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D 1211
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
Senior Assistant Jorma Arhippainen
HUMANIORA
University Lecturer Santeri Palviainen
TECHNICA
Docent Hannu Heusala
ACTA
U N I V E R S I T AT I S O U L U E N S I S
Aapo Aro
E D I T O R S
Aapo Aro
A
B
C
D
E
F
G
O U L U E N S I S
ACTA
A C TA
D 1211
ELECTROCARDIOGRAPHIC
RISK MARKERS OF SUDDEN
CARDIAC DEATH IN MIDDLEAGED SUBJECTS
MEDICA
Professor Olli Vuolteenaho
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 978-952-62-0178-8 (Paperback)
ISBN 978-952-62-0179-5 (PDF)
ISSN 0355-3221 (Print)
ISSN 1796-2234 (Online)
UNIVERSITY OF OULU GRADUATE SCHOOL;
UNIVERSITY OF OULU,
FACULTY OF MEDICINE, INSTITUTE OF CLINICAL MEDICINE;
OULU UNIVERSITY HOSPITAL;
HELSINKI UNIVERSITY CENTRAL HOSPITAL, HEART AND LUNG CENTER
D
MEDICA
ACTA UNIVERSITATIS OULUENSIS
D Medica 1211
AAPO ARO
ELECTROCARDIOGRAPHIC RISK
MARKERS OF SUDDEN CARDIAC
DEATH IN MIDDLE-AGED SUBJECTS
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 4 of Meilahti Hospital, Helsinki,
on 6 September 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 1211, 2013
Supervised by
Professor Heikki Huikuri
Docent Olli Anttonen
Reviewed by
Docent Antti Hedman
Docent Sinikka Yli-Mäyry
Opponent
Docent Vesa Virtanen
ISBN 978-952-62-0178-8 (Paperback)
ISBN 978-952-62-0179-5 (PDF)
ISSN 0355-3221 (Printed)
ISSN 1796-2234 (Online)
Cover Design
Raimo Ahonen
JUVENES PRINT
TAMPERE 2013
Aro, Aapo, Electrocardiographic risk markers of sudden cardiac death in middleaged subjects.
University of Oulu Graduate School; University of Oulu, Faculty of Medicine, Institute of
Clinical Medicine; Oulu University Hospital; Helsinki University Central Hospital, Heart and
Lung Center
Acta Univ. Oul. D 1211, 2013
University of Oulu, P.O. Box 8000, FI-90014 University of Oulu, Finland
Abstract
Sudden cardiac death (SCD) is a major medical and public health concern responsible for 50% of
cardiovascular deaths and as much as 15% to 20% of overall mortality. Coronary heart disease is
the underlying cause of most of these deaths, and in 50% of such cases, SCD is the first
manifestation of the disease. Researchers have investigated numerous noninvasive methods to
more accurately identify individuals at high risk of SCD, but most such studies have focused on
patients with specific heart disease. The standard 12-lead electrocardiogram (ECG) is a widely
available tool to analyze the electrical activity of the heart, but few epidemiological studies have
successfully identified specific electrocardiographic risk markers of SCD at the population level.
This thesis aims to clarify the prognostic implications of several ECG patterns in the general
population. We evaluated the 12-lead ECGs of 10899 middle-aged Finnish subjects (52% male)
recorded between 1966 and 1972, and followed the subjects for 30 ± 11 years.
The prevalence of a prolonged QRS duration ≥ 110 ms and nonspecific intraventricular
conduction delay (IVCD; defined as QRS ≥ 110 ms with no partial or complete bundle branch
block) in the population was 1.3% and 0.6%, respectively. Both were significantly associated with
an elevated risk of all-cause mortality and cardiovascular mortality. QRS duration ≥ 110 ms
doubled the risk of SCD, and IVCD was associated with a three-fold higher risk of SCD.
Two percent of the subjects presented with wide frontal QRS-T angle ≥ 100° (the angle
between the QRS axis and the T-wave axis in the frontal plane). A wide QRS-T angle was
associated with higher overall mortality and more than doubled the risk of SCD, which was mainly
due to an abnormal T-wave axis.
Inverted T-waves in the right precordial leads (V1–V3) or beyond were present in 0.5% of the
population. No increase in mortality or SCD was associated with right precordial T-wave
inversions. In contrast, inverted T-waves in other leads than V1–V3 were associated with higher
risk of cardiovascular mortality and SCD.
Altogether 2.1% of the study participants presented with a prolonged PR interval > 200 ms. No
rise in overall mortality, SCD, or hospitalizations due to heart failure, atrial fibrillation, or stroke
was observed among these subjects during the follow-up period.
In conclusion, of the electrocardiographic parameters studied, prolonged QRS duration, IVCD,
and wide QRS-T angle are associated with SCD in the general population, and such changes in an
ECG should therefore alert the physician to more closely evaluate and follow the patient. On the
other hand, a prolonged PR interval and right precordial T-wave inversions seem to have no
prognostic implications in the absence of other features suggestive of underlying heart disease.
Keywords: arrhythmia, ECG, IVCD, PR interval, QRS complex, QRS-T angle, sudden
cardiac death, T wave
Aro, Aapo, Sydänperäistä äkkikuolemaa ennustavat tekijät EKG:ssä.
Oulun yliopiston tutkijakoulu; Oulun yliopisto, Lääketieteellinen tiedekunta, Kliinisen
lääketieteen laitos; Oulun yliopistollinen sairaala; Sydän- ja keuhkokeskus, HYKS
Acta Univ. Oul. D 1211, 2013
Oulun yliopisto, PL 8000, 90014 Oulun yliopisto
Tiivistelmä
Sydänperäinen äkkikuolema on yleisin kuolinsyy länsimaissa, missä puolet sydänkuolemista ja
15–20 % kokonaiskuolleisuudesta johtuu äkillisestä sydänpysähdyksestä. Sepelvaltimotauti on
yleisin taustalla oleva syy, ja jopa puolessa sepelvaltimotautikuolemista äkkikuolema on taudin
ensimmäinen oire. Jo pitkään on yritetty kehittää menetelmiä, joilla voitaisiin tunnistaa suurimmassa äkkikuoleman vaarassa olevat. 12-kanavainen EKG on laajalti käytössä oleva tutkimus,
jolla tutkitaan sydämen sähköistä toimintaa, mutta sydänperäistä äkkikuolemaa spesifisti väestössä ennustavia EKG-poikkeavuuksia ei ole juuri pystytty osoittamaan.
Tämän väitöskirjatyön tarkoituksena oli tutkia, miten EKG:ssä nähtävät ilmiöt kuten QRS
kompleksin kesto, QRS-kompleksin ja T-aallon välinen kulma, kääntyneet T-aallot sekä PR-aika
korreloivat ennusteeseen väestötasolla. Tutkimme 10899 suomalaisen keski-ikäisen henkilön
(52 % miehiä) EKG:t, jotka oli rekisteröity 1966–1972, ja seurasimme tutkittavia keskimäärin
30 (± 11) vuotta.
Leventynyt QRS kompleksi ≥ 110 ms löytyi 1.3 %:lta ja epäspesifi kammionsisäinen johtumishäiriö eli IVCD (QRS ≥ 110 ms ilman osittaista tai täydellistä haarakatkosta) 0.6 %:lta tutkituista. Molemmat muutokset liittyivät lisääntyneeseen kokonaiskuolleisuuteen sekä sydänkuoleman riskiin. QRS kompleksin kesto ≥ 110 ms assosioitui lisäksi kaksinkertaiseen ja IVCD kolminkertaiseen äkkikuolemariskiin.
2 %:lla tutkituista sydänlihaksen depolarisaation suuntaa kuvaavan QRS-kompleksin akselin
ja repolarisaatiota kuvaavan T-aallon akselin välinen frontaalitason QRS-T kulma oli
leveä ≥ 100°. Näillä henkilöillä kokonaiskuolleisuus oli lisääntynyt, ja sydänperäisen äkkikuoleman riski oli yli kaksinkertainen verrattuna henkilöihin jolla QRS-T kulma oli < 100°.
Oikeanpuoleisissa rintakytkennöissä V1–V3 todettiin negatiiviset T-aallot 0.5 %:lla tutkituista, mutta näillä ei ollut vaikutusta kuolleisuuteen. Sen sijaan henkilöillä, joilla todettiin negatiiviset T-aallot muissa kytkennöissä, oli yli kaksinkertainen sydänkuoleman ja äkillisen sydänpysähdyksen vaara muihin tutkittuihin verrattuna.
Osallistujista 2.1 %:lla todettiin pidentynyt PR-aika > 200 ms. Tämä ei kuitenkaan vaikuttanut henkilöiden kuolleisuuteen eikä sydämen vajaatoiminnasta, eteisvärinästä tai aivoverenkiertohäiriöistä johtuvien sairaalahoitojen määrään.
Tutkituista EKG:n poikkeavuuksista siis pidentynyt QRS-kompleksin kesto, IVCD ja leveä
QRS-T kulma liittyvät selvästi lisääntyneeseen äkillisen sydänpysähdyksen riskiin. Sen sijaan
pidentynyt PR-aika tai T-inversiot oikeanpuoleisissa rintakytkennöissä ilman muuta viitettä
sydänsairaudesta eivät vaikuta ennusteeseen keski-ikäisessä väestössä.
Asiasanat: EKG, IVCD, PR-intervalli, QRS kompleksi, QRS-T kulma, rytmihäiriö,
sydänperäinen äkkikuolema, T-aalto
To Matias and Aamos
8
Acknowledgements
This study was conducted between 2009 and 2013 at the Division of Cardiology,
Heart and Lung Center at the Helsinki University Central Hospital (HUCH) and
at the Department of Internal Medicine at the University of Oulu.
I would like to express my sincere gratitude and appreciation to Professor
Heikki Huikuri for the priviledge of having him as the supervisor of this thesis.
He is an internationally respected authority in the field of cardiac
electrophysiology and sudden cardiac death, and his vast expertise and vision,
optimism and constructive critisism have been essential to this project. I am
especially thankful to him that, even though my visits to Oulu have been fewer
than maybe would have been appropriate, our communication via email has
always been swift, and I almost always recieved answers and comments to my
questions within hours.
The subject of the present thesis was proposed to me by Docent Olli
Anttonen, my second supervisor. I am deeply grateful to Olli for introducing me
to the magical world of research. His enthusiasm and continuous support
throughout this study have proved invaluable, and I have also learned a great deal
from him about clinical cardiology while I was working as a fellow in the PäijätHäme Central Hospital.
My warmest thanks go to my other co-authors, whose contribution has been
crucial to this project. I am deeply indebted to Jani Tikkanen for his enormous
effort and efficacy in gathering data for this project and for his help in preparing
the publications. I wish to thank Juhani Junttila for his innovative ideas and deep
scientific knowledge that helped me maintain focus during this study project, for
his valuable comments in preparing the manuscripts, and for enduring the
bureaucratic task of serving as the chairperson of the follow-up committee of this
thesis. Tuomas Kerola has also made an important contribution to the study and is
responsible for initially persuading me to come to the Päijät-Häme Central
Hospital as a fellow in cardiology, for which I am grateful. I deeply appreciate the
support and positive attitude of the Institute of Health and Welfare towards this
project and thankfully acknowledge the indispensible assistance of Harri Rissanen
during the data analysis. I also thank Antti Reunanen for his most useful advice
on the study protocol.
I thank the official reviewers of this thesis, Docent Antti Hedman and Docent
Sinikka Yli-Mäyry, for their valuable feedback and comments, which helped
considerably to improve this thesis.
9
While carrying out my research work, I worked in clinics and specialized in
cardiology, first in the Päijät-Häme Central Hospital in Lahti and later in the
Helsinki University Central Hospital. In Lahti, I learned the basics of cardiology,
for which I especially thank Juha Heikkilä, Liisa Kokkonen and Seppo
Voutilainen. Despite the sometimes hectic pace at work, they always had the time
and patience for my questions and guidance.
I have recently enjoyed the priviledge and pleasure of working at the Division
of Cardiology at the Helsinki University Central Hospital. I am grateful to the
head of the clinic, Professor Markku Kupari, for providing an encouraging and
academic athmosphere in which to work, as well as to Professor Lauri Toivonen
for imparting to me some of his exceptional knowledge and perception in the field
of cardiac electrophysiology. I also express my gratitude to all my colleagues for
their friendship and support. I owe special thanks to Petri Korhonen, Lasse
Oikarinen, Hannu Parikka, and Matti Viitasalo for sharing with me their expertise
in electrophysiology, and to Sami Pakarinen and Mika Lehto for their friendly
collaboration in the field of cardiac pacing. I also wish to thank Jere, Jussi, and
Kristian, my roommates in the basement of the hospital, for sharing with me the
joys and struggles of everyday life at work.
I wish to thank my many dear friends outside this clinic, with whom I have
enjoyed countless unforgettable moments, for reminding me that there is also life
beyond cardiology.
I am deeply grateful to my mother, Hillevi, and my late father, Seppo, for
providing me with a solid foundation and unconditional love. I also wish to thank
my mother and my grandparents, Raija and Pentti, and my parents-in-law, Liisa
and Heimo, for their essential help in childcare and everyday life. I also thank my
brother Tuomas for helping me to keep my tennis strokes in shape during these
busy years.
Finally, my warmest thoughts and gratitude go to my wonderful wife, Katri,
for her everlasting love, patience and support, and to our children, Matias and
Aamos, for bringing so much joy and happiness into our lives.
The research for this thesis was supported by grants from the Finnish
Foundation for Cardiovascular Research, the Finnish Medical Foundation, the
Onni and Hilja Tuovinen Foundation, the Aarne Koskelo Foundation, the Aarne
and Aili Turunen Foundation, and the Maud Kuistila Memorial Foundation, as
well as by a special federal grant (EVO) for the Päijät-Häme Central Hospital,
which I acknowledge with gratitude.
10
Abbreviations
AF
ARVC
AV
CHD
CI
CPVT
DAD
DCM
EAD
ECG
ER
HCM
HF
HR
ICD
IVCD
LAHB
LBBB
LVEF
LVH
LQTS
MI
NYHA
PEA
RBBB
SCD
TIA
VF
VPB
VT
Atrial fibrillation
Arrhythmogenic right ventricular cardiomyopathy
Atrioventricular
Coronary heart disease
Confidence interval
Catecholaminergic polymorphic ventricular tachycardia
Delayed afterdepolarization
Dilated cardiomyopathy
Early afterdepolarization
Electrocardiogram, electrocardiography
Early repolarization
Hypertrophic cardiomyopathy
Heart failure
Hazard ratio
Implantable cardioverter-defibrillator
Nonspecific intraventricular conduction delay
Left anterior hemiblock
Left bundle branch block
Left ventricular ejection fraction
Left ventricular hypertrophy
Long QT syndrome
Myocardial infarction
New York Heart Association functional class
Pulseless electrical activity
Right bundle branch block
Sudden cardiac death
Transient ischemic attack
Ventricular fibrillation
Ventricular premature beat
Ventricular tachycardia
11
12
List of original publications
This thesis is based on the following publications, which are referred to in the text
by their Roman numerals.
I
Aro AL, Anttonen O, Tikkanen JT, Junttila MJ, Kerola T, Rissanen HA, Reunanen A
& Huikuri HV (2011) Intraventricular conduction delay in a standard 12-lead
electrocardiogram as a predictor of mortality in the general population. Circ Arrhythm
Electrophysiol 4(5): 704–710.
II Aro AL, Huikuri HV, Tikkanen JT, Junttila MJ, Rissanen HA, Reunanen A &
Anttonen O (2012) QRS-T angle as a predictor of sudden cardiac death in a middleaged general population. Europace 14(6): 872–876.
III Aro AL, Anttonen O, Tikkanen JT, Junttila MJ, Kerola T, Rissanen HA, Reunanen A
& Huikuri HV (2012) Prevalence and prognostic significance of T-wave inversions in
right precordial leads of a 12-lead electrocardiogram in the middle-aged subjects.
Circulation 125(21): 2572–2577.
IV Aro AL, Anttonen O, Kerola T, Junttila MJ, Tikkanen JT, Rissanen HA, Reunanen A
& Huikuri HV (2013) Prognostic significance of prolonged PR interval in the general
population. European Heart Journal [Epub ahead of print 14 May, 2013].
13
14
Table of contents
Abstract
Tiivistelmä
Acknowledgements
9
Abbreviations
11
List of original publications
13
Table of contents
15
1 Introduction
17
2 Review of the literature
19
2.1 Sudden cardiac death .............................................................................. 19
2.1.1 Epidemiology and etiology........................................................... 19
2.1.2 Risk stratification ......................................................................... 21
2.2 Cardiac action potential and ion currents ................................................ 25
2.2.1 Action potential in the electrocardiogram .................................... 27
2.2.2 Mechanisms of ventricular arrhythmias ....................................... 28
2.3 Clinical significance of different electrocardiographic patterns.............. 29
2.3.1 PR interval .................................................................................... 29
2.3.2 QRS duration ................................................................................ 31
2.3.3 J wave and early repolarization .................................................... 34
2.3.4 T-wave inversion .......................................................................... 35
2.3.5 QRS-T angle ................................................................................. 37
2.3.6 QT interval ................................................................................... 39
2.3.7 Other electrocardiographic risk markers ...................................... 40
3 Purpose of the study
43
4 Participants and methods
45
4.1 Study population ..................................................................................... 45
4.2 Electrocardiographic measurements ....................................................... 45
4.3 Follow-up ................................................................................................ 47
4.4 Statistical analysis ................................................................................... 48
5 Results
49
5.1 Long-term outcome associated with prolonged QRS duration and
nonspecific intraventricular conduction delay (IVCD) ........................... 49
5.2 QRS-T angle as a predictor of sudden cardiac death .............................. 51
5.3 Prevalence and prognostic significance of T wave inversions ................ 52
5.4 Prognostic significance of prolonged PR interval in middle-aged
subjects .................................................................................................... 55
15
6 Discussion
59
6.1 QRS duration and IVCD as predictors of sudden cardiac death ............. 59
6.2 QRS-T angle as a risk marker of sudden cardiac death ........................... 61
6.3 Prognostic implications of right precordial T-wave inversions............... 62
6.4 Natural history of prolonged PR interval, or first-degree AV
block ........................................................................................................ 64
6.5 Future aspects of electrocardiography in SCD prevention ...................... 65
6.6 Potential limitations of the studies .......................................................... 67
7 Conclusions
69
References
71
Original publications
91
16
1
Introduction
Sudden cardiac death (SCD) is defined as a natural, unexpected death occurring
within one hour of an acute change in clinical status. In the great majority of
cases, SCD results from ventricular arrhythmias (Deo & Albert 2012). SCD
accounts for an estimated 50% of all cardiovascular mortality, with coronary
artery disease being responsible for up to 80% of these fatal events (Huikuri et al.
2001). Subjects with preexisting cardiac pathology and depressed left ventricular
function are at elevated risk of SCD. However, at least 50% of SCD cases occur
in individuals with no previously identified structural cardiac disease or in
subjects considered at low risk (Zipes et al. 2006). This has lead to the
investigation of a variety of noninvasive techniques in order to more accurately
identify high-risk individuals before the fatal arrhythmia. Most of these studies
have focused on patients with a particular cardiac disease, and apart from the
traditional risk factors for atherosclerosis, epidemiological surveys have not been
successful in identifying specific risk markers for SCD in the general population
(Goldberger et al. 2008).
The standard 12-lead electrocardiogram (ECG) has been the most important
tool in clinical medicine to detect abnormalities in the electrical activity of the
heart. The surface ECG records cardiac electrical fields generated by
transmembrane ionic currents during the action potential of atrial and ventricular
myocytes. This electrical activity of the heart was first demonstrated already in
the last half of the 19th century, and in 1887, Waller first managed to record the
electrical potentials of the human heart from the body surface. However, it is the
recording of the human electrocardiogram by the string galvanometer, reported by
Willem Einthoven in 1902, which really marks the beginning of the era of
electrocardiography (Kligfield 2002). Even today, over a century after its
invention, innumerable ECGs are recorded every day with the intention of
diagnosing arrhythmias, myocardial ischemia, cardiomyopathies, conduction
disturbances, and genetic ion channelopathies.
A vast number of ECGs are also recorded from asymptomatic individuals for
various reasons. Sometimes this raises the question of what the clinical
significance of the electrocardiographic abnormalities incidentally found in these
subjects is. For example, a prolonged PR interval, or first-degree atrioventricular
block, implying decelerated atrioventricular conduction, has traditionally been
considered benign (Mymin et al. 1986). In most cases, the delayed conduction
occurs in the atrioventricular node, which is strongly influenced by the present
17
autonomic tone; thus, a prolonged PR interval is a frequent finding in conditioned
athletes (Corrado et al. 2009). However, PR prolongation has recently been
associated with elevated risk of atrial fibrillation, pacemaker implantation, and
mortality (Cheng et al. 2009).
Conduction delay in the His-Purkinje system can manifest as a wider QRS
complex reflecting prolonged depolarization of the ventricles, usually caused by a
bundle branch block. In the presence of structural cardiac disease, prolonged QRS
duration has been associated with higher mortality (Desai et al. 2006, Morin et al.
2009, Schinkel et al. 2009), but in the general population, the prognostic
significance of prolonged QRS duration or nonspecific intraventricular
conduction delay (IVCD) is not well established.
Repolarization of the ventricular myocardium manifests in the ECG mainly
as the T-wave, thus abnormalities observed during the repolarization period often
change the direction or shape of the T-wave. The QRS-T angle is a concept
representing differences between the directions of depolarization and
repolarization vectors. The spatial QRS-T angle has been studied in risk
prediction in various populations, and a wide QRS-T angle has been associated
with higher mortality (Kardys et al. 2003, Kors et al. 2003, Rautaharju et al.
2006b). However, an easier way to assess the QRS-T angle is from the frontal
leads of the 12-lead ECG by calculating the difference between the frontal QRS
axis and the T axis. Whether an abnormally wide frontal QRS-T angle has
prognostic implications in the general population has not been well studied.
Inverted T waves can represent another form of abnormal repolarization. In
children and adolescents, T-wave inversions are common in the right precordial
leads V1–V3, but these T waves become upright after pubertal development. If
inverted T waves persist into adulthood, they may raise suspicions of underlying
cardiac pathology, such as arrhythmogenic right ventricular cardiomyopathy
(ARVC) (Marcus 2005). However, the clinical significance of inverted T waves in
right precordial leads without overt cardiac disease remains unknown.
The present thesis aims to study the prognostic significance of various
electrocardiographic parameters (e.g. QRS duration, IVCD, PR interval, QRS-T
angle, and T-wave inversion) in the general population. The ultimate goal is to be
able to better identify those individuals who are at higher risk of SCD, so that
preventive measures can be undertaken before this terminal event occurs. An
additional purpose is to define electrocardiographic patterns which carry benign
prognosis and need not worry the patient or the treating physician.
18
2
Review of the literature
2.1
Sudden cardiac death
Sudden cardiac death (SCD) refers to death due to unexpected circulatory arrest,
usually caused by a cardiac arrhythmia, occurring within an hour of the onset of
symptoms in a person with or without previously known cardiac disease (Zipes et
al. 2006). The specificity of this SCD definition varies greatly depending on
whether or not the event was witnessed. A case is considered an established SCD
if an unexpected death without obvious extracardiac cause is associated with
witnessed collapse or if the death occurs within one hour of new or accelerating
symptoms. A probable SCD, in turn, is an unexpected death with no obvious
extracardiac cause, occurring in the previous 24 hours (Fishman et al. 2010).
Further, the term sudden cardiac arrest describes SCD cases in which medical
intervention (e.g. defibrillation) reverses the event (Zipes et al. 2006).
2.1.1 Epidemiology and etiology
The annual incidence of SCD in the Western world is estimated to range from 50
to 200 per 100 000 in the general population (Fishman et al. 2010, Zipes et al.
2006). Despite great improvements in primary and secondary prevention that
have substantially reduced overall coronary heart disease (CHD) mortality over
recent decades, SCD rates in particular have declined to a lesser extent. Estimates
indicate that SCD accounts for approximately 50% of all CHD deaths and up to
15% to 20% of all deaths (Deo & Albert 2012, Zipes et al. 2006). Ventricular
fibrillation (VF), often preceded by ventricular tachycardia (VT), is the
mechanism underlying most SCD episodes, but pulseless electrical activity (PEA)
and bradycardias can also cease mechanical activity of the heart resulting in
absence of signs of circulation (Bayes de Luna et al. 1989, Gang et al. 2010).
Other potential causes of SCD include stroke, pulmonary embolism, aortic
rupture, and other noncardiac causes (Estes 2011).
The risk of SCD increases markedly with age, with a 100-fold lower
incidence in adolescents and adults under 30 than in adults older than 35 (Zipes et
al. 2006). For example, the annual incidence of SCD among 35- to 44-year-old
men is around 35 per 100 000 compared with over 1300 per 100 000 for 75- to
84-year-old men (Zheng et al. 2001). The characteristics of SCD also differ
19
between men and women in several ways. Apart from the very old, women of any
age have a significantly lower incidence of SCD than do men, even after adjusting
for cardiovascular risk factors (Zheng et al. 2001). Approximately two-thirds of
women presenting with SCD have no previously detected cardiac disease,
compared with 50% in men. In addition, women suffering from SCD seem to
have a higher prevalence of structurally normal hearts than do men (Chugh et al.
2009b).
The pathophysiology of SCD is complex and is believed to include an
abnormal myocardial or electrical substrate as well as transient factors that trigger
the electrical instability and lethal ventricular arrhythmias that lead to
hemodynamic collapse and cardiac arrest. However, in a significant number of
cases of SCD, no apparent arrhythmia trigger can be identified (Fishman et al.
2010).
The most common underlying cardiovascular condition predisposing to SCD
is CHD, which accounts for approximately 80% of all SCDs. On the other hand,
approximately 50% of all CHD-related deaths are due to SCD (Myerburg &
Junttila 2012). The mechanisms underlying SCD in CHD include lethal
arrhythmias initiated by transient ischemia, often in the absence of previously
recognized coronary artery disease; arrhythmias occurring during acute
myocardial infarction or in the early weeks after the acute phase during scar
stabilization; and sudden cardiac arrest in the chronic phase of ischemic
cardiomyopathy occurring months or years after the myocardial infarction due to
ventricular remodeling and the evolution of heart failure (Myerburg & Junttila
2012).
Cardiomyopathies, such as dilated cardiomyopathy (DCM), hypertrophic
cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy
(ARVC), account for the second largest number of sudden deaths from cardiac
causes. In DCM, SCD accounts for at least 30% of overall mortality, occurring
annually in 8% to 10% of New York Heart Association (NYHA) functional class I
patients, and in 20% of class II–IV patients. However, at least 50% of deaths
among NYHA class I DCM patients are sudden, in contrast to only 20% to 30%
among NYHA class IV, in which the progressive heart failure and not the primary
arrhythmia is the most common mechanism of death (Kjekshus 1990).
Among patients with HCM, the combined rate of life-threatening arrhythmias
and SCD is lower, around 1% per year, although the number is much higher in the
presence of one or more risk factors (Sen-Chowdhry & McKenna 2012). The
reported risk of SCD in ARVC varies markedly, possibly due to the different
20
baseline characteristics among patients, with annual rates of SCD or ventricular
fibrillation ranging from 0.1% in affected relatives to as high as 5% to 8% in ICD
recipients (Sen-Chowdhry & McKenna 2012). Other structural cardiac diseases,
such as valvular and congenital heart disease, as well as acquired inflammatory
and infiltrative cardiac disorders account for only a small number of SCDs
occurring in the general population.
Often included in the category of SCD with no overt heart disease are patients
with subclinical structural cardiac diseases such as myocarditis and coronary
spasm, and sometimes sarcoidosis (Modi & Krahn 2011). However, 5% to 15% of
cardiac arrest victims show no evidence of structural abnormalities at autopsy
(Napolitano et al. 2012). The conditions responsible for SCD in these cases are
largely those that cause abnormalities in cardiac depolarization and repolarization,
usually due to inherited ion channel abnormalities or metabolic-, electrolyte-, or
drug-induced ion channel dysfunction. These primarily electric diseases, or
channelopathies, include long-QT syndrome (LQTS), Brugada syndrome, shortQT syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT),
and early repolarization syndrome (ERS).
2.1.2 Risk stratification
Despite advances in cardiopulmonary resuscitation and post-resuscitation care,
outcomes after cardiac arrest remain poor. Vast majority of the sudden cardiac
arrests occur in the community, and 90% to 95% of these individuals do not
survive, even when treated by emergency medical personnel (Nichol et al. 2008).
Survival depends on the rapidity of intervention (e.g. defibrillation in VF) as well
as on the presenting arrhythmia. The documented survival of patients with VF has
been as high as 25%; however, when PEA presents as the initial rhythm, survival
is only around 2% (Chugh et al. 2004).
At least 50% of cases of SCD occur in subjects with no previously identified
CHD or among subgroups of patients considered to be at low risk of SCD (Zipes
et al. 2006); thus the persisting challenge has been to more accurately identify
these individuals before the devastating SCD event. Since CHD accounts for as
much as 80% of SCDs and pre-existing CHD itself is associated in as much as a
five-fold higher risk of SCD (Cupples et al. 1992), it is logical that conventional
risk factors for CHD such as age, male sex, hypertension, hypercholesterolemia,
diabetes mellitus, kidney dysfunction, obesity, and smoking should predict SCD
in the population (Deo & Albert 2012). Intuitively, optimization of these
21
traditional cardiovascular risk factors would lead to a lower incidence of SCD,
but robust evidence supporting this view is currently lacking (Estes 2011).
Left ventricular dysfunction and NYHA functional class, with either ischemic
or nonischemic cardiomyopathy, are even more powerful risk factors for SCD
(Stevenson et al. 1993). Reduced left ventricular ejection fraction (LVEF) is one
of the strongest predictors of SCD, and in the clinical practice guidelines, LVEF
< 35%, together with NYHA class, identify patients who will benefit the most
from implantable cardioverter-defibrillator (ICD) therapy to prevent sudden death
from arrhythmia (Zipes et al. 2006).
However, even though reduced LVEF can well identify the group of patients
at highest risk, the majority of SCDs will occur in the large general population of
individuals without reduced LVEF and whose relative risk is considered low
(Stecker et al. 2006). This problem, illustrated in Figure 1, poses a challenge to
SCD-preventive strategies, since the individuals at highest risk according to
current criteria comprise only a small proportion of the total number of SCD in
the population. On the other hand, some patients with LVEF < 35% may still be at
low risk of SCD and gain no benefit from ICD implantation (Goldenberg et al.
2008). This has generated great interest in studying different methods in order to
more accurately identify individuals at high risk of SCD.
22
Fig. 1. Incidence and the annual prevalence of SCD in specific patient populations.
Most SCD events occur in subjects at low to moderate risk. Modified from Myerburg et
al. 1998 (published by permission of Wolters Kluwer Health).
In the presence of ischemic or nonischemic heart disease, whether clinically silent
or not, factors known to trigger VT or VF include changes in the autonomic
nervous system, electrolyte disturbances, metabolic abnormalities, ischemia,
acute volume or pressure overload of the ventricles, ion channel abnormalities,
and the proarrhythmic action of cardiac or noncardiac drugs. These triggers
together with underlying substrate such as scar formation, alterations in the
chamber geometry, and electrical or anatomical remodeling, can induce and
sustain potentially lethal ventricular arrhythmias (Goldberger et al. 2008).
Detection of these arrhythmia substrates, triggering factors and abnormalities in
ventricular depolarization and repolarization forms the theoretical base for the
developing of different noninvasive approaches with the purpose of enhancing
SCD risk stratification.
To identify imbalances in autonomic function, studies have used techniques
such as heart rate variability, baroreflex sensitivity, heart rate turbulence, and
heart rate recovery after exercise to stratify risk of SCD among cardiac patients
(Goldberger et al. 2008). The extent of myocardial damage and LVEF have
traditionally been assessed with echocardiography, but recent studies have
23
suggested that contrast enhanced magnetic resonance imaging can be of
additional value in detecting the arrhythmia substrate by carefully delineating the
extent and morphology of myocardial scar tissue (Villuendas & Kadish 2008).
Prolonged duration of ventricular depolarization in an electrocardiogram
(ECG) due to intraventricular or interventricular conduction delay or block may
reflect the presence of myocardial damage and scar tissue, and can manifest as
increased duration of the QRS complex. Signal-averaged ECG can serve to detect
late activation within the myocardium, known as late potentials, that occur after
the end of the QRS complex and are so small in amplitude that several hundred
QRS complexes are needed to average for their detection. Prolonged duration of
the filtered QRS, low-amplitude signal duration and abnormally low voltage of
the terminal 40 ms of the QRS are the parameters commonly assessed for
evidence of late potentials, which can correspond to the substrate of sustained
ventricular arrhythmias (Stein 2008).
Heterogeneities in ventricular repolarization can also predispose individuals
to risk of SCD. Besides the QT interval, QT interval variability and T-wave
alternans have been employed to detect repolarization abnormalities (Goldberger
et al. 2008). Finally, the presence of ventricular premature beats (VPBs) and
nonsustained ventricular tachycardia could trigger a fatal arrhythmia, so several
studies have evaluated their value in risk stratification (Stein 2008).
In summary, specific efforts to prevent SCD have focused on the population
groups at greatest risk (e.g. patients with previous malignant ventricular
arrhythmias, severely depressed left ventricular function due to ischemic or
nonischemic cardiomyopathy, and symptomatic primary electrical diseases). In
these patients, treatment of ventricular arrhythmias with an implantable
cardioverter-defibrillator (ICD) has led to improved survival rates in several large
clinical trials (Epstein et al. 2008). However, because the subjects at highest risk
account for only a minority of SCD cases, preventing SCD in this population will
only slightly reduce the total number of SCD victims. Consequently, researchers
are searching for other specific risk markers with the aim of identifying high-risk
individuals in the general population. Indeed, many noninvasive techniques have
been developed and studied with the intention to more accurately identify
individuals at elevated risk of fatal arrhythmias. However, the ability of each of
these techniques to provide additional prognostic information varies, so the best
way to combine and use these techniques in clinical practice remains unclear.
Low LVEF < 35% is the parameter most widely used to decide whether to
implant an ICD for the primary prevention of SCD, but how to optimally define
24
the group of patients who do not have low LVEF but are nonetheless at
substantial risk of SCD remains to be determined (Goldberger et al. 2008). Many
of the methods described above also require special equipment or software and
have limited use outside clinical trials. In contrast, the standard 12-lead
electrocardiogram is readily available, and its role in detecting abnormalities in
ventricular depolarization and repolarization and risk stratification has recently
attracted growing interest.
2.2
Cardiac action potential and ion currents
Contraction of the cardiac muscle cells, cardiomyocytes, is initiated by action
potentials. Disorders of this electrical activity can create serious and potentially
lethal disturbances in cardiac rhythm. Action potentials occurring in normal atrial
and ventricular myocytes are divided into five phases. During the resting phase,
the interior of the cell has more negative voltage than the exterior, with a
membrane voltage of around –90 mV. This gradient results from different
intracellular and extracellular ion concentrations that various ion transporters and
pumps maintain with energy-dependent mechanisms. The stimulation of excitable
myocytes evokes depolarization, which suddenly renders the membrane potential
of the cells positive. This change is then followed by a gradual repolarization of
the membrane voltage until restoration of the original negative resting value. This
action potential is rapidly conducted throughout the heart and is responsible for
initiating each heartbeat (Rubart & Zipes 2008). The different phases of the
cardiac action potential are associated with changes in cell membrane
permeability, mainly to Na+, K+, Ca++ and Cl- ions, thus inducing changes in the
membrane voltage (Pappano 2008).
25
Fig. 2. Different phases of the ventricular action potential and some of the underlying
ionic currents. Modified from Nerbonne & Kass 2005 (published by permission of the
American Physiological Society).
Different phases of the action potential and the principle ion currents responsible
for these changes in cardiac myocytes appear in Figure 2. Rapid depolarization or
upstroke is initiated in phase 0, when a depolarizing stimulus exceeds a certain
threshold potential. This induces a dramatic change in the cell membrane
properties, causing fast Na+ channels to rapidly open; Na+ thus enters and thereby
depolarizes the myocyte. These Na+ channels then abruptly inactivate and remain
so until the cell becomes fully repolarized.
Repolarization begins in phase 1 with a brief period of activation of a
transient outward current (Ito) carried mainly by K+, which creates the notch in the
action potential between the end of the upstroke and the beginning of the plateau
(Pappano 2008). The plateau (phase 2) may last several hundred milliseconds and
is mainly maintained by a balance between outward current carried by K+ moving
26
through IK, IK1, and Ito channels, and inward current carried by Ca++ through open
L-type Ca++ channels (ICa.L), which serves as a trigger for the cardiac muscle
contraction (Pappano 2008). Final rapid repolarization (phase 3) begins when the
efflux of K+ ions from the cells begins to exceed the influx of Ca++. The transient
outward (Ito) current together with the slow and rapid components of the delayed
rectifier potassium current (IKs and IKr) together initiate the final repolarization;
once phase 3 has been initiated, the inwardly rectified current (IK1) influences the
rapidity of the repolarization (Pappano 2008). In phase 4, the membrane potential
has returned to the resting voltage and remains steady throughout diastole in atrial
and ventricular cells, which is mainly the contribution of the efflux of K+ by
inwardly rectifying K+ channels (IK1) compensating for the slow influx of the Na+
ions.
However, in the sinus node, certain parts of the atria, the distal portion of the
atrioventricular (AV) node, and the His-Purkinje fibers, the resting membrane
potential does not remain constant but gradually depolarizes, and in the absence
of a stimulus to generate rapid depolarization, these cells can themselves initiate a
spontaneous action potential (Rubart & Zipes 2008).
2.2.1 Action potential in the electrocardiogram
A normal cardiac cycle comprises two basic electrocardiographic processes:
depolarization and repolarization of the atria and ventricles. Under normal
conditions, the sinus node is the pacemaker of the heart and initiates the spread of
action potentials throughout the atria. This atrial depolarization represents the P
wave in the ECG. Atrial repolarization is normally of low amplitude and obscured
by the QRS complex, so it is seldom visible in the ECG. Atrial action potential
reaches the ventricles via the AV node, where the conduction is significantly
delayed in order to permit optimal ventricular filling during atrial contraction. On
the ventricular side, the excitation wave passes to the bundle of His, which then
divides into the right and left bundle branches. The left bundle branch splits into a
thin anterior division and a thick posterior division, and ultimately the right
bundle branch and the two divisions of the left bundle branch subdivide into a
complex network of Purkinje fibers (Pappano 2008).
The propagation of ventricular depolarization manifests in the
electrocardiogram as the QRS complex, with its morphology and electrical axis
depending on the endocardial and transmural activation sequences of the
ventricles. The rapid phase of the repolarization of the ventricles is mainly
27
depicted in the ECG as the T wave, but the ST segment, the J-wave and
sometimes the U wave are also considered to represent the repolarization (Yan et
al. 2003). Although activation of the ventricles moves from the endocardium to
the epicardium, the ventricular electrical recovery, in contrast to ventricular
activation, passes from the epicardium to the endocardium. As a result, the QRS
complex, the ST segment and T waves are generally concordant (i.e. pointing to
the same direction in healthy individuals) (Mirvis & Goldberger 2008).
2.2.2 Mechanisms of ventricular arrhythmias
Potential mechanisms of ventricular arrhythmias include automaticity, reentry,
and triggered activity due to early or delayed afterdepolarizations. In addition, the
heterogeneity of local action potential durations facilitates the genesis of certain
arrhythmias (Josephson 2008b). An episode of arrhythmia caused by one
mechanism can also precipitate an arrhythmia caused by a different mechanism,
as when a premature ventricular complex caused by automaticity initiates an
episode of ventricular tachycardia sustained by reentry.
Automaticity refers to the property of cardiac cells to initiate action potential
spontaneously without the need for prior stimulation. In contrast, triggered
activity occurs as a result of a preceding impulse. In the ventricles, these
afterdepolarizations have been demonstrated in the Purkinje fibers and the
ventricular myocardium (Rubart & Zipes 2008). Early afterdepolarizations
(EADs) can occur before full repolarization of the cardiac cells in phases 2 or 3 of
the action potential and are related to increased Ca2+ influx through L-type Ca2+
channels. They are more likely to occur in cardiac cells with prolonged action
potential at slower heart rates. EAD are thought to be responsible for torsades de
pointes (TdP) associated with long-QT syndrome and some antiarrhythmic drugs
that prolong the cardiac action potential (Rubart & Zipes 2008). Delayed
afterdepolarizations (DADs) occur after the completion of repolarization (phase
4) and are associated with elevated intracellular calcium concentrations. DADs
are more likely to occur with higher heart rates and have been linked to
arrhythmias in, for example, catecholaminergic polymorphic ventricular
tachycardia (CPVT) (Rubart & Zipes 2008). In patients with prior myocardial
infarct, reentry is the predominant mechanism of ventricular tachycardia.
Necessary conditions for reentry are a closed conduction loop, an unidirectional
block at some point of the reentry circuit, and an area of sufficiently slow
28
conduction enabling continuous propagation of the impulse (Rubart & Zipes
2008).
2.3
Clinical significance of different electrocardiographic patterns
Numerous studies, conducted among subjects both with and without structural
heart disease, have addressed the prognostic significance of several
electrocardiographic patterns. Especially in the general population, the positive
predictive value and specificity of these risk markers have remained relatively
low. Despite this, research has successfully identified several changes in the ECG
that have been associated with higher risk of cardiovascular mortality and
morbidity.
2.3.1 PR interval
The time from the beginning of atrial depolarization to the onset of ventricular
depolarization measured for the surface ECG is known as the PR interval. The
upper limit of the PR interval following a normally timed P wave is 200 ms, and
prolongation of the PR interval > 200 ms is known as a first-degree
atrioventricular (AV) block. A second-degree AV block is defined as the
inconsistent conduction of atrial impulses to the ventricles, and in a third-degree
AV block, no atrioventricular conduction occurs. A prolonged PR interval can
result from a conduction delay in the atrium (intra-atrial delay), the AV node, and
the His-Purkinje system. In most cases, the AV node is responsible for the delayed
conduction, although more than one site can contribute to a prolonged PR interval
in an individual patient (Schwartzman 2004).
The PR interval and heart rate share an inverse relationship; the PR interval
becomes shorter with higher rates and vice versa (Atterhog & Loogna 1977). The
autonomic nervous system strongly influences impulse propagation in the AV
node (Josephson 2008a); consequently, the PR interval also shows significant
circadian variation depending on the prevailing vagal tone (Dilaveris et al. 2001).
Among trained athletes with higher parasympathetic tone and lower resting
sympathetic activity, a prolonged PR interval mediated by delayed conduction in
the AV node may occur in > 10% of the individuals (Corrado et al. 2009).
Evidence also suggests that genes contribute considerably to the cardiac
conduction. The PR interval reportedly has significant hereditability (NewtonCheh et al. 2007, Smith et al. 2009), and several common genetic variants seem
29
to modulate heart rate, PR interval, and QRS duration (Holm et al. 2010, Pfeufer
et al. 2010). This is in accordance with a recent report that showed prolonged PR
interval and other conduction abnormalities to be highly prevalent among the
parents of children with idiopathic congenital AV block (Baruteau et al. 2012).
In the general population, the prevalence of prolonged PR interval is around
0.5% to 1.5% in young adults from 20 to 40 years of age, 2% to 3% in subjects
between 40 and 60 years of age, and still higher with advanced age (Bexton &
Camm 1984, Hiss & Lamb 1962, Mymin et al. 1986, Perlman et al. 1971, Rose et
al. 1978). Traditionally, decelerated AV conduction has been considered a benign,
functional phenomenon. Most early studies of the prognostic significance of
prolonged PR duration examined only young and healthy men from the military.
The first estimation of the prognosis associated with the PR interval involved
1000 young aviators from the US Army, but during the ten-year follow-up period,
heart disease proved very rare and only one cardiac death occurred, rendering
impossible the detection of any differences in outcomes in the few subjects with
prolonged PR interval (Packard et al. 1954). Further studies conducted with
nearly 4000 pilots recruited after World War II with a 30-year follow-up period
(Mymin et al. 1986), and with 18 000 middle-aged male civil servants with a 5year follow-up (Rose et al. 1978), demonstrated no differences in the prognosis of
subjects with prolonged PR interval compared to that of the rest of the population.
However, one international study of over 12 000 men suggested that prolonged
PR interval might be associated with coronary artery disease during the five-year
follow-up, but the analysis was unadjusted and the number of events was low
(Blackburn et al. 1970). On the other hand, another study reported that prolonged
PR interval was associated with fewer coronary events in their study sample
(Erikssen & Otterstad 1984).
Only two major community-based studies have investigated the prognostic
significance of prolonged PR interval in the general population. The first,
conducted among 4678 participants in the 1960s in Tecumseh, Michigan, with a
follow-up of four years, demonstrated no significant difference in cardiovascular
morbidity or mortality between subjects with PR ≥ 220 ms compared to the rest of
the population; among those over 60 years of age, however, there seemed to be a
correlation with cardiac disease (Perlman et al. 1971). Thus, until recently, a
prolonged PR interval, or first-degree AV block, has been considered a benign
finding in the ECG. However, a recent report from the Framingham Heart Study
population has challenged this longstanding perception. In their general
population-based sample of 7575 individuals, PR interval > 200 ms predicted
30
overall mortality with a multivariable-adjusted hazard ratio of 1.4 during the
follow-up period that was censored after 20 years. The participants with a
prolonged PR interval experienced significantly more atrial fibrillation, and
pacemaker implantations were also more common in this group than in those with
normal PR interval (Cheng et al. 2009).
2.3.2 QRS duration
The QRS complex on the electrocardiogram marks the rapid depolarization of the
ventricular myocardium. Abnormalities in the intraventricular propagation of
supraventricular impulses prolong QRS duration and can alter the shape of the
QRS complex. These changes in ventricular depolarization may result from
abnormalities in the His-Purkinje conduction system or the ventricular
myocardium due to fibrosis, necrosis, calcification, infiltrative lesions, or
ischemia, or they can be functional and depend on the current heart rate. In
addition, abnormal atrioventricular connections can produce QRS widening due
to ventricular preexcitation.
According to the AHA/ACC/HRS recommendations for the standardization
and interpretation of the electrocardiogram on intraventricular conduction
disturbances published in 2009, QRS duration over 110 ms is considered
abnormal in adults (Surawicz et al. 2009). Electrocardiographically, a prolonged
QRS may result from incomplete or complete left and right bundle branch block
(LBBB and RBBB), as well as nonspecific intraventricular conduction
disturbance (IVCD). In complete bundle branch block, QRS duration is ≥120 ms.
In incomplete LBBB and RBBB, QRS duration falls between 110–119 ms, but the
morphology of the QRS complex is otherwise similar to that of a complete bundle
branch block. According to these criteria, IVCD is defined as QRS duration
greater that 110 ms but not fulfilling the criteria for incomplete or complete
LBBB or RBBB (Surawicz et al. 2009). A summary of the diagnostic criteria for
complete bundle branch blocks appears in Table 1.
31
Table 1. Diagnostic criteria of complete LBBB and RBBB according to Surawicz et al.
(2009).
LBBB
RBBB
QRS ≥ 120ms
QRS ≥ 120ms
Broad R waves in I, aVL, V5, and V6
rsr’, rsR’, or rSR’ in V1 or V2
(occasionally RS pattern in V5 and V6)
(R’ or r’ usually wider than the initial R wave)
R peak time > 60 ms in V5 and V6, but normal in V1–V3
S wave duration greater than R wave or > 40 ms
(when small initial r waves present)
in I and V6
ST and T waves usually opposite to QRS direction
Normal R peak time in V5 and V6, but > 50 ms in
(positive T wave in leads with upright QRS may be
V1 (when pure dominant R wave with or without
normal)
a notch in V1)
Q waves absent in I, V5, and V6
Prolonged duration of the QRS complex has generally been associated with
adverse prognosis in patients with cardiac disease. In patients hospitalized for
heart failure, LBBB is the most common cause of prolonged QRS duration,
followed by IVCD and RBBB, respectively (Sandhu & Bahler 2004). In these
patients, QRS duration is associated with more advanced left ventricular
dysfunction and is also an independent predictor of morbidity and mortality
(Kashani & Barold 2005, Wang et al. 2008). In the presence of coronary artery
disease, prolonged QRS duration is associated with increased risk of sudden death
(Teodorescu et al. 2011), and in patients with acute coronary syndrome, QRS
prolongation, particularly in the presence of LBBB, associates with additional
mortality (Baslaib et al. 2010). When patients with coronary artery disease also
have depressed left ventricular function, QRS prolongation resulting from LBBB
or IVCD predicted a 50% increase in their risk of arrhythmic death and total
mortality (Zimetbaum et al. 2004), and even when coronary artery disease is only
suspected, QRS duration is an independent predictor of cardiac death and nonfatal
myocardial infarction (Schinkel et al. 2009).
In a general medical population sample without bundle branch block, those
with QRS duration > 130 ms were at nearly twice the risk of cardiovascular death
as those with QRS duration ≤ 110 ms, and in this population the presence of
LBBB and RBBB together with markedly prolonged QRS duration associated
with a greater risk of cardiovascular death (Desai et al. 2006). In addition,
subjects with hypertrophic cardiomyopathy (Bongioanni et al. 2007) and
asymptomatic patients with aortic stenosis (Greve et al. 2012) presenting with
prolonged QRS duration are at greater risk of cardiovascular and sudden cardiac
death. In hypertensive patients with electrocardiographic left ventricular
32
hypertrophy (LVH), QRS duration predicts cardiovascular and all-cause mortality
(Morin et al. 2009, Oikarinen et al. 2004) and identifies patients at higher risk of
SCD (Morin et al. 2009).
Most studies of QRS duration conducted in the general population have
examined only the prognostic significance of prolonged QRS duration attributable
to RBBB and LBBB. While several studies among patients with bundle branch
block and concomitant cardiovascular disease have indicated higher mortality
(Freedman et al. 1987, Go et al. 1998, Newby et al. 1996, Sumner et al. 2009),
studies on the prognostic significance of RBBB and LBBB in the general
population have yielded conflicting results, partly due to small sample sizes, short
follow-up periods, or different characteristics of the subjects.
Complete RBBB is an exceptionally rare finding in young adults, but its
prevalence increases rapidly with advancing age (Bussink et al. 2013,
Thrainsdottir et al. 1993). Complete RBBB may be associated with various
cardiac conditions such as ischemic heart disease, different cardiomyopathies,
myocarditis, hypertension, congenital heart disease, cor pulmonale, and
pulmonary embolism (Fernández-Lozano & Brugada 2013), but in the absence of
any overt cardiac disease, RBBB is generally not associated with higher mortality
risk, although it can predict a future high-degree atrioventricular block (Eriksson
et al. 2005, Fahy et al. 1996, Schneider et al. 1981). However, a recent report
from the Copenhagen City Heart Study reported higher cardiovascular mortality
associated with RBBB. In the study, age, male gender, and higher blood pressure
associated with incident RBBB (Bussink et al. 2013).
Similarly to RBBB, LBBB seldom occurs in subjects under the age of 55, but
its incidence grows significantly with age (Haataja et al. 2012). In many cases,
LBBB may be the first manifestation of underlying cardiac disease. However,
abnormal asynchronous contraction patterns induced by LBBB can compromise
ventricular performance even in the absence of identifiable structural cardiac
disease, and the adverse impact of LBBB on cardiac function can often be
reversed by the resynchronization of systole with biventricular pacing. Besides
dyssynchrony and reduced left ventricular function, LBBB can induce regional
ischemia, cause an abnormal increase in pulmonary artery pressure during
exercise, and provoke functional mitral regurgitation (Breithardt & Breithardt
2012). It is therefore unsurprising, that compared not only with normal
intraventricular conduction, but also with RBBB, LBBB has generally been
associated with poorer prognosis, with a number of studies suggesting that LBBB
33
is associated with greater risk of cardiovascular mortality and morbidity (Eriksson
et al. 2005, Fahy et al. 1996, Miller et al. 2005, Rabkin et al. 1980).
Only a few studies have investigated the prognostic significance of prolonged
QRS duration and IVCD in the general population. In a community-based cohort
of the Framingham Heart Study, even minor QRS prolongation indicated a greater
risk of pacemaker implantation, even after excluding subjects with bundle branch
block (Cheng et al. 2010). More recently, Kurl et al. (2012) demonstrated that
among middle-aged men from Eastern Finland, each 10 ms increase in QRS
duration associated with a 27% higher risk of SCD. In that study, the subjects
with QRS over 110 ms were at a 2.5-fold higher risk of SCD than were those with
QRS duration in the lowest quintile, and the results remained similar even after
excluding men with bundle branch block.
2.3.3 J wave and early repolarization
The J wave is the deflection sometimes observed following the QRS complex on
the surface electrocardiogram. An early repolarization (ER) pattern is a broad
expression referring to distinct J waves or J-point (QRS-ST junction) elevation,
notching or slurring of the terminal QRS complex, and ST segment elevation
(Antzelevitch et al. 2011). For decades, the pattern of J-point elevation
predominantly found in the mid-precordial leads V2 to V4 of healthy young men
has been considered a benign phenomenon in the absence of symptoms
attributable to myocardial ischemia or pericarditis (Klatsky et al. 2003,
Rautaharju et al. 2009, Uberoi et al. 2011).
The J wave, previously also known as the Osborn wave, can occur in various
cardiac and extracardiac conditions, such as hypothermia, hypercalcemia,
hypervagotonia and brain injury (Derval et al. 2011). Recently, however, this Jwave pattern, especially in the inferior and lateral leads accompanied by slurring
or notching of the terminal QRS complex, has been associated with vulnerability
to ventricular fibrillation (Haissaguerre et al. 2008, Nam et al. 2008). The precise
etiology of the J wave has yet to be determined, but it likely results from
transmural differences in the early phases of cardiac action potential
(Antzelevitch et al. 2011). Both ER syndrome, which is associated with lifethreatening arrhythmias, and Brugada syndrome present somewhat similar
abnormal J-wave manifestations, although in different regions of the heart;
consequently, some authors have proposed the expression “J wave syndrome” to
describe these phenotypic changes (Antzelevitch et al. 2011).
34
The ER pattern occurs in 1% to 9% of the general population, but it is found
in 15% to 70% of cases of idiopathic ventricular fibrillation (VF) (Benito et al.
2010). In the Finnish population, ER in the inferior leads with a J-point elevation
of more than 0.2 mV was associated with greater risk of cardiac and sudden
arrhythmic death (Tikkanen et al. 2009). In athletes, ER is a very frequent
finding, but is mainly associated with an ascending ST segment, which is not
associated with higher risk of arrhythmic death. In contrast, when a horizontal or
descending ST segment accompanies ER, the risk of arrhythmic death is higher,
especially in the presence of a higher amplitude ER pattern (Tikkanen et al.
2011). The several different J-wave or ER patterns carry different prognoses. The
inferolateral ER pattern associated with idiopathic VF seems to be an entity
resembling Brugada syndrome. In contrast, the inferolateral ER pattern associated
with greater mortality risk in the general population may more closely resemble a
risk modifier that exposes an individual to an increased risk of proarrhythmia in
the presence of other risk factors, such as ischemia (Junttila et al. 2012).
2.3.4 T-wave inversion
The T wave corresponds to the phase of rapid repolarization (phase 3) of the
ventricular action potential. Polarity of the T wave is normally concordant with
the QRS complex, suggesting that normal ventricular electrical recovery, unlike
ventricular activation, spreads from the epicardium to the endocardium (Burgess
1979). After the discovery of midmyocardial M cells, it is now generally accepted
that the ventricular myocardium is not uniform, but composed of at least three cell
types with distinct electrophysiological properties, with M cells having longer
action potential duration than the endocardial and epicardial cells (Yan et al.
1998). According to this theory, the genesis of an upright T wave begins during
the plateau phase with separation of the epicardial action potential from that of
the M cells stemming from earlier repolarization of the epicardial cells. The peak
of the T wave coincides with the full repolarization of the epicardium, and the
gradual repolarization of the endocardium and M cells contributes to the
descending limb of the T wave, which ends when the M cells are fully repolarized
(Yan et al. 2003).
In the 12-lead ECG of adults, the normal T wave is inverted in aVR; upright
or inverted in leads aVL, III, and V1; and upright in limb leads I and II, as well as
in precordial leads V3 to V6. In general, the T-wave amplitude is most positive in
leads V2 and V3. Minor T-wave inversions in V2 and aVF can exhibit normal
35
variation, especially in young adults (Rautaharju et al. 2009), and is not
considered a codeable abnormality according to the Minnesota code classification
system for electrocardiographic findings (Prineas et al. 1982).
Several benign and pathological conditions can induce changes in
repolarization detected as an alteration of the ST segment or T wave. These
primary repolarization abnormalities include myocardial ischemia and other
structural heart diseases, electrolyte disturbances, drugs, changes in sympathetic
tone, and hyperventilation (Alexopoulos et al. 1996, Atterhog et al. 1981, Blom
1951, Rautaharju et al. 2009, Toivonen et al. 1997). Abnormal ST segment and Twave patterns can also stem from changes in the sequence and duration of
ventricular depolarization attributable to bundle branch blocks, ventricular
preexcitation, and ventricular pacing, that cause secondary changes in
repolarization (Rautaharju et al. 2009).
Changes in the ST segment and T waves can be early markers of underlying
cardiovascular disease, and even minor ST-T abnormalities have predicted
reduced survival rates in the adult population (Cuddy & Tate 2006, Greenland et
al. 2003b, Sigurdsson et al. 1996). However, the clinical significance of inverted
T waves in the right precordial leads V1–V3 is less clear. In children and
adolescents, T-wave inversion is a common physiological finding in chest leads
beyond V1, but these juvenile T-wave inversions usually become upright after
pubertal development (Suarez & Suarez 1946). In 0.1% to 3% of apparently
healthy individuals, however, this electrocardiographic pattern persists into
adulthood and most commonly occurs in young women (Hiss et al. 1960, Marcus
2005, Papadakis et al. 2009, Pelliccia et al. 2007).
Although right precordial T-wave inversions can be just an
electrocardiographic variation of no clinical significance, it can also be a sign of
underlying structural heart disease such as hypertrophic cardiomyopathy,
myocardial ischemia, or ARVC (Okada et al. 1994, Thiene et al. 1988). In a
report by Pellicia et al. (2008) from Italy, the prevalence of marked T-wave
inversions was 1% in young, trained athletes, over one-third of whom
demonstrated evidence of structural heart disease. Disturbingly, in spite of
thorough initial workup to diagnose underlying cardiac diseases in these patients,
6% of the individuals with inverted T-waves but no initial evidence of cardiac
abnormalities ultimately proved to have cardiomyopathy during the follow-up.
However, in another Italian study of asymptomatic children with inverted Twaves at preparticipation screening, only 2.5% were diagnosed with
cardiomyopathy (Migliore et al. 2012).
36
Abnormalities of repolarization observed in a standard 12-lead ECG could
imply the presence of a structural heart disease such as hypertrophic
cardiomyopathy or coronary artery disease, but they play an especially important
role in the diagnosis of ARVC. ARVC is a predominantly genetically determined
myocardial disease characterized pathologically by replacement of the right
ventricular myocardium with adipose and fibrous tissue. Clinical manifestations
of the disease include ventricular arrhythmias, heart failure and SCD (Basso et al.
2009, Marcus et al. 1982). The diagnosis of ARVC is based on the presence of
abnormalities in several categories, including structural and histological
alterations of the right ventricle, depolarization and repolarization abnormalities
in the ECG, arrhythmias, and family history. Recently, the old diagnostic criteria
for diagnosing ARVC were modified in order to facilitate diagnosis (Cox et al.
2010, Marcus et al. 2010, McKenna et al. 1994).
In the category of depolarization abnormalities, an epsilon wave in the right
precordial leads is considered a major criterion. The prevalence of an epsilon
wave ranges from 8% to 33% in ARVC patients (Cox et al. 2009, Nasir et al.
2004), but an epsilon wave in the general population is a very rare finding (Uhm
et al. 2011). Repolarization abnormalities seem to be early and more sensitive
markers of disease expression in ARVC, and inverted T waves through V3 have
demonstrated the most optimal sensitivity and specificity for identifying these
patients (Jain et al. 2009). The prevalence of right precordial T-wave inversions
in ARVC is reportedly as high as 85% (Nasir et al. 2004), with the extent of
inverted T waves reflecting the degree of right ventricular involvement (Nava et
al. 1988). Therefore, in the repolarization category of the new guidelines for the
diagnosis of ARVC, T-wave inversions in the right precordial leads V1–V3 were
upgraded as major, and T-wave inversion in V1–V2 or V4–V6 as minor criteria. In
the presence of complete RBBB, inverted T waves beyond V3 are considered
minor criteria (Marcus et al. 2010).
2.3.5 QRS-T angle
Abnormalities of ventricular depolarization depicted in the QRS complex reflect
changes in impulse propagation through the conduction system and ventricular
myocardium, whereas repolarization abnormalities observed as changes in the ST
segment and T wave represent regional pathophysiological changes in the ionic
channels that may be associated with electrical instability. Combining both
37
phenomena may thus provide addition information on the heterogeneities of
ventricular action potential.
The spatial QRS-T angle corresponds to the angle between the QRS complex
and the T wave in three-dimensional space. A similar measurement sometimes
used to define the global angel between depolarization and repolarization is total
cosine R-to-T (TCRT). The spatial QRS-T angle has been demonstrated to predict
outcomes in different patient populations (Kors et al. 2003, de Torbal et al. 2004,
Rautaharju et al. 2007, Zabel et al. 2000). In the Women’s Health Initiative study,
wide QRS-T angle was a significant predictor of congestive heart failure,
coronary heart disease events, and mortality in postmenopausal women
(Rautaharju et al. 2006a, Rautaharju et al. 2006b); also, in the clinical setting, the
spatial QRS-T angle has proved to be a significant and independent predictor of
cardiovascular mortality (Yamazaki et al. 2005). Moreover, in a general
population cohort of 6134 women and men aged 55 years and older from the
Rotterdam Study, Netherlands, abnormal spatial QRS-T angle was strongly
associated with cardiac and sudden arrhythmic death, as well as all-cause
mortality (Kardys et al. 2003).
Although information about the spatial QRS-T angle could be incorporated
into the automated reports of modern electrocardiographic machines, it is
generally unavailable in clinical practice (Okin 2006). However, frontal QRS and
T-wave axes are generally included in ECG reports and can also be fairly easily
estimated from the limb leads. It is thus possible to simply calculate the frontal
QRS-T angle as the difference between the frontal plane QRS axis and the T axis.
The normal limits of the frontal QRS-T angle vary according to age and sex, with
the difference between the lower and upper normal values ranging from around
100° to 120°. For example, the normal limits of the QRS-T angle are between 47° to 61° in women aged 30 to 39, and between -89° and 26° in women over 50
years of age (Macfarlane & Lawrie 1989). The frontal QRS-T angle can
sometimes underestimate the true spatial QRS-T angle (Macfarlane 2012), but it
has proved to be a suitable clinical substitute for the spatial QRS-T angle for risk
prediction, as reported in the ARIC Study (Zhang et al. 2007). Frontal QRS-T
angle > 90° has shown additional prognostic value in patients with nonischemic
cardiomyopathy (Pavri et al. 2008) and can predict ventricular arrhythmias in
patients with ischemic heart disease (Borleffs et al. 2009).
An abnormal frontal QRS-T angle can result from an abnormal QRS-axis or
T-wave axis. Normally, frontal QRS-axis lies between -30° and +90°, and the Twave axis between 0° and 75°. A rightward QRS axis is rare and can result from,
38
for example, right ventricular hypertrophy and pulmonary diseases (Mirvis &
Goldberger 2008), whereas a left-axis deviation occurs more frequently. Potential
causes for leftward deviation of the QRS axis include left ventricular hypertrophy,
horizontal position of the heart in the chest, and inferolateral myocardial
infarction, but it is most commonly due to left anterior hemiblock (LAHB), which
is generally associated with a benign prognosis (Elizari et al. 2007).
In contrast, a shift in the T-wave axis reportedly indicates mortality risk (de
Torbal et al. 2004). In an elderly population with no overt coronary heart disease,
Rautaharju et al. (2001) reported that a spatial T axis was associated with
increased risk of incident coronary heart disease events, cardiovascular deaths,
and all-cause mortality. Kors et al. (1998) obtained similar results from the
Rotterdam study, in which participants with an abnormal T axis had substantially
higher risk of cardiac mortality and SCD.
2.3.6 QT interval
The QT interval is measured from the onset of the QRS complex to the end of the
T wave and represents the sum of the ventricular action potential durations. The
QT interval shortens as the heart rate increases and is commonly corrected (QTc)
with Bazett’s formula (the QT interval divided by the square root of the R-R
interval), although widely acknowledged limitations of this method have led to
the proposition of various other approaches for QT-rate correction (Rautaharju et
al. 2009). The QT interval is slightly longer in women, but this gender difference
becomes less prominent in older age groups. Some discussion has focused on the
appropriate upper normal limits of the QT interval, but recent recommendations
consider QTc 450 ms or more in men and QTc 460 ms or more in women to be
prolonged (Rautaharju et al. 2009). Several other factors (e.g. hypokalemia,
hypomagnesemia, hypocalcemia, myocardial ischemia, cardiomyopathies,
autonomic influences, and hypothermia) also influence the QT interval, but the
most important clinical causes of prolonged QT interval are numerous QTprolonging drugs and long QT syndrome (LQTS) (Goldenberg & Moss 2008).
LQTS is an arrhythmogenic disorder in a structurally normal heart presenting
with a prolonged QT interval associated with peculiar T-wave morphology,
syncope, and SCD. In most cases, LQTS results from a decrease in repolarizing
K+ currents or an inappropriately late entry of Na+ into the myocyte (Goldenberg
& Moss 2008) with an estimated prevalence of approximately 1:2000 (Schwartz
et al. 2009). However, QTc prolongation has also been associated with increased
39
risk of SCD in non-LQTS population-based cohorts (Algra et al. 1991, Straus et
al. 2006, Zhang et al. 2011) as well as in the presence of coronary artery disease
(Chugh et al. 2009a), generating interest in the potential role of prolonged QTc in
the SCD risk prediction. In contrast, short QTc intervals show no association with
adverse outcomes in the general population (Anttonen et al. 2007), although short
QTc intervals occur in short QT-syndrome, which is associated with hastened
ventricular repolarization and higher risk of SCD (Giustetto et al. 2006).
2.3.7 Other electrocardiographic risk markers
Left ventricular hypertrophy
Left ventricular hypertrophy (LVH) is an indicator of target organ damage in
chronic hypertension and in various studies has predicted greater morbidity and
mortality (Hsieh et al. 2005, Sullivan et al. 1993, Tikkanen et al. 2009). The
prevalence and prognostic significance of electrocardiographic LVH varies
depending on the criteria used (Hancock et al. 2009), and in the presence of LVH,
P-terminal force (PTF), left axis deviation, left ventricular strain, T-wave
inversion, and prolonged QRS duration are associated with incremental risk
(Hsieh et al. 2005, Morin et al. 2009). On average, electrocardiographic LVH is
associated with a hazard ratio (HR) of 1.6 for subsequent cardiovascular events
(Chou et al. 2011).
Ventricular premature beats
Ventricular premature beats (VPBs) and nonsustained VTs have proved to be risk
factors for sudden death after myocardial infarction (MI), especially in patients
with left ventricular dysfunction (10 or more VPBs per hour in most studies).
Patients with nonischemic cardiomyopathy also frequently present with
ventricular ectopy, but the relationship between VPBs and SCD is less clear in
this population (Goldberger et al. 2008). The suppression of ventricular
arrhythmias in post-MI patients with anti-arrhythmic drugs has been associated
with increased mortality (Echt et al. 1991).
In the absence of structural heart disease, frequent VPBs have reportedly
caused tachycardia-related cardiomyopathy (TCM), but fortunately TCM
develops only in a minority of subjects (Prystowsky et al. 2012). In the general
40
population, VPBs are associated with traditional risk factors for coronary heart
disease (CHD), as well as with greater incidence of CHD events (Massing et al.
2006) and heart failure (Agarwal et al. 2012, Niwano et al. 2009). According to
some studies, VPBs also predict increased risk of mortality and SCD in the
population (Abdalla et al. 1987, Bikkina et al. 1992, Engel et al. 2007)
independently of baseline CHD risk factors and history or symptoms of
underlying CHD (Massing et al. 2006). In other studies, however, subjects with
no heart disease have shown no mortality risk implications associated with VPBs
(Engstrom et al. 1999, Kennedy et al. 1985).
Heart rate
Elevated resting heart rate has reportedly been a predictor of cardiovascular and
non-cardiovascular mortality and SCD in the general population (Benetos et al.
1999, Cooney et al. 2010b, Engel et al. 2007, Gillum et al. 1991, Jouven et al.
2005). Elevated heart rate may only be a marker of an underlying
pathophysiological abnormality, but accumulating evidence suggests that heart
rate may be an independent risk factor and not just an indicator of risk (Hall &
Palmer 2008). This is supported by a study in which reducing the heart rate in the
heart failure population with elevated heart rate led to improvement in clinical
outcomes (Swedberg et al. 2010).
41
42
3
Purpose of the study
This study aimed to elucidate the prevalence and prognostic significance of
various electrocardiographic parameters available from the standard 12-lead
electrocardiogram in the general population. We were especially interested in the
risk of sudden cardiac death associated with these changes.
The specific aims of the study were:
1.
2.
3.
4.
To assess the significance of prolonged QRS duration and nonspecific
intraventricular conduction delay (IVCD) on all-cause mortality, cardiac
mortality, and sudden cardiac death (SCD).
To study the prognostic significance of wide QRS-T angle, and to evaluate
separately the contribution of the QRS-axis and the T-wave axis to the risk of
SCD.
To evaluate the prevalence and characteristics of T-wave inversions
especially on the right precordial leads V1–V3, and to assess the clinical
outcome associated with these changes.
To assess the clinical significance of prolonged PR interval, or first-degree
AV block, in apparently healthy middle-aged subjects.
43
44
4
Participants and methods
4.1
Study population
The original study population consisted of 10 899 men and women between 30
and 59 years of age (52% male, mean age 44.0 ± 8.5 years) who had an
electrocardiogram recorded as part of the Finnish Social Insurance Institution’s
Coronary Heart Disease Study (CHD Study), which was part of the larger
prospective Mobile Clinic Health Survey carried out in 35 population groups in
Finland. Baseline examinations of the CHD Study were carried out by the Mobile
Clinic between 1966 and 1968, and in 1972 (Reunanen et al. 1983). Of the invited
subjects, 89.6% participated in the study. The study population comprised 12
population groups from four different geographical areas in Finland with variable
mortality and morbidity rates representative of the middle-aged Finnish
population.
During the initial visit, besides recording a standard 12-lead ECG, the
participants were measured and weighed, and had their blood pressure and serum
cholesterol measured. Prior to the examination, subjects filled a questionnaire
about their previous illnesses, smoking habits, and medication during the past
three months. A specially trained nurse then checked the questionnaire to ensure
that all the questions were properly answered. 4% of the subjects used AV-nodal
blocking medication, mainly digitalis, since betablockers were rare at the time.
Any cardiovascular symptoms were documented during the examination using the
Rose angina questionnaire (Rose 1962). Between 1973 and 1976, a median of six
years after the initial examination, the majority of the participants underwent a
repeated evaluation which required another 12-lead ECG.
4.2
Electrocardiographic measurements
Thirty minutes after arrival at the Mobile Clinic, a standard 12-lead ECG was
recorded with the subject at rest in the supine position. A four-channel recorder
(Elema-Schönander Mingograf type 34) was used with a paper speed of 50 mm
per second and a calibration of 1 mV per 10 mm, with each ECG sheet containing
on average seven to eight QRS complexes. Eight trained technicians supervised
by a doctor carried out initial measurements.
45
PR interval, QRS complex, and QT interval were measured for the nearest 10
ms from the bipolar limb lead in which the interval was longest, and the presence
or abscence of electrocardiographic LVH according to the Sokolow-Lyon criteria
was assessed. Afterwards, the QT interval was corrected for heart rate according
to the Bazett’s formula (the QT interval divided by the square root of the R-R
interval). The frontal QRS axis and the T axis were determined manually from the
six limb leads at 10° intervals using a hexaxial reference system. The QRS-T
angle was then calculated as the absolute value of the difference between the QRS
axis and the T axis, yielding values between 0° and 180°. Figure 3 demonstrates
the measurement of ECG intervals and the QRS-T angle.
A
B
QRS axis
0°
I
QRS-T angle
90°
PR interval
QRS
interval
QT interval
T-wave axis
aVF
Fig. 3. Illustration of the measurement of electrocardiographic intervals (A) and the
QRS-T angle (B).
To minimize errors in the process, all readers were continuously evaluated using
separate ECG material. When compared with the reference values, the intraclass
correlation coefficient of r = 0.90 was demonstrated between all readers and the
test material for measuring the PR interval, r = 0.97 for measuring the QRS-axis,
and r = 0.98 for measuring the T-axis.
Later, five physicians independently reevaluated all baseline ECGs for the
presence of IVCD, bundle branch blocks, and T-wave inversions, and the duration
of the QRS complex was measured were the widest complex was observed. We
46
used the standard criteria for defining LBBB and RBBB, and IVCD was defined
as QRS duration ≥ 110 ms not fulfilling the criteria for a partial or complete
bundle branch block. We evaluated the presence of inverted T waves of 0.1 mV or
more in leads other than aVR, aVL, III, and V1, with more precise
characterization of T-wave inversions in the right precordial leads V1 to V3. All
ECGs with IVCD, bundle branch block or T wave inversions were later doublechecked, and to further ensure the reliability of the electrocardiographic
measurements, 270 ECGs were reassessed for interobserver and intraobserver
variation (the kappa-values for QRS duration were 0.66 and 0.68, respectively).
4.3
Follow-up
Subjects were followed from the baseline visit that took place between 1966 and
1972 through the end of 2007, with a mean follow-up of 30 ± 11 years. Most of
the subjects underwent a reexamination between 1973 and 1976. Fewer than 2%
of the subjects were lost as a result of moving abroad, but the survival status of
most of these subjects could still be determined. All episodes of hospitalization
due to atrial fibrillation, transient ischemic attack (TIA) or stroke, heart failure,
coronary heart disease, and ventricular arrhythmias were obtained from the
Finnish Hospital Discharge Register, which includes nationwide data on all
inpatient episodes in Finland at an individual level. Mortality data were obtained
from the Causes of Death Register maintained by Statistics Finland, which
records every death in the country. The quality and reliability of these extensive
registers has previously been well validated (Pajunen et al. 2005, Rapola et al.
1997). Death certificates were obtained for each deceased individual. Death from
cardiac causes was determined according to the appropriate International
Classification of Diseases codes (ICD codes).
To identify cases of definite or probable arrhythmic deaths, all deaths from
cardiac causes were reviewed using death certificates, hospital records, and
autopsy reports (if available) according to the definitions presented in the Cardiac
Arrhythmia Pilot Study (Greene et al. 1989). According to these criteria,
arrhythmia was judged to be the cause of death, defined as spontaneous cessation
of respiration and circulation with loss of consciousness, in one of the following
situations: (1) witnessed and instantaneous with no new or accelerating
symptoms, (2) witnessed and preceded or accompanied by symptoms attributable
to myocardial ischemia in the absence of shock or congestive heart failure, (3)
witnessed and preceded by symptoms attributable to cardiac arrhythmia (e.g.
47
syncope or near-syncope), or (4) unwitnessed but without evidence of another
cause. In the presence of severe congestive heart failure, arrhythmia was judged
not to be the cause of death if death from heart failure appeared probable within
four months of the fatal episode.
During the follow-up, 56.5% of the 10 899 subjects died (n = 6155). Death
from cardiovascular causes accounted for 32.2% of all deaths (n = 1980), and
40.5% of this cardiovascular mortality was due to SCD (n = 801). Overall, SCD
accounted for 13.0% of all-cause mortality.
4.4
Statistical analysis
Continuous data in each study are presented as means ± SD, and categorical
variables as a percentage (%) of the participants. The general linear model served
to compare the age- and sex-adjusted mean values for continuous variables and
the prevalence of categorical variables between the different groups. Hazard ratios
and 95% confidence intervals (CI) were calculated with the Cox proportionalhazards model for the primary and secondary endpoints used in each study. The
primary adjustments in these models were for age and sex, with further
adjustment for covariates that differed between the groups in each study. Age,
heart rate, serum cholesterol, systolic blood pressure, QRS duration, JTc duration
(QTc - QRS duration) and body mass index (BMI) were added as continuous
variables; and sex, smoking, chronotropic medication, cardiovascular disease,
ECG signs of coronary artery disease, history of angina pectoris or myocardial
infarction, or the presence or absence of electrocardiographic LVH were added as
categorical variables in the multivariate models. To further assess differences in
mortality between groups, we used the log-rank test to plot Kaplan-Meier survival
curves and evaluate their statistical significance. We also generated the receiver
operating characteristic (ROC) curves (Study I) and calculated the area under the
curve with 95% CI to assess the performance of QRS duration as a risk predictor.
P values of less than 0.05 were considered statistically significant.
48
5
Results
5.1
Long-term outcome associated with prolonged QRS duration
and nonspecific intraventricular conduction delay (IVCD)
Prolonged QRS duration (QRSd) ≥ 110 ms was present in 1.3% (n = 147) of the
study participants. The prevalence of partial or complete LBBB was 0.3%
(n = 33), and partial or complete RBBB, 0.4% (n = 44). IVCD, defined as QRSd
≥ 110 ms with no bundle branch block or preexcitation, was present in 0.6%
(n = 67) of the population. Subjects with IVCD were older and predominantly
men, and had lower cholesterol levels than did the rest of the subjects, but we
found no differences in the history of prior myocardial infarction or angina
pectoris (Table 2).
Table 2. Characteristics of the subjects with IVCD at baseline.
Characteristics
Males (%)
No IVCD
IVCD
(n = 10 862)
(n = 67)
P value
52.0
93.0
<0.001
44.0 ± 8.5
46.2 ± 9.9
0.03
Current smoker (%)
34.0
26.1
0.14
Total cholesterol (mmol/l)
6.51
6.11 ± 1.34
0.01
25.9 ± 3.9
26.2 ± 3.6
0.59
76 ± 15
77 ± 17
0.49
Age (y)
BMI
Heart rate (bpm)
Systolic blood pressure
138 ± 21
143 ± 28
0.10
QTc duration (ms)
408 ± 28
419 ± 30
0.002
QRS duration (ms)
87 ± 8
112 ± 6
<0.001
LVH (%)
31.4
15.6
0.004
Prior MI (%)
1.1
0.0
0.19
History of angina pectoris (%)
2.3
0.2
0.26
Plus-minus values are means ± SD
During the mean follow-up of 30 ± 11 years, subjects with QRSd ≥ 110 ms had
higher all-cause mortality (multivariate-adjusted hazard ratio [HR] 1.48, 95% CI
1.22–1.81, P < 0.001), higher cardiovascular mortality (HR 1.94, 95% CI 1.44–
2.63, P < 0.001), and elevated risk of sudden arrhythmic death (HR 2.14, 95% CI
1.38–3.33, P = 0.002). Partial or complete LBBB was associated with increased
risk of sudden arrhythmic death (HR 2.71, 95% CI 1.20–6.11, P = 0.04), but
RBBB did not predict increased mortality. Subjects with IVCD were at even
49
greater risk of adverse outcomes. IVCD was associated with increased all-cause
mortality (HR 2.01, 95% CI 1.52–2.66, P < 0.001), increased cardiovascular
mortality (HR 2.53, 95% CI 1.64–3.90, P < 0.001), and even higher risk of
sudden arrhythmic death (HR 3.11, 95% CI 1.74–5.54, P = 0.001) (Figure 4).
The results remained similar when subjects with no evidence of heart disease
were analyzed separately. Also in this group, subjects with QRSd ≥ 110 ms had
higher overall mortality (HR 1.34, 95% CI 1.07–1.68, P = 0.02), higher
cardiovascular mortality (HR 1.72, 95% CI 1.20–2.46, P = 0.007), and increased
risk of sudden arrhythmic death (HR 2.03, 95% CI 1.21–3.41, P = 0.02). In these
subjects with no suspected cardiac disease, IVCD was associated with increased
all-cause mortality (HR 1.75, 95% CI 1.27–2.40, P = 0.002), cardiovascular
mortality (HR 1.87, 95% CI 1.08–3.25, P = 0.04), and the risk of sudden
arrhythmic death (HR 2.90, 95% CI 1.49–5.63, P = 0.007).
Fig. 4. Kaplan-Meier survival plots for sudden arrhythmic death in subjects with IVCD.
50
5.2
QRS-T angle as a predictor of sudden cardiac death
In the middle-aged subjects studied, median QRS axis was 40°, median T-wave
axis 30°, and median QRS-T angle 20°. In the study, QRS-T angle 0° to 90°, QRS
axis -30° to 90°, and T axis 0° to 90° were considered normal. Of the subjects,
2.1% had a left-axis deviation with QRS-axis ≤ -40°, and 1.3% a right-axis
deviation with QRS-axis ≥ 100°. Negative T axis ≤ -10° was present in 4.4% of
the subjects, and 0.7% had T axis ≥ 100°. A wide QRS-T angle ≥ 100° occurred in
2.0% (n = 212) of the population. Subjects with QRS-T angle ≥ 100° were older
and more often men, were more likely to smoke, and had a higher heart rate and
systolic blood pressure. They also had a slightly longer QRS duration, and were
more likely to present with inverted T waves, but no difference was noted in the
history of prior myocardial infarction or electrocardiographic LVH (Table 3).
Table 3. Characteristics of the subjects with wide QRS-T angle at baseline.
Characteristics
Males (%)
Age (y)
Current smoker (%)
QRS-T angle 0-90°
QRS-T angle ≥100°
(n = 10 501)
(n = 212)
P value
52.0
59.6
0.03
43.9 ± 8.4
48.7 ± 8.7
<0.001
33.8
40.0
0.04
Total cholesterol (mmol/l)
6.50 ± 1.31
6.60 ± 1.53
0.26
BMI
25.9 ± 3.8
25.5 ± 4.7
0.09
75 ± 15
81 ± 16
<0.001
<0.001
Heart rate (bpm)
Systolic blood pressure
138 ± 21
144 ± 28
QTc duration (ms)
408 ± 27
411 ± 34
0.18
QRS duration (ms)
87 ± 8
90 ± 10
<0.001
Electrocardiographic LVH (%)
31.6
31.7
0.97
Prior MI (%)
1.1
0.1
0.14
History of angina pectoris (%)
2.3
0.0
0.004
Plus-minus values are means ± SD
During the long follow-up, subjects with QRS-T angle ≥ 100° had higher allcause mortality (multivariate-adjusted HR 1.57, 95% CI 1.34–1.84, P < 0.001)
and a higher risk of SCD (HR 2.26, 95% CI 1.59–3.21, P < 0.001) (Figure 5), but
no significant difference was noted in non-arrhythmic cardiac mortality (HR 1.34,
95% CI 0.93–1.92, P = 0.13). The results remained similar when subjects with
suspected cardiovascular disease were excluded from the analysis. When the QRS
axis and the T axis were analyzed separately, no additional mortality was
associated with an abnormal QRS-axis (≤ -40° or ≥ 100°). In contrast, abnormal T
51
axis (≤ -10° or ≥ 100°) was associated with increased risk of all-cause mortality
(HR 1.39, 95% CI 1.24–1.55, P < 0.001), non-arrhythmic cardiac mortality (HR
1.87, 95% CI 1.50–2.34, P < 0.001), and SCD (HR 2.13, 95% CI 1.63–2.79,
P < 0.001).
Fig. 5. Kaplan-Meier survival plots for sudden arrhythmic death in subjects with QRST angle ≥ 100°.
5.3
Prevalence and prognostic significance of T wave inversions
Among the study participants, the overall prevalence of inverted T waves in
frontal or precordial leads was 1.2% (n = 130). Right precordial T-wave
inversions in V1–V3 were present in 0.5% (n = 54) of the entire population. Most
of these subjects were women, and their mean heart rate was slower than among
the rest of the population. The baseline characteristics of the subjects appear in
Table 4.
52
Table 4. Characteristics of the subjects with right precordial T-wave inversions at
baseline.
Characteristics
Males (%)
No TWI
TWI V1-V3
(n = 10 734)
(n = 54)
P value
52.4
12.9
<0.001
44.0 ± 8.5
43.6 ± 8.4
0.77
34.0
43.1
0.98
Total cholesterol (mmol/l)
6.50 ± 1.31
6.56 ± 1.78
0.72
BMI
Age (y)
Current smoker (%)
25.9 ± 3.8
26.0 ± 4.4
0.94
Heart rate (bpm)
76 ± 15
69 ± 13
<0.001
Systolic blood pressure
138 ± 21
135 ± 22
0.18
4.2
2.3
0.48
Chronotropic medication (%)
Cardiovascular disease (%)
7.9
14.1
0.08
QTc duration (ms)
408 ± 27
408 ± 31
0.93
QRS duration (ms)
87 ± 8
87 ± 6
0.86
Electrocardiographic LVH (%)
31.4
23.7
0.22
Prior MI (%)
1.1
0.4
0.63
History of angina pectoris (%)
2.3
0.0
0.17
TWI indicates T-wave inversion, plus-minus values are means ± SD
For most of these individuals, the T-wave amplitude fell between -0.1mV and 0.4mV, and only four subjects presented with negative T waves of -0.5mV or
deeper. In over half of the subjects with right precordial T-wave inversion, right
precordial T-wave inversions continued to V4 or beyond. Only one subject with
inverted T-waves in V1–V3 also had an epsilon wave, thus fulfilling the diagnostic
criteria of ARVC. Most subjects with right precordial T-wave inversion on initial
examination also had a control ECG available a median of six years later. In most
cases, similar T-wave inversions were still present, and in only 20% of these
individuals did T-wave inversions disappear during the follow-up. An example of
isolated right precordial T-wave inversion appears in Figure 6.
Inverted T-waves confined only to leads other than V1–V3 were present in
0.7% (n = 76) of the population. These subjects were older, had higher blood
pressure, and were more likely to have chronotropic medication and
cardiovascular disease. They also had a slightly longer QRS duration, but the
groups showed no significant differences in sex distribution, LVH, or history of
angina pectoris or prior myocardial infarction.
53
I
II
III
V1
aVR
V3
aVL
V4
aVF
V2
V5
V6
Fig. 6. ECG presenting typical mildly inverted right precordial T waves in leads V1–V3.
The clinical outcomes associated with right precordial T-wave inversions and Twave inversions in other leads appear in Table 5. No excess in mortality or
increase in hospitalizations due to congestive heart failure, ventricular arrhythmia,
or coronary artery disease occurred in subjects with right precordial T-wave
inversions at V1–V3 or beyond. In contrast, inverted T waves with leads other than
V1–V3 were associated with a significant increase in all-cause and cardiovascular
mortality, as well as SCD. Moreover, these T-wave inversions predicted heart
failure and coronary heart disease hospitalizations.
54
Table 5. Clinical outcomes associated with T-wave inversions in right precordial leads
(TWI V1-3) and in other than right precordial leads (TWI other).
Outcome
No TWI
TWI V1-3
P value
TWI other
P value
(n = 10 734)
(n = 54)
(TWI V1-3)
(n = 76)
(TWI other)
0.81
1.65
All-cause mortality
No. of deaths
Age- and sex-adjusted HR
6049
25
1
0.95
(95% CI)
Multivariate adjusted HR
59
(0.64–1.41)
1
(95% CI)*
0.93
<0.001
(1.28–2.14)
0.71
(0.61–1.40)
1.49
0.004
(1.15–1.93)
Cardiac mortality
No. of deaths
Age- and sex-adjusted HR
1929
9
1
1.18
(95% CI)
Multivariate adjusted HR
31
0.63
(0.61–2.27)
1
(95% CI)*
1.06
2.65
<0.001
(1.86–3.78)
0.88
(0.53–2.12)
2.10
<0.001
(1.46–3.00)
Sudden arrhythmic death
No. of deaths
Age- and sex-adjusted HR
779
2
1
0.76
(95% CI)
Multivariate adjusted HR
(95% CI)*
14
0.69
(0.19–3.06)
1
0.74
(0.18–2.97)
3.16
<0.001
(1.86–5.36)
0.66
2.38
0.005
(1.39–4.08)
* Adjusted for age, sex, heart rate, systolic blood pressure, chronotropic medication, and history of
cardiovascular disease
5.4
Prognostic significance of prolonged PR interval in middleaged subjects
Altogether 2.1% (n = 222) of the study cohort had a prolonged PR interval > 200
ms, and the prevalence of a more pronounced PR prolongation ≥ 220 ms was
1.1% (n = 123). Only 20 individuals (0.2% of the population) had PR
intervals > 240 ms. 70% of the subjects with a prolonged PR interval on initial
examination also had a prolonged PR interval at the control ECG a median of six
years later. Subjects with a prolonged PR interval were older, more likely to be
male, had a higher BMI and lower heart rate, and more often had chronotropic
medication and suspected cardiovascular disease than did those with a normal PR
interval (Table 6).
55
Table 6. Characteristics of the subjects with prolonged PR interval at baseline.
Characteristics
Males (%)
PR ≤ 200ms
PR > 200ms
(n = 10 563)
(n = 222)
P value
51.8
71.9
43.9 ± 8.4
45.4 ± 8.7
0.01
34.1
29.5
0.12
Total cholesterol (mmol/l)
6.51 ± 1.32
6.36 ± 1.34
0.09
BMI
25.9 ± 3.8
26.6 ± 4.0
0.01
Heart rate (bpm)
76 ± 15
71 ± 14
<0.001
Systolic blood pressure
138 ± 21
139 ± 22
0.53
4.2
8.8
<0.001
Age (y)
Current smoker (%)
Chronotropic medication (%)
Cardiovascular disease (%)
<0.001
7.9
12.9
0.005
PR interval (ms)
155 ± 20
222 ± 17
<0.001
QTc duration (ms)
408 ± 27
406 ± 28
0.20
QRS duration (ms)
87 ± 8
87 ± 8
0.18
Electrocardiographic LVH (%)
31.3
36.2
0.11
Prior MI (%)
1.1
1.5
0.57
History of angina pectoris (%)
2.3
2.3
0.97
Plus-minus values are means ± SD
After adjusting for age and sex, a prolonged PR interval > 200 ms showed no
association with increased mortality or hospitalizations due to coronary heart
disease, heart failure, atrial fibrillation, TIA or stroke during the follow-up period
(Table 7). When subjects with suspected cardiovascular disease, nodal blocking
medication, and a prolonged QRS duration ≥ 120 ms were excluded, the results
remained unchanged. Using the cutoff PR ≥ 220 ms to define a prolonged PR
interval did not affect the results, either (P = non-significant for all endpoints).
56
Table 7. Mortality and risk of hospitalizations associated with a prolonged PR interval.
Outcome
PR ≤ 200ms
PR > 200ms
(n = 10 563)
(n = 222)
P value
All-cause mortality
No. of deaths
5933
140
Age- and sex-adjusted HR (95% CI)
1
1.04 (0.88–1.23)
0.67
Multivariate-adjusted HR (95% CI) *
1
1.05 (0.89–1.24)
0.56
Cardiac mortality
No. of deaths
1904
44
Age- and sex-adjusted HR (95% CI)
1
0.95 (0.71–1.29)
0.75
Multivariate-adjusted HR (95% CI) *
1
0.94 (0.70–1.27)
0.68
Sudden arrhythmic death
No. of deaths
766
23
Age- and sex-adjusted HR (95% CI)
1
1.18 (0.78–1.78)
0.46
Multivariate-adjusted HR (95% CI) *
1
1.16 (0.76–1.75)
0.51
Hospitalization for AF
No. of deaths
1591
35
Age- and sex-adjusted HR (95% CI)
1
1.10 (0.79–1.55)
0.57
Multivariate-adjusted HR (95% CI) *
1
1.03 (0.74–1.45)
0.85
Hospitalization for TIA or stroke
No. of deaths
1877
50
Age- and sex-adjusted HR (95% CI)
1
1.30 (0.98–1.72)
0.08
Multivariate-adjusted HR (95% CI) *
1
1.23 (0.92–1.62)
0.17
Hospitalization for HF
No. of cases
1673
43
Age- and sex-adjusted HR (95% CI)
1
1.27 (0.94–1.72)
0.14
Multivariate-adjusted HR (95% CI) *
1
1.22 (0.90–1.65)
0.22
Hospitalization for CHD
No. of cases
3465
74
Age- and sex-adjusted HR (95% CI)
1
1.02 (0.81–1.29)
0.84
Multivariate-adjusted HR (95% CI) *
1
0.97 (0.77–1.22)
0.80
* Adjusted for age, sex, BMI, heart rate, chronotropic medication, and cardiovascular disease
57
58
6
Discussion
6.1
QRS duration and IVCD as predictors of sudden cardiac death
Prolonged duration of the QRS complex and IVCD in the electrocardiogram have
been associated with increased mortality and risk of SCD in the presence of
coronary artery disease and heart failure (Teodorescu et al. 2011, Wang et al.
2008, Zimetbaum et al. 2004). In the LIFE study of hypertensive patients with
electrocardiographic LVH, prolonged QRS duration was independently predictive
of increased risk of SCD (Morin et al. 2009). Previously, however, little has been
known of the prognostic significance of prolonged QRS duration and IVCD in
individuals with no overt cardiac disease. In Study I, we examined the prognostic
impact of prolonged QRS duration and IVCD in the middle-aged general
population. Because the optimal cutoff to define prolonged QRS duration in the
study population seemed to be 110 ms, we included partial and complete bundle
branch blocks and IVCD in the analysis. In the study, we defined IVCD as QRS
duration ≥ 110 ms with no bundle branch block-like morphology or ventricular
preexcitation. Traditionally, prolonged QRS duration has been defined as QRS
≥ 120 ms, which has also served as the historical cutoff for IVCD (Blackburn et
al. 1960). However, recent recommendations for standardizing and interpreting
the electrocardiogram defined IVCD similarly to the definition used in our study
(Surawicz et al. 2009).
The prevalence of prolonged QRS duration and IVCD vary widely depending
on the population studied. Among patients with reduced left ventricular ejection
fraction hospitalized for heart failure, markedly prolonged QRS duration ≥ 120
ms occurs in up to 40% (Wang et al. 2008). In the general population, however,
prolonged QRS duration is rare. Overall prevalence of prolonged QRS duration
≥ 110 ms was 1.3% in our study population. Partial or complete RBBB was
present in 0.4% and LBBB in 0.3% of the subjects. IVCD was present in 0.6% of
the subjects.
During the mean 30-year follow-up, IVCD was associated with a markedly
increased risk of SCD in the middle-aged general population studied, together
with an increase in all-cause mortality and cardiovascular mortality. The risk of
SCD associated with IVCD remained three-fold, however, even after adjusting for
other traditional risk factors. Prolonged QRS duration ≥ 110 ms itself (including
bundle branch blocks) also proved to be an independent predictor of SCD. The
59
results presented in Study I were recently confirmed in another general
population-based sample from Eastern Finland (Kurl et al. 2012). In their
population-based sample of over 2000 men with a 19-year follow-up, the risk of
SCD increased by 27% for each 10-ms increase in QRS duration with a 2.5-fold
higher risk of SCD associated with QRS duration of > 110ms.
Several mechanisms could contribute to the adverse prognostic impact of
prolonged QRS duration. QRS complex prolongation may be merely a marker of
underlying cardiac disease and left ventricular dysfunction, which have a wellestablished relationship with mortality and SCD. The development of a bundle
branch block correlates strongly with age, suggesting that it may be a marker of
progressive cardiac degeneration associated with aging (Eriksson et al. 1998).
Future high-degree atrioventricular block is also strongly associated with the
presence of bundle branch block, especially LBBB (Eriksson et al. 2005).
Another potential explanation for the adverse prognostic impact of increased
QRS duration may be related to markedly abnormal electrical and mechanical
activation of the left ventricle. Changes in the ventricular activation sequence in
LBBB can induse functional abnormalities manifested by abnormal septal motion
as well as a reduction in the global ejection fraction and left ventricular diastolic
filling times (Grines et al. 1989, Lee et al. 2003), thereby producing functional
mitral regurgitation (Erlebacher & Barbarash 2001). In addition, research has
shown left ventricular asynchrony itself to be an independent predictor of severe
cardiac events (Bader et al. 2004, Fauchier et al. 2002). Ventricular pacing can
also cause abnormalities in ventricular function, and recent research has
demonstrated that prolonged paced QRS duration is a major risk factor for future
heart failure in patients with continuous right ventricular apical pacing (Chen et
al. 2013). On the other hand, the resynchronization of systole with biventricular
pacing in patients with wide QRS complex and reduced left ventricular ejection
fraction has improved outcomes (Moss et al. 2009).
While bundle branch blocks are primarily defects of the conduction system,
IVCD is suggestive of a conduction delay in the myocardium outside the HisPurkinje system. This delayed and heterogeneous depolarization can play a direct
role in facilitating arrhythmias by acting as a substrate for reentrant ventricular
tachycardia (de Bakker et al. 1988, Horwich et al. 2003) and can thus increase
one’s risk of SCD. Prolonged QRS duration and IVCD may also indicate the
presence of increased myocardial fibrosis and interstitial remodeling. In the
Framingham Heart Study population with no cardiac disease, increasing QRS
duration was associated with left ventricular mass and dimensions (Dhingra et al.
60
2005). This is supported by an early study that found a positive correlation
between the presence or absence of myocardial fibrosis and QRS duration
(Mazzoleni et al. 1975). Finally, genetic factors influencing QRS duration are
beginning to emerge (Sotoodehnia et al. 2010), so genetic predisposition may also
play a role in one’s vulnerability to ventricular arrhythmias in subjects with QRS
prolongation.
6.2
QRS-T angle as a risk marker of sudden cardiac death
In Study II, we assessed for the first time the mortality risk associated with a wide
frontal QRS-T angle in the middle-aged general population. A QRS-T angle
≥ 100° was associated with a more than two-fold risk of SCD, but the risk of nonarrhythmic cardiac death showed no significant increase. This implies that a wide
QRS-T angle may be more than a marker of underlying cardiovascular disease,
but could also specifically predict one’s vulnerability to lethal arrhythmias. This is
supported by a study of subjects with ischemic cardiomyopathy and ICD that
demonstrated a markedly higher risk of ventricular arrhythmias associated with a
wide QRS-T angle (Borleffs et al. 2009). Another ICD trial with nonischemic
cardiomyopathy patients also demonstrated that a wide QRS-T angle predicted
increase in mortality and ICD shocks even after adjusting for different clinical
variables such as left ventricular ejection fraction and NYHA class (Pavri et al.
2008).
In our study, an abnormal QRS axis alone showed no association with
adverse outcome. A negative QRS axis is often the result of a left anterior
hemiblock (LAHB), which is generally considered a benign finding (Elizari et al.
2007). In contrast, an abnormal T-wave axis seemed to confer most of the
increased risk concomitant with a wide QRS-T angle, since it was associated with
a similar two-fold risk of SCD. This is in accordance with the results of some
previous studies on elderly populations, which have demonstrated that an
abnormal T-wave axis is an independent risk factor for cardiac death and nonfatal cardiac events (Kors et al. 1998, Rautaharju et al. 2001).
However, an abnormal T-wave axis does not automatically mean abnormal
QRS-T angle. In our study population, the prevalence of a wide QRS-T angle
≥ 100° was 2.0%, while that of a negative T-axis ≤ -10°, implying a T-wave
inversion in lead aVF, was 4.4%, and that of a positive T-axis ≥ 100°, suggesting
a T-wave inversion in lead I, was 0.7%. Thus, many more individuals had an
abnormal T-wave axis than an abnormal QRS-T angle. Some of the negative T
61
axes, however, can be regarded as nonspecific changes due to a normal QRS-T
angle, which the Minnesota Code already recognized half a century ago. In this
electrocardiographic coding system, T-wave inversion in the inferior lead aVF
was considered a non-codeable finding, if the QRS complex was not mainly
upright in this lead (Macfarlane 2012).
6.3
Prognostic implications of right precordial T-wave inversions
Inverted T waves in the right precordial leads beyond V1 are a common finding in
children, but these inverted T-waves usually become upright after puberty (Suarez
& Suarez 1946). In some individuals, however, this electrocardiographic pattern
persists into adulthood, which can pose a clinical problem since right precordial
T-wave inversions are also present in various forms of structural cardiac disease
potentially capable of causing SCD (Nava et al. 1988, Okada et al. 1994, Thiene
et al. 1988). In Study III, we assessed the prevalence and prognostic value of Twave inversions in our study cohort of 30 to 59-year-old subjects from the general
population. T-wave inversions in the right precordial leads V1–V3 occurred in
0.5% of the subjects, which is in the range of 0.1% to 3% previously reported by
other investigators (Hiss et al. 1960, Marcus 2005, Papadakis et al. 2009,
Pelliccia et al. 2007). In most cases, the T-wave inversions were mild to
moderate; they were also significantly more common in women than in men.
Only 0.03% of the subjects presented with deeply inverted T waves of 5 mm or
more.
Nearly 80% of the subjects with T-wave inversions in V1–V3 showed inverted
T waves in a control ECG taken a median of six years after the initial
examination. This suggests that in most cases, T-wave inversion is a constant
finding and not due to transient factors capable of causing repolarization
abnormalities such as hyperventilation or transient emotional incitement, which
can trigger sympathetic activation (Alexopoulos et al. 1996, Atterhog et al. 1981,
Blom 1951, Toivonen et al. 1997).
An early repolarization pattern in the right precordial leads is especially
common in black athletes, and T-wave inversion associated with this
electrocardiographic pattern is often considered benign in this setting (Corrado et
al. 2009); in the presence of deep inverted T-waves, however, a thorough clinical
check-up is recommended, even for athletes (Wilson et al. 2012). In our study
population, fewer than 20% of the individuals with inverted T-waves in V1–V3
62
presented with ST-segment elevation in these leads consistent with early
repolarization.
The right precordial leads can reveal changes in the ECG due to various
cardiac conditions such as myocardial ischemia, myocarditis, and hypertrophic or
dilated cardiomyopathy, but the electrocardiographic criteria for depolarization
and repolarization abnormalities play an especially important role in the diagnosis
of ARVC (Marcus et al. 2009, Marcus & Zareba 2009, McKenna et al. 1994). The
prevalence of ARVC in the population has been estimated to range from 1 in 1000
to 1 in 5000 (Basso et al. 2009, Peters et al. 2004, Rampazzo et al. 1994),
although mutations predisposing to ARVC seem to be much more common in the
populace (Lahtinen et al. 2011). According to the new diagnostic criteria for
diagnosing ARVC, T-wave inversions in V1–V3 represent major criteria in the
category of repolarization abnormalities and epsilon waves major criteria in the
category of depolarization abnormalities (Marcus et al. 2010).
In ARVC, right precordial T-wave inversions have been reportedly been
present in around 48% to 85% of patients, thus reflecting the level of right
ventricular involvement (Marcus et al. 2009, Nasir et al. 2004, Nava et al. 1988),
whereas the epsilon wave is considered more specific, if less sensitive, for the
disease (Cox et al. 2009, Nasir et al. 2004, Uhm et al. 2011). In our study, only
one subject with right precordial T-wave inversions showed epsilon waves, thus
fulfilling the diagnostic criteria for ARVC, but due to the rarity of the disease and
the low sensitivity of these ECG changes, one can draw no direct estimations of
the prevalence of ARVC in the Finnish population based on this study.
The prognosis associated with inverted T-waves in the right precordial leads
V1–V3 was favorable in our study, and mortality and SCD rates did not differ
from that of the rest of the population. No differences in hospitalizations for heart
failure or ventricular arrhythmias were observed between the groups, either. In
contrast, T-wave inversions restricted to other leads than V1–V3 were associated
with higher cardiovascular mortality and SCD. This suggests, that mild T-wave
inversions in V1–V3 found incidentally in a subject without symptoms, family
history or clinical finding suggestive of underlying structural heart disease such as
ARVC are likely to be an innocent finding and not an early sign of underlying
cardiomyopathy. T-waves in leads other than the right precordial leads, however,
may be a sign of underlying cardiac pathology and warrant closer clinical
evaluation of these subjects.
63
6.4
Natural history of prolonged PR interval, or first-degree AV
block
In Study IV, we sought to clarify the prognostic significance of prolonged PR
interval in middle-aged subjects. Prolonged PR interval, or first-degree AV-block,
has long been regarded as a benign phenomenon (Bexton & Camm 1984).
Recently, however, this perception has been challenged by a few studies
indicating that prolonged PR interval may be associated with higher risk of atrial
fibrillation in some populations (Cheng et al. 2009, Magnani et al. 2013, Soliman
et al. 2009). Moreover, PR prolongation has been suggested to predict heart
failure hospitalizations (Magnani et al. 2013), pacemaker implantations and allcause mortality (Cheng et al. 2009). In our study, we observed no increase in allcause mortality, cardiovascular mortality, or SCD in subjects with a PR interval >
200ms during the mean 30-year follow-up. These subjects showed no increase in
hospitalizations due to heart failure, atrial fibrillation, transient ischemic attack or
stroke, either. The results remained unchanged when PR prolongation was defined
as PR ≥ 220 ms.
Prolonged PR interval is most often the result of delayed conduction in the
AV node, although delayed conduction in the atrium and in the His-Purkinje
system can also cause PR prolongation. The AV node is strongly influenced by
the autonomic nervous system, and over 10% of conditioned athletes, for
example, can present with a prolonged PR interval due to increased vagal tone
and decreased sympathetic tone (Corrado et al. 2009, Pelliccia et al. 2000). The
PR interval is generally longer in men and prolongs further with age (Magnani et
al. 2011). Electrophysiological studies have demonstrated that aging results in
increased conduction times and refractoriness in the atria (Kistler et al. 2004), and
in decelerated conduction of the AV node and the more distal conduction system
(Taneja et al. 2001). Changes in the atrioventricular conduction associated with
vagal tone and aging may explain why the results of most previous studies and
our present work conducted on young or middle-aged subjects seem to differ from
those of some recent publications.
In the Framingham population, a PR interval > 200 ms predicted all-cause
mortality with an unadjusted hazard ratio of 2.7 and a multivariate-adjusted
hazard ratio of 1.4. The adjusted risk of atrial fibrillation was two-fold, and the
risk of pacemaker implantation was three-fold higher than that of the rest of the
population (Cheng et al. 2009). However, the mean age of the subjects with
prolonged PR interval was 55 years –almost 10 years more than the average age
64
of the rest of the cohort, which might explain why the outcomes in this study
differed from those of previous reports. Similar results have also been obtained
from patients with stable coronary artery disease, in whom a PR interval ≥ 220 ms
was associated with heart failure and cardiovascular death (Crisel et al. 2011).
A prolonged PR interval can be a marker of more extensive calcification and
fibrosis of the conduction system (Lev 1964), and especially in the elderly, this
could forecast more severe disturbances of the AV conduction influencing the
prognosis. Degenerative changes and fibrosis of the sinus node and the atria
associated with aging could also predispose an individual to a higher risk of atrial
arrhythmias. Moreover, a prolonged PR interval can disturb left ventricular filling
and cause diastolic mitral regurgitation (Appleton et al. 1991, Barold et al. 2006,
Schnittger et al. 1988), which may be hemodynamically important, especially in
older individuals with systolic or diastolic ventricular dysfunction.
Taken together, in the middle-aged population with no cardiovascular disease,
a prolonged PR interval seems to be an innocent electrocardiographic finding
with no prognostic implications. However, this may not be true in subjects with
prolonged QRS duration, which implies that conduction delay does not occur
solely in the AV node but is due to disturbed conduction in the His-Purkinje
system. In the elderly, on the other hand, PR prolongation is more likely to be
associated with structural cardiac disease and a risk of adverse outcome, and thus
requires a more meticulous approach.
6.5
Future aspects of electrocardiography in SCD prevention
The 12-lead ECG is an invaluable tool in the diagnosis of a variety of cardiac
diseases, including arrhythmias, myocardial ischemia, and hereditary ion channel
disorders, and can also prove helpful in identifying individuals with underlying
cardiomyopathy. The role of ECG as a screening method to prevent SCD in
susceptible individuals has recently sparked great interest.
A special group that may potentially benefit from the early detection of
underlying cardiac abnormalities is athletes engaged in competitive sports. A
variety of clinical, experimental and epidemiological evidence suggests that
regular physical activity decreases one’s risk of cardiovascular events and SCD,
but on the other hand, vigorous exercise transiently increases one’s risk of acute
coronary events and potentially lethal ventricular arrhythmias in susceptible
individuals (Thompson et al. 2007). Among young athletes, cardiomyopathies,
coronary anomalies, and premature coronary artery disease are among the most
65
important cardiac pathologies responsible for SCD. In Italy, preparticipation
screening of athletes that includes the 12-lead ECG has already began three
decades ago and has led to a marked decline in the incidence of SCD, mainly due
to fewer sudden deaths from cardiomyopathies (Corrado et al. 2006). This
encouraging experience has led the European Society of Cardiology to
recommend electrocardiographic screening for all young athletes involved in
competitive sports (Corrado et al. 2005).
The preparticipation screening protocol is currently implemented in many
countries, although the rate of false positive ECGs in athletes (i.e.
electrocardiographic changes leading to further investigations revealing no
underlying cardiac pathology) has reportedly risen to as high as 9% (Corrado et
al. 2011). However, the efficacy and cost-benefit of the systematic screening of
athletes has recently come under discussion (Halkin et al. 2012, Steinvil et al.
2011).
Among individuals over 35 years of age, coronary artery disease is by far the
most common cause of SCD (Corrado et al. 2011); thus, traditional risk factors
such as older age, male sex, high blood pressure, abnormal serum low- and highdensity lipoprotein (LDL and HDL) concentrations, smoking, and diabetes can
prove helpful in predicting future cardiovascular risk (Greenland et al. 2003a).
However, although these factors may be associated with SCD, their predictive
value is low; consequently, interest has grown in additional methods such as
resting and exercise ECG in order to assist in risk stratification and to guide
therapies in reducing the risk of future cardiovascular events (O'Malley &
Redberg 2010).
A wide range of electrocardiographic abnormalities such as prolonged QRS
duration, LBBB, IVCD, LVH, ER, QTc-interval, wide QRS-T angle and even
minor ST-T abnormalities have been associated with increased risk of
cardiovascular death (Aro et al. 2011, Aro et al. 2012, Daviglus et al. 1999,
Greenland et al. 2003a, Tikkanen et al. 2009). However, effect on clinical
outcomes obtained with the screening of asymptomatic individuals with resting
ECGs versus no screening remains poorly demonstrated. The problem of
screening is highlighted by a recent study that randomized type II diabetics for
screening of asymptomatic coronary artery disease. It is well established that
diabetic patients are at higher risk of coronary events, but even in this high-risk
population, a randomized trial failed to show any benefit from a systematic search
for ischemia in asymptomatic individuals (Young et al. 2009). Moreover,
evidence on how identifying high-risk persons with ECG affects the use of
66
medical and other interventions in reducing cardiovascular risk is inadequate
(Chou et al. 2011). Another problem with systematic electrocardiographic
screening of the population is that the majority of coronary events occur in the
absence of prior ECG abnormalities, so the sensitivity and specificity of the
screening would likely be low (Corrado et al. 2011).
In their recent clinical guidelines, the U.S. Preventive Services Task Force
(USPSTF) recommended against routine electrocardiographic screening of lowrisk asymptomatic adults for the prediction of cardiac events (Moyer & U.S.
Preventive Services Task Force 2012). In clinical practice, however, innumerable
ECGs are recorded every day for a wide variety of reasons from individuals with
and without overt cardiac disease. When an abnormal electrocardiographic pattern
is encountered in a routine ECG, its clinical significance is of great interest to
both the physician and the patient. Although the evidence may not be sufficiently
robust to recommend systematic ECG screening, it seems reasonable to assume
that an individual with an electrocardiographic pattern associated with greater risk
will benefit from further clinical evaluation and closer follow-up. The positive
predictive accuracy of each of these ECG risk markers remains relatively low, so
further efforts are still needed to improve the risk stratification of our patients and
to develop strategies for SCD prevention.
6.6
Potential limitations of the studies
The number of deaths classified as SCD varies significantly between different
studies due to the different definitions they used to define SCD and whether the
arrhythmia itself was documented. In our studies, we used a widely accepted
criterion to define probable arrhythmic death (Greene et al. 1989). This endpoint,
however, is somewhat biased. Even though rapid ventricular arrhythmias are
considered the most common mechanism of SCD, many other conditions than
arrhythmias can evolve rapidly and lead to sudden death. In fact, studies of
patients with ICD have demonstrated that many deaths defined as sudden were
not due to arrhythmias, but to other cardiac and noncardiac causes (Grubman et
al. 1998, Pratt et al. 1996).
Another potential limitation in the present studies relates to the manual
measurements of the different electrocardiographic parameters. The use of
automated ECG machines could have yielded more precise information on the
various intervals in the electrocardiogram even though great care was taken to
ensure the accuracy and reproducibility of the data. The PR interval is itself a
67
dynamic interval, and measuring it to the nearest millisecond rather than in 10-ms
intervals is unlikely to significantly change the outcomes. The automated
measurement of QRS duration, however, may have altered the results. Our
method of measuring QRS duration to the nearest 10 ms in Study I would, if
anything, result in a conservative bias and does not explain the significant
survival difference observed based on QRS duration. The same holds true for the
estimation of the frontal QRS-T angle in Study II.
The demographics of the Finnish population have changed considerably over
the past 40 years, with significant changes in lifestyle and a reduction of the
cardiovascular risk factors and mortality (Cooney et al. 2010a, Harald et al.
2008), as well as profound changes in the diagnosis and treatment of various
cardiovascular conditions. Consequently, some of the observations presented here
may prove inapplicable in more contemporary population.
The baseline visit in 1966–1972 entailed a detailed cardiovascular risk
assessment that included routine laboratory samples; the participants were
carefully interviewed for the presence of chest pain, dyspnea, and peripheral
artery disease, but underwent no further diagnostic testing, such as an exercise
test or echocardiography. Consequently, some of the subjects may have had an
underlying cardiac disease undiscovered during the initial workup. This resembles
normal clinical practice, however, and makes the results of the studies
generalizable to everyday clinical work, in which electrocardiography still holds
an important place 110 years after its inception.
68
7
Conclusions
The aim behind this thesis was to identify electrocardiographic patterns that may
predict SCD in the general population, as well as to recognize patterns that have a
relatively benign prognosis.
The results of Study I show that in the middle-aged general population, QRS
duration ≥ 110 ms is a relatively rare finding, with a prevalence of 1.3%, but is
associated with increased mortality. IVCD, defined as QRS ≥ 110 ms with no
partial or complete bundle branch block, was present in 0.6% of the subjects. The
risk of cardiac mortality associated with IVCD was more than two-fold, and the
risk of SCD, three-fold higher than that of the rest of the population.
In Study II, we examined the value of the frontal QRS-T angle, the angle
between the QRS-axis, representing the direction of depolarization, and the Taxis, representing the vector of repolarization in the frontal plane, in SCD risk
stratification in the same population. We demonstrated that a wide QRS-T angle
≥ 100° was associated with increased mortality and doubled one’s risk of SCD
during the follow-up period. This seemed to result mostly from an abnormal Twave axis, since the QRS axis had no effect on prognosis.
In Study III, we investigated the prognostic implications of T wave
inversions. Inverted T waves in the right precordial leads V1–V3 often manifest in
children and adolescents, but when they persist into adulthood, these changes may
raise a suspicion of underlying cardiac disease. In the middle-aged population
studied, the prevalence of right precordial T-wave inversions was 0.5%. The main
finding of this study was that these T-wave inversions showed no association with
reduced survival or SCD. In contrast, inverted T waves in leads other than the
right precordial leads predicted increased cardiovascular mortality.
Study IV aimed to examine the effect of the prolonged PR interval, or firstdegree AV block, on mortality and morbidity, since conflicting results exist on the
clinical significance of this phenomenon. In the middle-aged population studied, a
PR interval > 200 ms occured in 2.1% of the subjects, but no increase in mortality
or hospitalizations due to AF, stroke, or heart failure was associated with PR
prolongation.
Taken together, IVCD or wide QRS-T can represent early signs of underlying
cardiac pathology or vulnerability to ventricular arrhythmias on even an
asymptomatic individual, and their presence on an ECG should lead to closer
clinical evaluation and follow-up. On the other hand, in the middle-aged subjects
with no suspected cardiac pathology, a prolonged PR interval and right precordial
69
T-wave inversions seem to be innocent findings that show no association with
adverse outcome.
70
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Original publications
I
Aro AL, Anttonen O, Tikkanen JT, Junttila MJ, Kerola T, Rissanen HA, Reunanen A
& Huikuri HV (2011) Intraventricular conduction delay in a standard 12-lead
electrocardiogram as a predictor of mortality in the general population. Circ Arrhythm
Electrophysiol 4(5): 704–710.
II Aro AL, Huikuri HV, Tikkanen JT, Junttila MJ, Rissanen HA, Reunanen A &
Anttonen O (2012) QRS-T angle as a predictor of sudden cardiac death in a middleaged general population. Europace 14(6): 872–876.
III Aro AL, Anttonen O, Tikkanen JT, Junttila MJ, Kerola T, Rissanen HA, Reunanen A
& Huikuri HV (2012) Prevalence and prognostic significance of T-wave inversions in
right precordial leads of a 12-lead electrocardiogram in the middle-aged subjects.
Circulation 125(21): 2572–2577.
IV Aro AL, Anttonen O, Kerola T, Junttila MJ, Tikkanen JT, Rissanen HA, Reunanen A
& Huikuri HV (2013) Prognostic significance of prolonged PR interval in the general
population. European Heart Journal [Epub ahead of print May 14, 2013].
Reprinted with permission from Wolters Kluwer Health (I & III) and Oxford
University Press (II & IV).
Original publications are not included in the electronic version of the dissertation.
91
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ACTA UNIVERSITATIS OULUENSIS
SERIES D MEDICA
1195. Meriläinen, Sanna (2013) Experimental study of acute pancreatitis in a porcine
model, especially tight junction structure and portal vein cytokines
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
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1204. Arvonen, Miika (2013) Intestinal immune activation in Juvenile idiopathic arthritis
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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
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