that the ERP
amplitude and therefore the recognition of the whole pattern varies from day to
day depending on heart rate and neurovegetative tone (Mizumaki et al. 2012).
This divergence may well be explained by the possibility that there are structural
abnormalities behind the ERP pattern observed in our middle-aged populations, in
whom subclinical cardiac disease could be expected.
89
In athletes, the dominant ST-segment type following ERP was rapidly
ascending: 96% and 85% of ST-segments were classified as ascending in the
Finnish and US athletes, respectively. In the general population (study population
A), ascending ST-segment was present in 28.5% of subjects with ERP, and
horizontal/descending ST-segment in 71.5%. In a subsequent analysis, the ST
segments were classified as follows in Health 2000 and Framingham cohorts:
42.4% horizontal and 57.6% ascending in the Health 2000, 64.2% horizontal and
35.8% ascending in the Framingham (Sinner et al. 2012). These results are
consistent with more recent data from a French general population sample, in
which the prevalence of ERP was 13.3%, and 66% of the ERP positives displayed
horizontal or non-ascendant ST-segment (Rollin et al. 2012).
7.3
Demographic features, clinical correlates and heritability of
early repolarization pattern (I-III)
In studies I and III (study population A), differences were observed in the
demographic characteristics between those with and without ERP. Subjects with
ERP in the inferior leads were more often men and smokers, had a lower average
resting heart rate, had a lower body mass index, had a lower blood pressure, had a
shorter QTc interval and a longer QRS duration, and were more likely to have
electrocardiographic signs of coronary artery disease (according to Minnesotacriteria) than those without the pattern (study I). ERP in lateral leads was
associated with electrocardiographic evidence of left ventricular hypertrophy (I).
The predomination of male gender in the early repolarization pattern has been
observed in several other studies. Over two thirds of ERP carriers seem to be men,
and they also exhibit greater J wave amplitudes as compared to women.
(Haissaguerre et al. 2008, Rosso et al. 2008, Sinner et al. 2010, Tikkanen et al.
2009a)
Subjects with various types of ST-segment after the J waves had certain
differences in the baseline characteristics (III): Those with a rapidly ascending
ST-segment were younger, their heart rate and blood pressure were lower, and
they more commonly exhibited ECG signs of left ventricular hypertrophy. In
contrast, subjects with horizontal or descending ST-segment after ERP were
somewhat older and had longer QRS duration than those without ERP. Overall,
these findings from the third study revealed that those subjects with ERP and
rapidly ascending ST-segment were healthier and likely to be more physically
90
active than the others, leading to the presumption that the ascending ST-segment
ERP variant might be a reflection of athlete-type ECG changes such as left
ventricular hypertrophy voltage in lateral precordial leads. This concept has
support from a study, in which ERP (mainly ascending ST-segment types, and
predominantly in lateral leads) was found to have strong clinical associations
among competitive athletes, as the prevalence of ERP increased after intense
physical training (Noseworthy et al. 2011c). Furthermore, the ascending STsegment with ERP was the dominant form in healthy young athletes in another
major study (Rosso et al. 2011), compared to patients with idiopathic ventricular
fibrillation, among which the horizontal ST dominated.
The second study (study populations B and C) established the independent
predictors of ERP in a multivariable model in unselected, community-based
cohorts. The following independent associations of ERP were identified; male
gender, lower systolic blood pressure, higher Sokolow-Lyon index, and lower
Cornell voltage. Other than the lower Cornell voltage, similar associations with
ERP and male gender, lower blood pressure and higher Sokolow-Lyon index have
been described elsewhere (Haissaguerre et al. 2008, Nam et al. 2008, Riera et al.
2008b).
One noteworthy observation is the considerable age-dependency of early
repolarization prevalence among males. The pattern is over-represented among
young males compared to females, but the high prevalence seems to decline
rapidly during middle age (Noseworthy et al. 2011b), which points to a strong
influence of testosterone as a modifier of the ERP presence. A similar
phenomenon has also been observed in Brugada syndrome (Shimizu et al. 2007).
Among competitive athletes, the early repolarization pattern has strong
associations with clinical factors. A causal role between exercise and ERP was
observed in a cohort of collegiate athletes in whom intense physical training
increased the prevalence of ERP from 37% to nearly 53% (Noseworthy et al.
2011c), but unfortunately no data is available of the distribution of ST-segment
types in these athletes. In this set of athletes, the increased occurrence of early
repolarization was independent of the echocardiographic findings related to
athletes’ heart remodelling (Noseworthy et al. 2011c). The prevalence of early
repolarization pattern was 30% in another collegiate athlete cohort in the US; of
these 85% exhibited the ascending ST-variant (Junttila et al. 2010, Tikkanen et al.
2011).
The second publication demonstrated that the ERP observed in the general
population might have a heritable basis, with a doubled increased risk in siblings
91
of an individual with ERP. The sibling recurrence risk was attenuated in the older
age stratum. Whether this reflects a chance effect due to the lower prevalence in
this age group or a smaller contribution of genetic factors in relation to
environmental and non-genetic clinical factors at older ages will require further
investigation. Subsequently, similar observations have been published in other
populations. In UK families, a 2.5-fold occurrence of ERP was observed in the
offspring if at least one parent was carrying ERP (Reinhard et al. 2011), and
subsequently the familial occurrence of ERP was also demonstrated among the
relatives of sudden arrhythmic death syndrome probands (Nunn et al. 2011).
Further discussion on the genetics of ERP will be continued in chapter 6.6.
7.4
Prognosis of early repolarization pattern and the significance
of ST-segment morphology (I, III)
As presented in the literature review, in the milestone publication of Haissaguerre
and colleagues (Haissaguerre et al. 2008), there was an obvious overrepresentation of early repolarization ECG pattern in those with idiopathic VF
(31%) compared to controls (5%), and the J waves were greater in amplitude in
these cases than in the controls. Furthermore, those with extreme J waves (>5mm)
had the highest occurrences of ventricular fibrillation episodes during the followup. These findings were shortly thereafter confirmed in multiple case-control
studies (Nam et al. 2008, Rosso et al. 2008). Nam and colleagues reported ERP
to be present in 58% in IVF patients vs 3% in controls. Rosso and colleagues
similarly described a significantly increased prevalence of ERP in IVF patients
when they were compared to matched controls (42% vs 13%). These findings of
JERP occurring significantly more frequently among IVF survivors than in
matched controls have now been confirmed in several other case-control studies
(Abe et al. 2010, Derval et al. 2011, Merchant et al. 2009).
The first study of this thesis revealed that the early repolarization pattern in
the inferior leads was associated with a significantly increased risk of death from
cardiac causes in middle-aged subjects among the general population. The results
of this publication were consistent with the observations from previous casecontrol studies. The presence of high amplitude (>0.2mV) J waves in the inferior
leads was a stronger predictor of death from cardiac causes than other well-known
electrocardiographic risk markers, such as the QTc interval and signs of left
ventricular hypertrophy. ERP remained an independent prognostic marker even
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after adjustments for several other risk factors. The observations of inferior
manifestation being a stronger predictor of cardiac death than lateral ER patterns
and the prognostic value of the J wave amplitude were similar to phenomena also
reported in survivors of primary ventricular fibrillation (Rosso et al. 2008).
Although the average long-term prognosis of subjects with ERP was observed to
be significantly worse than among the community, the mechanisms accounting
for these higher mortality rates could not be investigated with the present kind of
retrospective study design.
An interesting discovery from the first study was the fact that the survival
curves for cardiac mortality started to diverge 15 years after the baseline
recordings (in the early 1980s) and continued to diverge at a constant rate
throughout the follow-up period, even though the treatment and prognosis for
patients with cardiac disease overall have improved during recent years. This led
to the hypothesis that ERP may be a trigger of fatal events during myocardial
ischemia (study IV).
The third study was the first to show that inferolateral ERP in a standard 12lead ECG was not uniformly associated with an increased risk of arrhythmic
death. It was demonstrated that differences in the ST-segment morphology
following the J waves had important prognostic significance. The highest risk for
arrhythmic death was observed with the combination of ERP in the inferior limb
leads, high amplitude (>0.2 mV) J waves, and a dominant horizontal or
descending ST-segment after the J waves. The rapidly ascending ST-segment after
EPR was the dominant type encountered in athletes, and notably less common in
the middle-aged general population. Moreover, this pattern was not associated
with adverse outcomes. This finding was consistent with the concept that ERP in
athletes is generally benign, although there might be some exceptions to this rule
(Cappato et al. 2010). The present observations on the significance of the ST
segment morphology have subsequently been confirmed in a series of IVF
patients (Rosso et al. 2011) and in another general population sample (Rollin et
al. 2012). Recently, this ERP pattern with horizontal/descending ST-segments in
inferior or inferolateral leads was observed as a marker of higher risk of
arrhythmic events in patients with malignant arrhythmias, if the pattern persisted
during exercise (Bastiaenen et al. 2013).
It was not possible to identify any parameter to distinguish between terminal
QRS notching and slurring (independent of the following ST-segment
morphology) in the analyses of the third study, as the results were contradictory.
When all ERP cases were pooled together, subjects with a notched J wave had a
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worse prognosis, but in other comparisons, the results were ambiguous. A high
amplitude slurred ERP type in the inferior leads was associated with the highest
risk of arrhythmic death in combination with the horizontal/descending STsegment. However, it should be acknowledged that the small sample size in these
subgroups precluded any firm conclusions from being drawn from these analyses
despite the fact that statistical significance was reached. Prior to this publication,
terminal left precordial QRS notching had been reported to be more prevalent in
the malignant (idiopathic ventricular tachycardia/fibrillation) than in the benign
variants of ERP (Merchant et al. 2009). Similarly, a notched ERP was found to
be more prevalent in patients with idiopathic ventricular fibrillation than in
matched control subjects, whereas the presence of slurred ERP did not differ
between the groups (Rosso et al. 2008). Furthermore, recently, ERP with the
notching pattern followed by horizontal or descending ST segments was
associated with a nearly 9-fold risk for suffering cardiovascular death in a French
population (Rollin et al. 2012), whereas the slurring pattern was not associated
with increased mortality rates.
7.5
Significance of early repolarization pattern during acute
coronary events (IV)
The fourth study observed that there was a significant and independent
association in the general population sample between ERP, documented in a
random ECG recording prior and remote to the event and the risk of sudden
cardiac death at the time of an ischemic event. The risk for sudden death was
doubled even after multivariate adjustments, with the highest risk being observed
for ERP with horizontal or descending ST-segments, which supported the
working hypothesis. Although there were demographic and clinical differences
between the victims and controls, the association between ERP and SCD was
independent of those factors suggesting, although not confirming, the
vulnerability of individuals with ERP to suffer malignant arrhythmias during
ischemia. Furthermore, the SCD victims had a lower prevalence of previously
diagnosed cardiac disease in support the concept that ERP increases the risk of
SCD in those subjects who suffer sudden death as their first manifestation of
cardiac disease. The prevalence was notably high in this elderly population as
compared to values from previous publications, which may well be explained by
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the higher prevalence of cardiac disease in the studied subjects, if structural heart
disease itself is thought to increase the presence of ERP.
The results of the fourth study provided one plausible mechanistic link
between ERP and risk of SCD: the presence of ERP might act as a factor
facilitating the occurrence of fatal arrhythmia during an acute ischemic event.
This proposal agrees with previous results from the first study, in which
arrhythmic death among middle-aged subjects with ERP occurred at a relatively
high age (>55 years). In this age group, SCD has been most commonly caused by
an acute ischemic coronary event in the Finnish population (Hookana et al.
2011a). ERP with a non-ascending ST-segment has also been demonstrated to
increase the incidence of cardiac events in vasospastic angina patients without
fixed coronary artery disease (Oh et al. 2012). Vasospastic angina is a
consequence of a coronary artery spasm, which provokes transient myocardial
ischemia. Furthermore, the risk for ventricular fibrillation during the first 48
hours after myocardial infarction has recently been shown to be higher in patients
who exhibited ERP with horizontal/descending ST segments in the pre-morbid
ECG (Naruse et al. 2012, Rudic et al. 2012). In patients with ST-elevation
myocardial infarction (STEMI), previous ERP was more common in patients with
subsequent ventricular tachyarrhythmias (26% vs 4%), especially when present in
the inferior leads (Patel et al. 2012). In another recent study examining acute
STEMI patients, the presence of ERP was associated with ventricular arrhythmias
and VF (Nakayama et al. 2013). When these observations are combined, one can
speculate that patients with the early repolarization ECG pattern suffer an
increased risk for ventricular fibrillation during events such as those present in
myocardial ischemia that further shorten the action potential and increase the
repolarization dispersion.
7.6
Genetics of early repolarization pattern (V)
The fifth study of this thesis, a multicenter meta-analysis of GWAS attempted to
identify if single nucleotide polymorphisms were associated and evaluated ERP in
almost 15 000 individuals from the general population. Although the initial results
of GWAS suggested promising results e.g. with KCND3, which encodes the
voltage-gated potassium channel, none of the signals could be replicated. This
might have been due to the lack of statistical power, but the negative results are
more likely related to the possibility that the characteristic early repolarization
95
ECG pattern could be caused by multiple differential underlying changes. Further
studies to identify genetic loci associated with ERP are required.
Elsewhere, several independent studies have pointed to a heritable basis for
early repolarization ECG pattern. In an investigation from UK families, a 2.5 fold
occurrence of ERP was observed in the offspring if at least one parent was
carrying ERP (Reinhard et al. 2011). In the second study of this thesis, similarly
increased odds of ERP were observed in the siblings of ERP positive individuals
(Noseworthy et al. 2011a). These estimates are within the same range as reported
for other heritable ECG parameters such as the PQ and QT intervals (Hanson et
al. 1989), for which chromosomal loci have been identified through genome wide
association studies (Newton-Cheh et al. 2009, Pfeufer et al. 2009, Pfeufer et al.
2010). Furthermore, recently the familial occurrence of ERP was demonstrated
among the relatives of sudden arrhythmic death syndrome probands (Nunn et al.
2011). However, it should be noted that these observational results of increased
occurrence in siblings could also be explained by shared clinical and behavioural
factors, such as exercise habits within the same family, since physical activity is
known to strongly influence at least the ascending ST -phenotype of early
repolarization pattern. Nevertheless, recently, the transmission of early
repolarization was found to be compatible with an autosomal dominant form of
inheritance in four families affected with ERP (Gourraud et al. 2013).
Several mutations have been reported in individuals with ERP and sudden
cardiac arrest, i.e. those with the early repolarization syndrome. A single study
has described mutations in the cardiac L-type calcium channel among probands
diagnosed with Brugada syndrome, idiopathic ventricular fibrillation and early
repolarization syndrome (Burashnikov et al. 2010). The L-type calcium channel
mutations have been previously associated with Brugada and short QT syndromes
(Antzelevitch et al. 2007b, Cordeiro et al. 2009). KCNJ8 is nother susceptibility
gene for J-wave syndromes; this gene encodes the cardiac ATP-sensitive
potassium (KATP) channel (Barajas-Martinez et al. 2012, Delaney et al. 2012,
Haissaguerre et al. 2009a, Medeiros-Domingo et al. 2010). Some other variants
have been identified (Watanabe et al. 2011) affecting genes that encode sodium,
potassium, and calcium currents, thus supporting the repolarization abnormality
hypothesis as the underlying cause of ERP (Antzelevitch 2012). However, in the
recent study on familial ERS (Gourraud et al. 2013), none of these mutations
could be detected, suggesting further heterogeneity of ERS and IVF.
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7.7
Early repolarization – overall evidence
As already mentioned in the literature review, the terms early repolarization
syndrome and early repolarization ECG pattern should be acknowledged as being
distinct from each other. The syndrome of early repolarization should be used
only to refer to patients with resuscitated cardiac arrest, documented VF or
polymorphic VT, or possibly in the future, in relatives with genetic mutations
associated with early repolarization syndrome. By contrast, the early
repolarization pattern is an ECG variant commonly observed in several conditions
and asymptomatic states. The vast majority of individuals investigated during this
thesis work were asymptomatic carriers of ERP. This pattern seems to be
associated with adverse events over the long term, but the risk of VF is extremely
low if there are no other symptoms suggestive of a malignant etiology.
7.7.1 The overall evidence of ERP among general population in the
literature
In the general population, a total of six large population-based studies have been
published, of which one is the initial study of this thesis. Two of these studies
have concluded that the early repolarization pattern is benign (Klatsky et al.
2003b, Uberoi et al. 2011), whereas four have associated the pattern with adverse
outcomes including cardiovascular and arrhythmic death (Haruta et al. 2011,
Olson et al. 2011, Sinner et al. 2010, Tikkanen et al. 2009b).
In 2003, Klatsky and colleagues found that individuals with early
repolarization, defined as ST segment elevation ≥0.1mV, displayed no increased
risk of death or hospitalization during a follow up of 2 years (Klatsky et al.
2003b). In this cohort, only 29% of patients with ST segment elevation had also J
waves present. Recently, another group found no significant associations between
early repolarization and cardiac mortality, again mainly focusing on ST segment
elevation (Uberoi et al. 2011), in fact they observed decreased mortality rates
associated with ST-elevations.
In 2009, the first publication of this thesis indicated increased cardiac and
arrhythmic mortality rates in middle-aged subjects with the early repolarization
pattern, especially those with inferior and high amplitude J waves. These
observations were soon confirmed in a German population of 1,945 subjects, in
which the early repolarization pattern was associated with a two to four fold
increased risk of cardiac mortality and inferior manifestation of ERP elevated the
97
risk even more extensively (Sinner et al. 2010). Thereafter Haruta with his
colleagues stated that ERP was associated with a decreased risk of cardiac and allcause mortality, but a significantly elevated risk of unexpected sudden death in
5,976 atomic-bomb survivors in Japan (Haruta et al. 2011). The observed risk of
unexplained death was again a doubling, given the fact that the prevalence was
strikingly high (23.9%) when compared to previous publications. In another
prospective population-based study on 15,141 subjects (Olson et al. 2011), a
prevalence of 12.3% was observed for J waves, and these were associated with a
doubled risk of sudden cardiac death in whites and in females, but not in blacks or
males. Recently, a prevalence of 13% and nearly a nine-fold risk for
cardiovascular death was observed in a French general population sample of
1,161 subjects (Rollin et al. 2012).
The prognostic value of early repolarization pattern has also been evaluated
among patients with chronic coronary artery disease and an implanted
cardioverter-defibrillator. With a case-control setup, the prevalence of early
repolarization pattern was significantly higher among patients who had
appropriate ICD therapy for ventricular arrhythmias than in those without such
events (32 vs 8%) (Patel et al. 2010). In another study, the J-point amplitude
recorded in right ventricular intracardiac implantable cardioverter-defibrillator
electrogram was significantly augmented immediately before the onset of
polymorphic ventricular tachycardia or VF in patients with structural heart
disease (Tereshchenko et al. 2012).
The prognostic significance of ERP in the general population seems to
fluctuate according to the definitions and methods being used. The most apparent
and significant difference between these studies has been that those describing a
benign nature have focused mainly on ST-segment elevation in contrast to the
others with the higher mortality rates, which have placed more recent emphasis
on the J waves regardless of the presence or absence of ST-segment elevation.
Overall, the current evidence suggests that ERP is an independent predictor of
adverse outcomes at the community level. In a recent meta-analysis of
publications on ERP prognosis (Wu et al. 2012), the estimated absolute
difference of subjects with J waves was 70 cases of arrhythmic death per 100,000
subjects per year, indicating that although the ECG variant is associated with
arrhythmias, the absolute risk is very low.
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7.7.2 Analogies with QT syndromes
The inherited short and long QT syndromes are associated with a high risk of
sudden cardiac death, and furthermore, the prolongation of the QT interval is a
risk factor for SCD also in the population level. However, there is significant
overlapping between the normal limits of the QT interval and the associated
mutations. Furthermore, the mortality risk among the general population is
moderate (Chugh et al. 2009, Straus et al. 2006, Tikkanen et al. 2009b).
Similarly early repolarization syndrome (J waves in the verified absence of
structural heart disease) is associated with a high risk of IVF and sudden death,
and the early repolarization pattern (idiopathic occurrence of J waves in
asymptomatic healthy individual with or without possible cardiac condition) have
been linked with a moderate risk of sudden death in the general population. Thus,
one might consider ERP to be analogous to the normal variation of the QT
interval, whereas the so-called syndrome of early repolarization might be
analogous to the situation in individuals affected by long or short QT syndromes.
There are also several analogies in the risk factors of ventricular arrhythmias
in LQTS and early repolarization: QT prolongation is comparable to
augmentation of J waves, and fever to hypothermia. Additionally, in both LQTS
and early repolarization, bradycardia and acute myocardial ischemia seem to
increase the risk for arrhythmias.
Similarly in early repolarization and QT syndromes, it is important to search
for additional markers to identify those patients who are at a high risk of suffering
adverse events, since all of these conditions are present in a wide range of patients
with abnormal ECG patterns which are not all associated with a similar risk.
7.7.3 Association with Brugada syndrome
The early repolarization syndrome and Brugada syndrome have been speculated
to represent a continuous spectrum of diseases under the term J wave syndromes
(Anzelevitch & Yan 2010). There are indeed several significant similarities
between BrS and early repolarization pattern in IVF patients: the average age of
the first event is under 40 years, a significant male predominance is present in
both phenomena, there is a strong temporal variation in the expression of the
patterns, and furthermore the pattern is normalized by quinidine exposure,
catecholamine stimulation and faster heart rates. (Myerburg & Castellanos 2008)
99
In fact, inferolateral ERP (J waves) have been reported to be present in as
high as 11-15% of Brugada patients, and furthermore their presence has been
shown to have a strong adverse effect on prognosis (Kamakura et al. 2009,
Letsas et al. 2008, Sarkozy et al. 2009). Recently, ERP in multiple leads followed
by horizontal ST-segments were claimed to be highly arrhythmogenic substrates
in BrS patients (Takagi et al. 2012).
As discussed in the literature review, there is recent data pointing to the
possibility of delayed depolarization in the right ventricular outflow tract as a
mechanism contributing to J waves, arrhythmia expression, and possibly both
phenomena in BrS (Nademanee et al. 2011, Wilde et al. 2010). Similarly to the
situation in most diseases, it is very likely that Brugada syndrome and early
repolarization are not fully attributable to one single mechanism, but possibly
they are the outcomes of several various underlying pathophysiologies.
7.7.4 Early repolarization or delayed depolarization?
As mentioned earlier, there has been an on-going debate on whether the pattern of
early repolarization is truly due to accelerated repolarization or is it rather because
there is delayed depolarization present (Antzelevitch et al. 2011, Borggrefe &
Schimpf 2010, Littmann 2010, Littmann & Tenczer 2011, Surawicz & Macfarlane
2011, Wellens 2008).
It is highly probable that individuals with ERP consist of a heterogeneous
group of individuals with diverse clinical backgrounds and different
electrophysiologic mechanisms. In IVF patients with marked J waves and without
any signs of structural heart disease, accelerated repolarization is likely to be the
mechanism; Steep repolarization gradients have been demonstrated with
electrocardiographic imaging (Ghosh et al. 2009), suggesting that J waves are
markers of an increased dispersion of repolarization. In contrast, in many elderly
patients, the pattern might be caused by abnormal depolarization due to
underlying subtle heart disease as postulated by Littman in his letter (Littmann
2010). The depolarization concept is supported by the findings from a large
cohort in which ERP with the presence of Q waves or T wave inversions
predicted cardiovascular death, but plain ERP was not associated with any
increased risk (Uberoi et al. 2012). In fact, another study recently demonstrated
that patients with inferior ER have a high prevalence of late potentials in signal
averaged ECG (SAECG) and that some of the J waves seem to persist during
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isoprenaline challenge, which is suggestive of an involvement of depolarization
abnormalities in a subset of patients with early repolarization (Roten et al. 2012a).
This finding was supported by the expected normalization of ERP in the lateral
leads during beta-adrenergic (isoprenaline) stimulation (Roten et al. 2012a).
Furthermore, Abe and colleagues demonstrated that the repolarization
abnormality markers such as T-wave alternans or QT dispersion were not
associated with J waves in IVF patients, but the incidence of late potentials,
which are reflections of a depolarization abnormality, was higher in those with
ERP than those without this pattern (Abe et al. 2010). Augmentation of J waves
prior to the onset of ventricular fibrillation has been demonstrated in case reports
and larger scale studies, indicative of a causal relationship between ERP and VF
(Bernard et al. 2009, Nam et al. 2008, Shinohara et al. 2006b). Recently, another
study presented data that the augmentation of J waves occurred immediately
before spontaneous VF episodes, but not before the onset of monomorphic
ventricular tachycardia in patients with ICDs (Tereshchenko et al. 2012). These
observations strongly support the previous hypotheses that different
pathophysiologies might be underlying the various regional J waves. Regional
differences in ion channel characteristics are possible, but there is more likely to
be involvement of depolarization defects. Bastiaenen and colleagues found that
60% of patients in whom ERP persisted during exercise displayed evidence of
subtle structural heart disease (Bastiaenen et al. 2013). To further provoke
discussion, Littmann and Tenczer have suggested even an accessory pathway
conduction to possibly underlie the pattern (Littmann & Tenczer 2011), as
recently two cases were presented with unmasking of ERP in pre-exication
(Nagao et al. 2011). Based on these observations, the patient population with
inferolateral ERP seem to be reflecting a broad range of various
pathophysiologies.
Hoogendijk and colleagues have discussed possible explanations between
early repolarization pattern and VF in their recent editorial (Hoogendijk et al.
2012). Changes in the cardiac action potential, as presented in the literature
review, have generally been believed to underlie the early repolarization pattern in
both healthy individuals and in those with idiopathic ventricular fibrillation.
However, this explanation is at odds with the fact that idiopathic ventricular
fibrillation is a very rare condition, but early repolarization pattern and thus these
abnormal currents can be observed in a significantly larger proportion of healthy
individuals. It has also been speculated that the mechanism causing early
repolarization pattern might be the same as that responsible for ventricular
101
fibrillation by providing a trigger or substrate for VF through the loss of the
action potential dome and the initiation of re-entrant arrhythmias, as discussed in
chapter 2.1.4 of this thesis. The J waves might serve as a way of identifying of
those individuals with a deep notch in the action potential and who have at least a
hypothetical risk of suffering re-entry arrhythmias. Furthermore, ERP in
idiopathic VF patients may only mimic the early repolarization pattern in healthy
individuals and reflect activation abnormalities. Hoogendijk and colleagues also
proposed, that a deeper notch in the action potential (suggested to underlie also J
waves) would indicate a shift in the balance towards more repolarizing current
meaning that there would be less depolarizing current available in the adjacent
cells, hence impairing conduction and theoretically resulting in increased
susceptibility to unidirectional block and VF during transient arrhythmogenic
conditions, such as ischemia (Hoogendijk et al. 2012). This theory would partly
explain the association between ERP and arrhythmic mortality at the population
level and is consistent with the findings of increased risk of SCD during ischemic
events in those with ERP (study IV). Overall, all of these pieces of evidence
demonstrate that the exact mechanisms underlying early repolarization pattern are
far from clear and require further work.
7.7.5 Markers of higher risk of adverse events
Similarly to other arrhythmia syndromes, syncope, aborted SCD and a family
history of SCD are major markers of increased risk also in the case of early
repolarization. Watanabe and colleagues reported younger age, family history of
SCD and history of electrical storms as the most significant markers for
arrhythmia recurrences in ERS patients (Watanabe et al. 2012).
Overall, not all manifestations of ERP across the ECG leads are equally
proarrhythmic, since the localization and ST segment morphology seems to play
an important prognostic role. In asymptomatic healthy individuals, J-point
elevation is most prominently seen in mid-precordial leads (V2 to V4), especially
in young male athletes. Terminal QRS notching accompanied by ST-elevation in
left-precordial (V4 to V6) and inferior (II, III and aVF) leads is likewise a common
finding among young healthy individuals. In contrast, evidence is accumulating in
support of the finding that terminal QRS changes in the absence of ST-elevation
confer the highest risk of adverse events. As discussed, ERP with horizontal or
descending ST segments has been shown to possess the highest risk of adverse
102
outcomes in IVF patient samples, as well as in general population samples
(Bastiaenen et al. 2013, Rollin et al. 2012, Rosso et al. 2011, Tikkanen et al.
2011). Terminal QRS notching or slurring without ST-elevation are most often
seen in the inferior leads, but are frequent also in left limb leads (I, aVL). They
are seen less often in left-precordial leads, and practically never in midprecordials. Figure 15 demonstrates ERP in two young, healthy athletes (study
III), and Figure 16 illustrates the typical ECGs of two middle-aged persons with J
waves and different ST segment morphologies. A recent study, already discussed
in the previous chapter, also demonstrated that there might be significant
differences in the pathophysiological mechanism of inferior and lateral ERP
manifestations, as lateral J waves invariably normalized during beta-adrenergic
stimulation, but precordial and inferior J waves persisted in a subset of patients
(Roten et al. 2012a).
The amplitude of J waves also impacts on the prognostic evaluation of ERP.
In case-control studies, the amplitude of the J waves has been significantly greater
in patients with idiopathic ventricular fibrillation than controls (Abe et al. 2010,
Haissaguerre et al. 2008, Nam et al. 2008, Rosso et al. 2008) and high amplitude
J waves have been shown to possess prognostic significance among healthy
individuals in the general population (studies I, III).
The augmentation of J waves has also been demonstrated to predispose
ventricular arrhythmias (Kitazawa et al. 2011, Nam et al. 2008, Tereshchenko et
al. 2012). Furthermore, the dynamicity of ERP, observed as an augmentation after
sudden R-R interval prolongation, has been demonstrated to be highly specific for
idiopathic ventricular fibrillation (Aizawa et al. 2012). Therefore transient
augmentation of J waves should be regarded as a sign of a risk of suffering fatal
arrhythmias. Figure 14 describes the various early repolarization patterns and the
associated risks in a simplified matter.
An attempt has been made to find associations between common markers of
ventricular arrhythmogenesis (ventricular late potentials in signal averaged ECG,
depressed heart rate variability and presence of ventricular ectopy) and early
repolarization pattern in patients referred to ambulatory 24-hour ECG recording
(Holter) with negative results (Soliman et al. 2011). These results suggest that the
arrhythmogenic potential in ERP is not likely to be mediated through pathological
pathways, which could be detected by these markers, although the definition of
ERP used in this study emphasized ST elevation (not the presence of J waves),
and was based on an automated recognition of the pattern. Another recent study
reported the Tpeak-Tend interval to be significantly increased and the Tp-Te/QT
103
ratio to be significantly increased in patients with the early repolarization pattern
as compared to their age- and sex matched controls (Karim Talib et al. 2012).
The Tpeak-Tend and Tp-Te/QT ratio are known markers of spatial dispersion of
the repolarization underlying the development of high-risk ventricular
arrhythmias in various cardiac conditions.
Fig. 14. Early repolarization patterns and magnitude of sudden cardiac death risk.
104
Fig. 15. Inferior J waves followed by rapidly ascending ST segments in two young and
healthy athletes.
105
Fig. 16. Four example ECGs of two middle-aged subjects carrying J waves with (A,C)
and without (B,D) ST segment elevation in two distinct patient populations.
106
7.8
Screening for early repolarization and patient management
Thus far there are no validated techniques to provoke ERP, or reliable methods
recognition of the malignant patterns of early repolarization. The amplitude of J
waves in infero-lateral leads is strongly associated with vagal tone and
hypothermia; ventricular pauses and bradycardia tend to increase the amplitude of
the J waves (Bastiaenen et al. 2010, Gross 2010, Kaneko et al. 2010, Wilhelm et
al. 2010), and thus one could hypothesize that Holter monitoring could possibly
unmask pathological J waves during bradycardia. Furthermore, in patients with
early repolarization and ICD, the incidence of ventricular tachyarrhythmias has
been shown to undergo significant circadian variation with nighttime peaks (Kim
et al. 2012). Sodium-channel blockade, the method used to unmask the malign
Brugada pattern, has recently been shown to attenuate infero-lateral J waves in
patients with idiopathic VF conversely to the situation in patients with Brugada
syndrome (Kawata et al. 2012, Roten et al. 2012b). A recent report suggested that
the Valsalva maneuver might be a potential method to reveal the ECG pattern in
family members of sufferers of early repolarization syndrome, but the prognostic
value of this test is yet uncertain (Gourraud et al. 2013). Gourraud and colleagues
demonstrated that the Valsalva maneuver revealed an early repolarization pattern
in 28% of unaffected relatives, and increased the J wave amplitude in 85% of
ERP affected relatives. One could argue that genetic testing may be a potential
definite screening tool in family members of early repolarization syndrome, but it
is likely that it will not be available in the very near future.
All of the major automatic commercial programs for ECG analyzes are still
using the traditional definition of early repolarization with its high take-off ST
segment elevations. Those algorithms do not yet permit the recognition of ERP (J
waves in infero-lateral leads), and therefore are of little or even no help for the
clinician attempting to identify the malignant form of early repolarization.
With the present knowledge, it is not possible to offer any detailed
counselling of treatment of individuals with early repolarization ECG pattern.
Overall, in asymptomatic subjects, screening for ERP is not legitimate, as the
associated arrhythmia risk is extremely low. However, in patients with idiopathic
VF or resuscitated cardiac arrest in whom there is no obvious etiology, the correct
diagnosis of early repolarization has clinical importance, as patients with ERP are
exposed to frequent shocks and electrical storms after the implantation of a
cardioverter-defibrillator, and these events can be prevented by quinidine
107
(Haissaguerre et al. 2009c). Further longitudinal as well as observational studies
on early repolarization patterns are required. Currently the only reasonable
recommendation is that individuals with ERP should reduce their long-term risk
for ischemic cardiac events by minimizing all modifiable risk factors for coronary
artery disease, due to their possible higher risk of suffering arrhythmias during
myocardial ischemia.
7.9
Remaining questions and future directions
Many questions in ERP pathogenesis and magnitude of risk remain unanswered.
The interest in early repolarization has grown tremendously in recent years
resulting in a huge increase in the number of publications, and therefore it can be
anticipated that novel data on this topic will emerge in the following years. The
turnaround in the attitude from viewing early repolarization as a benign towards a
malign phenomenon has raised the problem of confusing terminology (Perez et al.
2012, Surawicz & Macfarlane 2011), as already discussed in this thesis. Although
the used terminology surrounding the terms J waves and early repolarization can
be misleading in many ways, this recently described electrocardiographic pattern,
referred to as early repolarization or J waves, has been shown to have the
potential for arrhythmia prediction in several case-control and general population
samples. The so-called J waves and early repolarization patterns, i.e. terminal
QRS changes, appear to reflect a continuum of risk for arrhythmias. Regardless of
the origin of these patterns, this phenomenon appears to have significant
usefulness in risk prediction in a number of clinical circumstances. Whether ERP
could or should be applied in prospective screening programs is another question.
As previously discussed (Hlatky et al. 2009), the evaluation of novel risk
markers, such as ERP, needs to be conducted in several phases including
prospective validation, proof of incremental value when added to standard risk
markers, and the assessment of outcomes after patient management.
Understanding ERP and other electrophysiological phenomena, and their value in
the mixture of old and novel risk markers, is still an ongoing challenge that
certainly will continue in the years ahead.
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8
Strengths and limitations of the thesis
The most significant strength of all studies of the thesis was that all of the
cohorts’ ECGs were analysed and interpreted one by one, and inter-observer as
well as intra-observer estimations were performed. In none of the studies were
any automatic digital analysers used, which has tended to be the standard
methodology used in many of the other ECG investigations during recent years.
Another major strength of studies I and III was the large population based sample
size and the unique long follow-up period with a vast amount of data available.
Furthermore, the classification of cardiovascular deaths into sudden arrhythmic
deaths and other deaths by experienced cardiologists from the description of the
death certificate was a unique feature of study population A. The second study
had similar strengths: a large community based cohort and a uniform adjudication
process between the two populations (B and C), as well as the inter-/intraobserver analyses.
One major limitation of this thesis is the observational and retrospective
nature of all of its studies, and therefore any conclusions drawn of the underlying
mechanisms remain only speculative.
The general population samples (study populations A, B and C), as well as
the case-control populations (study population D), included only middle-aged and
elderly subjects for the prognostic assessments, which can be considered as a
methodological limitation. It is not appropriate to generalize the prognostic results
directly to younger populations. Furthermore, all populations consisted of
individuals of European ancestry, and therefore the findings may not be
extrapolated to other races.
The small sample size and the case-control nature of the cross-sectional
fourth study are potential limitations, and therefore one cannot generalize the
results drawn from these results (study IV). Prospective follow-up studies would
give more reliable information in this respect. Furthermore, it should be noted that
several demographic and clinical differences were present between the case and
control groups due to the lower incidence of prior medical admissions in those
suffering sudden cardiac death.
One important potential limitation is the lack of a definitive way of
measuring the J-point. The J-point elevation in the studies conducted in this thesis
was measured either from the highest point of terminal QRS notching or slurring
(studies I and III), or from the point of apparent QRS offset according to adjacent
leads (studies II and IV). Additionally, defining the point of QRS offset is not
109
always straightforward, as the duration of the QRS complex varies within
different areas of the myocardium. These can cause potential variations in the
measurements of the J-point between publications, and therefore visual
interpretation by a physician is always required. This is not an easy task, as the
majority of general practitioners consider the interpretation of the standard ECG
to be very challenging.
A minor limitation of all the studies in this thesis is the small number of
example ECGs in the publications, which probably could have been higher in
order to illustrate the typical electrocardiographic features associated with adverse
outcomes. The ECGs presented in the first study are subject to speculation of
overlapping with peri-infarction block (Littmann 2010), which cannot definitely
be ruled out, but was probably present in only a minority of the positive cases
displaying the early repolarization pattern. Nevertheless, as discussed earlier in
this thesis, several pathophysiological phenomena might be underlying the typical
early repolarization pattern and the aetiology cannot be defined from a planar
ECG. The focus of this thesis was to investigate early repolarization pattern in a
standard ECG, regardless of its exact etiology.
The understanding of the results of the publications in this thesis among
general physicians around the globe has proved to be difficult. The first
publication (study I) caused much confusion and alarm that what had been
thought of as a common but completely benign electrocardiographic finding,
could be life-threatening. The classical definition of ascending ST-segments with
high take-off especially in the anterior leads became confused with the recent
definition of emphasis on J waves in infero-lateral leads. Fortunately, the findings
in the third study relieved some of the pressure on the clinical interpretation of the
relevance of incidental early repolarization patterns.
Regardless of the academic study designs in this thesis, as well as in other
publications reporting significant and independent ECG risk factors in specific
patient groups and general population, it is necessary to rationally evaluate the
actual clinical impact of these observations. As discussed in a recent review,
screening of these ECG abnormalities is somewhat questionable (Chou et al.
2011), as there is no data available on how ECG screening could affect clinical
outcomes as compared to no screening. In addition to statistical multivariate
models, there is usually no evidence for any value of adding ECG abnormalities
to the conventional risk factors. Furthermore, it is not possible to draw any
straightforward conclusions about whether an ECG abnormality should change
110
the status of a patient from a low-risk to a higher risk category. For example, a
doubling in the risk of sudden death in a younger patient does not mean that the
patient should be considered at high-risk when the absolute risk for adverse
events (fatal arrhythmias) in this patient group is extremely low.
111
112
9
Conclusions and clinical implications
The results of this thesis have added new valuable information on this potentially
life threatening arrhythmogenic ECG variant. Until the results of this thesis and
its accompanying publications, there was no data available on the prevalence and
long-term prognosis of early repolarization ECG pattern (infero-lateral J waves).
The results of this thesis suggest that the long considered benign early
repolarization, i.e. ST-segment elevation in the absence of conduction defect or
chest pain, should probably continue to be assessed as a benign phenomenon in
young and healthy individuals with no other cause to suspect cardiac illness.
More importantly, these results have demonstrated that ERP with horizontal or
descending ST-segments, i.e. terminal QRS changes especially in the inferior
leads, are associated with markedly increased cardiac mortality in the general
population, and that individuals carrying this variant are at an increased risk of
suffering fatal arrhythmia during myocardial ischemia. In conclusion, J waves and
ST-segment elevation should be considered as independent ECG patterns carrying
divergent prognostic significance instead of regarding them as a benign marker of
good health.
Although the early repolarization ECG pattern increases the relative risk of
arrhythmic events at the population level, the absolute risk in an individual is low
and therefore ERP generally should not be interpreted as a high-risk marker.
Although clinical awareness is warranted, the majority of individuals carrying this
ECG pattern have a benign prognosis. The only reasonable recommendation as a
consequence of the results of this thesis is that all modifiable risk factors for
coronary artery disease should be addressed in patients with ERP to reduce their
long-term risk for fatal events. To date, there is no experimental evidence of any
benefits of screening for ERP in asymptomatic subjects.
113
114
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Original publications
This thesis is based on the following original articles, which are referred to in the
text by their Roman numerals.
I
Tikkanen JT, Anttonen O, Junttila MJ, Aro AL, Kerola T, Rissanen HA, Reunanen A
& Huikuri HV (2009) Long-term outcome associated with early repolarization on
electrocardiography. N Engl J Med 361: 2529–2537
II Noseworthy PA*, Tikkanen JT*, Porthan K*, Oikarinen L, Pietilä A, Harald K,
Peloso GM, Merchant FM, Jula A, Väänänen H, Hwang SJ, O’Donnel CJ, Salomaa V,
Newton-Cheh C & Huikuri HV (2011) The early repolarization pattern in the general
population: clinical correlates and heritability. J Am Coll Cardiol 57: 2284–2289
III Tikkanen JT, Junttila MJ, Anttonen O, Aro AL, Luttinen S, Kerola T, Sager SJ,
Rissanen HA, Myerburg RJ, Reunanen A & Huikuri HV (2011) Early repolarization:
electrocardiographic phenotypes associated with favorable long-term outcome.
Circulation 123: 2666–2673
IV Tikkanen JT, Wichmann V, Junttila MJ, Rainio M, Hookana E, Lappi O, Kortelainen
ML, Anttonen O & Huikuri HV (2012) Association of early repolarization and sudden
cardiac death during an acute coronary event. Circ Arrh Electrophysiol 5: 714–718.
V Sinner MF*, Porthan K*, Noseworthy PA*, Havulinna AS*, Tikkanen JT*, MüllerNurasyid M, Peloso G, Ulivi S, Beckmann BM, Brockhaus AC, Cooper RR, Gasparini
P, Hengstenberg C, Hwang SJ, Iorio A, Junttila MJ, Klopp N, Kähönen M, Laaksonen
MA, Lehtimäki T, Lichtner P, Lyytikäinen LP, Martens E, Meisinger C, Meitinger T,
Merchant FM, Nieminen MS, Peters A, Pietilä A, Perz S, Oikarinen L, Raitakari O,
Reinhard W, Silander K, Thorand B, Wichmann HE, Sinagra G, Viikari J, O'Donnell
CJ, Ellinor PT, Huikuri HV, Kääb S, Newton-Cheh C & Salomaa V (2012) A metaanalysis of genome-wide association studies of the electrocardiographic early
repolarization pattern. Heart Rhythm 9: 1627–1634.
Reprinted with permission from Massachusetts Medical Society (I), Elsevier (II,
V), and Wolters Kluwer Health (III, IV).
Original publications are not included in the electronical version of the
dissertation.
143
144
ACTA UNIVERSITATIS OULUENSIS
SERIES D MEDICA
1196. Koivikko, Minna (2013) Cardiac autonomic regulation and repolarisation during
hypoglycaemia in type 1 diabetes
1197. Aro, Ellinoora (2013) Prolyl 4-hydroxylases, key enzymes regulating hypoxia
response and collagen synthesis : the roles of specific isoenzymes in the control
of erythropoiesis and skeletogenesis
1198. Koivumäki, Janne (2013) Biomechanical modeling of proximal femur :
development of finite element models to simulate fractures
1199. Paavola, Liisa (2013) Salla disease – rare but diverse : a clinical follow-up study of
a Finnish patient sample
1200. Vesterinen, Soili (2013) Osastonhoitajien johtamistyylit osana johtamiskulttuuria
1201. Huusko, Tuija (2013) Genetic and molecular background of ascending aortic
aneurysms
1202. Pisto, Pauliina (2013) Fat accumulation in liver and muscle : association with
adipokines and risk of cardiovascular events
1203. Yannopoulos, Fredrik (2013) Remote ischemic preconditioning as a means to
protect the brain against hypothermic circulatory arrest : an experimental study
on piglets
1204. Arvonen, Miika (2013) Intestinal immune activation in juvenile idiopathic arthritis
1205. Ahonkallio, Sari (2013) Endometrial thermal ablation : a choice for treatment of
heavy menstrual bleeding
1206. Penttilä, Matti (2013) Duration of untreated psychosis : association with clinical
and social outcomes and brain morphology in schizophrenia
1207. Wikström, Erika (2013) Epidemiology of Chlamydia trachomatis infection in Finland
during 1983–2009
1208. Jokela, Tiina (2013) Analyses of kidney organogenesis through in vitro and in vivo
approaches : generation of conditional Wnt4 mouse models and a method for
applying inducible Cre-recombination for kidney organ culture
1209. Hietikko, Elina (2013) Genetic and clinical features of familial Meniere’s disease in
Northern Ostrobothnia and Kainuu
1210. Abou Elseoud, Ahmed (2013) Exploring functional brain networks using
independent component analysis : functional brain networks connectivity
1211. Aro, Aapo (2013) Electrocardiographic risk markers of sudden cardiac death in
middle-aged subjects
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UNIV ER S IT Y OF OULU P. O. B R[ 00 FI-90014 UNIVERSITY OF OULU FINLAND
U N I V E R S I TAT I S
S E R I E S
SCIENTIAE RERUM NATURALIUM
Professor Esa Hohtola
HUMANIORA
University Lecturer Santeri Palviainen
TECHNICA
Postdoctoral research fellow Sanna Taskila
MEDICA
Professor Olli Vuolteenaho
ACTA
EARLY REPOLARIZATION
IN THE INFEROLATERAL
LEADS OF THE ELECTROCARDIOGRAM
PREVALENCE, PROGNOSIS AND CHARACTERISTICS
SCIENTIAE RERUM SOCIALIUM
University Lecturer Hannu Heikkinen
SCRIPTA ACADEMICA
Director Sinikka Eskelinen
OECONOMICA
Professor Jari Juga
EDITOR IN CHIEF
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PUBLICATIONS EDITOR
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ISBN 978-952-62-0230-3 (Paperback)
ISBN 978-952-62-0231-0 (PDF)
ISSN 0355-3221 (Print)
ISSN 1796-2234 (Online)
U N I V E R S I T AT I S O U L U E N S I S
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E D I T O R S
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