Download Arrhythmogenic right ventricular cardiomyopathy Is it right?

Linköping University Medical Dissertations No. 1257
Arrhythmogenic right
ventricular cardiomyopathy
Is it right?
Meriam Åström Aneq
Division of Cardiovascular Medicine
Department of Medical and Health Sciences
Linköping University, Sweden
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Meriam Åström Aneq, 2011
Cover illustration drawn by Jasmine Åström Aneq
Published article has been reprinted with the permission of the copyright holder.
Printed in Sweden by LiU-Tryck, Linköping, Sweden, 2011
ISBN
ISSN
978-91-7393-089-5
0345-0082
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To Jasmine & Linda
You do not know what you can miss before you try
Franklin P. Adams
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TABLE OF CONTENTS
ABSTRACT .................................................................................................................. 9
POPULÄRVETENSKAPLIG SAMMANFATTNING ....................................... 11
LIST OF ORIGINAL PAPERS................................................................................ 15
ABBREVIATIONS .................................................................................................... 17
INTRODUCTION..................................................................................................... 19
ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY .... 21
1. Etiology ............................................................................................................ 21
1:1 Molecular genetics .................................................................................. 21
1:2 Other possible pathogenic mechanisms .............................................. 23
2. Pathophysiology ............................................................................................. 23
3. Histopathology ............................................................................................... 24
4. Clinical features and imaging ..................................................................... 24
4:1 Clinical presentation ............................................................................... 25
4:2 Electrocardiography ............................................................................... 26
4:3 Exercise testing ........................................................................................ 28
4:4 Echocardiography ................................................................................... 28
4:5 Magnetic resonance imaging ................................................................ 29
4:6 Other modalities...................................................................................... 29
5. Differential diagnosis ................................................................................... 30
6. Natural history ................................................................................................ 31
7. Management of ARVC patients .................................................................. 31
7:1 Physical activity ...................................................................................... 31
7:2 Anti-arrhythmic pharmacological therapy ......................................... 32
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7:3 Implantable cardioverter defibrillator (ICD) ...................................... 32
7:4 Evaluation of relatives ............................................................................ 32
AIM OF THE THESIS .............................................................................................. 35
STUDY POPULATIONS ......................................................................................... 37
METHODS ................................................................................................................. 39
1. Echocardiography .......................................................................................... 39
2. Magnetic resonance imaging ....................................................................... 42
3. Signal-averaged electrocardiogram ............................................................ 45
4. Genetic analysis ............................................................................................. 45
5. Reproducibility studies ................................................................................ 47
STATISTICS .............................................................................................................. 49
RESULTS .................................................................................................................... 51
GENERAL DISCUSSION ....................................................................................... 57
1. Aspects on right ventricular anatomy and physiology .......................... 57
2. Challenges in right ventricular imaging ................................................... 59
2.1 Echocardiography ................................................................................... 59
2.2 Magnetic resonance imaging ................................................................ 62
3. Signal- averaged electrocardiography in ARVC ...................................... 63
4. Genetics in ARVC .......................................................................................... 64
CONCLUSION .......................................................................................................... 67
IMPLICATIONS AND FUTURE PERSPECTIVES ............................................ 69
APPENDIX 1 .............................................................................................................. 71
ACKNOWLEDGEMENTS ...................................................................................... 79
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REFERENCES ............................................................................................................ 83
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Abstract
ABSTRACT
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited
uncommon heart disease, where sudden cardiac death in young seemingly
healthy persons may be the first symptom. ARVC is probably more common
than previously known, due to diagnostic difficulty. A combination of clinical
findings and results from non-invasive as well as invasive investigations is
used to diagnose the disease. However non-invasive visualisation of the right
ventricle (RV), the predominantly affected part in ARVC, and assessment of its
function have some limitations due to RV anatomy and function. The aim of
this thesis is the evaluation of new non-invasive modalities in the assessment
of right ventricular volume and function with focus on patients with ARVC.
Clinical and non-invasive follow-up of fifteen patients with ARVC during a
mean period of 8 years disclosed that progression of the disease is not uniform
but generally "slow" in well controlled patients. However individual variation
may occur. The determination of RV volume on magnetic resonance imaging
relies on short axis (SA) views obtained as a spinoff from assessing short axis
LV. These LV slices do not follow the curvature of the long axis of the RV and,
segmentation of the inflow and outflow region of the RV is difficult in this
view. A new axially rotated long axis acquisition (RLA) was tested and its
feasibility in assessment of RV volume was evaluated. The RLA acquisition
seems to be able to improve assessment of RV volume and function by
reducing the uncertainty in defining the basal slice of the RV.
A third study concentrates on analysis of RV regional and general function
based on echocardiographic speckle tracking. Two dimensional (2D)
longitudinal strain based on speckle tracking as well as tissue Doppler
Imaging was used on patients with ARVC, their first degree relatives and in
healthy subjects. 2D strain showed a good feasibility in the analysis of RV
function in relatives and controls but less in ARVC patients probably due to
the progressive myocardial cell death with fibro-fatty replacement of the RV
wall. In order to detect and follow up echocardiographic changes in this
patient category, an index was developed combining dimensional and
functional parameters for the left and for the right ventricle. This index could
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be used as a tool in the echocardiographic evaluation and serial assessment of
RV function. Advances in the molecular genetics of ARVC have provided new
insights into the understanding of the disease. Hitherto, 9 candidate genes
have been identified. A new mutation in the plakophilin 2 gene was detected
in a three generation family. The clinical phenotype related to this mutation
was highly variable, from sudden cardiac death (SCD) or anatomical changes
at an early age to non-penetrance. This suggested the need to include genetic
testing as a part of the diagnostic work-up of ARVC patients and in relatives,
to rule out mutation carriers.
The studies have evaluated and developed methods for studying the right
ventricle with special emphasis on ARVC. With the ultimate goal of
preventing sudden death in ARVC, a combination of genetic testing and
improved diagnostic methods may create an improved algorithm for risk
stratification and selection to prophylactic treatment
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Summary in Swedish
POPULÄRVETENSKAPLIG
SAMMANFATTNING
Plötslig död under ansträngning hos unga personer beror oftast på en dold
hjärtsjukdom. Varje fall är en tragedi och innebär, förutom förlust av en ung
människas liv, svåra konsekvenser för familj och omgivning. En orsak till
plötslig död hos unga är en ärftlig hjärtsjukdom, arytmogen högerkammarkardiomyopati (ARVC), som medför att hjärtmuskelväggen omvandlas till
fett- och bindväv vilket ger en benägenhet för rytmrubbningar som kan
utlösas av fysisk ansträngning. Sjukdomen är svår att diagnostisera i tidiga
stadier med de undersökningstekniker som finns, dels på grund av dess
diskreta utbredning initialt, och pga. svårigheter att bedöma höger kammare,
den mest drabbade delen av hjärtat vid ARVC. På senare år har 9 olika
genetiska avvikelser kopplade till sjukdomen identifierats.
Syftet med denna avhandling är att utveckla metoder för att förbättra
känsligheten vid diagnostik av ARVC med bildgivande
hjärtundersökningsmetoder och vid genetisk undersökning av patienter och
anhöriga.
Uppföljning av femton patienter med ARVC under en period på 6-10 år har
visat att sjukdomsutvecklingen oftast är långsam, men individuella skillnader
kan förekomma. Det har också noterats att vänster kammare drabbas tidigt i
sjukdomsförloppet.
Användning av magnetkameraundersökning för bedömning av höger
kammare har visat sig ge värdefull tilläggsinformation. Beräkning av volymen
baseras dock på tvärsnittsbilder som är framtagna för vänster kammare och
tar mindre hänsyn till höger kammares annorlunda form och rörlighet. Detta
försvårar avgränsningen av framförallt det översta (basala) snittet i höger
kammare och ger en osäkrare volymberäkning. Vi har utvecklat ett nytt sätt att
samla in bilderna genom att utgå från högerkammares längsgående axel
mellan klaffen och hjärtspetsen. Bildinsamlingen sker från 6 roterande snitt
med 30 graders vridning runt längs axeln. Metoden ökar tillförlitligheten i
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mätningen av höger kammares volym genom tydligare avgränsning av höger
kammares samtliga delar.
Ultraljudsundersökningar med nya metoder som mäter storleken av
muskelns förkortning (longitudinell och radiell strain) har utvecklats under de
senaste åren för bedömning av vänster kammare. Tillämpning av metoden på
höger kammare hos en grupp patienter och deras anhöriga samt en
åldersmatchad grupp friska frivilliga har visat att metoden är genomförbar i
höger kammare och visar avvikande fynd hos patienter med ARVC. Anhöriga
kunde däremot inte skiljas från friska med denna metod. För att väga samman
tidiga diskreta förändringar och följa deras utveckling har vi tagit fram ett
ekokardiografiskt index för höger respektive vänster kammare baserat på
diameter och funktion.
Genetisk diagnostik av ARVC har nyligen startat i Sydöstra sjukvårdregionen,
varvid en tidigare inte beskriven genetisk avvikelse som orsakar ARVC har
påvisats. Undersökning av familjemedlemmar i tre generationer med denna
mutation har visat stor variation i sjukdomsbilden, från plötslig död hos en 18
årig man till helt friska anlagsbärare. Dessutom visar studien vikten av
genetisk och klinisk bedömning i kombination med känsliga metoder för
hjärtundersökningar för att ställa rätt diagnos vid ARVC.
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List of papers
LIST OF ORIGINAL PAPERS
This thesis is based on the following original publications, which will be
referred to in the text by their Roman numerals:
I
Åström Aneq M; Lindström L; Fluur C; Nylander E.
Long-term follow-up in arrhythmogenic right ventricular
cardiomyopathy using Tissue Doppler Imaging.
Scand Cardiovasc J 2008; 42(6): 368-74
II
Åström Aneq M; Nylander E; Ebbers T; Engvall J.
Determination of right ventricular volume and function using
multiple axially rotated MRI slices.
Clin Physiol Funct Imaging 2011; 31(3): 233-9
III
Åström Aneq M; Engvall J; Brudin L; Nylander E
Evaluation of right and left ventricular function using speckle
tracking echocardiography in patients with arrhythmogenic right
ventricular cardiomyopathy and their first degree relatives.
Submitted
IV
Åström Aneq M; Fluur C; Rehnberg M; Söderkvist P; Engvall J;
Nylander E; Gunnarsson C.
Novel plakophilin2 mutation in a three generation family with
arrhythmogenic right ventricular cardiomyopathy
Submitted
(Articles reprinted with permission)
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Abbreviations
ABBREVIATIONS
ARVC
SCD
TFC
RV
LV
LDAC
ECG
SAECG
LBBB
RBBB
PVC
RVOT-T
LVOT VTI
RVOT/BSA
RVIT/BSA
WMSI
TAPSE
TAPSV
Sw
2D-strain
AVO
AVC
MRI
SA
RLA
bSSFP
ICD
Arrhythmogenic right ventricular cardiomyopathy
Sudden cardiac death
Task Force Criteria
Right ventricle
Left ventricle
Left-dominant arrhythmogenic cardiomyopathy
Electrocardiogram
Signal-,averaged electrocardiogram
Left bundle branch block
Right bundle branch block
Premature ventricular contraction
Right ventricular outflow tract tachycardia
Left ventricular outflow tract velocity time integral
Right ventricular outflow tract related to body surface
area
Right ventricular inflow tract related to body surface
area
Wall motion score index
Tricuspid annular plane systolic excursion
Tricuspid annular plane systolic velocity
Systolic velocity in the myocardial wall
Two dimensional strain
Aortic valve opening
Aortic valve closure
Magnetic resonance imaging
Short axis
Rotated long axis
Balanced Steady-state free precession sequence
Implantable cardioverter defibrillator
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Introduction
INTRODUCTION
Sudden cardiac death (SCD) is still a problem although mortality from
cardiovascular disease has decreased in recent decades. In Europe as well as in
the United States, the incidence of SCD is estimated at almost 50-100
cases/100.000 people per year with some geographic variation [1, 2].
Resuscitation is still unsuccessful in 70% to 95% of the cases of Out-of-Hospital
Cardiac Arrest [3, 4].
Sudden cardiac death is defined as unexpected death due to heart problems
within a short time period, generally one hour from the onset of symptoms, in
a person without any prior fatal condition[5]. For unwitnessed deaths, the
World Health Organization definition extends to up to 24 hours [6].
The main cause of SCD is coronary heart disease but in people younger than
35 years, the leading cause is arrhythmia due to cardiomyopathies,
abnormalities of the cardiac conducting system or coronary artery anomalies.
One cardiomyopathy recognised as a cause of SCD is arrhythmogenic right
ventricular cardiomyopathy (ARVC). It is considered as a cause of SCD in 3%
of young athletes in the US and up to 20% in northern Italy. This geographical
variation may be due to a more prevalent genetic abnormality or to more
investigations with focus on this disease being performed in Italy.
In many cases, sudden death is the first manifestation of ARVC. In a cohort of
100 patients with ARVC, Corrado et al. found that sudden death was the first
manifestation of the disease in 22 patients [7]. Similar numbers were reported
by other authors where SD accounted for 20-75% of the fatal outcome in
ARVC [8, 9].
The prevalence of ARVC is estimated to 1 per 1000 to 1 per 5000 [10]. However
this value could be higher as in many cases the disease is first recognized post
mortem.
Although ARVC is relatively uncommon in the general population, the
increased risk for SD during exercise in adolescence or young adulthood is not
only devastating for families, but also has impact on the community and the
system of medical care.
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The research in this thesis focuses on the diagnosis and follow-up of
arrhythmogenic right ventricular cardiomyopathy using anatomical and
functional myocardial parameters obtained from echocardiography and
magnetic resonance imaging as well as initial experiences from molecular
genetic testing.
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ARRHYTHMOGENIC RIGHT
VENTRICULAR CARDIOMYOPATHY
Arrhythmogenic right ventricular dysplasia/cardiomyopathy was first
described by G Fontaine et al. 1978[11]. Shortly thereafter, in 1982, Marcus et
al. described 24 cases of ARVC [12] followed by multiple case reports from all
over the world. ARVC is a disease of cardiac muscle causing replacement of
muscle cells by fatty tissue and fibrosis mainly in the right ventricle. The
disease was originally considered as a dysplastic process (ARVD) with
congenital absence of ventricular myocardium but clinical and pathological
studies have shown that the abnormalities are acquired and are of a
progressive character.
1. Etiology
1:1 Molecular genetics
In 30-50% of cases, ARVC has a familial occurrence, usually with an autosomal
dominant inheritance pattern [13, 14]. A rare autosomal recessive variant,
Naxos disease, with similar myocardial involvement and typical
palmoplantar keratosis and wooly hair has also been described [15]
There is evidence that ARVC is predominantly a disease of the desmosome.
Five genes encoding the desmosome have been identified hitherto, in addition
to 5 other genes or loci that have not yet been tracked to individual gene
modification. Desmosomes are protein structures in the cell membrane
permitting cell-to-cell adhesion. They occur in almost all solid tissues, but
diseases related to mutation in these proteins are manifested only in the heart
muscle cells and in the skin. This has been explained by continuous
mechanical stress of the epithelium and the myocardium that at least in part
alters the biomechanical behaviour of cells leading to myocyte detachment and
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death. Two of the desmosomes containing proteins are intercellular;
desmoglein-2 and desmocollin-2 and three are intracellular; plakoglobin,
plakophilin-2, and desmoplakin (Fig. 1). In addition to cell adhesion, they have a
function in cell-cell communication and tissue differentiation.
The first identified gene in the dominant form of ARVC (ARVC2) is coding for
the ryanodine receptor-2. This gene is now known to be present in
cathecholaminergic polymorphic ventricular tachycardia (CPVT) suggesting a
CPVT phenocopy rather than true ARVC. [2, 16-18].
Fig. 1. Schematic figure of Desmosomal Structure
The desmosomal complex comprises two intercellular proteins: desmoglein (DSG)-2
and desmocollin (DSC)-2. The intracellular portions of these proteins interact with
three other proteins: junctional plakoglobin (JUP), plakophilin (PKP)-2 and
desmoplakin. The desmoplakin terminal part anchors Desmin filaments, the
cytoskeleton. Modified from Sen-Chowdhry et al. [19].
In addition, two other non-desmosomal protein mutations have been reported
to cause ARVC; the transmembrane protein 43 encoded by the TMEM43 gene
[8], and the transforming growth factor beta -3 (Tb3), a cytokine-stimulating
fibrosis and modulating cell adhesion [20]. The causative effect of these two
mutations in relation to ARVC is still controversial.
Patients carrying multiple mutations in a single gene (compound
heterozygosity) or in two different genes (digenic heterozygosity) are more
frequent than previously suspected (almost 13%) and this may contribute to
the complexity of disease inheritance and variable penetrance of ARVC. This is
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also a reason for an extended mutation screening beyond the identification of
one mutation especially in families with a particularly severe phenotype [21].
However, it is noteworthy that failure to identify a mutation in the known
genes does not exclude the disease and additional contributing gene mutations
may still await detection.
1:2 Other possible pathogenic mechanisms
1:2:1 The role of inflammation in ARVC is still unresolved. The presence of
inflammatory infiltrates in histology specimens particularly during the acute
‘hot phases’ of the disease suggests that ARVC could be either a sequel or
trigged by a myocarditis. However if the inflammation is causative or just an
effect of cell death is still unkown [22]. The causative role of viral infections
[23, 24] and a genetic predisposition to infection/immune reaction in ARVC
patients has also been proposed.
1:2:2 The mechanism of cell death by apoptosis has been discussed as
apoptotic nuclei were found in up to 35% of patients in some studies [25, 26],
but the role of apoptosis as a pathogenic pathway in ARVC is still to be
defined.
2. Pathophysiology
The prevailing hypothesis on desmosomal gene mutations causing ARVC is
based on the effect of mechanical stress leading to the weakness of the
intercellular junction causing disruption and degeneration of myocytes and
their replacement by fibrofatty scar tissue. In this structural model,
environmental factors such as exercise or inflammation could exacerbate
impairment of cell adhesion and hasten disease progression.
Progressive atrophy of the myocardium in ARVC occurs from the
subepicardium to the endocardium. The residual islands of surviving
myocardial cells left within the affected fibro-fatty area constitute a substrate
for ventricular arrhythmias. Initially the disease has a regional distribution but
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later on it becomes more global. Transmural atrophy of the myocardium
causes aneurysmal dilatation and wall motion abnormalities which lead, in
advanced stages, to heart failure.
Although ARVC was initially considered to be strictly confined to the right
ventricle, autopsy and sensitive imaging techniques have shown that most
patients with ARVC have biventricular involvement [27-29]. It has been
suggested that regular intense exercise causing volume overload and cavity
enlargement of a thin-walled RV with high distensibility is a reason for the
predominating RV involvement of ARVC.
LV changes usually affect both the septum and the LV free wall, often
regionally, with a predilection for the posteroseptal and posterolateral wall.
3. Histopathology
Based on histology findings in different cohorts, two histopathologic variants
have been described [30]; fibrolipomatosis type I with almost only fatty
replacement and a small amount of fibrosis surrounding the surviving
myocardial cells leading to an increased wall thickness, ‚pseudohypertrophy‛ of the RV, and the fibrolipomatosis type II with extensive
replacement of myocytes by fibrosis and fatty tissue leading to thin wall and
saccular aneurysm [31].
4. Clinical features and imaging
ARVC is generally diagnosed in young adults. In at least 80% of cases the
diagnosis is made in patients below 40 years of age, although the disease has
been described up to the ninth decade and in children [32, 33]. The disease is
extremely uncommon below the age of 10 years. For unclear reasons, men are
more frequently affected than women [34]. For a definite diagnosis, histology
compatible with ARVC on specimens from autopsy, an explanted heart or
from endomyocardial biopsy is required. However, diagnosis by
endomyocardial biopsy is difficult due to the patchy involvement of the
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disease. The septum, where the biopsy is usually taken, is not often involved.
This, in combination with multiple potential etiologies of arrhythmias of RV
origin, and difficulties in the assessment of RV structure and function, has
prompted the establishment of standardized diagnostic criteria.
The Task Force Criteria (TFC) proposed by Mc Kenna et al [35] are subdivided
into major and minor criteria according to the specificity of their association
with ARVC. They are based on structural, histological, electrocardiographic,
arrhythmic, and familial features of the disease (Appendix 1).
Occasionally, the left ventricle may be the predominant site of involvement.
Left-dominant variants of ARVC (LDAC) that primarily affect the left ventricle
have been identified in vivo and on post-mortem examination [36, 37]. Clinical
features include arrhythmia of RBBB morphology and progressive structural
abnormalities of the left ventricle. This disorder can be difficult to differentiate
from other causes of left ventricular dysfunction. Marked arrhythmias in
conjunction with relatively mild LV dysfunction may suggest the presence of
regional LDAC.
Accordingly, ARVC may manifest as cardiac failure involving both ventricles
and may be difficult to distinguish from other forms of global heart failure.
4:1 Clinical presentation
The most common clinical manifestations in ARVC are related to arrhythmia
and conduction disturbances. Ventricular arrhythmia with an origin in the
right ventricle display left bundle branch block morphology (LBBB).
Advanced disease with extended left ventricular involvement may display
ventricular ectopy with right ventricular branch block (RBBB) morphology. A
history of syncope or dizziness, especially during exercise can be reported.
Over time, symptoms related to heart failure, such as dyspnoea, oedema and
fatigue may occur. However, ARVC is frequently asymptomatic, with the
initial manifestation being sudden unexpected death.
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4:2 Electrocardiography
The electrocardiogram (ECG) is one of the most important diagnostic methods
in ARVC. Abnormalities of depolarisation, conduction and repolarisation
secondary to atrophy of ventricular walls reflect the pathophysiology of the
disease.
4:2:1 Twelve lead-ECG
T-wave inversion in anterior precordial leads (beyond V1) in the absence of
RBBB is a sensitive finding in ARVC, reported to be present in between 37 and
81% of cases [38, 39], but the common pattern of T-wave inversion in ischemic
heart disease and other cardiopulmonary diseases reduces its specificity.
However, in the absence of RBBB, the presence of T-wave inversion in V1-V3
in young adults or middle aged subjects who have no apparent heart disease is
uncomman, less than 3% in the study by Marcus [40]. Furthermore T-wave
inversion in combination with ectopic ventricular beats of LBBB morphology
should raise the suspicion of ARVC. Depolarisation and prolongation of
conduction involving right precordial leads in the absence of RBBB can be
detected as prolongation of the QRS complex (exceeding 110 ms in V1-V3).
This was seen in 35 to 76% of cases [41, 42]. The epsilon wave (Fig. 2a) is a
distinct deflection between the end of the QRS complex and the onset of the T
wave. The presence of an epsilon wave is a major criterion but detected only in
1-25% of cases [43]. Finally selective prolongation of the S-wave duration in
V1-V3 is seen in 34 to 71% of patients [44].
The variable presence of these findings in several studies can be related to the
extent of right ventricular structural and functional abnormalities in the
patients studied [45].
4:2:2 Signal-averaged electrocardiogram (SAECG)
SAECG permits the registration of low-amplitude potentials within the
terminal portion of the QRS complex (late potential) that are not of sufficient
amplitude to be visible on the 12-lead ECG. ARVC was one of the first
pathologic non-ischemic disorders in which the presence of late potentials
were identified [46] (Fig. 2b).
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Fig. 2
a.
ECG showing Epsilon wave
b.
Pathological late potentials on the SAECG
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4:2:3 Ambulatory ECG monitoring
This is performed to detect spontaneous arrhythmia. Monitoring is usually
done for 24-48 hours, but in symptomatic patients longer registrations may be
indicated to capture arrhythmia.
The presence of more than 1000 premature ventricular contractions (PVC) of
LBBB morphology on 24h Holter monitoring is a minor criterion in ARVC.
When the subject has a family member with confirmed ARVC the presence of
500 PVC of LBBB type constitutes a major diagnostic criterion for ARVC . The
presence of sustained or non-sustained ventricular tachycardia of LBBB
morphology can also be detected [47].
4:3 Exercise testing
Exercise testing in general is recognized for its ability to unmask ventricular
arrhythmia during physical exercise. However, in ARVC, the diagnostic utility
in clinical decision making and in follow-up remains to be established. It is
noteworthy that lack of arrhythmia during exercise should not be considered
as reassuring [48].
4:4 Echocardiography
Identification of right ventricular morphological abnormalities by
echocardiography is difficult as the abnormalities due to ARVC may be
limited to small regions in the ventricular wall. Typical echocardiographic
findings are often localized to the inflow and/or outflow tracts. The apex
region was described earlier as part of the affected ‚triangle of dysplasia‛ but
recent observations have shown that involvement of the apex is a late finding.
The main changes are regional dilatation of the RVOT and/or the inflow part.
Structural wall abnormalities such as localized wall tinning are important
diagnostic features but hard to find in the trabeculated thin right ventricular
wall. Micro-aneurysms in the anterior or inferior RV walls are specific for
ARVC. In other forms of ARVC, pseudo-hypertrophy of the RV wall with a
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thick moderator band can be seen [49]. In this variant, histology shows a
predominance of fatty tissue and less fibrosis. Myocardial dysfunction is
regional in the early stages without apparent effect on global RV function.
Early changes in regional function can easily be overlooked.
Later on, dilatation and dysfunction of both ventricles may occur accompanied
by mural thrombosis within aneurysms or in the atrial appendages when heart
failure is complicated by atrial fibrillation.
4:5 Magnetic resonance imaging
MRI offers an extensive visualisation of the right ventricular chamber,
permitting the detection of microaneurysm and wall bulging. Furthermore, the
calculation of right and left ventricular volumes and ejection fraction is more
precise with MRI compared to echocardiography [50].
Myocardial delayed enhancement MRI can detect fibrosis especially in the
advanced form [51]. However, the detection of intramyocardial fat in the RV
wall is unreliable. The presence of pericardial fat in contact with the thin RV
wall as well as the high prevalence of adipose infiltration in normal hearts [52]
makes this finding less specific for the diagnosis of ARVC.
4:6 Other modalities
4:6:1 Computer Tomography
Most centers use MRI in the diagnosis and follow up of ARVC patients.
However in many cases the prophylactic implantation of a cardioverter
defibrillator (ICD) is necessary to prevent SCD. After such implantation, MRI
is contraindicated but CT may help in the serial assessment of right ventricular
function [53].
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4:6:2 Angiography
Angiography was previously the gold standard for detection of RV
abnormalities [54]. However, recent development of new methods has
obviated the need for angiography.
4:6:3 Electrophysiologic study (EPS)
EPS may have a role in the differential diagnosis of arrhythmia of right
ventricular origin [55, 56].
5. Differential diagnosis
In the presence of RV tachycardia and /or dilatation of the RV, other structural
diseases should be ruled out e.g. congenital heart disease such as left- right
shunts at the atrial level, and acquired diseases such as pulmonary
hypertension, myocardial infarction and systemic inflammatory and
infiltrative diseases[57].
Idiopathic right ventricular outflow tract tachycardia (RVOT-T) is a benign,
non-familial disorder that is often difficult to differentiate from ARVC in early
stages, especially since recent MRI studies have shown structural
abnormalities in the outflow tract in RVOT-T. A definite diagnosis may not be
possible at first presentation. Case studies have reported patients that have
been assigned a diagnosis of RVOT-T but later developed typical features of
ARVC [58]. Brugada syndrome is another disorder that can be difficult to
differentiate from ARVC in some cases. Clinical and histopathological studies
have shown a definite overlap between Brugada and ARVC [59, 60].
Myocarditis, usually viral and predominantly involving the RV may be
difficult to differentiate from ARVC particularly during the acute phase with
arrhythmias [61, 62]. For differential diagnosis, the progress during follow-up
is important.
The RV may dilate as a normal adaptation to regular intensive physical
activity in the so called ‛athlete´s heart‛. This has to be considered in the
differential diagnosis of ARVC [63, 64].
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6. Natural history
Four distinct phases have been described in the natural history of ARVC [7]
1. The early ‚concealed‛ phase is associated with minor ventricular
arrhythmia and subtle structural changes. Patients are often asymptomatic,
but nonetheless at risk of SCD especially during physical activity.
2. In this stage, an overt electrical disorder is manifest, with symptomatic
ventricular arrhythmia and more obvious morphological and function
abnormalities of the right ventricle.
3. RV failure caused by disease progression.
4. Biventricular heart failure in advanced stages which can be difficult to
differentiate from dilated cardiomyopathy.
However the evaluation of familial patterns suggests that a distinct stepwise
progression to more advanced stages of disease seldom occurs.
7. Management of ARVC patients
7:1 Physical activity
Athletes with probable or definite diagnosis of ARVC should be excluded
from most competitive sports, according to the 36th Bethesda conference [65]
In the larger group of non competitive young patients who are asymptomatic
or mildly symptomatic there is usually a desire to have an active recreational
lifestyle. However the definition of low intensity activity is difficult.
Recommendations on exercise need to be individualized for each patient and
the intensity of physical activity considered. As a help for the clinician, Maron
et al. categorized sports activities into high, moderate, and low level intensity
[66]. Participation in intensive exercise should be avoided even in the presence
of antiarrhythmic protection afforded by an implanted ICD [67]
31
31
7:2 Anti-arrhythmic pharmacological therapy
Pharmacological therapy is the recommended initial treatment for a patient
with mild, well tolerated arrhythmia. Treatment consists of beta blockers and
class I and class III antiarrhythmic drugs. Sotalol has been reported to be the
most effective pharmacological antiarrhythmic treatment in ARVC [68]
7:3 Implantable cardioverter defibrillator (ICD)
ICD is an effective method for terminating malignant ventricular
tachyarrhythmias. However the most relevant question is whether there is a
balance between the benefit of preventing arrhythmic death and the risk of
complications and side effects from ICD implantation. A correct diagnosis of
the disease on the basis of detailed investigations is essential before ICD
implantation is considered.
Recommended indications for ICD implantation in ARVC include secondary
prevention after survived cardiac arrest or documented sustained VT. ICD
therapy as primary prophylaxis in asymptomatic patients or relatives with
high risk profile must be based on individual risk assessment because of the
lack of data supporting this approach. The main indication for primary
prophylactic ICD is currently based on either history of SCD in early age in the
family, or evidence of extensive RV dysfunction as well as involvement of the
LV.
In a cohort of 42 ARVC patients with ICD, Rogin et al. showed that 78% of
patients experienced at least one appropriate discharge during an average of
3,5 years of follow-up [69]. Similar findings were reported by other authors
[70-72].
7:4 Evaluation of relatives
First degree relatives of deceased or living patients with ARVC should
undergo a cardiac evaluation[13]. Modified Task Force Criteria have been
proposed because the original TFC are highly specific but not sensitive enough
to evaluate relatives who may have an early form of the disease (Appendix 1)
32
32
[13, 73]. Further investigations are needed regarding the sensitivity and
specificity of these criteria, the need and frequency of repeated follow-up and
risk stratification of relatives.
33
33
34
34
Aim of th thesis
AIM OF THE THESIS
The general aim of this thesis is to investigate how non- invasive methods may
improve diagnosis in arrhythmogenic right ventricular cardiomyopathy.
Specific aims:
 To study the progress and the rate of change in
echocardiographic parameters during long term follow-up in
patients with ARVC (Paper I)
 To explore the value of using tissue Doppler imaging in the
follow-up of patients with ARVC (Paper I)
 To evaluate whether a new axial orientation modality for the
assessment of RV volume and function by MRI will help to
overcome the limitations of the standard short axis orientation
(Paper II)
 To study the feasibility of using two dimensional strain analysis
based on speckle tracking applied to the RV (Paper III)
 To test the ability to detect regional RV dysfunction at early
stage, in relatives of ARVC patients using myocardial strain
based on speckle tracking (Paper III)
 To describe the phenotype of a new mutation in the plakophilin
2 gene in a three generation family with ARVC (Paper IV)
35
35
36
Study populations
STUDY POPULATIONS
Healthy controls (II,III)
Totally 25 healthy volunteers were included, whereof 20 were examined by
both MRI (II) and echocardiography with analysis of myocardial strain (III).
Three of the remaining subjects underwent MRI alone and two had only
echocardiography. The healthy subjects were recruited by advertisements on
the university web page and among medical students. All were asymptomatic
and lacked family history of premature cardiovascular disease. No one
received cardiac medication. All underwent a bicycle ergometer exercise test
to confirm the absence of heart disease. Those who had abnormal ECG or
exercise test were excluded.
ARVC patients (I,III,IV)
In paper I, all patients from the South East region with a diagnosis of ARVC
for more than 6 years were included. There were fifteen patients, 9 male and 6
female. The diagnosis was based on the conventional Task Force Criteria.
Patients were examined regularly according to a follow-up program. In this
analysis we focused on the first and last echocardiographic examination
during the study period. Two of these patients were also reported in paper IV.
In paper III, we studied all males with an ARVC diagnosis, which included
nine patients from study I, and eight patients with an ARVC diagnosis of less
than 5 years.
First degree relatives (paper III)
Since 1995, a screening protocol for first degree relatives (children, parents or
siblings) of ARVC patients has been followed. In this cohort nineteen males, 18
years or older were included and underwent echocardiogram with focus on
right ventricular function.
37
37
Table 1. Characteristics of the male (M) and female (F) population studied.
Patients
I
Relatives
Controls
15(9M*,6F)
22-58 yr ** (mean 40)
23 M‡
22-64 (mean 39)
II
III
17 M
32-70 yr † (mean 49)
19 M
19-73 yr (mean 29)
IV
8 subjects (4M, 4F) in an ARVC affected family
22 M
24-66 yr (mean 36)
* All included in paper III, and two included in paper IV.
** Age at the time of the first investigation
† Age at the examination
‡ 20 of these controls are included in paper III
Ethical approval for studies (I,II,III,IV) was obtained from the Regional Ethical
Review Board in Linköping.
38
38
Methods
METHODS
1. Echocardiography
Paper I, III, IV
The echocardiogram was performed with the subject in the left lateral
decubitus position. A 2-dimensional, colour, pulsed and continuous-wave
Doppler examination was recorded following the recommendations of the
American Society of Echocardiography for transthoracic studies [74]. We used
the ultrasound systems Acuson 128XP (Acuson corporation, Mountainview,
CA,USA) for the first examination in paper I and Vivid 5 or Vivid 7 (GE
Medical Systems, Horten, Norway) for the last examination in paper I and in
paper III. Data were obtained from multiple standard views of the left and
right ventricle (Figure 1, paper I). At least three regular beats of each view
were recorded during quiet respiration.
In paper I, wall motion score index (WMSI) was assessed in a sixteen (LV) and
seven (RV) segment model. Each segment was classified according to a scale
with 6 levels: 0=not visualised, 1= Normal, 2=Mild hypokinesia, 3=Severe
hypokinesia, 4=Akinesia and 5= Dyskinesia. A score was calculated for each
ventricle as an average value of analysed segments. The presence of isolated
sacculation (S) and wall thinning (T) was reported. All analyses were
performed by a single observer.
1:1 Annular motion analysis by M-mode
A 2-dimensionally–guided M-mode cursor was placed on the lateral or the
septal part of the mitral annulus to record the annular motion towards the
cardiac apex in systole from a standard apical 4-chamber view (paper I). An
identical recording was obtained from the lateral (paper I,III) and posterior
(paper I) part of the tricuspid annulus. Care was taken to orient the beam
perpendicularly to the motion of the annular structure. The total
39
39
systolic displacement was measured from end-diastole (the initial deflection of
the QRS complex in the ECG) to the highest point of contraction as initially
validated by Kaul et al. [75].
1:2 Longitudinal strain based on speckle tracking
The strain measured by two dimensional echocardiography is called
Langrangian strain (e) and is defined as the change of myocardial fibre length
during stress at end-systole compared to its original length in a relaxed state at
end-diastole. Negative strain indicates fibre shortening or myocardial
thinning, whereas a positive value describes lengthening or thickening. The
two dimensional loops from routine echocardiographic examinations were
processed offline. The end-systolic frame was identified from by definition on
the parasternal or apical long axis (3-chamber) view, where the aortic valve is
‚optimally visible‛. The time point of aortic valve closure was marked. The
four chamber view with focus on the left and then on the right ventricle was
recorded with a frame rate ranging between 40 to 70 frames/s. All images were
stored digitally and analyzed on the Echo Pac work station (GE Medical
Systems, EchopacPC, version 6.0.1). A complete cardiac cycle was required for
processing. Offline analysis began with tracing the endocardial border. The
software then automatically defined an epicardial and midmyocardial line and
processed all frames of the loop based on the identification of natural acoustic
markers in the myocardium. Myocardial deformation was defined as strain an
expressed in terms of percent shortening. The length of each wall was
automatically divided into 3 segments; base, mid and apex. Since the apex of
the RV can be difficult to expose on echocardiography, we chose to focus on
the basal and mid ventricular segments (Fig. 3)
40
40
Methods
Fig. 3. Determination of longitudinal strain in an apical four chamber view.
Left upper panel:The lateral wall of the right ventricle is divided into 3 segments;
base, mid and apex. M-mode representation of peak systolic strain (left lower panel).
The right upper panel shows time –curves of longitudinal strain for each myocardial
segment, and the right lower panel displays the calculated values.
1:3 Echocardiography index
Multivariate discriminant analysis was used to detect differences between
ARVC-patients and controls in order to investigate the relative role of
parameters from the right and left ventricle for the discrimination of the two
groups. The parameters used for the right ventricle were right ventricular
outflow and right ventricular inflow tract related to body surface area
(RVOT/BSA, RVIT/BSA), tricuspid annular plane systolic excursion (TAPSE),
tricuspid annular systolic velocity and longitudinal strain based on speckle
tracking of the basal and mid RV free wall segments. For the left ventricle the
parameters were LV diameter, left ventricular outflow tract velocity time
integral (LVOT VTI), mitral annular systolic velocity from the lateral and
septal walls, strain based on speckle tracking of the basal and mid segments of
the septum and lateral wall. Significant components were reassembled to
create separate indices for the right and left ventricles and recalculated for
each individual showing the distribution of the first degree relatives related to
patients and healthy controls.
41
41
2. Magnetic resonance imaging
Paper II
The MRI image acquisition was performed in a Philips 1.5T Achieva scanner
(Philips Healthcare, Best, the Netherlands), using a five-element cardiac
synergy surface coil. Cine-MR, synchronised using retrospective ECG gating,
was performed with a balanced steady-state free precession sequence (bSSFP).
bSSFP uses a high number of excitation pulses to provide a high signal-tonoise ratio (SNR) and better definition of structure compared with gradient
echo-sequences. The echo time (TE) was 1.5 ms, repetition time (TR) 3.0 ms,
flip angle 60º and pixel size 1.25x1.25 mm2 for all image acquisitions.
Three long axis planes of the left ventricle (2- and 4- chamber views as well as
the apical long-axis view) were obtained for orientation. The short axis plane
was planned on the LV, covering the entire heart with on average 19 (range
17-25) short axis, 8mm thick slices. Using sensitivity encoding (SENSE)
reconstruction, each SA slice took 6 heart beats to acquire.
A long axis was drawn in the RV cavity joining the middle of the tricuspid
annulus to the RV apex. Six long axis slices were acquired, by incrementally
rotating 30 º rotation around this original RV long axis. Every long axis slice
was acquired during 12 hearts beats. Six slices were considered as a suitable
compromise between potential spatial information and time spent for image
acquisition. The order of the sequence of axial and short-axis acquisition was
assigned randomly for each patient.
In addition, two-dimensional cine through-plane PC-MRI velocity data were
acquired in a plane perpendicular to the main flow direction in the ascending
aorta (AoA), just downstream from the aortic valve (AoV). All scans were
performed by a single operator.
To test the accuracy of the volume estimation for different geometries, a
phantom study was performed using both SA and RLA acquisitions. We used
symmetrical objects such as a bottle and a pear, in addition to a banana
simulating the irregular crescentric right ventricular cavity.
For all phantoms, six RLA slices were acquired, and sufficient SA slices to
cover the complete phantom. Imaging parameters were identical for both the
RLA and SA acquisitions (Fig. 5). True phantom volumes were measured
immediately after the MR investigation, by immersing the objects in a beaker
of water.
42
42
Methods
Fig. 4. 3D visualization of the six slices rotated around the long axis. A. depicts a
pear and B. the right ventricular chamber as seen from the apex with the septum at
the left.
Image analysis
All calculated volumes from the phantom studies were based on still images
and were, as well as the cine images, evaluated using the freely available
analysis software Segment (v1.702, http://segment.heiberg.se) (Fig. 3). Two
observers measured all the data independently. For the short axis datasets, a
consensus was reached before segmentation on which basal slice to include.
The volume of added, as well as of deleted slices was analyzed independently
and the stroke volume recalculated. For the left ventricular volumes, at least
half of the periphery of each ventricular slice had to be present in each time
frame to allow its inclusion in the volume. When this rule was applied, a
consensus procedure was not necessary for the left ventricle. Aortic flow
volume (stroke volume) was calculated by multiplying aortic cross sectional
area with mean flow from a slice placed cranial to the coronary ostia.
43
43
Fig. 5 The right ventricular end diastolic ED (A-C) and end systolic ES(B-D) slices on
short axis (upper) and rotated long axis (Lower) acquisitions.
A
B
C
D
44
44
Methods
3. Signal-averaged electrocardiogram
Paper I, III, IV
SAECG is recorded using bipolar XYZ ECG leads. The X lead is positioned at
the fourth intercostal space in both midaxillary lines. The Y lead is positioned
on the superior aspect of the manubrium and on either the upper left leg or
left iliac crest and the Z lead between the fourth intercostal space (V2 position)
and directly posterior on the left side of the vertebral column. The signal is
filtered using a high and low pass-filter (25 or 40-250HZ). Between 250- 400
beats are averaged to improve the signal-to noise ratio and facilitate the
detection of low-amplitude potentials. Analysis of the filtered QRS complex
includes 1) the filtered QRS duration(fQRS) ; 2) the root-mean-square voltage
in the last 40 ms of the filtered QRS (RMS 40ms); and 3) the duration of the
high frequency low-amplitude signal of the filtered QRS not exceeding 40 μV
(HFLA < 40 μV)
Criteria for normal values in SAECG were published in 1991 and 1996 by a
joint committee of the AHA and the ESC [76, 77] and are the following:
1) fQRS ≤ 114ms
2) RMS 40 >20 μV
3) HFLA 40 <38 ms
These limits are applicable in the absence of bundle branch block with an
unfiltered QRS duration less than 120ms. Pathological late potentials are
considered to be present when at least two of three parameters exceed the
normal range.
4. Genetic analysis
Paper IV
During a genetic consultation, the first degree relative to a deceased
proband(the first one in the family who have been in contact with medical
45
45
care) received oral and written information and the issue of genetic testing
was discussed. A blood sample was collected, DNA extracted and a
Polymerase Chain Reaction method (PCR) used to amplify the coding parts of
the candidate genes followed by DNA sequencing. Genetic alterations were
assessed for plakophilin2 (PKP2), desmoplakin (DSP), desmoglein 2 (DSG2),
desmocollin 2 (DSC2) and the detected pathological mutations was compared
and novel variants were deposited to international ARVC-Database
(http://www.arvcdatabase.info)[78].
Based on the patient pedigree, and after informed consent, blood samples
were collected from remaining first degree relatives for mutation analysis.
46
46
Methods
5. Reproducibility studies
In paper II, for the determination of the intra- observer variability, one
observer repeated measurements of RV volumes on MRI both SA and RLA
orientation, at least three months after the first measurements. In the second
analysis, the operator was blinded to the results of the first measurements.
In paper III, all strain measurements were repeated by the same observer who
was blinded to the initial values, at least 5 weeks after the first analysis, in a
random sample of 12 echocardiographic studies (4 patients, 4 relatives and 4
controls). To define interobserver variability, measurements in the same
random sample were assessed by a second independent observer blinded to
the results obtained by the previous investigator.
47
47
48
48
Statistics
STATISTICS
All values are presented as mean ± SD (Paper II, III). The statistical significance
of differences was calculated using the paired Student’s t-test. Significance
was based on p values of less than 0.05 (Paper I).
In paper II, to test the agreement between the two orientations, the method of
Bland and Altman was used [79]. Agreement was determined as the mean
difference between the two views, with limits determined from the mean
value ± 1.96 standard deviations.
The intra- and inter-observer variabilities were expressed as the coefficient of
variability, which is the standard deviation of the differences divided by the
mean of the measurements and expressed as a percentage (Paper II) or as
standard error of a single determination (Smethod) using the formula first
proposed by Dahlberg [80]. Smethod was also expressed as % over all means
(Paper III).
Statistical analysis were performed using Statistica 8.0 (Statsoft Inc, Tulsa,
Oklahoma, USA).
49
49
50
50
Results
RESULTS
Paper I
We performed a long- term follow up in 15 patients with ARVC using ECG,
SAECG and echocardiography including tissue Doppler imaging. The mean
follow-up period was 8.7 years (6-10). No death occurred during this period.
The reason for referral to our department was ventricular tachycardia in 6/15
(40%), syncope in 3/15 (20%) and family history of ARVC or SCD with ARVC
findings at autopsy in 4/15 (27%).
Table 2. Symptoms and findings at the first examination (left column) and those
occurring during follow-up in addition to the initial symptoms (right column).
First investigation
n/total
%
Ventricular arrhythmias
6/15
(40%)
Syncope
3/15
(20%)
T-wave inversion beyond V1 12/15
(80%)
Patol. SAECG( 2/3 or 3/3)
9/15
(60%)
RVOT dilatation (>2cm/m2) 6/15
(40%)
RVIT dilatation
10/15
(67%)
Sacculation/bulging
2/14
(14%)
Follow-up
n/total
%
8/15
(53%)
3/15
(20%)
12/15
(80%)
10/15
(67%)
7/15
(47%)
11/15
(73%)
5/14
(36%)
Echocardiographic results of the right ventricular function during follow-up
are shown in (Fig.6)
51
51
Fig. 6. Variation in tricuspid annular plane systolic excursion (TAPSE) and systolic
velocity on tissue Doppler imaging at the first (1) examination and at the follow-up (2)
A
B
A. TAPSE: Tricuspid annular motion on M-mode at the first (1) and the last (2)
examination
B. TALs: Tricuspid lateral systolic annular velocity at the first (1) and the last (2)
examination
The data indicate a progression of the recorded signs of disease. The rate of
progression was generally slow, but with individual variation.
Paper II
A method for the determination of RV volume using MRI was developed and
tested in phantoms and healthy individuals. The phantom result shows no
significant difference between volumes acquired with the two MRI methods
and the reference method which based on the displacement of water (Table 3).
Table 3. Volume of 3 phantoms measured with MRI in short axis and rotated long
axis orientations compared to the displaced volume of water.
Bottle
Pear
Banana
Short axis
515 ml
216ml
126ml
Rotated long axis
516 ml
214ml
132ml
52
52
Real volume
515ml
215ml
129ml
Results
A consensus between the two observers whether to include or exclude the
basal slice from the RV volume was necessary in 9/23 (39%) controls leading to
a difference in EDV of 6-20ml (8-21%) or ESV 12-21ml (20-27% of the total
volume). After the consensus, EDV, ESV, SV and EF for the right ventricle did
not differ between the SA and RLA views with p-values in excess of 0.05.
Thus, it was confirmed that a problem with the short axis method is the
difficulty to define the basal limits of the right ventricle and that in many
cases, consensus was needed to obtain an acceptable reproducibility. This
seems to be overcome with our axial method that is planned to be tested in
different RV pathologies in the future.
Paper III
Sensitive methods for the detection of early signs of ARVC in patients and
their relatives are needed. The development of genetic methods cannot replace
phenotypic characterization but provide additional building blocks for a
deeper understanding of the disease. In this study, we compared ARVC
patients with first degree relatives and healthy age- matched controls.
Table 4. Clinical and electrocardiographic characteristics of the study population
Age (years)
Arrhythmiarelated
symptoms
T-inversion
beyond V1
Late potentials
on SAECG
ARVC
(n=17)
Median
(range or %)
Relatives (n=19)
Median
(range or %)
Controls
(n=22)
Median
(range or %)
P-values
49 (32-70)
29 (19-73)
36 (24-66)
0,44
13 (76%)
2 (11%)
0
13(76%)
0
0
9/14* (64%)
3/19 (16%)
0
SAECG: Signal-averaged electrocardiogram.
*SAECG was not recorded in 3 patients due to frequent arrhythmia or ongoing
cardiac pacing.
53
53
Using discriminant analysis on left and right ventricular echocardiography
parameters, an LV and an RV index was developed based on data from ARVC
patients and controls (Fig. 7).
Fig. 7. Distribution of first degree relatives in relation to patients and healthy
volunteers. The lower the index (<0) the closer to normal (healthy controls).
Paper IV
Methods for the detection of genetic alterations are now being developed and
applied in patients. 25 of the patients with ARVC in our region have been
tested for mutations in Plakophilin 2, Desmoplakin, Desmocollin 2 and Desmoglein
2. In this process, we detected novel genetic alterations, and the inheritance
pattern of p. Trp 123X, in a 3-generation family and the nature of the mutation
indicates a functional consequence resulting in the ARVC phenotype.
Genetic analysis of the first degree relatives to a patient who suffered a sudden
cardiac death showed new mutation in the plakophilin 2 gene. The proband´s
mother, sister and two of her three children were shown to carry the same
mutation (Fig. 8).
54
54
Results
Fig. 8. Pedigree of a three generation family with a novel mutation in PKP2.
55
55
56
56
Discussion
GENERAL DISCUSSION
The right ventricle was until recently considered as a passive conduit[81].
However, during the past three decades the function of the RV has gained
attention. A better understanding of the prognostic role of right ventricular
function for many acquired and congenital heart diseases as well as its
influence on global cardiac function through biventricular interaction has
raised the interest in RV physiology and function [82-91]. However, the
assessment of RV function is still incomplete in daily practice partly because of
its difficult and inaccessible morphology [92, 93].
1. Aspects on right ventricular anatomy and
physiology
The right ventricle has a complex and unique morphology. In contrast to the
ellipsoid outline of the LV, the shape of the RV is more or less triangular when
viewed laterally. In a normal heart with normal loading and electrical
conduction, the RV appears crescentic in cross-section, wrapping around the
left ventricle with the septum concave to the LV [94].
Three components have been described forming the RV: 1.the inlet portion
extending between the hinge line of the tricuspid valve and the insertion of the
papillary muscles 2.the apex with thick muscular trabeculations and 3. the
outlet or infundibulum. Furthermore, there is a thick muscular band, crista
supraventricularis, between the inflow and outflow tract, participating in the
contraction of the free wall. The right ventricle has a thin wall (3-5mm) as it
pumps at a lower systolic pressure than the LV.
Over the years, the architectural arrangement of the myocytes within the
ventricular mass remains a subject of controversy.
In the Torrent-Guasp helical model, the cardiac fibres are described as a
continuous band connecting the two ventricles as a helix with two loops: An
apical loop with descending and ascending oblique fibres that build the
septum and left ventricular wall and a basal loop with transverse fibres that
57
57
form the right ventricular free wall and overlap the septum [95]. The
myocardial structure of the right ventricular wall was described as two
principal layers; an inner layer with longitudinal fibres and a superficial layer
with circumferential fibres in the inflow region becoming more longitudinal in
the outflow tract [96]. The LV chamber has an oblique subepicardial, a
longitudinal subendocardial and predominantly a circular fibre direction in
between [97] (Fig.9).
Fig. 9. The helical myocardial model
The helical model of the heart when
unfolding the basal loop of the RV.
showing the transverse fibre
orientation of free walls inflow and
longitudinal on the outflow tract.
PA:pulmonary artery. Ao: Aorta
(Fig. Torrent-Guasp. Reprinted with
permission. Copyright 2011 Elsevier)
Advocating a different model, RH Anderson describe the myocardial structure
as arranged with each myocyte anchored to other myocytes within a
supporting fibro-collagenous matrix, forming different bundles, the bundles of
myocardial fibres having various orientation [98] (Fig.10).
Fig. 10. Various fibre orientation in the myocardium
Short axis views at apex, mid and
basal level showing variation in fibre
orientation within the ventricular mass.
Histological sections in the upper
panels and their schematic
representation in the lower panels.
(Fig. RH Anderson reprinted with permission.
Copyright 2011, Elsevier)
The contraction of the right ventricle occurs in a "peristaltic" manner with the
outflow tract contracting 25-50ms after the inflow [99]. The right and left
stroke volumes are almost equivalent, as the bronchial circulation could be
58
58
Discussion
considered as non-significant. Normally the RV ejects the same stroke volume
as the LV using only one-fourth of the LV stroke work. This is possible in part
because of the low systolic pressure and high compliance of the pulmonary
circulation and the high compliance of the thin RV wall [100].
2. Challenges in right ventricular imaging
An attempted complete visualization of the RV and careful assessment of its
function are still incompletely done in most cardiac investigations. A number
of difficulties need to be addressed to successfully image the RV:
1. The anterior retrosternal location of the RV limits acoustic access by
echocardiography.
2. The three components of the RV chamber; inlet, apex and infundibulum are
located in different planes which require different views for visualization of
the entire RV by echocardiography.
3. The complex, triangular and crescentic shape of the RV is difficult to model
geometrically, unlike the LV
4. The extensive wall trabeculation can be challenging for delineation in MRI,
CT and echocardiography
5. The thin wall of the inflow tract can be difficult to differentiate from right
atrial wall in the delineation of the RV using MRI, CT and radionuclide
ventriculography.
The solution has often been to resort to using visual estimation only, in clinical
routine.
2.1 Echocardiography
Echocardiography plays an important role in the screening, diagnosis, and
follow up of ARVC patients and their relatives as it is non-invasive, available
and relatively inexpensive. It is invaluable in the presence of an ICD, which
excludes using MRI.
Due to RV morphology, contraction along the long axis is the predominant
systolic motion pattern in the RV.
59
59
M-mode and Tissue Doppler imaging
Tricuspid annular systolic motion (TAPSE) reflects the long axis oriented
motion of the RV. Kaul et al showed in 1984 that tricuspid annular systolic
excursion on echocardiography correlates with radionuclide right ventricular
ejection fraction, which then was the gold standard for characterization of RV
systolic function [75]. Different studies have shown a good reproducibility of
TAPSE and have used this method as a diagnostic tool for RV dysfunction
[101-107]. Samad et al. found that TAPSE below 15 mm was associated with
increased mortality in patients with a first acute myocardial infarction [107]. In
the follow up of 817 patients with heart failure for 4 years, Kjaergaard et al.
found that TAPSE below 14 mm was related to higher mortality and adverse
outcome [82]. Later on, the contraction of subendocardial longitudinal fibres
was reliably assessed from apical views, using tissue Doppler imaging [108,
109]. In a study of patients with advanced heart failure, Meluzin et co-workers
showed that tricuspid annular plane systolic velocity TAPSV <12cm/s
identified RVEF <45% on first-pass radionuclide ventriculography with 90%
sensitivity and 88% specificity [110]. TAPSV was also compared to RVEF
determined by MRI. Wahl et al. showed that TAPSV <9cm/s had a high
specificity for RV dysfunction with a negative predictive value of 99%[111]. As
we found in our long term follow-up of ARVC patients in paper I, TAPSE and
systolic tricuspid annular velocity are robust methods for the follow up of
patients with a progressive disease such as ARVC. We showed a higher
change in TAPSV than in TAPSE over time. This can be interpreted in terms of
a higher sensitivity in detecting RV dysfunction using wall velocity than
annular displacement. Similar findings were shown by other authors [112].
A limitation in tissue Doppler imaging (both spectral and color Doppler) is the
dependency on the angle of Doppler insonation. This can be more important
in the right ventricle as the triangular shape of the RV can complicate the
alignment with the ultrasound beam, especially when investigating bulging
RV wall segments beneath the RV base.
Strain measurement based on speckle tracking
Speckle tracking echocardiography is based on the distribution of myocardial
fibres that create a unique pattern of backscattered ultrasound, ‚speckles‛.
60
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Discussion
These speckles create a unique fingerprint that enables tracking myocardial
motion during the cardiac cycle. Since each speckle may move in relation to its
neighbours, local deformation may be determined [113, 114].
The computer-based solutions for speckle tracking are basically ‚black boxes‛
but their output may be assessed by comparison with other techniques. Unlike
tissue Doppler imaging, speckle tracking is robust, shows less angle
dependency, and can track the myocardium in the transverse as well as in the
axial direction. In our hands, the assessment of the basal and mid segments of
the left and right ventricles was highly feasible and reproducible in our
population of healthy volunteers and relatives to patients with ARVC (Paper
III). However in the study of the right ventricular free wall of ARVC patients,
this was less feasible (59% compared to 95% in relatives and 86% in the
volunteers) due to the thinning of the myocardium in pathologic segments of
the wall. We limited our measurements to basal and mid segments of the
ventricular wall as the apex of the right ventricle frequently is inaccessible
with echocardiography. Furthermore, previous studies have shown that
measurements of velocity and strain in the apex of normal left and right
ventricles have displayed low accuracy compared to measurements in the
basal and mid segments [115-117].
Longitudinal strain based on speckle tracking showed no difference between
first degree relatives and controls (Paper III). Several contributory factors may
be operative. The probability that all 19 relatives in our cohort would lack a
mutation is low, as the penetrance in ARVC has been reported to be 30-66%
[118-121]. At the time of the investigation, all relatives may have had a normal
phenotype, i.e. the ARVC genotype had not yet become clinically obvious, or
the strain method is not sensitive enough to detect slight abnormalities in
myocardial deformation. It is noteworthy that the ARVC disease process starts
in the subepicardium and advances towards the endocardium. That may
suggest that longitudinal deformation of the right ventricle is affected later on.
As the abnormalities in early stages of ARVC might be subtle and difficult to
recognize with echocardiography, we used discriminant analysis to develop
an index for the left and for the right ventricle including both dimensional and
functional echocardiographic parameters. Using these indices we found that
some of the relatives had an index closer to that of the ARVC patients than
other relatives. Further evaluation of this index is needed; including female
patients and relatives as well as controls and extending the cohort to recently
detected patients and relatives. Incorporating diastolic functional data is also
possible. Including the results of genetic analysis in future studies might help
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61
detect different phenotypic expressions of genetic mutations. In the future, left
and right ventricular indices may be used clinically as tools for detection as
well as following the appearance of typical features of ARVC patients and
their relatives.
2.2 Magnetic resonance imaging
The superiority of MRI over other techniques for right ventricular assessment
rests on its unique ability to image the entiree ventricle. It is useful for
diagnosing ARVC especially in cases where regional motion abnormalities on
MRI correspond to areas with high signal intensity on late enhancement
(Delayed contrast-enhanced viability using Gadolinium). Quantitative
measurements of the RV volume and function are however subject to a
relatively large degree of variability compared to the LV [122, 123]. The
reproducibility of MRI measurements is crucial in follow-up. In clinical
practice, RV volume analysis relies on short axis (SA) views obtained
simultaneously when assessing the LV. An important difficulty to overcome
in using the SA is how to define the basal slice and how to reliably exclude
atrial volume from the ventricular measurement. Errors in defining the
boundaries of this large slice can result in significant differences in serial
measurement [124-126].
The interstudy measurements by the same reader showed a good
reproducibility even if it was lower compared to that of the LV. However the
intraobserver and interobserver variability were large indicating that observer
subjectivity is a limiting factor in the interpretation of the right ventricular MR
images [123, 127]. To reduce this variability, different methods have been used
to 1. improve definition of the inflow/outflow tract, e.g identification of the
right atrioventricular ring by the visualization of the right coronary artery
[128], combination of long-axis sections with short-axis sections in the same
dataset [129], axial slice orientation with orthogonal stack covering the heart
from a level below the diaphragm to the pulmonary bifurcation [130-132] or
modified RV short axis slices located with respect to the RV long axis [133]. 2.
to reduce variability and analysis time in post-processing by utilisation of
automatic or semi-automatic segmentation [134, 135]. Each one of these
changes showed some improvement in volume measurement. However,
despite these suggestions, serious limitations due to RV shape and heart
position in the thorax still remain. We used cut planes rotated along the long
62
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Discussion
axis of the RV to obtain an optimal visualization of the RV inflow and outflow
tract thereby reducing the uncertainty due to the basal slice in SA (paper II).
Improvement of RV volume assessment has become necessary as the modified
Task Force Criteria rely on quantitative data from RV volume and function
[73]. However, delineation of the endocardium and the trabeculae of the thin
RV wall create difficulties. A consistent approach to delineation is crucial. The
RLA method to analyze global and regional wall motion is promising
especially in the population of ARVC patients and their relatives, but further
studies are necessary.
3. Signal- averaged electrocardiography in ARVC
In the early 1980´s, SAECG was recommended in patients recovering from
myocardial infarction to help determine their risk for sustained ventricular
tachyarrhythmia. The presence of pathologic late potentials has been
determined by criteria suggested by Breithardt et al. In post myocardial
infarction patients, SAECG has a high negative predictive value between 9598%, but the positive predictive value is low, in the range of 15-22%[76]. The
use of SAECG has now been expanded to other non-ischemic causes of
ventricular tachyarrhythmia.
In our paper I, nine of fifteen patients had late potentials (60%) at the first
examination. Among these patients, five (56%) had experienced sustained
ventricular tachycardia (VT). However in 3 patients (38%) with documented
sustained VT, the SAECG was normal. In paper III, nine of fourteen (64%)
men with ARVC had late potentials on the SAECG. In numerous series of
patients with ARVC, late potentials were observed in 50 to 85% of patients [12,
136-139]. Mehta et al and Nava et al found a good correlation between the
presence of late potentials and the extent of the disease, but less correlation
with ventricular arrhythmia[138, 140].
In 75 members of 11 families with ARVC (both healthy and with various
degree of disease), Oselladore et al. found that 91% of patients with an
abnormal SAECG had the disease but only 44% of the subjects with pathologic
late potentials had ventricular arrhythmia [141]. The abnormality on the
SAECG appears to be correlated with the severity of the disease and does not
give precise information about electrical instability in these patients [141]. In a
study of the correlation between two-dimensional echocardiography
parameters and SAECG in a group of thirty-three ARVC patients, Park et al.
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63
found a pathologic SAECG in the absence of significant abnormalities on the
echocardiogram (RV and LV dimension, RV fraction shortening and LVEF),
suggesting that electrical late potentials may occur before detectable
morphological changing on echocardiography[142].
The presence of 2 or 3 pathological parameters in SAECG has been considered
a minor criterion for the diagnosis of ARVC. Marcus et al. showed that using
one pathological parameter instead of two for the diagnosis of pathologic late
potentials, increased the sensitivity at a slightly reduced specificity [73].
The presence of one of three pathological parameters is now accepted as
criterion for the presence of late potentials in the modified Task Force Criteria
for ARVC (Appendix 1).
In the normal population, there is a small fraction with abnormal SAECG; 18
of 482 normal healthy (3.7%) in the study of Yakubo et al., about 4% in other
studies [138, 139, 143]. As with many other measurements, the distribution of
late potentials apparently overlaps between samples of healthy and sick
people drawn from the population.
4. Genetics in ARVC
The detection of a pathogenic mutation in a patient fulfilling the diagnostic
criteria of ARVC has important implications for family members. Screening
will identify relatives who are unknown mutation carriers. This enables
diagnosis and facilitates prevention of possible complications. In addition,
excluding a pathogenic mutation in a family member justifies ‚dismissal‛
from regular cardiological follow-up. However, pathogenic mutations are at
present only identified in approximately 40-60% of ARVC patients [144],
which implicates additional disease causing genes to be identified.
ARVC can lead to sudden death, heart failure or have a completely
asymptomatic course, probably due to effects of different mutations. However,
this cannot explain variation in the disease expression between families
carrying the same mutation, and among members of the same family. A
suggestion that modifier genes or environmental influences contribute to the
phenotype expression has been made. However, study of monozygotic twins
showed different clinical expression and severity of ARVC, even if they were
exposed to similar lifestyle [145].
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Discussion
Mutations in the PKP2 gene described by Gerull et al. were found in up to 43%
of ARVC patients, and affected family members carries mutations in up to 70%
[118]. Several studies [146, 147] indicates an increased susceptibility with a
lower mean age of onset for ARVC in patients carrying PKP2 mutations
compared to ARVC patients with mutations in the other disease causing
genes. Furthermore, a high clinical variability is sometimes reported, varying
from complete lack of symptoms to a severe disease phenotype among carriers
with the same mutation. The majority of affected subjects have predominant
right ventricular involvement and a high degree of penetrance (66% to 100%)
with a large variation in the age at the earliest manifestation of disease. The
youngest patient with ARVC was 8 years old and two 15 year old patients
showed advanced RV abnormalities at post-mortem [120]. In the Van Der
Zwaag cohort of 53 mutation carriers, 7 (13%) persons died a SCD before age
30, while 40% did not experience any symptoms at age 60. A possible
explanation for this high variability may be the presence of more than one
contributing mutation, since multiple gene mutations results in a more severe
phenotype and more frequent SCD [148]. However, this was not found in the
population described by van der Zwaag despite analysis for other
desmosomal genes. In our reported three generation family with the novel
PKP 2 mutation, there was a heterogeneous expression of the disease. The
mother, subject II:2, was phenotypically normal beside a positive biopsy, while
her daughter III:3 and grandchild IV:1 have extensive right ventricular
abnormalities. Subject III:1 was the victim of SCD (Fig. 8). Analysis of other
desmosomal genes showed no other concomitant mutations. The ARVC
diagnosis is difficult and clinically challenging and minor signs may escape
detection, where genetic information may aid. A false-positive diagnosis in
subject III:2 was first assigned, based on pathological late potentials and slight
RV abnormalities on echocardiography and MRI. Syrris et al. reported 5 false
positive cases in relatives, relying on wall motion abnormalities and
premature ventricular beats exceeding 2000 in a 24-hour period [120].
This emphasizes the need to include genetic information in the diagnosis of
ARVC as it is proposed in the modified TFC [73].
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65
66
66
Conlusion
CONCLUSION
This thesis has shown that the development of noninvasive modalities
provides new insights in characteristics and diagnostics of arrhythmogenic
right ventricular cardiomyopathy.
 The progression of echocardiographic abnormalities in patients with an
established ARVC diagnosis was generally slow over an 8- year
observation period but with individual exceptions.
 Tissue Doppler imaging contributed in diagnosis and follow-up of wall
abnormalities.
 A new axial orientation modality in right ventricular volume assessment
by MRI has shown improvement in visualisation of the basal RV.
 Two- dimensional strain analysis was feasible in the RV free wall as well
as in the LV, at least in non advanced cases of ARVC. Longitudinal
strain based on speckle tracking could be used in assessment of wall
function in ARVC patients.
 An index combining echocardiographic measurements of dimensions
and functional parameters was developed for the right and left ventricle
respectively, aiming at early detection of subtle abnormalities in
relatives of ARVC patients.
 In a family with a new mutation in the plakophilin 2 gene, we found
that disease symptoms including SD occurred in young adults (below 20
years of age) with high penetrance in first degree relatives. Combining
genetic testing with other clinical and imaging findings may help to
enhance diagnosis in relatives.
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68
68
Implications
IMPLICATIONS AND FUTURE
PERSPECTIVES
Patients diagnosed with ARVC in our region and their first degree relatives
have been subject to systematic follow-up according to a specific clinical and
non-invasive protocol since the mid nineties. Integrating the results of the
studies in this thesis, developed MRI and echocardiographic examination in
the follow-up schedule will, in addition to improve the diagnosis for the
patients and relatives, also constitute a platform for further research in the
field.
Detection of morphologic abnormalities will help to refine the algorithm for
identification of minor deviations from normal, indicating probable phenotype
expression, as well as providing a deeper knowledge of the natural history of
the disease. Extended analysis to further test the strength of the developed
MRI orientation, two dimensional strain as well as LV and RV
echocardiographic indices are needed.
It is important to further develop 3D-echocardiographic determination of RV
volumes as a substantial number of patients with ARVC and their relatives are
provided with a primary or secondary prophylactic ICD, which makes it
difficult to use MRI for follow-up.
Developing a genetic cascade screening will make it possible to focus the
investigations and follow-up on those first degree relatives who are mutation
carriers. Further studies of the phenotype-genotype correlation will aim at
clarifying whether the rate of progression or propensity for ventricular
arrhythmia can be explained by certain genetic variants. Further work is also
needed to identify more of the genes that cause ARVC.
In the hope of preventing SCD in ARVC, combination of genetic testing and
improved diagnostic methods may create a better algorithm for risk
stratification and selection to primary preventive ICD-treatment.
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70
Appendix
APPENDIX 1
Original and Revised Task Force Criteria for the
diagnosis of ARVC
Definite diagnosis:Two major or one major and two minor criteria, or four
minor criteria, from different categories.
Borderline diagnosis: One major and one minor, or three minor criteria from
different categories.
Possible diagnosis: One major or two minor criteria from different categories.
The diagnosis of familial ARVC, in the context of proven ARVC in a firstdegree relative, is based on one of the following in a family member:
 T-wave inversion in right precordial leads V1, V2, and V3 in
individuals over the age of 14 years.
 Late potentials by signal-averaged ECG (SAECG).
 Ventricular tachycardia of left bundle-branch block morphology
on ECG, Holter monitor, or during exercise testing, or > 200 premature
ventricular contractions in 24 hours.
 Either mild global dilatation or reduction in RV ejection fraction with
normal LV or mild segmental dilatation of the RV or regional RV
hypokinesis.
(Modified Task Force Criteria 2010 [73] )
71
71
72
72
Reviseted
TFC
Original TFC
 Mild global RV dilatation and/or ejection fraction
with normal LV
 Mild segmental dilatation of the RV
 Regional RV hypokinesia
By 2D Echo
Regional RV akinesia, dyskinesia or aneurysm and 1 of the
following (end diastole):
 PLAX RVOT ≥29 to <32mm
 PSAX RVOT ≥32 to <36mm
 Or fractional area change >33% to ≤40%
By MRI
Regional RV akinesia, dyskinesia or aneurysm or
dyssynchronous RV contraction and one of the following:
 Ratio of RV end-diastolic volume to BSA ≥100 to
<110 mL/m2 (male) or ≥90 to <100 mL/m2 (female)
 Or RV ejection fraction >40% to ≤45%
 Severe dilatation and reduction of RV ejection
fraction with no (or only mild) LV impairment
 Localized RV aneurysms (akinetic or dyskinetic
areas with diastolic bulging)
 Severe segmental dilatation of the RV
By 2D Echo:
Regional RV akinesia, dyskinesia or aneurysm and 1 of the
following (end diastole):
 PLAX RVOT ≥32mm
 PSAX RVOT ≥36mm
 Or fractional area change ≤33%
By MRI:
Regional RV akinesia, dyskinesia or aneurysm or
dyssynchronous RV contraction and one of the following:
 Ratio of RV end-diastolic volume to BSA
≥110 mL/m2 (male) or ≥100 mL/m2 (female)
 Or RV ejection fraction ≤40%
By RV angiography:
 Regional RV akinesia, dyskinesia or aneurysm
Minor
Major
1. Global or regional dysfunction and structural alterations
 Fibrofatty replacement of myocardium on endomyocardial
biopsy
 Residual myocytes <60% by morphometric analysis (or
<50% if estimated), with fibrous replacement of the RV
free wall myocardium in ≥1 sample, with or without fatty
replacement of tissue on endomyocardial biopsy
Original TFC
Reviseted
TFC
Major
Minor
 Residual myocytes 60% to 75% by morphometric
analysis (or 50% to 65% if estimated), with fibrous
replacement of the RV free wall myocardium in ≥1
sample, with or without fatty replacement of tissue
on endomyocardial biopsy
2. Tissue characterization of wall
Appendix
73
73
74
74
Reviseted
TFC
Original TFC
 Inverted T waves in right precordial leads (V1, V2 and V3)
or beyond in individuals >14 years of age (in the absence of
complete right bundle-branch block, QRS ≥120 ms)
Major
Minor
 Inverted T waves in leads V1, V2, V3, and V4 in
individuals >14 years of age in the presence of
complete right bundle-branch block
 Inverted T waves in leads V1 and V2 in individuals
>14 years of age (in the absence of complete right
bundle-branch block) or in V4, V5, or V6
Inverted T waves in right precordial leads (V2 and
V3) (people age >12 years, in absence of right
bundlebranch block)
3. Repolarization abnormalities
Reviseted
TFC
Original TFC
 Late potentials (SAECG)
 Late potentials by SAECG in ≥1 of 3 parameters in
the absence of a QRS duration of ≥110 ms on the
standard ECG
 Filtered QRS duration (fQRS) ≥114 ms
 Duration of terminal QRS <40 microV (lowamplitude signal duration) ≥38 ms
 Root-mean-square voltage of terminal 40 ms ≤20
microV
 Terminal activation duration of QRS ≥55 ms
measured from the nadir of the S wave to the end of
the QRS, including R’, in V1, V2, or V3, in the
absence of complete right bundle-branch block
 Epsilon wave (reproducible low-amplitude signals
between end of QRS complex to onset of the T wave)
in the right precordial leads (V1 to V3)
Minor
 Epsilon waves or localized prolongation (>110 ms) of the
QRS complex in right precordial leads (V1 to V3)
Major
4. Depolarization/conduction abnormalities
Appendix
75
75
76
76
Reviseted
TFC
Original TFC
 Nonsustained or sustained ventricular tachycardia of left
bundle-branch morphology with superior axis (negative or
indeterminate QRS in leads II, III, and aVF and positive in
lead aVL)
Major
Minor
 Nonsustained or sustained ventricular tachycardia of
RV outflow configuration, left bundle-branch block
morphology with inferior axis (positive QRS in leads
II, III, and aVF and negative in lead aVL) or of
unknown axis
 >500 ventricular extrasystoles per 24 hours (Holter)
on Holter).
 Left bundle-branch block–type ventricular
tachycardia (sustained and nonsustained) (ECG,
Holter, exercise)
 Frequent ventricular extrasystoles (>1000 per 24 hours
5. Arrhythmias
Reviseted
TFC
Original TFC
 History of ARVC/D in a first-degree relative in
whom it is not possible or practical to determine
whether the family member meets current Task
Force criteria
 Premature sudden death (<35 years of age) due to
suspected ARVC/D in a first-degree relative
 ARVC/D confirmed pathologically or by current
Task Force Criteria in second-degree relative
 Familial disease confirmed at necropsy or surgery
 ARVC/D confirmed in a first-degree relative who meets
current Task Force criteria
 ARVC/D confirmed pathologically at autopsy or surgery in
a first-degree relative
 Identification of a pathogenic mutation categorized as
associated or probably associated with ARVC/D in the
patient under evaluation.
Minor
 Family history of premature sudden death (<35
years of age) due to suspected ARVC/D
 Familial history (clinical diagnosis (based on
present criteria)
Major
6. Family History
Appendix
77
77
78
78
Acknowledgements
ACKNOWLEDGEMENTS
This thesis would not have been possible without the contribution and
support from colleagues, friends and family. I would like to thank all of you. I
would like to express a special gratitude to:
Eva Nylander, professor and my supervisor, for always trusting my ability. I
am heartily thankful for your encouragement and guidance making this work
possible. Your great scientific knowledge and valuable discussions have been
an enormous source of inspiration for me.
Jan Engvall, associate professor and my co-supervisor, for support and
constructive criticism in all the parts of the research process. I am deeply
grateful for your presence in difficult times and also for all help with the
English language. Thank you Jan!
Lena Lindström, PhD, colleague and co-author, for introducing me into the
mysteries of the right ventricle and ARVC.
Christina Fluur, Lars Brudin, Tino Ebbers, Cecilia Gunnarsson and Peter
Söderkvist and Malin Rehnberg co-authors for contributions in the studies
and valuable discussions.
Gudrun Lövdahl, sonographer, for the skilful technical and administrative
assistance during all these years.
Inger Ekman, sonographer, for valuable help with echocardiography and
measurements of reproducibility, and Elin Wistrand, administrative assistant,
for help and support in many ways.
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79
My colleagues at the Department of Clinical Physiology, for providing a
positive working climate. I want to thank you for substituting for me in the
daily clinical work when I was absent for research.
Jan Ohlsson, associate professor, and Pearl Ohlson, for revising my English.
Kjell Jansson and Birgitta Janerot Sjöberg , present and former head of the
Department of Clinical Physiology, Linköping, for enabling me to focus on the
research and writing the thesis.
My friends from near and far, for keeping the social life alive and pleasant.
Ouafa and Zineb for the great time together.
Mother, for the unequivocal love and support throughout, as always, for
which my mere expression of thanks likewise does not suffice.
Fatiha, my sister, for the support despite the long distance between us. Thank
you for the encouragement and for all laughs.
At last but absolutely not least, Linda and Jasmine, my wonderful girls. For
enduring the evenings with a mother behind a computer instead of being with
you. You brighten my life. Peter, my husband for great support and love.
Financial support was obtained from ALF Grants, County Council of
Östergötland, the Swedish Heart- Lung foundation, the Medical Research
Council of Southeast Sweden, FORSS, the Carldavid Jönsson Foundation, the
Stina and Birger Johansson Foundation and the Swedish Council for Research
in Sports
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