Sudden Death-Genetic Risk [602781]

“Sudden Death-Genetic Risk”
Living with the risk of serious arrhythmias and
sudden cardiac death
-A prospective multicenter-study on patient-reported outcomes in individuals
with familial Long QT syndrome and Hypertrophic cardiomyopathy who
received genetic investigation and counseling in Norway, 2005-2007.
Anniken Hamang

Dissertation for the degree philosophiae doctor (PhD)
at the University of Bergen

2012

II
Scientific environment
This work was carried out at the Centre of Medical Genetics and Molecular
Medicine, Haukeland University Hospital, Department of Pathology and Medical
Genetics, St. Olavs Hospital HF, and the Department of Public health and General
Practice, Norwegian University of Science and Technology (NTNU). The project was
funded by the Western Norway Regional Health Authority and the Faculty of
Medicine and the Genetic Epidemiology Research Group, University of Bergen
(UIB). The PHD-candidate was granted admission at the Faculty of Medicine (UIB)
and has followed doctoral training and PhD-courses at UIB and NTNU.
Professor Nina Øyen from Centre of Medical Genetics and Molecular Medicine,
Haukeland University Hospital and the Genetic Epidemiology Research Group, UIB
has been the principal advisor. Co-advisors have been Professor and Deputy Rector
of the UIB, Berit Rokne, and Professor Karin Nordin, both from the Department of
Public Health and Primary Health Care.
Further, there was scientific collaboration during parts of the study with Cathrine
Bjorvatn, Gunilla Bergstrøm, Gottfried Greve, Trond Leren, Knut Erik Berge, Geir
Egil Eide, Gerd Kvale, and Lars Fredrik Engebretsen.
Geir Egil Eide og Cathrine Bjorvatn is also co-authors of various papers in the study.
The Phd fellow is employed as genetic counselor and researcher at Department of
Pathology and Medical Genetics, St. Olavs Hospital HF.

III
LIST OF ILLU STRATIONS …………………………………………………………………………………………… .. VII
ACKNOWLEDGEMENTS …………………………………………………………………………………………….. VI II
ABSTRACT ………………………………………………………………………………………………………. ………………. X
LIST OF PAPERS …………………………………………………………………………………………………. ………… XV
LIST OF ABBR EVIATIONS ………………………………………………………………………………………….. XVI
GLOSSARY ………………………………………………………………………………………………………. ……….. XVIII
LIST OF APPENDICES ……………………………………………………………………………………………… …… XX
1. INTRODUCTION ………………………………………………………………………………………………… ….. ……1
2. FAMILIAL LONG QT SYNDROME AND FAMILIAL HYPERTROPHIC
CARDIOMYOPATHY …………………………………………………………………………………………………. …….. 4
2.1. LONG QT SYNDROME – A CHANNELOPATHY …………………………………………………………………. …4
2.2. HYPERTROPHIC CARDIOMYOPATHY – A SARCOMERE DISEASE …………………………………………….. 7
2.3. COMMON CHARACTERISTICS OF LONG QT SYNDROME AND HYPERTROPHIC CARDIOMYOPATHY 8
2.4. INTERNATIONAL GUIDELINES FOR MANAGEMENT OF PATIENTS WITH VENTRICULAR
ARRHYTHMIAS AND THE PREVENTION OF SUDDEN CARDIAC DEATH ……………………………………….. ….8
3. GENETIC INVESTIGATION AND COUNSELING OF FAMILIAL LONG QT
SYNDROME AND FAMILIAL HYPERTROPHIC CARDIOMYOPATHY ………………………… 10
3.1. GENETIC INVESTIGATION …………………………………………………………………………………………….. 10
3.2. GENETIC COUNSELING ………………………………………………………………………………………………… 15
3.3. CURRENT PRACTICE OF GENETIC INVESTIGATION , COUNSELING AND THE NORWEGIAN
LEGISLATION ……………………………………………………………………………………………………………… …… 16
3.4. PROCEDURE OF THE GENETIC COUNSELING SESSIONS ………………………………………………………. 17

IV
4. PATIENT-REPORTED OUTCOMES IN PATIENTS UNDERGOING GENETIC
INVESTIGATION AND COUNSELING FOR FAMILIAL LONG QT SYNDROME
AND HYPERTROPHIC CARDIOMYOPATHY ……………………………………………………………….. 21
4.1. HEALTH STATUS ……………………………………………………………………………………………………….. 29
4.2. GENERAL ANXIETY AND DEPRESSION ……………………………………………………………………………. 30
4.3. HEART -FOCUSED ANXIETY ………………………………………………………………………………………….. 31
4.4. SELF-EFFICACY EXPECTATIONS ……………………………………………………………………………………. 33
4.5. SATISFACTION WITH GENETIC COUNSELING …………………………………………………………………… 34
4.6. STATE OF THE ART (SUMMARY ) …………………………………………………………………………………… 35
5. AIMS ……………………………………………………………………………………………………….. …………………… 36
5.1. OVERALL AIM …………………………………………………………………………………………………………… 36
5.2. SPECIFIC AIMS …………………………………………………………………………………………………………… 36
6. METHODS …………………………………………………………………………………………………….. …………….. 39
6.1. STUDY DESIGNS ………………………………………………………………………………………………………… 39
6.2. SAMPLE ……………………………………………………………………………………………………………… …… 40
6.3. PROCEDURE ……………………………………………………………………………………………………………… 42
6.4. THE PATIENT -REPORTED OUTCOME MEASURES ………………………………………………………………. 44
6.4.1. Short Form-36 Health Survey (SF-36) …………………………………………………………………. 44
6.4.2. The Hospital Anxiety and Depression Scale (HADS) ……………………………………………… 45
6.4.3. The Cardiac Anxiety Questionnaire (CAQ) …………………………………………………………… 45
6.4.4. The Bergen Genetic Counseling Self-efficacy Scale (BGCSES) ……………………………….. 45
6.4.5. Satisfaction with Genetic Counseling …………………………………………………………………… 46
6.5. SOCIO -DEMOGRAPHIC AND CLINICAL VARIABLES …………………………………………………………… 46
6.6. STATISTICAL METHODS ………………………………………………………………………………………………. 49

V
6.7. ETHICAL CONSIDERATIONS ………………………………………………………………………………………….. 50
7. RESULTS …………………………………………………………………………………………………….. ……………….. 52
7.1. SAMPLE CHARACTERISTICS ………………………………………………………………………………………….. 52
7.2. HEALTH STATUS IN PATIENTS AT RISK OF INHERITED ARRHYTHMIAS AND SUDDEN UNEXPECTED
DEATH COMPARED TO THE GENERAL POPULATION (PAPER I) …………………………………………………… 58
7.3. GENERAL ANXIETY , DEPRESSION AND PHYSICAL HEALTH IN RELATION TO SYMPTOMS OF HEART -FOCUSED
ANXIETY – A CROSS SECTIONAL STUDY AMONG PATIENTS LIVING WITH THE RISK OF SERIOUS ARRHYTHMIAS
AND SUDDEN CARDIAC DEATH (PAPER II) …………………………………………………………………………….. 58
7.4. PREDICTORS OF HEART -FOCUSED ANXIETY IN PATIENTS UNDERGOING GENETIC INVESTIGATION AND
COUNSELING OF LONG QT SYNDROME OR HYPERTROPHIC CARDIOMYOPATHY : A ONE YEAR FOLLOW -UP
(PAPER III) ………………………………………………………………………………………………………….. …………. 60
8. DISCUSSION ………………………………………………………………………………………………….. …………….. 61
8.1. SUMMARY OF FINDINGS ………………………………………………………………………………………………. 61
8.2. METHODOLOGICAL ISSUES ………………………………………………………………………………………….. 62
8.2.1. Study Designs ……………………………………………………………………………………………. ……… 62
8.2.2. Sample ………………………………………………………………………………………………….. …………. 64
8.2.3. The patient-reported outcomes …………………………………………………………………………….. 67
8.3. PATIENT – REPORTED HEALTH STATUS , LEVELS OF GENERAL ANXIETY AND DEPRESSION , AND SYMPTOMS
OF HEART -FOCUSED ANXIETY …………………………………………………………………………………………….. 69
8.3.1. The impact of having a family history of sudden cardiac death ………………………………… 73
8.3.2. The role of heart-focused anxiety …………………………………………………………………………. 74
8.3.3. Explanations for differences in hear t-focused anxiety up to one year after genetic
counseling …………………………………………………………………………………………………….. …………… 75
8.4. EMERGING ISSUES RELATED TO GENETIC INVESTIGATION AND COUNSELING NOW AND
IN THE FUTURE ……………………………………………………………………………………………………………… …. 77

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9. CONCLUSIONS …………………………………………………………………………………………………. ………… 80
10. CLINICAL IMPLICATIONS ………………………………………………………………………………………. 83
11. IMPLICATIONS FOR FURTHER RESEARCH ………………………………………………………….. 86
12. REFERENCES …………………………………………………………………………………………………. …………. 88
ORIGINAL PAPERS ………………………………………………………………………………………………… ……. 103
Appendices

VII
Illustrations
Tables
TABLE 2.1. DIAGNOSTIC CRITERIA FOR LONG QT SYNDROME (LQTS) ACCORDING TO EKG FINDINGS ,
CLINICAL HISTORY , AND FAMILY HISTORY ……………………………………………………………………………… 6
TABLE 3.1. SUMMARY OF EXPERT CONSENSUS RECOMMENDATIONS ……………………………………….. 12
TABLE 3.2. MOLECULAR GENETICS OF LONG QT SYNDROME (LQTS) ……………………………………… 13
TABLE 3.3. MOLECULAR GENETICS OF HYPERTROPHIC CARDIOMYOPATHY (HCM) ……………………. 14
TABLE 3.4. SUBJECT TO BE COVERED ACCORDING TO PROTOCOL FOR PRE -TEST GENETIC COUNSELING SESSION
OF PATIENTS WITH FAMILIAL LQTS OR FAMILIAL HCM …………………………………………………………. 20
TABLE 4.1. AN OVERVIEW OF STUDIES THAT ASSESSES PATIENT -REPORTED OUTCOMES IN PATIENTS WITH
FAMILIAL LONG QT SYNDROME OR FAMILIAL HYPERTROPHIC CARDIOMYOPATHY IN THE PERIOD
OF 2000-2011 ……………………………………………………………………………………………………… ………….. 23
TABLE 6.1. EXPLANATION OF THE PATIENT REPORTED OUTCOME MEASURES ; QUESTIONNAIRE , INCLUDING
SUBSCALES , SUMMARY OF CONTENTS , NUMBER OF ITEMS , RANGE AND TOTAL RANGE ………………… 47
TABLE 7.1. SOCIO -DEMOGRAPHIC VARIABLES AND CLINICAL VARIABLES OF 127 INDIVIDUALS WITH FAMILIAL
LONG QT SYNDROME OR FAMILIAL HYPERTROPHIC CARDIOMYOPATHY WHO RECEIVED GENETIC
INVESTIGATION AND COUNSELING IN NORWAY IN THE YEARS 2005-2007 …………………………………. 53
TABLE 7.2. DESCRIPTIVE INFORMATION OF THE PATIENT – REPORTED OUTCOMES ……………………….. 56
Figures
FIGURE 2.1. DIFFERENCE BETWEEN A NORMAL HEART AND HYPERTROPHIC CARDIOMYOPATHY . ……. 7
FIGURE 5.1 MODEL SHOWING INVESTIGATED RELATIONSHIPS OF THE PATIENT -REPORTED OUTCOMES , SOCIO –
DEMOGRAPHIC VARIABLES AND CLINICAL VARIABLES OF PATIENTS REFERRED TO GENETIC COUNSELING
BECAUSE OF FAMILIAL LQTS OR FAMILIAL HCM, AND THE COMPARISONS MADE BETWEEN THE SCORES OF
THE STUDY GROUP , EXPECTED SCORES , OR NORMS OF THE GENERAL POPULATION . …………………….. 38
FIGURE 6.1 AN OVERVIEW OF THE PATIENT -REPORTED OUTCOME MEASURES AND NUMBER OF PARTICIPANTS
AT VARIOUS ASSESSMENT TIMES …………………………………………………………………………………………. 43

VIII
Acknowledgements
Many have contributed to that “ I have reached my destination and arrived safely
from this journey”
First of all I want to acknowledge the effort of all the women and men that
participated in the study.
Further, I greatly acknowledge the Western Norway Regional Health Authority and
the University of Bergen for financially supporting this work through a Doctoral
Fellowship of four years, and a 6 months extra fellowship to finish the thesis.
Extra special thanks to my main supervisor, Nina Øyen, who with her skillful
comments and advice has challenged me to go the extra mile. Her talent has truly
been inspirational for me, and her belief in me has provided the most valuable
support.
Warm thanks also go to my co-supervisors Berit Rokne and Karin Nordin for
encouragement and sharing their expertise in methodology and psychology. Thanks
also to Geir Egil Eide for statistical support and good proof reading.
I also would like to thank the multidisciplinary FUGE research group lead by Gerd
Kvale that played a big part in planning and initiating of this project.
A big thanks to ISM at NTNU, that most generously included me in their scientific
environment and for giving me a place to do the work in Trondheim through the
years of 2005-2009, and where especially Marit Solbjør and Sigmund Simonsen
made the days interesting. Also special thanks to Torbjørn Øien for his friendship and
for sharing his insights.
I also would like to thank my fellow PhD-students at ISF that I learned a lot from
during the doctoral seminars and especially thank you to my close friend Nina
Strømsvik for support on the way.

IX
Also big thanks to my colleges at the Medical Genetic Departments at St. Olav’s
University Hospital, Haukeland University Hospital and Rikshospitalet that provided
the patients. A big acknowledgement to Torill Asphaug, who handled the
administration of questionnaires at Haukeland. Special thanks go to Trond Leren and
Knut Erik Berge at Rikshopitalet for sharing their expertise with regard to the present
patient group and for including their patients in the project. I am also especially
thankful to Harald Årset, Inga Bjørnevoll and all my other colleagues at the
Department of Pathology and Medical Genetics for letting me go on this journey and
for welcoming me back again.
Also many thanks to the Faculty and participants of the European Academy of
Nursing Science (EANS), for sharing experiences and giving valuable advice during
three doctoral summer schools at the Universities of Maastricht (NL), York (UK) and
Dublin (IRL), where I also met my new friend Marjorita Sormunen, who I must have
known in a previous life.
My deepest gratitude goes to my family, especially my mother, Lillian for asking
every single day how I am doing, for showing genuine interest and for seeing to it
that I am grounded, My father Åge for showing me it is possible to fly and that there
are no destinations that are too far away, My handsome and talented son Kim and my
beautiful and interesting daughter Ida, for both being patient with a busy mum, and
reminding me that there is always sunshine above the clouds, Jan Eise and Sylke for
showing me that it is still fun to play, and finally to my love of life, Arjan, that came
onboard the plane and sat down next to me at the start of this journey, and that give
me the feeling that it is not dangerous if I fall down, thank you for your love,
encouragement and for that you are interested in who I am, what I am doing and
where I am going.

October, 2011
Anniken Hamang

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1. Abstract
Background: Patients with a clinical diagnosis or a family history of the two distinct
entities Long QT syndrome (LQTS) and Hypertrophic cardiomyopathy (HCM) have
a higher genetically based risk of serious arrhythmias and sudden cardiac death
(SCD) than the general population. Living with this health threat may affect health
status and cause anxiety. The scientific development in the field of genetics has
made it possible to offer these patients genetic investigation. However, in what way,
this health threat affects the patients receiving genetic investigation and counseling is
unknown. Patient- reported outcome measures may provide better understanding of
these individuals’ situation, which is essential for the further development of
improving quality of care in cardio-genetic counseling.
Aims: The overall aim of this study was therefore to obtain more knowledge about
the health status, levels of general anxiety and depression, and symptoms of heart-
focused anxiety in individuals receiving genetic investigation and counseling because
of familial LQTS or familial HCM. The specific aims were;
I) To investigate health status; in comparison to expected scores of Norwegian
general population, and in relation to socio-demographic variables and clinical status;
II) To investigate general anxiety, depression, and physical health, in comparison to
expected scores of Norwegian general population or norm scores, in patients with
familial LQTS as compared to patients with familial HCM, and in relation to the role
of three distinct symptoms of heart-focused anxiety (avoidance, attention, and fear);

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and III) To explore if factors such as a family history of sudden cardiac death, patient
knowing whether other relatives’ previously had undergone genetic testing, perceived
general health, self-efficacy expectations, and satisfaction with genetic counseling
(affective, instrumental, procedural) predict heart-focused anxiety up to one year after
the genetic counseling.
Methods: In a prospective multi-site study at three university hospitals in Norway
during 2005-2007, all patients referred for medical genetic investigation and
counseling because of familial LQTS or familial HCM, over 17 years of age, and not
previously genetically tested, were eligible to participate. Patients referred were
family members and other appropriate relatives subsequently following the
identification of a LQTS or HCM- causative mutation in an index case or individuals
in whom a cardiologist had established or suspected a clinical diagnosis of LQTS or
HCM. Among 175 patients asked, 127 (126) patients completed a questionnaire
before the counseling session, and were asked to fill in questionnaires at several time
points after the counseling session (right after, 4 weeks, 6 months, and 1 year after).
The patient-reported outcomes were based on The SF-36 Health Survey, Hospital
Anxiety and Depression Scale, Cardiac Anxiety Questionnaire, Bergen Genetic
Counseling Self-efficacy Scale, Satisfaction with Genetic counseling, socio-
demographic and clinical variables. Descriptive, comparative and prospective
analyses were performed. Expected scores of Norwegian general population were
calculated for health status, general anxiety and depression, for baseline comparisons.
Multiple linear analyses were used to evaluate the relationship of socio-demographic,
clinical variables and health status. Hierarchical regression analyses were used to

XII
assess the ability of three distinct symptoms of heart-focused anxiety (avoidance,
attention, and fear) to predict levels of general anxiety, depression, and physical
health. Mixed linear modelling (MLM) was used to investigate predictors and changes
over time of the subscales of Cardiac Anxiety Questionnaire (CAQ); avoidance,
attention, and fear. All predictors were entered into MLMs to assess both their main
effects and their possible interaction with time.
Results: I) Among the 127 study participants, 88 patients (69.3 %) were referred for
familial LQTS, whereas 39 patients (30.7 %) were referred for familial HCM.
Ninety-five patients (74.8 %) were family members and other appropriate relatives at
genetic risk of LQTS or HCM, whereas individuals in whom a cardiologist had
established a clinical diagnosis, 12 patients (9.4 %) were affected with LQTS and 20
patients (15.7 %) were affected with HCM. Fifty-seven patients (44.9%) reported to
have experienced a sudden cardiac death in a family member. Overall, patients
reported significant poorer general health as compared to expected scores of the
general population. Better health status scores were related to patients’ employment,
higher education level, and referral to genetic counseling by a relative. Patients with a
clinical diagnosis of HCM had markedly reduced health status as of compared to the
general population, as compared to the patients at genetic risk of LQTS or HCM, and
also compared to patients with a clinical diagnosis of LQTS. II) Overall, the patients
reported significant higher levels of general anxiety as compared to expected scores.
Patients at genetic risk for LQTS or HCM scored better on physical health as
compared to expected scores, whereas the patients with a clinical diagnosis of LQTS
or HCM showed poorer physical health as compared to expected scores. Compared to

XIII
the patients that were referred for familial LQTS, patients referred for familial HCM
had poorer physical health and higher scores of heart-focused anxiety. Two distinct
symptoms of heart-focused anxiety (avoidance and fear) were independently related
to levels of general anxiety and depression, as well as to physical health (beyond the
effect of gender, age, clinical diagnosis, and family history with a recent sudden
cardiac death. III) A family history of sudden cardiac death in close relatives,
uncertainty whether other relatives had genetic testing, poorer perceived health, low
self-efficacy expectations before genetic counseling, and low procedural satisfaction
immediately after the genetic counseling predicted higher levels of heart-focused
anxiety up to one year after the counseling session (beyond the effect of questionnaire
time points, age, gender, clinical diagnosis, and genetic test result). A mutation
positive result predicted higher scores of cardio-protective avoidance 6 months after
genetic counseling.
Conclusions: Patients living with the health threat of serious arrhythmias and sudden
cardiac death because of familial LQTS or familial HCM perceive their health to be
poorer and have a higher general anxiety level compared to expected scores in the
general population, before receiving genetic counseling. Distinct symptoms of heart-
focused anxiety such as the extent to which these individuals report cardio-protective
avoidance and fear about heart sensations seem to influence their reporting of general
anxiety, depression, and physical health. Predisposed individuals for heart-focused
anxiety were patients who had experienced a close relative’s sudden cardiac death
and patients uncertain whether other relatives previously had undergone genetic
testing. However, satisfaction with the procedural parts of genetic counseling was

XIV
predictive of decreased levels of heart-focused anxiety. The resources of greatest
prognostic importance to prevent heart-focused anxiety may be the way individuals
perceive their general health and their self-efficacy expectations. The present findings
indicate that individuals undergoing genetic investigation and counseling for familial
LQTS or familial HCM are vulnerable in both health-related and psychological
domains before genetic counseling, and may benefit from a closer collaboration
between the genetic counselor and the cardiologist addressing their experience of
cardiac symptoms to a greater extent.

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List of papers

Paper I
Hamang, A., Eide, G.E., Nordin, K., Rokne, B., Bjorvatn, C., & Øyen, N. (2010).
Health status in patients at risk of inherited arrhythmias and sudden unexpected death
compared to the general population. BMC Medical Genetics 11:27
http://www.biomedcentral.com/1471-2350/11/27
DOI 10.1186/1471-2350-11-27
Paper II
Hamang A, Eide GE, Nordin K, Rokne B, Øyen N. (2011). General anxiety,
depression, and physical health in relation to symptoms of heart-focused anxiety
among patient living with the risk of serious arrhythmias and sudden cardiac death.
Health and Quality of Life Outcomes , Under 2nd review
Paper III
Hamang A, Eide GE, Nordin K, Rokne B, Bjorvatn C, Øyen N. (2011). Predictors of
heart-focused anxiety in patients undergoing genetic investigation and counseling of
Long QT syndrome or Hypertrophic cardiomyopathy: A one year follow-up. Journal
of Genetic Counseling
http://www.springerlink.co m/content/y6u81618328378t2/fulltext.pdf
DOI 10.1007/s10897-011-9393-6

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List of abbreviations
ACC American College of Cardiology
AHA American Heart Association Task Force
ANOVA Analysis of variance
BGCSES The Bergen Genetic Counseling Self-
efficacy Scale
CAQ The Cardiac Anxiety Questionnaire
ESC European Society of Cardiology
/g533-blockers Beta blocker medication
DSM-IV The Diagnostic and Statistical Manual of
Mental Disorders of the American
Psychiatric Association
ECG Electrocardiogram
HADS Hospital Anxiety and Depression scale
HCM Hypertrophic cardiomyopathy
HUNT The Nord-Trøndelag Health Study
ICD Intracardial defibrillator
ICD-10 International Classification of Diseases-
10
IQOLA The International Quality of Life
Assessment Project

XVII
LQTS Long QT syndrome
LQT 1-3 Long QT phenotypes 1 to 3
MLM Mixed linear modeling
OMIM Online Mendelian Inheritance in Man
PROM Patient-reported outcome measures
SF-36 Short Form 36
TdP Torsade-de Pontes
WHO The World Health Organization

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Glossary
Autosomal Dominant : The situation in which the disease can be expressed even
when only one chromosome harbours the mutation.
Autosomal Recessive : The situation in which the disease can be expressed only
when both chromosomes of a pair are abnormal.
Cascade Testing : Procedure whereby all first-degree relatives of a genotype-positive
index case are tested in concentric circles of relatedness. If one of the family
members is genotype positive, all his/hers first-degree relatives should be tested
continuing this process following each genotype-positive family member.
Disease-causing Mutation : A DNA sequence variation that represents an abnormal
allele and is not found in the normal healthy population but exists only in the disease
population and produces a functionally abnormal product.
Expressivity : The level of expression of the phenotype, and when the manifestations
of the phenotype in individuals who have the same genotype are diverse, the
phenotype is said to exhibit variable expressivity.
First-Degree Relative : A blood relative who is a person’s parent, sibling, or child.
Founder Mutation : The occurrence of a particular gene mutation at increased
frequencies within a given population due to its presence in a small isolated group of
ancestors that directly gave rise to the current population.
Genotype : A person’s genetic or DNA sequence composition at a particular location
in the genome.
Index Case/Proband : The person or patient who first draws clinical attention to a
particular family in a genetic or epidemiologic investigation.
Mutation : A change of the DNA sequence within the genome.

XIX
Mutation- Disease Causing : A DNA sequence variation that represents an abnormal
allele and is not found in the normal healthy population and produces a functionally
abnormal product.
Penetrance : The likelihood that a gene mutation will have any expression at all. In
the situation in which the frequency of phenotypic expression is less than 100 %, the
genetic defect is said to be associated with reduced or incomplete penetrance.
Phenocopy : An individual who manifests the same phenotype (trait) as other
individuals of a particular genotype but does not possess this genotype
himself/herself.
Phenotype : A person’s observed clinical expression in terms of a morphological,
biochemical, or molecular trait.
Variants of Uncertain Significance (VUS) : A mutation or genetic variation with
uncertain clinical significance.

XX
List of appendices
Appendix 1: Questionnaires
Appendix 2: Invitation letters/consent form
Appendix 3: REK recommendation
Appendix 4: Act of Biotechnology (relevant chapters)

1
1. Introduction
International guidelines for management of patients with ventricular arrhythmias and
the prevention of sudden cardiac death (ACC/AHA/ESC 2006) emphasize the
importance of genetic testing in Long QT syndrome (LQTS) families and the
usefulness of testing in families with Hypertrophic cardiomyopathy (HCM) (Zipes et
al, 2006). LQTS is a channelopathy (Kramer & Zimetbaum, 2011) and HCM is a
sarcomere disorder (Watkins, et al., 2011). Common for the patients with familial
LQTS and familial HCM is a genetically based increased risk for serious arrhythmias.
Both patients with a clinical diagnosis, as well as their relatives who are at genetic risk
of developing the disease, therefore live with the threat of a premature sudden cardiac
death (Maron, 2003; Maron, 2009; Vincent, 2005). Living with such a health threat
may have big consequences for the health and wellbeing of these individuals.

In health sciences the concepts of health status, general anxiety and depression, and
heart-focused anxiety are often researched. These concepts may also be particularly
relevant to study in individuals who receive genetic investigation and counseling
because of familial LQTS or familial HCM. Firstly, the clinical diagnosis of LQTS or
the clinical diagnosis of HCM may by themselves give considerable discomfort, when
patients experience syncope, palpitations, or other debilitating symptoms. In addition,
emotional reactions are likely, since the risks of cardiac symptoms are so immediate
and possibly fatal. Secondly, LQTS and HCM are autosomal dominant disorders,
which mean children, siblings and parents of a mutation carrier have a 50 percent risk
of also being affected, thus they are also living with risk of serious cardiac symptoms.
The penetrance (likelihood for actually developing the disease) is however varying,
which leads to uncertainty of ever experiencing clinical symptoms of the disorder.
Thirdly, identifying individuals with a high risk implies medication and life-style
advice to prevent sudden cardiac death. Since the penetrance is not 100%, no-one will
ever know whether the medication which may have side-effects was necessary.

2
Moreover, relevant health advice implies that excessive physical activity should be
avoided as well as prolonged ‘stress’. Lastly, individual differences may potentially
influence on how patients adapt to living with familial cardiac disorders.

Patient perspective has become essential for quality of care. While the research
concerning LQTS and HCM has focused on genes, mutations, morbidity and
mortality, very little research has been based on patient-reported outcomes of adult
persons undergoing the process of genetic investigation and counseling for familial
LQTS or familial HCM. The impact of measuring patient-reported outcomes may
pertain to provision of important understanding of patients physical or psychological
vulnerabilities that otherwise might be overlooked. Further it may give information on
disease progression, results of interventions, and establishing a more common
understanding between the patient and the health-care provider (Valderas & Alonso,
2008).

The aim of genetic counseling is “helping people understand and adapt to the medical,
psychological and familial implications of genetic contributions to disease”. The
rapidly developing gene technology has made it possible to identify individuals with
an increased risk for familial disorders such as LQTS or HCM. This has resulted in
increasing needs to develop health communications, counseling services, and
interventions for helping patients to cope with genetic risk. Knowledge based on
patients’ perspective is essential for the continuation of developing cardio-genetic
counseling. Thus, the focus of this thesis will be from the patient perspective using
patient-reported outcome measures that reflect health status, levels of general anxiety
and depression, as well as symptoms of heart-focused anxiety. There will also be a
focus on patients’ self-efficacy expectations and satisfaction with genetic counseling.

3
One thing is for certain, these concepts are close to the heart in more ways than one.
Not only is it the physical side of a hearth that beats in a rhythm, but it is also all the
emotional components we attach to it, and that also may affect the physical heart.

4
2. Familial long QT syndrome and familial
hypertrophic cardiomyopathy
2.1 Long QT syndrome – a channelopathy
LQTS is a congenital disorder characterized by a prolongation of the QT interval on
electrocardiogram (ECG) and an increased risk of ventricular arrhythmia e.g.
Torsades-de Pointes (TdP), associated with increased risk for syncope, cardiac arrest,
or sudden cardiac death, especially in young individuals (Vincent, 2005). The
diagnosis is based on the measurement of the QT-interval in ECG, clinical history,
and/or a family history of LQTS and sudden cardiac death (Schwartz, 2006; Crotti et
al., 2008). Diagnostic criteria based on the characteristic features of LQTS are shown
in table 2.1.

Molecular genetic investigation has become an important supplement in the
diagnostics, after identification in the mid-nineties of the first three LQTS genes
KCNQ1, KCNH2 and SCN5A associated with the most common phenotypes of
LQT1, LQT2 and LQT3 (Wang et al., 1995; Curran et al., 1995; Wang et al., 1996).
The type of LQTS influences clinical course, in that most cardiac events are triggered
by exercise and stress in LQT1, by emotional stress such as auditory stimuli in LQT2,
while most cardiac events happen under sleep or rest for LQT3 (Schwartz et al., 2001).
The lethality of cardiac events is suspected to be in the range from 2 to 20 % (Zareba
et al., 1998). LQTS may be inherited as an autosomal dominant trait with either full or
reduced penetrance (Romano-Ward syndrome) (Ward, 1964; Romano, Gemme &
Pongiglione, 1963; Romano, 1965), or as an autosomal recessive trait (Jervell-Lange-
Nielsen syndrome with congenital deafness)(Schwartz et al., 2006; Jervell & Lange-
Nielsen, 1957). Mutation carriers may have symptoms or have prolonged QT-interval
in ECG, but carriers with neither symptoms nor prolonged QT-interval may also have

5
an increased risk for sudden cardiac death, making molecular testing essential for
initiating medication (/g533-blockers) and life-style advice for asymptomatic mutation
carriers. Reported prevalence varies from 1/10 000 to 1/2500 (Crotti et al., 2008). In
some parts of the world it is estimated to be higher due to founder mutations which are
also the case in Norway (Berge et al., 2008).

6
Table 2.1 Diagnostic criteria for Long QT syndrome (LQTS) according to EKG
findings, clinical history, and family history
Points
ELECTROCARDIOGRAPHIC
FINDINGS #
A QTc^ > 480 ms
460 – 470 ms
450 – 459
(male) ms 3
2
1
B Torsade de pointes * 2
C T wave alternans 1
D Notched t wave in 3 leads 1
E Low heart rate for age @ 0.5
CLINICAL HISTORY
A Syncope * With stress
Without stress 2
1
B Congenital deafness 0.5
FAMILY HISTORY $
A Family members with definite LQTS 1
B Unexplained sudden cardiac death below
age 30 among immediate family
members 0.5
Source: Crotti et al. (2008). Congenital long QT syndrome. Orphanet Journal of Rare Diseases, 3:18.
http://www.ojrd.com/content/3/1/18
# In the absence of medications or disorders known to affect these electrocardiographic features
^ QTc calculated by Bazett's formula where QTc = QT//g165RR
* Mutually exclusive
@ Resting heart rate below the 2nd percentile for age
$ The same family member cannot be counted in A and B
SCORE: /g148 1 point = low probability of LQTS, > 1 to 3 points = intermediate probability of LQTS, /g149
3.5 points = high probability of LQTS

7
2.2 Hypertrophic cardiomyopathy – a sarcomere disease
HCM is an excessive thickening of the heart muscle in the left and/or right ventricle
(Maron, 2002; Watkins et al., 2011) (Fig. 2.1), and it is defined by the presence of this
increased ventricular wall thickness or mass, having ruled out hypertension and valve
disease (Elliott et al., 2008).

Figure 2.1 Difference between a normal heart and hypertrophic cardiomyopathy.

Myocyte disarray and fibrosis is typical features (Maron, 2002; Watkins et al., 2011).
The symptoms are dyspnea, palpitations, syncope/near syncope’s, chest pains and
arrhythmias. Like in LQTS, sudden cardiac death can present as first manifestation of
the disorder (Maron, 2002). Diagnosis is made with 2-dimensional echocardiography,
and the cardiac disorder may be suspected because of a heart murmur, abnormal ECG,
symptoms and a positive family history (Maron, 2002). Molecular screening is
available. The genetic traits are mainly autosomal dominant with varying penetrance,
but also autosomal recessive, X-linked, and sporadic (5%). Established symptomatic

8
treatment exists, such as medications, pacemaker, intracardial defibrillator (ICD),
surgery, and advice for daily living. HCM is the most prevalent inherited cardiac
disorder, affecting 1/500. Overall, the annual mortality rate from HCM is estimated to
be 1 to 5 % (Maron, 2002).

2.3 Common characteristics of Long QT syndrome and
Hypertrophic cardiomyopathy
Although, LQTS is a channelopathy (Goldenberg & Moss, 2008) and HCM is a
sarcomere disease (Watkins et al., 2011), genetic investigation and counseling follows
the same protocol for both familial cardiac disorders. This is based on the two
disorders many common characteristics in the genetic setting. In addition, both LQTS
and HCM patients face a serious health threat, serious symptoms, the threat of sudden
cardiac death, and the possibility that their children have inherited the same disorder.
Both entities have incomplete penetrance and variable expression. There are great
uncertainties regarding symptoms, management and prevention, and both cardiac
disorders require adjustments of life style and avoidance of triggers. The complexities
in managing these patients and their relatives at risk, calls for clinicians with
considerable experience and knowledge of the disorders, and guidelines that reflect
international expert opinion (Garratt et al., 2010).
2.4 International guidelines for management of patients with
ventricular arrhythmias and the prevention of sudden
cardiac death
International guidelines specifically address familial cardiac disorders such as LQTS
and HCM with regards to management and the prevention of sudden cardiac death
(Zipes et al., 2006). Sudden cardiac death (SCD) is according to the Task Force of
Sudden Cardiac Death, European society of cardiology defined as “Natural, non

9
traumatic death due to cardiac causes, heralded by abrupt loss of consciousness within
one hour of the onset of symptoms. Pre-existing heart-disease may have been known
to be present, but the time and mode of death are unexpected” (Priori et al., 2002).
LQTS is responsible for a significant proportion of SCDs in young people without
structural heart disease (Berul, 2008). In young people and in athletes the most
common cause of death in the United States has been reported to be HCM (Maron,
2009; Maron, 2003). In Norway there is no available information at present of the
incidence of sudden cardiac death due to familial LQTS or familial HCM. It is
expected to be at least similar to international numbers.

The question if a sudden cardiac death or an episode of aborted cardiac arrest was
caused by a familial disorder such as LQTS or HCM, and the consequences that other
relatives may be at risk, are a concern that adds to the trauma for the families that
experience this. According to the guidelines, lifestyle changes such as avoidance of
competitive sports activity are recommended, for both LQTS and HCM patients. Beta
blockade is recommended for patients with a prolonged QT interval and is part of the
management of HCM. Implantation of ICD remains controversial however
recommended for LQTS patients with previous cardiac arrests and HCM patients who
have sustained ventricular tachycardy and /or ventricular fibrillation, receiving optimal
medical therapy and have prospects of good functional status for over 1 year. The
guidelines emphasize the importance of genetic testing in LQTS families and the
usefulness of testing in families with HCM , thus genetic investigation and counseling
is warranted in these families (Zipes et al., 2006).

10
3. Genetic investigation and counseling of familial
Long QT syndrome and familial hypertrophic
cardiomyopathy
3.1 Genetic investigation
Today, individuals with an increased risk of developing life-threatening arrhythmias
because of LQTS or HCM can be identified with a genetic investigation. Expert
Consensus Recommendations has been developed for the use and role of genetic
testing for potentially heritable cardiac conditions (Ackerman et al., 2011). A
summary of expert consensus recommendations for the state of genetic testing for both
LQTS and HCM is shown in table 3.1.

The genetic investigations of familial LQTS or familial HCM comprise mainly two
forms of genetic testing, diagnostic and predictive testing. Diagnostic testing involves
confirming a suspected or evident clinical diagnosis in an index case, whereas
predictive testing is used to determine whether a patient with a proven gene mutation
in a close family member has the gene mutation that involves risk for future disease.

Mutations in genes encoding cardiac potassium or sodium ion channels can be found
in two-thirds of patients affected with LQTS (Schwartz et al., 2001; Splawski et al.,
2000; Zareba et al., 1998). An overview over molecular genetics of LQTS in the
clinical setting is shown in table 3.2.

Predictive genetic testing is a valuable tool to identify at-risk individuals by “cascade
testing” (genetic testing of a mutation carrier’s first degree relatives) in the families

11
that are affected with LQTS. This is especially important, because predictive genetic
testing is the only way to rule out LQTS in such family members because of the
variable penetrance and expression of the disorder. However, because diagnostic
genetic testing identifies a disease causing mutation in approximately 75% to 80 % of
clinically affected LQTS patients (Schwartz, 2006; Ackerman et al., 2011), a negative
diagnostic genetic test cannot completely exclude the diagnosis of LQTS by itself.
Rare variants of uncertain significance (VUS) in the LQT1-3 genes also complicate
the interpretation of gene test results (Ackerman et al., 2011). Therefore, clinical
diagnostic genetic testing should not be performed on index cases without cardiology
consultation according to the recommendations (Ackerman et al., 2011).
Genetic investigation has also become available in families with HCM, where
dominant mutations in sarcomeric protein genes are associated with a high risk of
sudden cardiac death (Bos et al., 2009). The molecular genetics of HCM is shown in
table 3.3. Mutations in 14 genes that encode different proteins of the cardiac sarcomere
cause the autosomal dominant form of HCM. Two of the genes predominate; The
MYBPC3 (myosin-binding protein C) and MYH7 (/g533-myosin heavy chain) (Bos et al.,
2009). In HCM patients, mutations in one of those genes can be found in 30-80 %
depending on case ascertainment (Andersen et al., 2009; Maron et al., 2007; Van
Driest et al., 2005), thus more limitations apply as compared to LQTS diagnostic
testing in excluding a HCM diagnosis. However diagnostic genetic testing is
recommended for patients with a firm clinical diagnosis of HCM, first of all because it
may benefit family members and other relatives. Furthermore, predictive genetic
testing of patients with a proven gene mutation in a close family member is
recommended over clinical screening because ECG or echocardiographic
abnormalities may be absent or subtle, or develop at a later stage (Ackerman et al.,
2011).

12

Table 3.1 Summary of Expert Consensus Recommendations*
State of genetic testing for Long QT syndrome (LQTS)
Class I (is recommended)
/g120 Comprehensive or LQTS1-3 (KCNQ1, KCNH2, and SCN5A) targeted LQTS genetic
testing (diagnostic) is recommended for any patient in whom a cardiologist has
established a strong clinical index of suspicion for LQTS based on examination of the
patient’s clinical history, family history, and expressed electrocardiographic (resting
12-lead ECGs and/or provocative stress testing with exercise or catecholamine
infusion) phenotype.
/g120 Comprehensive or LQTS1-3 (KCNQ1, KCNH2, and SCN5A) targeted LQTS genetic
testing (diagnostic) is recommended for any asymptomatic patient with QT
prolongation in the absence of other clinical conditions that might prolong the QT
interval (such as electrolyte abnormalities, hypertrophy, bundle branch block etc., i.e.,
otherwise idiopathic) on serial 12-lead ECGs defined as QTc> 480 ms (prepuberty) or
> 500 ms (adults).
/g120 Mutation-specific genetic testing (predictive) is recommended for family members
and other appropriate relatives subsequently following the identification of a LQTS-
causative mutation in an index case.
Class II (may be considered)
/g120 Comprehensive or LQTS1-3 (KCNQ1, KCNH2, and SCN5A) targeted LQTS genetic
testing (diagnostic) may be considered for any asymptomatic patient with otherwise
idiopathic QTc values >460 ms (prepuberty) or > 480 ms (adults) on serial 12-lead
ECGs.
State of genetic testing for Hypertrophic cardiomyopathy*
Class I (is recommended)
/g120 Comprehensive or targeted (MYBPC3, MYH7, TNNI3, TNNT2, TPM1) HCM genetic
testing (diagnostic) is recommended for any patient in whom a cardiologist has
established a clinical diagnosis of HCM based on examination of the patient’s clinical
history, family history, and electrocardiography/ echocardiography phenotype.
/g120 Mutation-specific genetic testing (predictive) is recommended for family members
and appropriate relatives following the identification of the HCM-causative mutation in
an index case.
* Source: Ackerman et al. (2011). HRS/EHRA expert consensus statement on the state of genetic
testing for the channelopathies and cardiomyopathies: this document was developed as a
partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm
Association (EHRA). Europace., 13, 1077-1109.

13

Table 3.2. Molecular genetics of Long QT syndrome (LQTS)*†
Locus
Name Gene
Symbol Chromosomal
Locus Protein Name % of LQTS
attributed to
mutations in this
gene
LQT1 KCNQ1 11p15.5 Potassium voltage-gated
channel subfamily KQT
member 1 58%
LQT2 KCNH2 7q35-q36 Potassium voltage-gated
channel subfamily H
member 2 35%
LQT3 SCN5A 3p21 Sodium channel protein
type 5 subunit alpha 5%
LQT5 KCNE1 21q22.1-q22.2 Potassium voltage-gated
channel subfamily E
member 1 1%
LQT6 KCNE2 21q22.1 Potassium voltage-gated
channel subfamily E
member 2 1%
* http://www.ncbi.nlm.nih.gov/books/NBK1129/ accessed 6 June 2011, updated 20 October 2011,
publisher; National Center for Biotechnology information (NCB1)

14

Table 3.3 Molecular genetics of Hypertrophic cardiomyopathy (HCM)*†
Locus
Name Gene
Symbol Chromosomal
Locus Protein Name % of HCM attributed
to mutations in this
gene
CMH1 MYH7 14q12 Potassium voltage-gated
channel subfamily H
member 2 35%
CMH4 MYBPC3 11p11.2 Myosin-binding protein
C, cardiac-type 40%
CMH2 TNNT2 1q32 Troponin T, cardiac
muscle 5%
CMH7 TNNI3 19q13.4 Troponin I, cardiac
muscle 5%
CMH3 TPM1 15q22.1 Tropomyosin 1 alpha
chain 2%
CMH10 MYL2 12q23-q24.3 Myosin regulatory light
chain 2,
ventricular/cardiac muscle
isoform Unknown
CMH8 MYL3 3p Myosin light polypeptide
3 1%
ACTC1 15q14 Actin, alpha cardiac
muscle Unknown
CSRP3 11p15.1 Cysteine and glycine-rich
protein 3, muscle LIM
protein Unknown
CMH9 TTN 2q31 Titin
ACTN2 1q42-q43 Alpha-actinin-2 Unknown
TNNC1 3p21.3-p14.3
* http://www.ncbi.nlm.nih.gov/books/NBK1768/ accessed 6 July 2011, updated 20 October,
publisher; National Center for Biotechnology information (NCB1)

15
3.2 Genetic counseling
The new possibilities we have today through technology and in dealing with familial
cardiac disorders are reflected in the definition of genetic counseling from the National
Society of Genetic Counselors (NSGC)(Resta et al., 2006).

“Genetic counseling is the process of helping people understand and adapt to the
medical, psychological and familial implications of genetic contributions to
disease. This process integrates:

/g120 Interpretation of family and medical histories to assess the chance of disease
occurrence or recurrence.
/g120 Education about inheritance, testing, management, prevention, resources and
research.
/g120 Counseling to promote informed choices and adaptation to the risk or
condition”

The definition emphasize genetic counseling as a specialist field with the goal of
communicating inherited risk information that is based on genetic investigation
(Demarco et al., 2004), in a manner that can help the individual to adaptive coping
processes. The practice and procedure of genetic investigation as well as the
counseling to patients with familial LQTS or familial HCM is still under development,
in order to be able to reach this important goal.

16
3.3 Current practice of genetic investigation, counseling and
the Norwegian legislation
In Norway, the Act relating to the application of biotechnology in human medicine
(Biotechnology act of 1994, and later Act of 2003, see Appendix) regulates clinical
genetic activities first of all by paragraph 5-2 that states that “Genetic testing shall only
be carried out for medical purposes if it has a diagnostic or therapeutic objective”
(2003).

There has been a long tradition for genetic counseling that started already several
decades before the first Biotechnology Act, however the current practice of genetic
investigations in families with LQTS have only existed since approximately 2001
(Hamang et al., 2009), whereas HCM genetic investigations started approximately in
2004. The molecular genetic testing has been performed at Rikshospitalet in Oslo
(Haugaa et al., 2005), whereas the genetic counseling has been conducted at the main
regional tertiary hospitals throughout the country.

Today, the genetic investigation and counseling is mainly performed by a team of
medical geneticists and genetic counselors. However, cardiologists also increasingly
conduct diagnostic genetic testing as part of their clinical investigation in determining
a patient’s diagnosis. Collaboration between the heart departments and the specialized
cardio-genetic clinics is essential because of the importance of establishing firm
clinical diagnoses of index-cases (Ackerman et al., 2011).

In contrast to diagnostic genetic testing that can be performed without prior genetic
counseling, the current Act regulates predictive genetic testing more strictly. In
addition to the demand for a diagnostic or therapeutic objective for carrying out

17
testing, the law state that genetic counseling shall be given before, during, and after
predictive genetic testing of the person. In cases where a child under 16 years is
predictively tested, the child’s parents, or other person who has parental responsibility
should receive genetic counseling. Furthermore, written consent must be obtained of
the counselees. And finally, “unless the test can detect a condition for which treatment
may prevent or reduce damage to a child’s health”, testing children under 16 years of
age is prohibited. However, since both LQTS and HCM can affect children and
dangerous symptoms can be prevented, current practice performs predictive genetic
testing on children.
3.4 Procedure of the genetic counseling sessions
Before the genetic counseling session the patient information and family history is
verified in medical records, autopsy reports, and other relevant documents which are
collected after approval of the patient and relatives involved. Apart from verifying
diagnosis in medical records/autopsy reports etc, important parts of the genetic
investigation are collecting information pertaining to previous genetic testing,
incidence of the disease in the family, onset of disease in relatives with relevant
diagnosis/symptoms, and exploring circumstances around sudden cardiac deaths in the
family.

Typically the genetic counseling is offered over the course of two-three sessions. After
a medical genetic review of the family history and available information, one pre-test
session is offered to provide the patient and family with information (see table 3.4) and
one disclosure session where the genetic test result is disclosed to the patient. Subjects
discussed in the pre-test session, include prevalence, symptoms, clinical findings,
prognosis, recurrence risk, genes, mutations, and treatment, as well as questions
regarding genetic testing. Evaluation of the genetic risk is based upon family history,
symptoms, clinical findings, and age of onset. Information from a genetic test is only a

18
supplement to the risk assessment today, since in many families, it is currently
impossible to detect a gene mutation (see above). However once a gene mutation is
identified in a patient, genetic testing of other relatives is possible.

In the genetic counseling session the genetic counselor aims to individualize the
information based on the patient’s need of information and support. Identification of a
disease causing mutation may have implications for issues such as profession,
education, driver license and insurance. Therefore, it may be relevant to discuss these
matters as well.

Apart from that the patient is informed of the genetic test result and its implications in
the disclosure session, important information from the pre-test session is repeated. In
addition, the identification of other at-risk relatives is conducted together with the
patient.

Patients that are proven mutation carriers and patients with inconclusive results are
offered subsequent consultations and are referred for cardiac investigations, controls
and follow up, whereas patients that have tested negative for the specific family
mutation has no need for further cardiological follow up, from a medical standpoint.

The literature raises a number of ethical questions and emphasizes psychological
issues that one should be aware of with regard to genetic testing and management of
patients at risk of familial cardiac disorders (Aatre & Day, 2011; Charron et al., 2002;
Mularczyk et al.,; van Langen et al., 2004). However, this literature has mainly been
based on information from the clinician’s perspective, and more specific knowledge
about the patients’ is needed. Apart from that these patients face the risk of life

19
threatening events and are subjected to genetic testing, they may also experience
symptoms, disability and reduced wellbeing as a result of living with familial LQTS or
HCM. Patient perspectives of their health have not only become important in health
research, but essential knowledge to achieving high quality care (Black & Jenkinson,
2009). This is further outlined below.

20
Table 3.4 Subject to be covered according to protocol for pre-test genetic counseling
session of patients with familial LQTS or familial HCM

/g120 Review of personal and family medical history (symptoms, clinical diagnosis,
known heart-disorders in the family, anyone who died suddenly)
/g120 Identification of a possible genetic risk (family history of a certain cardiac disorder
or identification of a definite disease-causing mutation in an index case)
/g120 Explanation about the nature of the familial disorder (incidence, age at onset,
symptoms)
/g120 Explanation of possible inheritance patterns (autosomal dominant/recessive)
/g120 Review of appropriate testing options and its consequences (what does a test result
mean, and implications of disclosure of test result.)
/g120 Discussion of prevention strategies and disease management (prophylactic
treatment, avoidance of triggers)
/g120 Provision of genetic-related information and suggestion of reliable resources
(patient information, online patients websites)
/g120 Counseling to promote informed choices and adaptation to the risk or the disease
/g120 The opportunity of molecular genetic testing if appropriate

21
4. Patient-reported outcomes in patients undergoing
genetic investigation and counseling for familial
Long QT syndrome and Hypertrophic
cardiomyopathy
In contrast to measured physiological values, mortality and morbidity, patient-reported
outcome measures assesses the patients’ perspective of their own functional status and
wellbeing (Dawson et al., 2010). The impact of measuring patient-reported outcomes
may pertain to provision of important understanding of patients physical or
psychological vulnerabilities that otherwise might be overlooked. Further it may give
information on disease progression and results of interventions, and establishing a
more common understanding between the patient himself and the health-care provider
(Valderas & Alonso, 2008).

The patient-reported outcome measures may either be generic (measuring patients
perception of their general health and wellbeing), disease-specific (measuring patients
perception of their health and wellbeing in relation to specific conditions) (Dawson et
al., 2010), or dimension-specific (exploring particular domains to greater depth)
(Fayers & Machin, 2007a). The term patient- reported outcome indicates interest in a
whole range of outcomes (Fayers & Machin, 2007; Doward & McKenna, 2004). The
outcomes chosen for the present study were health status, general anxiety, depression,
physical health, heart-focused anxiety, general health perceptions, self-efficacy, and
satisfaction with genetic counseling.

A literature search in PubMed of journal articles published up to present time (October
2011) comprising either of the following search words in title or abstract; health status,
quality of life, physical health, mental health, anxiety, depression, psychological
distress, psychological, emotional distress, coping, self-efficacy, or satisfaction, and

22
comprising either Long QT syndrome, Hypertrophic cardiomyopathy or hereditary
heart disease, and either hereditary, familial, family history, inherited or genetic in any
field retrieved 86 articles. Only 17 of these articles present data on patient-reported
outcomes from patients with familial LQTS or familial HCM, and only three of these
were published before the present study was initiated, one of the latter was in Dutch
language. A review of the remaining 16 patient-reported outcome studies (with regard
to research question asked, sample characteristics, type of design, methods of
measuring variables and key findings) is presented in Table 4.1.

23
Table 4.1 An overview of studies that assesses patient-reported outcomes in patients with familial Long QT syndrome or familial Hypertrophic
cardiomyopathy in the period of 2000-2011(based on search in Pubmed)

Author Research question Sample Type of design Methods Key finding
Lane, RD et al. 2011 To investigate if stressed
individuals with greater
emotional awareness
would experience somatic
symptoms in a more
differentiated way
independent of
neuroticism 161 LQTS patients Descriptive
Cross-sectional
Ecological momentary
assessments of
symptoms over three
days Revised NEO
Personality
Beck Depression
Inventory (BDI)
Positive and Negative
Affect Scale (PANAS)
10 vignettes describing
emotion-provoking
interactions
Patients that are more
emotionally aware
report somatic
symptoms in a more
differentiated way.
Hamang, A et al. 2010 To investigate if there is a
relationship between
living with genetic risk of
inherited arrhythmia and
health status vulnerability
and investigate the
relationship between
socio-demographic
variables, clinical status
and health status domains 127 patients referred
to genetic counseling
because of familial
LQTS or familial
HCM Descriptive
Cross-sectional The Short Form 36
health survey (SF-36)
Clinical status
Socio-demographic
variables

Patients reported
significant lower SF 36
score as compared to
the general population
for the domain of
general health
Christiaans, I et al. To evaluate counselee’s
views and opinions on 123 predictively Descriptive Opinions on
information provision, Genetic counseling was
valued positively.

24
2009 predictive genetic
counseling and DNA
testing, and the cardiac
follow-up in HCM
mutation carriers tested HCM carriers Cross-sectional satisfaction with
counseling, social
pressure in DNA testing
and regret of DNA
testing, communication,
nervous anticipation,
reassurance, and
general disadvantages
Carriers also had a
positive attitude
towards the cardiac
follow-up, however
there was a low
frequency of patients
receiving cardiac
follow-up
Lane RD et al. 2009 To determine whether the
circumstances preceding
an arrhythmic event
differed from those
preceding a prior control
occasion 38 LQTS patients Case-crossover
interview 7- point scale used for
rating peak happiness,
general happiness, and
stress and a 7 point
scale used for rating
exertion
Characteristics Happiness was found
associated with a
reduction in the 24-hour
risk of cardiac events,
with stress having the
opposite effect
Christiaans, I et al.
2008 To assess long-term
quality of life and
psychological distress in
HCM mutation carriers,
and to identify socio-
demographic, clinical, and
risk and illness perception
related factors associated
to the outcomes 228 proven carriers
of a pathogenic
mutation in one of the
genes associated with
HCM Descriptive; A cross-
sectional cohort study The Short Form 36
health survey
The Hospital Anxiety
and Depression Scale
Demographic variables
The revised version of
the illness perception
questionnaire Levels of quality of life
and distress were not
impared compared to a
general population
Illness and risk
perception related
variables were major
determinants of quality
of life and distress.
Meulenkamp, T.M. et
al. 2008 How does children that
are mutation carriers
perceive their carrier 33 mutation carrier
children of either
LQTS, HCM or FH Qualitative Semi structured
audiotaped interviews
guided by Leventhals Positive future health
perceptions, but
feelings of

25
status and what are the
consequences they
experience concerning life
style modifications,
medication use and
worries modell of self-
regulation on
Illness perceptions, use
of medication, lifestyle
modifications, worries
and coping controllability varied,
worries about dying and
frustrations of being
different.

Andersen, J et al. 2008 To investigate the
psychosocial aspects of
living with LQTS 7 individuals who
had been tested for
Long Qt genetic
mutation Qualitative design In-depth interviews
with a semi-structured
interview guide on the
topics; living with risk,
family members, being
sick or not sick, and
healthcare services Main concern was for
their children’s health,
but experience of
worries and limitations
in their daily lives.

Giuffre, R.M. et al 2008 To compare children with
asthma to children with
Long QT syndrome in
terms of anxiety and
medical fears 7 children with Long
QT syndrome. 40
children with asthma
and their mothers Comparative design The Fear Survey
Schedule for Children-
Revised
The Revised Childrens
Manifest Anxiety Scale
The Achenbach Child
Behavior Checklist
The state-Trait Anxiety
Inventory Children with LQTS
had significantly more
internalizing problems,
and their mothers had
significantly more
anxiety.

Hendriks, K et. Al.
2008 To investigate the extent
and course of distress
caused by predictive
genetic testing 77 adult relatives of
LQTS index patients
in whome a causative
mutation was
detected and their Prospective design with
assessments 2 weeks
after consultation , and
2 weeks and 18 months Impact of event scale
Beck Depression
inventory Individuals who
received an uncertain
ECG seemed especially
vulnerable for distress.
In carriers and their

26
partners n= 57 after DNA disclosure partners disease-related
anxiety remained
elevated.
Ingles, J et al. 2008 To identify the
psychosocial factors that
impact on the emotional
well-being of those
attending a speciality
cardiac genetic clinic 109 participants
having a clinical
diagnosis of HCM Descriptive Demographics
Hospital Anxiety and
Depression Scale
A Patient Experience
Scale
Patient Satisfaction
Scales HCM patients who
attend specialized
cardiac genetic clinics
are better adjusted and
worry less, then those
who do not attend.
Anxiety was predicted
by adjustment to and
worry about HCM.
Depression was
predicted by adjustment
and location of patient
follow-up
Smets, E et al. 2008 How the quality of life of
carrier children compares
to the quality of life of
their peers
To what extent the
children’s health-related
quality of life and their
parents perception thereof
concurs 30 families with
familial
hypercholesterolemia,
hypertrophic
cardiomyopathy and
long QT syndrome,
comprising 35 carrier
children and 37
parents
Descriptive Socio-demographic
information
Children health-related
quality of life
(KIDSCREEN) There were no
differences found
between the children
and their peers.
Parents rated their
child’s psychological
wellbeing lower than
the child did.
Hoedemaekers, E et al.
2007 To investigate the
influence of two coping
styles (monitoring and
blunting) and perceived
control on emotional 114 adult family
members of index
patients with LQTS,
DCM, HCM or
ARVC offered Prospective design with
assessment after the
first consultation, after
test disclosure and 2
months after the test Pearlin’s Mastery List
The condition-specific
Health Locus of Less monitoring reflects
less emotional distress
before the outcome of
genetic testing, while a
stronger feeling of

27
distress in persons at risk
of hereditary heart disease genetic counseling disclosure Control (HLOC-) scale
Threatening Medical
Situations Inventory
(TMSI) mastery reflects less
emotional distress both
before and after DNA
test result.

Farnsworth, M et al.
2006 To describe the
experiences of parents
who have a child or
children with LQTS 31 parents Qualitative design A secondary analysis of
a phenomenological
study open-ended
questions about life
with LQTS, including
fear of death, quality of
life, education and
insurance Fear of their children
dying, different
strategies to manage
fear and frustrations
about lack of
knowledge of LQTS
among health care
providers
Hendriks, K et al. 2005
b To assess levels of
disease-related distress
and situational anxiety
and depression to find out
to what extent parents
were distressed 18 months
after having received a
DNA test result for LQTS
in their children 36 parents (17
parental couples an 2
single parents) who
had applied for
genetic testing of
their children Prospective design with
assessments 2 weeks
after consultation , and
2 weeks and 18 months
after DNA disclosure The Impact of Event
Scale (IES)
The Spielberger State
Anxiety Inventory
(STAI-s)
Beck Depression
Inventory (BDI) Parents of carriers
children reported more
distress, also over time.
High levels of distress
in prior assessment,
familiar with the
disease for a longer
time, experience of
sudden death in the
family, less educated
and unsatisfied with the
given information were
predictors.
Hendriks, K et al. 2005
a To assess the
psychological effect of
predictive testing in
parents of children
undergoing genetic 36 parents (17
parental couples an 2
single parents) who
were clinically
diagnosed LQTS Prospective design
assessments 2 weeks
after consultation , and
2 weeks after DNA The Impact of Event
Scale (IES)
The Spielberger State
Anxiety Inventory 50% of the parents of
carrier children showed
clinically relevant high
levels of distress.
Parents who were

28
testing of LQTS
The effect of carrier status
of the parent on parental
levels of distress
The effect of the
composition of test results
in a family on levels of
parental distress patients with a
mutation positive
result and partners disclosure (STAI-s)
Beck Depression
Inventory (BDI) familiar with the
disease for a longer
time, who had more
experience with the
disease, and received a
positive test result for
all their children were
most distressed.
Cox et al. 1997 To assess the health
related quality of life and
psychological wellbeing
of patients with
hypertrophic
cardiomyopathy, and to
correlate these with
symptoms, clinical, and
psychosocial factors. 137 hypertrophic
cardiomyopathy
patients Descriptive Short Form 36 Health
survey (SF-36)
Hospital Anxiety and
Depression Scale
(HADS)
Adjustment and worry
about Hypertrophic
cardiomyopathy
Patient satisfaction
Clinical data
HCM is associated with
with substantial
restrictions in Health
related quality of life.
Symptoms, adjustment,
and quality of
interaction with clinical
staff contribute to these
limitations.

29
4.1 Health status
The World Health Organization (WHO, 1948) defines health to be, not only absence
of disease, but a “state of complete physical, mental and social well-being”. There is
general consensus that health consists of these three aspects of well-being, however
there are big variations across studies as to how to define health, and most
investigators avoid the definitions and let the health domains speak for themselves
(Fayers & Machin, 2007).

The present study chose to include both physical and mental health domains as
measured by SF-36 Health Survey (Ware, Jr. & Gandek, 1998). This measure has been
used extensively in health research. In accordance with WHOs definition of health,
SF-36 measures not only health functioning but also well-being. Health functioning is
according to SF-36 literature, the extent to which health limits the patient in physical,
social and role activities. Perceived wellbeing is defined as frequency and intensity of
feeling states including general mental health, bodily pain and vitality. In addition,
patient perception of health in general is included in the health concept. Including
perceived general health may be a strength, given critical arguments of that health
status questionnaires mainly assess domains that are of clinical importance, but that
may not be the concern of the patient (Doward & McKenna, 2004). For example no
major differences were found in physical and mental health domains of children at risk
of inherited cardiac disorders compared to peers (Smets et al., 2008). However, other
research has found that children in this situation may feel a loss of control, worries
about dying, and frustrations of being different (Meulenkamp et al., 2008; Giuffre et
al., 2008; Meulenkamp et al., 2008), all of which most likely will affect the general
perception of health.

30
Previous research has shown that several clinical variables may affect health in
patients with familial cardiac disorders. With regard to the adult population clinically
affected with LQTS or HCM, health status has been measured quantitatively in HCM
patients (Christiaans et al., 2009b; Cox et al., 1997), and has been described
qualitatively in LQTS patients (Andersen et al., 2008). The results from these
investigations showed that HCM patients had major impairments in both physical and
mental health domains. LQTS patients experienced daily limitations such as having to
rest and not being able to work because of symptoms of fatigue, exhaustion,
palpitations and headaches (Andersen et al., 2008).

Health status has been strongly related to symptom patterns, although not consistently.
In one of the studies of HCM patients, both affected and unaffected patients were
included, comparing patient-reported outcomes in patients with clinical diagnosis and
patients at genetic risk for HCM in terms of predictors of physical health, mental
health and psychological distress (Christiaans et al., 2009b). The presence of a clinical
diagnosis or HCM related symptoms were strongly related to impaired physical health.
However, for both groups perceptions of risk and carrier-ship (perceived risk of
sudden cardiac death, or belief in serious consequences, or symptoms) greatly affected
physical and mental health as well as anxiety and depression levels. Thus there is a
need to further explore the health status in patients with familial cardiac disorders.

4.2 General anxiety and depression
General anxiety is most often associated with the emotion of fear, involving feelings
of tension, worry, apprehension, and dread for something perceived as threatening in
the future (Stein & Hollander, 2002), while depression is usually described as an
emotion of sadness, with feelings of sorrow, hopelessness, gloom, lack of energy and
adhedonia (Watson et al., 1995). Standard classification of mental disorders is

31
described and specified in the International Classification of Diseases ICD-10 (World
Health Organisation., 1992), or the Diagnostic and Statistical Manual of Mental
Disorders of the American Psychiatric Association (DSM-IV) (American Psychiatric
Association, 1987), which views anxiety and depression as discrete
psychopathological disorders. In contrast to this categorical approach, the dimensional
approach views symptoms of anxiety and depression as normal responses to demands
and threats measured on a continuum from absence to maximum intensity (Bjelland &
Dahl, 2008). In the present study the Hospital Anxiety and Depression scale dictates a
categorical approach (Zigmond & Snaith, 1983).

Addressing the psychological consequences of LQTS predictive testing in a
longitudinal study, general anxiety and depression levels were found to be close to that
of the normal population within 18 months after testing (Hendriks et al., 2008).
Depression levels were lower among those who were more satisfied with follow up,
thus HCM patients that attend follow up seem better adjusted and have less worry
(Cox et al., 1997; Ingles et al., 2008). How general anxiety and depression levels
compares to expected scores of the general population should be further investigated
in patients referred to genetic investigation and counseling for familial LQTS or
familial HCM. Further there is a need to investigate whether general anxiety and
depression differ between LQTS and HCM patient groups.
4.3 Heart-focused anxiety
In this study heart-focused anxiety is defined as the specific fear of cardiac-related
stimuli and sensation based on the perception that symptoms will be harmful, causing
i.e. serious arrhythmias or sudden cardiac death (Eifert et al., 2000a).

32
Responding to cardiac-related stimuli and sensations with cardio-protective avoidance,
heart-focused attention, and fear about heart sensations is associated with the presence
of heart-focused anxiety (Eifert, 2000a). The concept is identified as a psychological
process variable related to heightened anxiety levels (Eifert et al., 2000b). Heart-
focused anxiety was originally identified as a psychological problem closely related to
anxiety sensitivity and “cardiophobia” among patients without actual heart disease
(Eifert, 1992; Eifert & Forsyth, 1996a; Eifert et al., 1996b), but has also been shown to
be a relevant psychological variable to study in patients with actual heart-disease
(Hoyer et al., 2008). Based on that levels of anxiety increase among patients with
actual cardiac disease after receiving a diagnosis, and that physical healthy patients
can be as concerned as patients with a justifiable concern about heart disease, previous
findings indicate that heart-focused anxiety also may be an individual difference factor
(Eifert et al., 2000b; Eifert, 1992).
A conceptual and clinical review of heart-focused anxiety and chest pain suggest that
responding fearful to cardiac-related stimuli and sensations may be part of a vicious
circle that not only creates even higher levels of cardio-protective avoidance, heart-
focused attention, and fear about heart sensations, but also may contribute to greater
levels of perceived pain, disability, and future episodes of elevated anxiety or panic
(Eifert, 2000b). Therefore it is necessary to find out how symptoms of heart-focused
anxiety relate to general anxiety, depression and physical health in the present patient-
group.

Heart-focused anxiety may be explained by previous learning conditions relating to
separation issues and cardiac disease, psychological vulnerability, negative events, as
well as genetic and acquired biological vulnerability factors (Eifert, 1992).

LQTS patients participating in a qualitative study reported daily limitations and
anxiety because of their disorder (Andersen et al., 2008). Perceived symptoms or

33
family members worrying about them caused them to avoid certain activities.
Uncertainty, unresolved emotions and worries about other relatives at risk caused
anxiety (Andersen et al., 2008). A study showed that self-reported emotional stress are
related to cardiac events in LQTS patients, while positive emotions may be protective
for the arrhythmia risk (Lane et al., 2009), thus more knowledge of psychological
issues in affected individuals, is of utmost importance.

Although, general anxiety and depression levels seem to subside over time, disease-
related anxiety has been reported to remain high over time (Hendriks et al., 2008).
What factors influence heart-focused anxiety over time needs to be explored.

4.4 Self-efficacy expectations
Defined by Bandura, self-efficacy is the individual’s capabilities to exercise control
over events that affects his or her life (Bandura, 1977). Efficacy expectations and
outcome expectations are important components of self-efficacy. Efficacy expectations
pertain to a person’s beliefs about his or hers ability to perform the behavior that will
produce an expected outcome, while outcome expectations pertain to believing in that
a certain behavior will produce a specific outcome. Self-efficacy is strongly related to
stress, coping and health and may determine whether specific health behaviors are
initiated and maintained. The amount of stress and depression in individuals when
facing a health threat is determined by their own beliefs about their coping abilities
(Siela & Wieseke, 2000). Self-efficacy can be general or domain specific. In the
present study self-efficacy is defined as the individual’s beliefs or expectations in
coping with cognitive, emotional, and behavioral aspects in relation to the genetic
counseling. A feeling of less personal control have previously been shown to predict
higher level of distress both before and after genetic testing in persons at risk for

34
different familial cardiac disorders (Long QT syndrome, Hypertrophic
cardiomyopathy, Dilated cardiomyopathy or Arrhythmogenic right ventricle
cardiomyopthy)(Hoedemaekers et al., 2007). Therefore, the role of patients’ self-
efficacy expectations should be further explored.

4.5 Satisfaction with genetic counseling
Patient satisfaction is a significant issue in evaluating medical care (Shiloh et al.,
1990). In the genetic counseling setting it has been emphasized that there is a need to
assess satisfaction, in order to develop and improve counseling services for the
patients (Demarco et al., 2004). Typically, patient satisfaction comprises several
aspects, such as instrumental, affective and procedural satisfaction. The present study
defines satisfaction with genetic counseling as the patient satisfaction with the
counselors’ skills of providing medical information (instrumental satisfaction), ability
to provide psychological support (affective satisfaction), and to satisfaction with the
situational factors of logistics and practical matters (procedural satisfaction)(Shiloh et
al., 1990).

Genetic counseling has previously been valued positively among predictively tested
HCM mutation carriers (Christiaans et al., 2009a), and satisfaction with time spent in
the clinic, and satisfaction with communication in the clinic has been related to lower
levels of depression among patients with HCM. However the role of satisfaction with
genetic counseling in relation to patients’ anxiety is to our knowledge not studied in
the present patient groups.

35
4.6 State of the art (summary)
Previous research and clinical experience have identified health- related and
psychological vulnerabilities in patients with a clinical diagnosis of LQTS or HCM, as
well as in individuals at genetic risk of LQTS or HCM (Aatre & Day, 2011). However,
there is still a need for better understanding of the effect of the conditions themselves
in terms of self-reported health status, as well as a need to explore some of the
psychological effects (general anxiety and depression) of living with this health threat,
and further to find out how these patient-reported outcomes are influenced by other
factors. There is also a need to identify emotional reactions related to living with the
risk of serious arrhythmias and sudden cardiac death. Heart-focused anxiety may be a
particular concern for this population. Although several studies have reported cardiac
symptoms to be strongly related to emotional distress, none have focused on that
living with fear of cardiac symptoms may increase general anxiety and influence the
health in individuals who are living with the risk of serious arrhythmias and sudden
cardiac death. The previous literature has identified factors such as perceived control
and satisfaction with genetic counseling as important variables in relation to distress
among these patients. To our knowledge no studies exist on what factors predispose or
may be important for the prognosis of heart-focused anxiety in individuals with
familial LQTS or familial HCM who receives genetic investigation and counseling.

36
5. Aims
5.1 Overall aim
The overall aim of this study was to obtain more knowledge about the health status,
levels of general anxiety and depression, and symptoms of heart-focused anxiety in
individuals living with the risk of serious arrhythmias and sudden cardiac death,
receiving genetic investigation and counseling because of familial LQTS or familial
HCM. Figure 5.1 shows investigated variables and proposed relationships.
5.2 Specific aims
The aims of the various papers comprising this study are:
Paper I Baseline
1. To examine if there is a relationship between living with genetic risk of
inherited arrhythmia and health status vulnerability.
2. To explore relationship between socio-demographic variables, clinical status
and health status domains among the patients coming to genetic counseling.

Paper II Baseline
3. To investigate these patients’ level of general anxiety, depression and physical
health and compare the scores to expected scores of the general population.
4. To investigate the scores of general anxiety, depression, physical health, and
heart-focused anxiety (avoidance, attention, fear) in patients referred because of
familial LQTS as compared to the scores of patients referred because of familial
HCM.

37
5. To assess the role of heart-focused anxiety (avoidance, attention and fear
symptoms) in relation to general anxiety, depression, and physical health.

Paper III Follow-up
6. To assess heart-focused anxiety in patients with a clinical diagnosis of LQTS or
HCM as compared to patients at genetic risk of LQTS or HCM, measured by
the levels of cardio-protective avoidance , heart-focused attention , and fear
about heart sensations.
7. To investigate the independent influence on heart-focused anxiety by the
following putative predisposing factors; sudden cardiac death in close relatives,
a recent cardiac death of a relative; patient knowing whether other relatives
previously have undergone genetic testing; and by factors of possible
prognostic importance; perceived general health, self-efficacy expectations; and
satisfaction with genetic counseling (affective, instrumental, procedural
aspects); while controlling for effects of questionnaire time points, patient
gender, a clinical diagnosis of LQTS or HCM, and the result of genetic testing.

38
Figure 5.1 Model showing investigated relationships of the patient-reported outcomes,
socio-demographic variables and clinical variables of patients referred to genetic
counseling because of familial LQTS or familial HCM, and the comparisons made
between the scores of the study group, expected scores, or norms of the general
population.

39
6. Methods
6.1 Study Designs
In order to respond to the aims of the study, the following designs were applied in this
multi-centre study:
/g120 A cross-sectional design was used to investigate socio-demographic factors
related to health status domains (Paper I), and to explore if three distinct
symptoms of heart-focused anxiety (cardio-protective avoidance, heart-focused
attention and fear about heart sensations) would be related to levels of general
anxiety, depression, and physical health (Paper II).
/g120 A comparative design was used to compare SF-36 health status scores of
patients with familial LQTS or familial HCM (i.e. total sample of patients with
familial LQTS or familial HCM; patients at genetic risk of LQTS or genetic
risk of HCM; patients with a diagnosis of LQTS; patients with a diagnosis
HCM) to that of expected scores of the Norwegian general population, and to
compare scores according to clinical status (patients at genetic risk of LQTS or
at genetic risk of HCM; diagnosis of LQTS; diagnosis of HCM) (Paper I), to
compare general anxiety and depression scores to expected scores of
Norwegian general population, and physical health to US SF-36 norms, and to
compare general anxiety, depression, physical health, and heart-focused anxiety
according to familial disorder (LQTS or HCM)(Paper II), and to compare levels
of cardio-protective avoidance, heart-focused attention and fear about heart
sensations in patients at genetic risk of LQTS or genetic risk of HCM as
compared to patients with a diagnosis of LQTS or diagnosis of HCM (Paper
III).
/g120 A prospective design with measurement 2 weeks before genetic counseling, and
at three time points after the genetic counseling (4 weeks, 6 months and 1 year

40
after counseling) was used to explore relationships between possible predictors
as measured before, right after genetic counseling and 6 months after genetic
counseling) and the course and outcome of cardio-protective avoidance, heart-
focused attention and fear about heart sensations (Paper III).
6.2 Sample
The study comprised three samples; a consecutive sample consisting of patients who
was referred or self-referred for genetic investigation and counseling because of either
familial LQTS or familial HCM, and two reference populations that were used to
calculate expected scores of the Norwegian general population. In addition SF-36 US
norms were used.
Patients
The patients were family members and other appropriate relatives subsequently
following the identification of a LQTS or HCM- causative mutation in an index case
or individuals in whom a cardiologist had established or suspected a clinical diagnosis
of LQTS or HCM. Patients were over 17 years of age, not previously genetic tested for
a familial cardiac disorder, and were consecutively referred or self-referred to genetic
counseling at the medical genetic departments in Trondheim, Bergen and Oslo. One
hundred and seventy three patients were consecutively asked to participate in the
study. A total of 127 patients returned the first questionnaire (one patient was excluded
from this number in paper II and III because of not answering relevant questions in
questionnaire), which corresponds to a response rate of 73.4% (T1). Patients dropped
out during follow-up. Immediately after genetic counseling (T3) 122 patients filled in
the questionnaire, after four weeks (T4) 85 patients responded, after 6 months (T5) 65
patients responded, and finally the 1-year follow up (T6) comprised 68 patients. The
explanation for how the number of patients can increase from one point to the next (as
from T5 to T6) is that some participants were non-responders at T5, but responded at
T6. An overview of the number of participants and patient-reported outcome measures

41
at the various assessment times is given in figure 6.1. The characteristics of the
patients who did and did not complete the one year follow-up questionnaire at T6 did
not differ significantly for any of the variables.

Reference populations
The reference populations were based on ;
1) Normative data from the general Norwegian population. SF-36 expected scores
were calculated based on the data from the Short Form 36 (SF-36) health survey (Loge
& Kaasa, 1998). From the 3500 questionnaires sent out, a total of 2323 (67%)
Norwegian individuals aged 19-80 filled in and returned the questionnaire. Expected
scores of the general population were calculated based on age and gender of the
patients .

2) Expected scores of general anxiety and depression were calculated based on
normative data from the HUNT 2 study (Holmen et al., 2003). A total of 54867
subjects aged /g14920 years with complete data on Hospital Anxiety and Depression scale
(HADS), smoking and education variables, and without self- reported previous
cardiovascular disease was included in the reference population that formed the basis
of the regression formula. Expected scores were calculated based on age, gender,
educational level and smoking habits.

3) US physical health norms according to SF-36 norm-based scoring were used, when
comparing the physical health scores in the study with a general population (Ware,
2001).

42
6.3 Procedure
Ethical approval was obtained from the Regional Committee for Medical Research
Ethics in Western Norway in September 2004. Data was collected as part of a
prospective study on the psychosocial implications of diagnosis and counseling in
hereditary diseases. Information about the study was mailed to the patient together
with a consent form and the first questionnaire. The participants received one
reminder. Participants completed measures of health status, general anxiety,
depression, heart-focused anxiety, self-efficacy expectations, and satisfaction with
genetic counseling. Questionnaires were collected 2-4 weeks prior to the genetic
counseling (T1) and 4 weeks (T4), 6 months (T5) and one year after genetic
counseling (T6). The participants also received a questionnaire immediately prior to
(T2) and after the genetic counseling session (T3).

43
Figure 6.1 An overview of the patient-reported outcome measures and number of
participants at various assessment times

44
6.4 The patient-reported outcome measures
Data on health status domains, general anxiety and depression, heart- focused anxiety,
self-efficacy expectations, and satisfaction with genetic counseling were obtained from
patient-reported outcome measures. An explanation of the various patient reported
outcome measures is provided in table 6.1.
6.4.1 Short Form-36 Health Survey (SF-36)
SF-36 is a self-report questionnaire that measures health status (0 = worst health state.
100 = best health state) on eight sub-scales measuring physical domains (physical
functioning, role limitation-physical, bodily pain, general health), and mental domains
(vitality, social functioning, role limitation-emotional, mental health) (Ware &
Kosinki, 2001). An additional point reports changes in health over the last year. The
physical domains form the basis to calculate a physical component summary (PCS)
and the mental domains may be calculated into a mental component summary (MCS).
The questionnaire is generic and multidimensional and it is suitable for administration
to large populations and to subgroups such as patients. Its purpose is to be a measure
of health status or health outcome in cross-sectional and longitudinal studies
(Hutchinson et al., 1997).

SF-36 was chosen to be the health status measure to be translated in The International
Quality of Life Assessment (IQOLA) Project, where the goal was to develop and
validate translations of the health status measure for use in multinational clinical trials
and other international studies of health (WareJr. & Gandek, 1998). The Norwegian
translation of the acute version was used in the present study with a 1-week recall
period (Ware et al., 2001).

45
6.4.2 The Hospital Anxiety and Depression Scale (HADS)
The HADS measures symptoms of anxiety and depression on two subscales; HADS-
depression (7 items), and HADS-anxiety (7 items) (Zigmond & Snaith, 1983), and has
been developed not to be influenced by physical symptoms. A higher score means a
higher level of anxiety or depression (scores ranging from 0-21). It is well suited as a
screening tool for anxiety and depression, also in patients suffering inherited heart
diseases, with a cutoff score of 8 to detect cases (Poole & Morgan, 2006). A
Norwegian translation was available.

6.4.3 The Cardiac Anxiety Questionnaire (CAQ)
The CAQ consists of 18 items in three subscales pertaining to a) avoidance of
activities believed to elicit cardiac symptoms (avoidance) b) heart-focused attention
and monitoring of cardiac activity (attention) and, c) fear and worry about chest and
heart sensations and functioning (fear) (Eifert et al., 2000a). Each item is rated on a 5–
point likert scale; indicating how frequently the behavior or symptoms typically
occurs, ranging from 0 = never to 4 = always. The questionnaire was translated to
Norwegian by a professional translator with forward and backward translation
procedure. Subscales, item text, item number and interpretations of the subscales is
found in paper III, box 1.

6.4.4 The Bergen Genetic Counseling Self-efficacy Scale (BGCSES)
The BGCSES measures self-efficacy expectations related to genetic counseling. The
scale comprises of 21 items describing tasks and challenges that are likely to occur
during and after genetic counseling, and the individual’s beliefs that he or she will be
able to cope with these. Each item was rated on a scale from 0-10 (0=cannot do at all,

46
10 = can do without difficulty). The average total sum score of the scale was used. The
BGCSES has been developed using the guidelines of Bandura for constructing Self-
efficacy Scales (revised 2001) Albert Bandura, Stanford University, Palo Alto, CA,
USA, by a panel of medical geneticists, genetic counselors, and psychologists and has
been used in related studies (Bjorvatn et al., 2008; Bjorvatn et al., 2009).
6.4.5 Satisfaction with Genetic Counseling
The patient’s satisfaction with the genetic counseling was filled in immediately after
the genetic counseling session. The scale is a 9-item measure which has three
subscales measuring instrumental, affective and procedural satisfaction (range 3-12)
(Shiloh et al., 1990). Higher scores indicate greater satisfaction. A Norwegian
translation was available.
6.5 Socio-demographic and clinical variables
The socio-demographic variables were age, gender, marital status, number of
biological children, employment and education status, and referral by physician/self-
referral through family member. The socio-demographic variables were collected from
the baseline questionnaire (T1), together with self-constructed questions regarding
family history of sudden cardiac death, and if the patients knew whether other relatives
had previously undergone genetic testing (yes, no, uncertain). The rest of the clinical
variables (having a clinical diagnosis of LQTS, having a clinical diagnosis of HCM,
and number of patients detected to be mutation carriers) were collected from the
patients’ medical record.

47
Table 6.1 Explanation of the patient reported outcome measures; Questionnaire, including subscales, summary of contents, number of items, range and total
range
Questionnaire Subscale Summary of contents Items Range Total range
SF-36 Physical
health Physical
functioning Extent to which health limits physical activities such as self-care, walking,
climbing stairs, bending, lifting, and moderate vigorous exercises 10 1-3 0-100
(transformed)
Role physical
Extent to which physical health interferes with work or other daily activities,
including accomplishing less than wanted, limitations in the kind of activities,
or difficulty in performing activities 4 1-2
Bodily pain Intensity of pain an effect of pain on normal work, both inside and outside the
home 2 1-6
General health Personal evaluation of health, including current health, health outlook, and
resistance to illness 5 1-5
Mental
health Vitality Feeling energetic and full of pep versus feeling tired and worn out 4 1-6
Social
functioning Extent to which physical health or emotional problems interfere with normal
social activities 2 1-5
Role emotional Extent to which emotional problems interfere with work or daily activities,
including decreased time spent on activities, accomplishing less, and not
working as carefully as usual 3 1-2
Mental health General mental health, including depression, anxiety, behavioural-emotional
control, general positive affect 5 1-6
Health
transition Evaluation of current health compared to one year ago 1 1-5
Total 36

48
HADS Anxiety Restlessness and worry, as in generalized anxiety disorder, plus one item on
panic attacks 7 0-3 0-21
Depression Reduced pleasure response, in addition to psychomotor retardation and
depressed mood 7 0-3
Total 14
CAQ Avoidance Avoidance of activities believed to elicit cardiac symptoms 5 0-4 0-4
Attention Heart-focused attention and monitoring of cardiac activity 5 0-4
Fear Fear and worry about chest and heart sensations and functioning 8 0-4
Total 18
BGCSES Self-efficacy beliefs related to the ability to process and recall the information
given, to maintaining emotional control, and related to the consequences of
the counselling session 21 0-10 0-10
SCS Instrumental The extent to which the respondent evaluates that the counsellor has the
required skills, and gives the required treatment and reassurance 3 1-4 3-12
Affective Evaluation of the counsellors behaviour toward the patients as a person rather
than a case devoting time, showing interest and devotion 3 1-4
Procedural Satisfaction with the administrative procedures like waiting time, bureaucratic
arrangements, and conduct of administrative staff 3 1-4

SF-36 = Short Form 36, HADS = Hospital Anxiety and Depression scale, CAQ = Cardiac Anxiety and Depression scale, BGCSES = The B ergen genetic
counselling self-efficacy scale, SCS = Satisfaction with Genetic Counselling Scale

49
6.6 Statistical methods
The statistical analyses was performed with SPSS version 15 (Paper I), and 18 (Paper
II and III) (SPSS Inc., Chicago, IL, USA). Statistical significance was assessed with
two-sided P < 0.05. Depending on the research questions and the variables different
types of statistical methodology were used.

Descriptive statistics
Descriptive analyses have been used in all papers to describe the sample based on
mean values, standard deviations or standard error of mean, and ranges. SF-36
expected scores for each of the respondents were calculated for all health status
domains based on the normative data from the Norwegian population register (Loge &
Kaasa, 1998), controlling for age and sex (Paper I). Expected values for HADS were
based on Norwegian reference population data (Holmen et al., 2003), with formula
controlling for age, sex, educational level and smoking habits (Paper II). Preliminary
analyses were conducted to assess missing data, normality, and checking for outliers.
Cronbach’s alpha was computed to determine the internal consistency reliability for
all questionnaires applied in the study.

Statistical techniques to compare groups
The unpaired t–test was used to compare mean values,, the chi-square test for
proportions, and the Mann-Whitney U test for median values between independent
groups. The paired t-test was used to compare means with repeated measures and to
compare mean values to expected scores . One-way analysis of variance (ANOVA) with
post hoc comparisons was used to test differences in the mean scores between three
groups.

50
Statistical techniques to explore relationships among variables
Spearman rank correlation was used to explore correlations between the variables.
Multiple linear regression analyses were used to explore relationship between socio-
demographic, clinical status and health status domains. Hierarchical regression
analyses were used to assess the role of heart-focused anxiety (avoidance, attention
and fear symptoms) in relation to general anxiety, depression and physical health,
beyond relevant covariates. Mixed linear modelling (MLM) was used to investigate the
independent influence on heart-focused anxiety by the following putative predisposing
factors; sudden cardiac death in close relatives, a recent cardiac death of a relative;
patient knowing whether other relatives previously have undergone genetic testing;
and by factors of possible prognostic importance; perceived general health, self-
efficacy expectations; and satisfaction with genetic counseling (affective, instrumental,
procedural aspects); while controlling for effects of questionnaire time points, patient
gender, a clinical diagnosis of LQTS or HCM, and the result of genetic testing.
All predictors were entered into MLMs to assess both their main effects and their
possible interaction with time.
6.7 Ethical considerations
The present study has followed the ethical guidelines of the Declaration of Helsinki
(World Medical Association 1983. Approval from the Regional Committee for
Medical Research Ethics, Western Norway was obtained 01.09.04 (REK VEST #
128.04). In addition, the study was approved by the Norwegian Social Science Data
Services (# 11289).

Three primary ethical principles for protecting study participants are beneficence,
respect for human dignity, and justice (Polit & Beck, 2008). To protect the study
participants’ rights, procedures were followed to ensure that the individuals were

51
guaranteed anonymity and the right to withdraw from the study at any time. The
participants were provided with a letter with information needed to make a reasoned
decision about participation in the study, and additionally a consent form had to be
actively returned together with the first questionnaire. In a risk/benefit assessment it
was concluded that there was no high risk that participation in the study should lead to
any physical or psychological harm. However, the study provided possibility to refer
patients to a psychologist specialist if that was deemed necessary. The study
conformed to that patients have the right to fair treatment, and in accordance with the
biotechnology act that states that patients undergoing predictive genetic testing should
be provided with genetic counseling (Act of biotechnology in human medicine, 2003,
appendix), all patients were given the same intervention if they participated in the
study or not.

52
7. Results
A summary of the individual papers I-III with main results are presented in the
following chapters.
7.1 Sample characteristics
Socio-demographic and clinical variables of the sample are shown in Table 7.1. The
mean age was 45 years (range: 17-83), most were married or cohabitating (77.2 %),
had children (78.0 %), and were employed (67.7 %). Few had a clinical diagnosis of
LQTS (9.4%) or HCM (15.7 %). Approximately half of the sample (44.9 %) reported
that there had been a sudden cardiac death in a relative. More than half of the patients
(60.6%) knew that other relatives previously had undergone genetic testing. One
hundred and thirteen patients (89.0 %) were offered and consented to genetic testing.
The result of genetic testing in the current sample showed that a mutation was detected
in 44 individuals (34.6 %). Descriptive information of the patient-reported outcomes
are presented in table 7.2.

53
Table 7.1 Socio-demographic variables and clinical variables of 127 individuals with familial Long QT syndrome or familial hype rtrophic cardiomyopathy
who received genetic investigation and counseling in Norway in the years 2005-2007
Variable Total
n =127%
100Familial LQTS
n =88%
100Familial HCM
n =39%
100p-value
Sex
Female
Male
68
59
53.5
46.5
54
34
61.4
38.6
14
25
35.9
64.10.012a
Age Groups
29 or less:
30-39:
40-49:
50-59:
60-69:
70 or more:
26
20
31
27
11
12
20.5
15.7
24.4
21.3
8.7
9.4
22
14
21
20
4
7
25.0
15.9
23.9
22.7
4.5
8.0
4
6
10
7
7
5
10.3
15.4
25.6
17.9
17.9
12.80.025b
Marital status
Married/cohabitant
Single
Divorced/separated
98
17
7
77.2
13.4
5.5
70
11
4
79.5
12.5
4.5
28
6
3
71.8
15.4
7.7 0.590a

54
Widow/widower
Missing 4
13.1
0.82
12.3
1.12 5.1
Children
Have children
Missing
99
2
78.0
1.6
65
2
73.9
2.3
34
87.20.161a
Employment
Missing 86
167.7
0.861
169.3
1.125 64.1 0.538a
Education status
Primary school
High school
College/university
Missing
26
64
37
20.5
50.4
29.1
21
42
25
23.9
47.7
28.4
5
22
12
12.8
56.4
30.80.417a

Sudden cardiac death occurred in family
Sudden Death
Missing
57
25
44.9
19.7
39
13
44.3
14.8
18
12
46.2
30.80.259a
Patients knowing whether other relatives
previously had undergone genetic testing
Missing
77
14
60.6
11.0
64
11
72.7
12.5
13
3
33.3
7.7/g310.001a

55
Referral
By physician
Self referred through family
Missing
35
90
2
27.6
70.9
1.6
15
71
2
17.0
80.7
2.3
20
19
51.3
48.7/g310.001a
Clinical Status
Clinical diagnosis of LQTS or HCM
Diagnosis of both LQTS and HCM
No diagnosis
31
1
95
24.4
0.8
74.8
12

76
9.4

86.4
19
1
19
15.0
0.8
48.7/g310.001a

Type of genetic test offered
Predictive
Diagnostic
Missing
82
31
14
64.6
24.4
11
68
13
7
77.3
14.8
8.0
14
18
7
35.9
46.2
17.9/g310.001a
Result of genetic investigation
Mutation positive result
Mutation negative result
Missing

44
69
14
34.6
54.3
11.0
36
45
7
40.9
51.1
8.0
8
24
7
20.5
61.5
17.90.086 a
aExact two sided chi-square test, bWilcoxon-Mann-Whitney test.

Table 7.2 Descriptive information of the patient- reported outcomes
Questionnaires Time
point N Mean SD SEM Min/max Cron-
bach’s
alpha
Short Form 36 (SF-36)
Physical functioning T1 122 88.18 16.35 1.48 28.57-100.00 0.87
Role physical T1 126 78.24 35.54 3.17 0.00-100.00 0.89
Bodily pain T1 127 78.34 25.91 2.30 0.00-100.00 0.92
General health T1 126 69.54 20.54 1.83 0.00-97.00 0.71
Vitality T1 127 55.73 24.80 2.20 0.00-100.00 0.91
Social functioning T1 127 83.37 22.88 2.03 0.00-100.00 0.88
Role emotional T1 124 77.82 36.85 3.31 0.00-100.00 0.87
Mental health T1 127 76.30 19.47 1.73 4.00-100.00 0.90
PCS T1 120 50.55 8.61 0.79 24.87-64.28 0.88
MCS T1 120 48.93 11.63 1.06 6.41-63.44 0.94
Hospital Anxiety and
Depression Scale
(HADS)
General anxiety T1 125 4.90 4.00 0.36 0.00-18.00 0.83
Depression T1 125 3.11 3.72 0.33 0.00-17.00 0.87
The Cardiac Anxiety
Questionaire (CAQ)
Avoidance T1 125 0.93 0.82 0.07 0.00-3.30 0.88
T4 79 0.88 0.88 0.10 0.00-3.20 0.92
T5 64 1.01 0.95 0.12 0.00-3.20 0.91
T6 67 0.96 0.89 0.11 0.00-2.98 0.92
Attention T1 126 0.76 0.68 0.06 0.00-2.80 0.79
T4 79 0.75 0.71 0.08 0.00-3.40 0.66
T5 64 0.72 0.60 0.08 0.00-2.80 0.80
T6 67 0.73 0.67 0.08 0.00-2.80 0.82

57
Fear T1 125 1.19 0.79 0.07 0.00-3.50 0.84
T4 79 1.21 0.74 0.08 0.25-3.88 0.86
T5 64 1.23 0.74 0.09 0.00-3.63 0.84
T6 67 1.18 0.78 0.10 0.00-3.75 0.87
Self-efficacy
expectations (BGCSES) T1 121 8.27 1.90 0.17 0.44-10.00 0.96
Satisfaction with
Genetic Counseling
(SCS)
Instrumental (range:3-12) T1 113 10.61 1.51 0.14 5.00-12.00 0.67
Affective(range:3-12) T1 112 11.58 1.04 0.10 5.00-12.00 0.81
Procedural (range:3-12) T1 108 11.00 1.37 0.13 6.00-12.00 0.62

58
7.2 Health status in patients at risk of inherited arrhythmias
and sudden unexpected death compared to the general
population (Paper I)

When investigating health status domains, the results indicated that the total sample
(N =127) differed from the general population scores by perceiving their general
health to be poorer (controlled for age and gender). When comparing the individual
subgroups (genetic risk of LQTS or HCM, diagnosis of LQTS, diagnosis of HCM) to
expected general population scores, the patients at genetic risk and patients with a
clinical diagnosis of HCM had lower general health scores. In addition the latter
group had poorer perceived health related to physical functioning, role physical,
vitality and role emotional domains. Comparing the subgroups to each other further
supported that patients with a clinical diagnosis of HCM were the most vulnerable
group in physical health domains. In general, employment, higher education and
being referred to genetic counseling through a family member were associated with
better scores on the health status domains.
7.3 General anxiety, depression and physical health in
relation to symptoms of heart-focused anxiety- a cross
sectional study among patients living with the risk of
serious arrhythmias and sudden cardiac death (Paper II)

Assessing general anxiety and depression showed that 24.6 % of the patients had
scores above cut-off for anxiety and 13.5 % for depression. Overall the patients
included in the study (n = 126) reported significantly higher levels of general anxiety
compared to expected scores of the general population, but there were no significant
differences in depression levels. There were also no significant differences between
having a diagnosis of LQTS or HCM, and being at genetic risk of LQTS or HCM,

59
with regards to levels of general anxiety and depression. Moreover, physical health
did not differ significantly from expected scores. However, the subgroup of patients
with clinical diagnosis of LQTS or HCM (n = 31) showed poorer physical health as
compared to expected scores, whereas patients at genetic risk (n = 89) scored better
on physical health as compared to expected scores.

When comparing the patients with familial LQTS to patients with familial HCM,
there were no significant differences with regard to the level of general anxiety and
depression, whereas poorer physical health and higher scores of heart-focused anxiety
(avoidance, attention, fear) were found in the latter group.

When investigating the role of heart-focused anxiety (cardio-protective avoidance,
heart-focused attention and fear about heart sensations), the following was found;
higher avoidance and fear scores were independently related to higher scores of
general anxiety, depression, and lower scores of physical health beyond relevant
covariates (age, gender, having children, diagnosis of LQTS or HCM, and recent
cardiac death in the family). A recent cardiac death in the family made a significant
contribution to the final models predicting higher levels of general anxiety and
depression.

60
7.4 Predictors of heart-focused anxiety in patients
undergoing genetic investigation and counseling of Long
QT syndrome or Hypertrophic cardiomyopathy: A one year
follow-up (Paper III)

Investigating heart-focused anxiety over a time period of up to one year showed that
scores for avoidance, attention and fear were overall higher in patients with a clinical
diagnosis of LQTS or HCM as compared to patients at genetic risk. With exception,
at four weeks after genetic counseling (T4) avoidance and fear scores were not
significantly different across groups and at six months after genetic counseling (T5)
there was no significant difference in attention scores.

Results from mixed linear modelling showed that predisposing factors of heart-
focused anxiety were a close relative’s sudden cardiac death (predicting higher
attention and fear levels), uncertainty whether other relatives previously had
undergone genetic testing (predicting higher levels of attention). Factors of
prognostic importance for heart-focused anxiety were poorer perceived general health
(predicting higher avoidance, attention, and fear levels), higher levels of self-efficacy
expectations (predicting lower fear levels) and procedural satisfaction with genetic
counseling (predicting lower levels of avoidance and attention). In addition female
gender predicted higher levels of fear and receiving a mutation positive test result
predicted a higher avoidance level at 6 months after genetic counseling (T5).

61
8. Discussion
8.1 Summary of findings
The overall aim of this study was to obtain more knowledge about the health status,
levels of general anxiety and depression, and symptoms of heart-focused anxiety in
individuals receiving genetic investigation and counseling because of familial LQTS
or HCM. This study is the first in Norway investigating, by means of validated and
standardized patient-reported outcome measures, the health status, levels of general
anxiety and depression levels in the patients receiving genetic counseling for LQTS
or HCM. To the best of our knowledge it is also the very first to investigate the role
of heart-focused anxiety in relation to general anxiety, depression and physical
health, and exploring prospectively predictors of heart-focused anxiety among these
individuals who are living with the risk of serious arrhythmias and sudden cardiac
death.

Compared to expected scores of the general population the total group of patients had
poorer general health and higher levels of general anxiety. Patients with a clinical
diagnosis of HCM were especially vulnerable in both physical and mental health
domains. There were no significant differences between groups (patients at genetic
risk vs. patients with diagnosis; familial LQTS vs. familial HCM) in terms of levels
of general anxiety and depression. Especially two distinct symptoms of heart-focused
anxiety were related to general anxiety, depression and physical health, namely
avoidance and fear. By assessing heart-focused anxiety in patients with a clinical
diagnosis as compared to patients at genetic risk, it was found that patients with a
clinical diagnosis overall had significantly higher scores of avoidance, attention and
fear. However, predisposing factors for heart-focused anxiety over time were a close

62
relative’s sudden cardiac death and uncertainty whether other relatives previously had
undergone genetic testing. Other variables of prognostic significance for heart-
focused anxiety over time were perceived general health, self-efficacy expectations
and procedural satisfaction with genetic counseling.

The following sections will consider some methodological issues and discuss the
main findings of the study.
8.2 Methodological issues

The present study has several strengths such as the one-year follow up time, the
inclusion of consecutive patients at three University hospitals in Norway within a
specified time period, and the use of standardized and validated patient-reported
outcome measures. However, there are also some weaknesses that need to be
addressed pertaining to the study designs, sample and patient-reported outcomes. The
strength and weaknesses will be discussed further in the following sections.
8.2.1 Study Designs
In order to reach the specific aims of the study several non-experimental designs were
implemented; a cross-sectional design, a comparative design, and a prospective
design.

The cross-sectional design
A cross-sectional design was included as the first step in the present prospective
study, thus the socio-demographic, clinical variables, and patient-reported outcomes

63
were defined at baseline. Strengths of cross-sectional designs pertain to that they are
fast, inexpensive and there is no loss to follow-up (Hulley et al., 2007). For
descriptive purposes a cross-sectional design is adequate and the design can reveal
cross-sectional associations, however a limitation of the design was that it gave only a
snap-shot picture of the patient’s health status, general anxiety, and depression levels
as they were 2-4 weeks before the genetic counseling session (paper I and II).
Limitations in drawing conclusions about causality and direction of relationships
between the independent and dependent variables therefore exist.

The comparative design
The comparison of health status, general anxiety, and depression scores in the sample
with expected scores of the general population was a clear strength of the study, since
assessing symptoms based on cut-off points may have little clinical significance,
when a context for understanding the findings is not provided (Polit & Beck, 2008).
Confounding variables may be a weakness in a comparative design. The comparison
between health status in the samples and expected scores of the general population
were controlled for age and gender, and the comparison of general anxiety and
depression to expected scores of the general population were controlled for age,
gender, education level, and smoking habits. These variables were therefore
eliminated as confounding variables. In comparing the different groups the influences
of confounding variables were not controlled for, thus these results must be
interpreted with extra caution.

The prospective design
We were fortunate to have the possibility to follow-up patients up to one year after
genetic counseling. Prospective designs are used for assessing incidence, and are well
suited for investigating potential causes for a condition or an outcome (Hulley et al.,

64
2007). Thus, it was well suited for investigating predictors of heart-focused anxiety.
There are several strengths of using a prospective design. First of all it establishes the
time sequence of the variables. Second it prevents predictors from being influenced
by the outcome itself, and finally measuring variables prospectively will give a more
accurate and complete result, as compared to measuring variables retrospectively.
This was especially important in the present study, as predictors such as perceived
general health, self-efficacy expectations, and satisfaction may be difficult for the
patient to remember after some time. The general weaknesses of the design pertain to
the challenges of making causal inferences and controlling confounding variables
(Polit & Beck, 2008). In addition the design is time-consuming, costly, and
inefficient in studying rare outcomes. However, the design may be appropriate
studying an outcome such as heart-focused anxiety among patients that are living
with the risk of serious arrhythmias and sudden cardiac death, as compared to
studying heart-focused anxiety in for example a normal population.

8.2.2 Sample
Choosing the study subjects
To ensure that the findings in a study accurately represent the population in interest,
the selection of study subjects is very important (Hulley et al., 2007). At the time
when this study was initiated clinical genetic investigation of familial cardiac
disorders had just started in Norway. To obtain more knowledge about the patients,
the aim of the study was to investigate the health status, levels of general anxiety and
depression, and symptoms of heart-focused anxiety in individuals that were
undergoing genetic investigation and counseling for LQTS or HCM. The patients
were family members and other appropriate relatives subsequently following the
identification of a LQTS or HCM- causative mutation in an index case or individuals
in whom a cardiologist had established or suspected a clinical diagnosis of LQTS or

65
HCM. This heterogeneous study sample was chosen based on expectations that the
entities by themselves would not produce big enough sample sizes, thus a pragmatic
approach was needed. A pragmatic approach could be justified partly because, the
two entities, LQTS and HCM share a lot of common features, especially with regard
to the risk of arrhythmia, syncope, and sudden cardiac death, and how they are
managed in the genetic counseling setting, and partly because both patients with a
clinical diagnosis as well as their relatives at genetic risk may manifest serious
symptoms. We therefore investigated a sample of patients fulfilling the inclusion
criteria in their natural contact with the genetic outpatient clinic. Every accessible
person who met the entry criteria in three different regional tertiary hospitals was
consecutively included to minimize volunteerism and other selection biases (Hulley
et al., 2007).

Number of study subjects
A priori computations had been made regarding a needed sample size of 250 for
detecting small and moderate changes, and for comparisons within the group and
between groups based on two-tailed tests, alpha-level of 0.05, and power of 0.80.
However, despite that several steps were taken to increase the response rate, such as
pre-stamped, pre-addressed return envelopes, and one repeated contact attempt by
post asking non-responding patients to participate in the study, it was not possible to
reach this sample-size, partly due to the non-responders, but also that there were not
enough eligible participants within the time frame of the study. The limited number
of patients attending genetic counseling for familial LQTS or familial HCM made it
especially difficult to achieve sufficient sample sizes according to the previous power
estimates of the study. This may also explain some of the unexpected insignificant
results in the smaller subgroups.

66
Non-response and loss to follow-up
In achieving a representative sample a particular concern is non –response. The level
of non-response may compromise the generalizability of the study (Hulley et al.,
2007). Of 173 eligible patients, one hundred and twenty-seven patients were willing
to participate (73.4 %), which may be considered a satisfactory response rate.
However a non-response rate of 26.6% at baseline may influence the results. We do
not have any information about this group as we were not allowed to register
information on the decliners. For example, in case of an under-representation of
individuals with a “severe family history” this may result in weaker observed effects
on, for example, psychological variables.

Furthermore, on the course of the study patients dropped out, which may cause
attrition bias (Polit & Beck, 2008). The explanation for how the n can increase from
one point to the next (as from T5 to T6) is that some participants were non-
responders at T5, but responded at T6. At one year after genetic counseling, 58
individuals had dropped out. However, there were no significant differences between
the study sample and these drop-outs on any of the variables in the prospective study
(paper III, table 1). The fact that not all participants completed all time points could
potentially also cause problems for the statistical analysis. In order to meet this
weakness the method of Mixed Linear Method was used. It is designed for tracking
changes over time, even with missing data at certain questionnaire time points. The
method uses all available data and can account for correlations between repeated
measurements on the same subjects and has flexibility to model time effects.

Patients’ subcategories
At the time when the study started the patients attending genetic counseling for
familial cardiac disorders mainly consisted of LQTS or HCM patients and their at-
risk relatives. We therefore included patients with a clinical diagnosis as well as

67
unaffected patients with a presumed genetic risk. However, these subcategories may
be regarded as very different. We could not fully address these differences in the
present study, thus this could introduce bias, although we did subgroup analyses in all
of the papers. By considering patients at family risk, patients with a clinical diagnosis
of LQTS, and patients with a clinical diagnosis of HCM separately in the comparison
to expected scores of the general population, it was ensured that patients similar
according to clinical status were compared to the expected scores. It was however a
limitation that the groups were so different in size, when comparing them to each
other.

More patients with familial LQTS were included in the study as compared to patients
with familial HCM, despite that HCM is a more prevalent disease. The reason for this
may be that the possibility of genetic testing for LQTS started in 2001, whereas
molecular genetics for HCM was only possible from 2004, thus the possibilities of
genetic investigation may therefore not have been widely known among HCM
patients and their physicians in the study period. LQTS molecular testing may also be
perceived as more important for diagnostics, since patients with normal ECGs and no
clinical manifestations still may be at risk.
8.2.3 The patient-reported outcomes
The patient-reported outcome measures were selected based on the aims of the
present study, previous research, clinical experience, and the patient-reported
outcome literature. Main strengths of the study were the use of well-established,
standardized, validated questionnaires. An exception is the The Bergen Genetic
Counseling Self-efficacy Scale (BGCSES), which has not been validated, but has
been constructed based on Banduras guidelines (see section 6.4.4). The instrument
has shown high reliability in previous studies (Bjorvatn et al., 2008; Bjorvatn et al.,
2009). A generic questionnaire measuring patient general health and wellbeing, as

68
well as questionnaires that measured specific dimensions to a greater extent were
selected as patient-reported outcomes. The advantage of using generic instruments is
that they can be used in general population trials or across patients with different
disease conditions (Fayers & Machin, 2007). For example, SF-36 is not age, disease
or treatment specific, and has therefore several advantages. It is applicable to patients
with more than one disease, and it can be used to compare patient-groups who suffer
from different diseases (Loge et al., 1998). It is therefore appropriate in the present
study where the sample consists of patients presumed to be at genetic risk of LQTS or
HCM, as well as patients who already have a diagnosis of LQTS or HCM due to
clinical findings, and of two reference populations from which expected scores of the
general population were calculated.

The advantages of using a dimension-specific instrument pertain to documenting
dimensions that are of special interest or particularly important to the patient group in
question (Fayers & Machin, 2007). For example, it is likely that anxiety among
patients with a suspected risk of heart conditions will be related at some level to the
functioning and sensations of the heart. A dimension-specific instrument like CAQ
would capture this, whereas a generic questionnaire would be inadequate. A negative
consequence of including both generic and dimension-specific instruments in the
present study was that the questionnaire package took a long time to complete for the
patients. This may have led to missing items on some of the questions. Missing
substitution was performed according to standard procedures for the SF-36
questionnaire (Medical Outcomes Trust, 1994). For the remaining questionnaires
mean imputation were used, where over half of the questions were filled in (Fayers &
Sprangers, 2002).

The questionnaires have shown good reliability in previous studies. In the present
study, Cronbach’s alpha (Table 7.2) was in general good, with exception of the

69
subscale of procedural satisfaction. This may be due to the few items of this scale
(Fayers & Machin, 2007).

In the following sections, central findings regarding the patient-reported outcomes,
impact of socio-demographic and clinical variables, the influence of having a family
history of sudden cardiac death, and the role of heart-focused anxiety in relation to
patient-reported outcomes will be discussed. Furthermore, this discussion will
explore possible explanations for differences in patient-reported heart-focused
anxiety up to one year after genetic counseling, and discuss some emerging issues
relating to the contents and optimal dimensions of health care services in the future.
8.3 Patient- reported health status, levels of general
anxiety and depression, and symptoms of heart-focused
anxiety

Health status
The present study demonstrates reduced health status in the SF-36 domain of general
health in individuals receiving genetic investigation and counseling because of
familial long QT syndrome (LQTS) or familial hypertrophic cardiomyopathy (HCM).
Approximately 75 % of these individuals were termed “patients at genetic risk”
because they were family members and other appropriate relatives subsequently
following the identification of a LQTS or HCM- causative mutation in an index case,
and thus without a clinical diagnosis. In line with that the patients at genetic risk
currently were clinically unaffected by LQTS or HCM, these patients had better
health status scores on physical functioning and the bodily pain domains compared to

70
the expected scores of general population. However, by their own the patients at
genetic risk also had markedly reduced general health scores.

In our study general health is defined as current health, resistance to illness, and
health outlook, which can be considered to belong to one overall dimension of
perceived health (Bjorner & Kristensen, 1999). Perceived health allows the patients
to weigh together different aspects of their health in an overall score, thus the aspects
that the patient deem relevant is emphasized (Fayers & Sprangers, 2002). Living
with the risk of serious arrhythmias and sudden cardiac death implies a probability
for something adverse can happen in the future. LQTS and HCM are autosomal
dominant disorders, which mean children, siblings and parents of a mutation carrier
have a 50 percent risk of also being affected, thus they are also living with risk of
serious cardiac symptoms. The penetrance (likelihood for actually developing the
disease) is however varying, which leads to uncertainty of ever experiencing clinical
symptoms of the disorder. Living with this health threat may cause the patients to feel
vulnerable. In turn, this perceived vulnerability may result in poorer perceived
general health.

In contrast to the poorer perceived general health, physical functioning, role
limitation-physical, bodily pain, vitality, social functioning, role limitation-emotional,
and mental health domains were not significantly different as compared to expected
scores in the general population. However, all health status domains were influenced
by clinical variables as well as socio-demographic variables.

With regard to the adult population affected with LQTS or HCM, health status has
previously only been measured with well-established, standardized and validated
measures in HCM patients, indicating that patients with a clinical diagnosis of HCM

71
have major limitations on both physical and mental health domains (Cox et al., 1997).
Although many patients with HCM can be asymptomatic, clinical manifestations
such as dyspnea, dizziness, syncope and angina are common (Stroumpoulis et al.,
2010). The presence and severity of symptoms may most likely be the reason for
reduced scores in physical and role physical activities as well as the lower scores on
the vitality domain. The HCM patients in the present study were not significantly
different from the general population on levels of bodily pain, social functioning, or
mental health. However they did have poorer perceived general health.

In contrast to the limitations the HCM patients experienced, the scores of the LQTS
patients were not significantly different than those of the general population on any of
the health status domains. However, the group may have been too small to detect
significant differences, and it is worth to note that the scores on several of the health
status domains were moderately lower also among the LQTS patients. This was
especially pertaining to general health and vitality, where the differences in scores
may be an indication of poorer perceived health. Being a generic instrument,
measuring patients general health and wellbeing, the SF-36 may not completely
capture the health problems of LQTS patients, since qualitative research clearly have
found evidence of daily limitations related to periodic feelings of extreme fatigue,
exhaustion, palpitations and headaches in this patient group (Andersen et al., 2008).

Variables like gender, age and education status were expected to have an influence on
health status since they are common confounders in health research using patient-
reported outcome measures (Polit & Beck, 2008). Health status was therefore
investigated in relation to socio-demographic variables. As to gender differences
previous research has shown gender differences in anxiety disorders and symptoms
(Lewinsohn et al., 1998). We found that female gender was related to lower scores on
domains that measure well-being, such as bodily pain, vitality, and mental health.

72
Patients that had children also scored lower on mental health. This is understandable,
since much of the literature has identified raised anxiety levels in parents having
children at risk of these disorders (Hendriks et al., 2005b; Hendriks et al., 2005a).
Increasing age had an impact on physical health. Lower education level indicated
poorer health status, as can also be found in general population samples (Loge &
Kaasa, 1998). Physician referral to genetic counseling was related to poorer health
status on all health domains. Referral from a physician may therefore indicate that the
patient more likely was clinically affected.

General anxiety and depression
While there were large differences in health status according to clinical status, no
differences were found in terms of general anxiety and depression between patients at
genetic risk and patients with a clinical diagnosis. The anxiety levels were elevated
compared to the general population controlled for gender, age, education level, and
smoking status. The prevalence of general anxiety (scores over >8, HADS) in the
patients before genetic counseling was 25%, which is quite high in comparison to the
prevalence among Dutch HCM mutation carriers (Christiaans et al., 2009b), and the
prevalence in general population samples (13-18%). It was however comparable to
the proportion of patients anxious before attending genetic counseling for hereditary
cancer (Bjorvatn et al., 2008). Receiving the invitation to participate in the study and
the scheduled genetic counseling session may have actualized anxiety in some of the
individuals. However, it cannot be ruled out that living with this health threat in itself
may have an impact on levels of general anxiety.

Heart-focused anxiety
In contrast to that there were no differences in general anxiety between any of the
groups, patients with a clinical diagnosis had significant higher levels of heart-

73
focused anxiety than the patients at genetic risk, and patients receiving genetic
counseling because of familial HCM had higher levels of heart-focused anxiety
compared to patients receiving genetic counseling because of familial LQTS. In terms
of explaining possible reasons for a relationship between greater heart defect
complexity and higher levels of heart-focused anxiety, Ong and colleagues suggested
that patients with greater defect complexity may be more symptomatic, have greater
functional impairments, and have a history of more medical interventions that may
trigger heart-focused anxiety (2011). This may also be the case for patients with
clinical diagnoses, and especially the HCM patients. Therefore, higher heart-focused
anxiety among patients affected clinically, especially with HCM may most likely be
due to that they experience more symptoms, functional impairments, and contact with
health care services that can trigger fear for adverse outcomes.

In summary, patients with a clinical diagnosis had poorer physical health and higher
levels of heart-focused anxiety, whereas patients at genetic risk scored better on these
domains. Common for the patients at genetic risk of LQTS or HCM and patients with
a diagnosis of LQTS or HCM, were poorer perceived general health and higher levels
of general anxiety.

8.3.1 The impact of having a family history of sudden cardiac
death
One consequence of living in a family with a familial cardiac disorder is the
possibility that a relative suffers a cardiac arrest and dies unexpectedly. Fifty–seven
individuals (45%) had experienced sudden cardiac death in a relative. Thirty-five of
these individuals (28%) had experienced sudden cardiac death in a close relative (first
or second degree relative), and 25 individuals (20%) had experienced that a relative
had died of a cardiac arrest less than a year ago.

74
In the present study it was found that having a family history of sudden cardiac death
impacted on several of the patient- reported outcomes. Counter intuitively, when
investigating socio- demographic variables relationship to health status domains, it
was found that patients that had reported a sudden cardiac death event among any of
their relatives at any point in time, had higher scores on the health domain of bodily
pain (less bodily pain). This result may have been confounded, but it may also be
evidence of a response shift. Experiencing a relative’s death event may be very
dramatic, and it is possible that an event like that can change a person’s self-
evaluation as to having less bodily pain or no bodily pain, as opposed to more
(Schwartz et al., 2007). The better physical health scores than expected among the
patients at genetic risk in the present study may also be due to similar mechanisms.

Psychological processes may be involved, since we found that the experience of a
recent cardiac death of a relative was associated with higher levels of general anxiety
and depression. Patients may also not relate a sudden cardiac death event in the
family so negatively to general bodily pain as they would to specific perceived heart
symptoms, which more likely will represent a greater extent health threat. The latter
alternative was supported by the fact that a sudden cardiac death event in a close
relative (first or second degree relative) predicted higher levels of heart-focused
attention and fear about heart sensations up to one year after genetic counseling.
8.3.2 The role of heart-focused anxiety
The fear of cardiac-related events and sensations may potentially also in itself
contribute to higher levels of general anxiety and influence heart-related illness
(Eifert et al., 2000b). For example, in a study of patients undergoing cardiac surgery,
Hoyer et al.,(2008) found that heart-focused anxiety was significantly correlated with
higher levels of anxiety and depression and lower health –related quality of life, and
Zvolensky et al., (2003) found that heart-focused attention and fear about heart
sensations predicted self-reported chest pain intensity among patients with coronary

75
disease. In the present study two distinct symptoms of heart-focused anxiety, the
degree of cardio-protective avoidance and fear about heart sensations, could explain a
considerate part of the higher levels of general anxiety and depression in the patients,
in addition to patients lower scores on physical health. First, cardio-protective
avoidance is a recommendation to avoid aversive events in patients with the risk of
serious arrhythmias. Knowing that activity actually can trigger events may therefore
in itself cause patients to avoid all kinds of activity and fear any heart sensation,
which would impact on physical health as well as on general anxiety and depression.
Secondly, both avoidance and fear may be due to that the patients actually have
poorer health. It is therefore difficult to interpret whether avoidance and fears in
relationship to physical health is due to medical recommendations for patients that are
affected, or that the avoidance and fear is due to poorer health. However, high levels
of avoidance and fear may be considered as important risk factors for higher levels of
general anxiety and depression, as well as poorer health functioning.
8.3.3 Explanations for differences in heart-focused anxiety up to
one year after genetic counseling
Research on patients undergoing genetic counseling has so far mostly focused on the
possible negative effects of genetic testing. Complementary to this, the present
findings show that knowing whether other relatives had undergone genetic testing,
higher self-efficacy expectations, and higher levels of procedural satisfaction after
counseling actually reduced fearful responses to cardiac-related stimuli and
sensations over time. This indicates less heart-focused anxiety among patients that
knew there would be possibilities of genetic testing, that thought they would cope
with challenges connected to the genetic counseling, and that were more satisfied
with waiting time and administrative tasks around the counseling session.

76
In addition the present findings underline the importance of the patients’ perspective
of health. Interestingly, poorer perceived general health as measured before genetic
counseling was an important predictor for heart-focused anxiety, as it predicted
avoidance, attention, as well as fears up to one year after genetic counseling.
Perceived general health has previously been shown to influence clinical outcome, as
well as being a powerful predictor of mortality and morbidity (Fayers & Sprangers,
2002). In a study reporting predictors of 10-year survival in women after acute
myocardial infarction, those that perceived poorer general health had a two times
higher risk of dying (Norekval et al., 2010), thus it may be a variable of particular
interest to study in future studies in the present patient group, since they have poorer
perceived general health as compared to the general population.

77
8.4 Emerging issues related to genetic investigation and
counseling now and in the future

The rapidly developing gene technology has made it possible to identify individuals
with an increased risk for diseases. This development will likely have substantially
impact on future treatment and care. With an increasing number of individuals
seeking genetic investigation for familial cardiac disorders, finding ways to maintain
a high health functioning and emotional wellbeing among the patients are essential to
be able to argue for increased use of genetic testing in cardio-genetic care.

Today diagnostic genetic testing in Norway can be performed without prior genetic
counseling, whereas patients undergoing predictive genetic testing are protected by
the law and are entitled to genetic counseling before, during, and after the testing
(Act of biotechnology, 2003, appendix). Patients clinically affected by disease should
also be entitled to genetic counseling before genetic investigation, because finding a
mutation has further consequences than just confirming the diagnosis in that
individual. For example, higher levels of heart-focused anxiety were found in the
patients with a diagnosis compared to patients at genetic risk. The genetic counseling
provides a venue for addressing heart-focused anxiety. Further, current practice of
genetic counseling includes information and performance of cascade genetic testing
of at-risk relatives. As discussed in Hamang et al., (2009) the current Act of
Biotechnology does not automatically allow communication of genetic information to
persons other than the patient. This means that the patients themselves have to be
instrumental in informing other relatives of genetic test results and risks. Index
patients with clinical diagnosis may therefore have even greater need for genetic
counseling, because they have to inform others.

78
Common for LQTS and HCM patient groups, before genetic investigation and
counseling, were a higher general anxiety level compared to what is expected in the
general population beyond reported health status or whether the patients were
affected or unaffected with the familial disorder. The higher general anxiety level
may have been due to the upcoming genetic counseling session. However a more
likely explanation may be that general anxiety is an important determinant for
undergoing genetic testing in the first place, since previous research has shown
decreased levels of general anxiety over time in for example patients undergoing
predictive genetic testing for familial LQTS (Hendriks et al., 2008). In the present
study it was shown that the patients had high satisfaction with genetic counseling,
and that satisfaction with the procedural parts of genetic counseling decreased heart-
focused anxiety levels. The continuation of genetic counseling is therefore necessary
in the future.

Following the protocol of predictive genetic testing, most of the patients that were
offered genetic testing, underwent testing. This is clearly different from our
experience in cancer counseling, where more patients decline genetic investigation
after counseling. There may be several explanations for this. It may for example be
due to that the protocol of predictive testing of patients is different in cardiac
disorders compared to cancer, since the decision to undergo testing is not postponed,
because of the immediate risk of symptoms and sudden death, the greater risk in
young age, and that preventive measures are available. Alternatively, it may also be
due to that there are greater detection rates in the genetic testing of cardiac disorders,
and that the result of the testing has more consequences in terms of preventive
measures. Even though there are positive aspects of finding a mutation, like
surveillance and other medical strategies to reduce risk of sudden cardiac death, the
patients often have to wait a long time for a heart control. A more team-based
approach between the genetic counselor and cardiologist may be beneficial for the
patient to cope with a positive genetic test result.

79

The field of medicine has become highly specialized. The application of genetics to
cardiology is one example where the care of patients involves medical, psychological,
and familial challenges, of which the present health care system may lack expertise
and resources to oversee (Patterson, 2009). The purpose of a more team based
approach must be to offer the patients and their families an optimal cardiological and
genetic examination and follow-up as well as increasing knowledge among patients,
their families, and the health care personnel.

The clinical guidelines emphasize the importance of genetic testing in LQTS families
and the usefulness in families with HCM (Zipes et al., 2006) in the prevention of
serious arrhythmias and sudden cardiac death. The clinical guidelines should also
include the importance of genetic counseling as stated in the recent expert consensus
recommendations of genetic testing for the channelopathies and cardiomyopathies
(Ackerman et al., 2011).

80
9. Conclusions
The studies included in this thesis show that the use of patient-reported outcome
measures allows for better understanding, not only of the effect of the conditions
themselves, but also of some of the effects of living with this health threat, and finally
of how outcome is influenced over the course of the study. The three papers included
in the present thesis elaborate on these findings. The following conclusions were
made:

Paper I:
In a cross-sectional design it was found that living with the risk of serious
arrhythmias and sudden cardiac death most likely affects the perceived general health
in patients receiving genetic counseling for familial LQTS or familial HCM.
However the patients’ scores on the other health status domains were not impaired
compared to what is expected in the general population.

There were however significant differences of the effect of the conditions themselves.
Patients with a clinical diagnosis of HCM reported more impairment compared to the
general population in physical functioning, role physical, and vitality domains,
whereas patients with family risk of LQTS or HCM reported better physical
functioning and less bodily pain.

Several socio-demographic variables and clinical variables were related to better
perceived health status, notably employment, higher education level and referral to
genetic counseling by a family member. Better self-reported physical functioning and

81
general health were in addition predicted by that the patients were referred for
familial LQTS as opposed to familial HCM, supporting that the HCM patients were
the most vulnerable in physical health domains.
Paper II:

Before receiving genetic counseling, the individuals with familial LQTS and familial
HCM had higher levels of general anxiety than expected in the general population,
whereas their level of depression and overall physical health were no different.

Comparisons between familial LQTS and familial HCM revealed no difference
between the groups with regard to general anxiety and depression, whereas heart-
focused anxiety was higher and physical health was poorer in the familial HCM
group.

Both heart-focused avoidance and fear about heart sensations had important roles in
determining patients’ levels of general anxiety, depression and physical health. To
what extent these individuals experienced heart-focused avoidance and fear about
heart sensations, their reporting of general anxiety, depression, and physical health
were related to varying degrees by these distinct symptoms of heart-focused anxiety.
In addition, having a clinical diagnosis was of importance for their physical health,
whereas a recent SCD in the family was related to higher levels of general anxiety
and depression, regardless of disease status.

82
Paper III

In a prospective design the three distinct symptoms of heart-focused anxiety
(avoidance, attention, fear) were overall higher in patients with a clinical diagnosis of
LQTS or HCM as compared to patients at genetic risk of LQTS or HCM, indicating
that patients affected with a familial cardiac disorder have higher heart-focused
anxiety.

Predisposing factors for higher levels of heart-focused anxiety over time were a
family history of sudden cardiac death in a close relative and uncertainty whether
other relatives had undergone genetic testing. However, satisfaction with the
procedural parts of genetic counseling was predictive of decreased levels of heart-
focused anxiety. The resources of greatest prognostic importance may be the way
individuals perceive their general health and their self-efficacy expectations.

The present findings indicate that patients undergoing genetic investigation and
counseling for familial LQTS or familial HCM are vulnerable in both health-related
and psychological domains before genetic counseling, and may benefit from a closer
collaboration between the genetic counselor and the cardiologist addressing their
experience of cardiac symptoms to a greater extent.

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10. Clinical implications

For the continuation of developing genetic counseling for these patients it is
important to increase the understanding of the possibilities for improving quality of
care. The patient-reported outcomes in this study allows for a better understanding of
how this can be achieved.

As stated previously in this thesis the main aim of genetic counseling is to help
people to understand and adapt to the medical, psychological, and familial
implications of genetic contribution to disease. The present study showed that one
implication of living with the risk of serious arrhythmias and sudden cardiac death, in
individuals with familial LQTS or familial HCM, was a poorer perceived health and a
higher level of general anxiety than that of the general population. How may genetic
investigation and counseling improve perceived general health and anxiety levels?

Undergoing genetic investigation may in itself influence health perception and levels
of general anxiety, for example by reassuring patients when they test negative for the
family mutation (Aatre & Day, 2011), or by providing access to better follow-up and
that feelings of uncertainty is removed for persons testing positive for the family
mutation. Patients who already have a clinical diagnosis of LQTS or HCM may get
more information about the etiology of the disorder, and learn more about the
consequences for other relatives (Skrzynia, Demo, & Baxter, 2009).

Individualizing the genetic counseling session to an even greater extent may also be a
way to go. Today the protocol for pre-test counseling session of patients with familial

84
LQTS and familial HCM is more or less the same. Although the present study
showed that these patient groups were similar with regards to general anxiety levels,
the patients with a diagnosis of HCM demonstrated limitations in physical health
domains compared to the general population, and were identified as the most
vulnerable group with regards to health functioning. This indicates that the genetic
counseling should adapt to this, using a more individual based approach to families
with HCM, as they may have more concerns of health limitations, whereas LQTS
patients may have other needs in their management of potential health threat.

The genetic counselor may also try to educate the patients about their health and
normalize emotions patients may have in relation to living with the risk. A study
among individuals with panic disorder showed that individuals who perceived their
health as poorer were more likely to experience anxiety, anger, depression and
frustration (Gregor et al., 2005). This may indicate that by addressing general health
perception the genetic counselor may also become aware of unresolved emotions of
the patient. In the present sample poorer general health also predicted higher scores of
cardio-protective behavior, heart-focused attention, and fear about heart sensations,
which underlines the importance of addressing this patient-reported outcome.

Before the patient is undergoing genetic investigation and counseling, heart-focused
anxiety should be assessed. Being important in determining levels of general anxiety
and depression, and physical health, this assessment will give the genetic counselor
access to important information. Healthy persons that are heart-anxious are more
likely to report panic and other anxiety disorders, more hypochondrial beliefs,
physical symptoms, obsessive-compulsive concerns and negative affect (Eifert et al.,
1996). Our findings indicate that heart-focused anxiety may be a substantial problem
among patients receiving genetic counseling for familial LQTS or familial HCM,
most prevalent among clinically affected patients. Intervention aimed at heart-

85
focused anxiety may therefore increase health functioning and decrease general
anxiety both in patients with and without cardiac disease (Eifert et al., 2000a; Eifert,
2000b). Genetic investigation and counseling may be targeted as such intervention.

86
11. Implications for further research

This study indicates that there are differences as well as similarities between HCM
and LQTS patient groups.

Big differences were found in health status. LQTS patients’ health status should be
further investigated in bigger samples, and possibly with other patient-reported
outcome measures that more can reflect the health issues in this population.

In contrast to the differences in health status it was found that knowledge of a
heightened genetic risk for serious arrhythmias and sudden cardiac death most likely
is associated with anxiety pathology, regardless of disease status or familial LQTS or
familial HCM. Since previous research has shown that general anxiety may decrease
over time in patients at risk of familial LQTS (Hendriks et al., 2008), the role of
genetic counseling should be investigated.

Further, we have shown that specific anxiety for heart events may contribute to raise
levels of general anxiety and depression. In addition to that heart-focused anxiety is
related to poorer physical health. However, it still needs to be investigated what other
variables may influence general anxiety in these patients.

In addition, it is necessary to explore further if the high general anxiety before genetic
counseling is due to the upcoming counseling session, or if the individuals by
themselves are anxious because of living with this health threat and uncertainty.

87

In contrast to more general anxiety and distress levels that can be caused by many
factors, heart-focused anxiety is the specific fear of cardiac-related stimuli and
sensations because of their perceived negative consequences. Fearful responding to
symptoms and information about risk may also have a profound negative effect on
social and occupational life functioning (Eifert, 2000b), and this should be further
explored in HCM and LQTS patients.
The importance of understanding the association between perceived health and
emotional vulnerability processes such as heart-focused anxiety has been pointed out,
and suggests the need for further work investigating this cognitive variable as a
possible risk factor for developing such problems (Yartz et al., 2005). Even more
important in this patient group is the possible relationship between perceived health,
heart-focused anxiety, and mortality.

Finally, to what extent the present patient-reported outcomes may be different in
individuals undergoing genetic investigation and counseling because of familial
LQTS or familial HCM, from patients with other genetic diseases, or in healthy
persons, should be further explored in future research.

88
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Original papers