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1 Health anxiety and risk of ischemic heart disease: a prospective cohort study linking the Hordaland Health Study (HUSK) with the Cardiovascular Diseases in Norway (CVDNOR) project Journal: BMJ Open Manuscript ID bmjopen-0-0 Article Type: Research Date Submitted by the Author: 0-Jun-0 Complete List of Authors: Berge, Line; Haukeland University Hospital, Psychiatric division; Universitetet i Bergen Det medisinsk-odontologiske fakultet, Global Public Health and Primary Care Skogen, Jens Christoffer; Norwegian Institute of Public Health Sulo, Gerhard; University of Bergen, Department of Global Public Health and Primary Care Igland, Jannicke; Faculty of Medicine and Dentistry, University of Bergen, Global Public Health and Primary Care Wilhelmsen, Ingvard; Faculty of Medicine and Dentistry, University of Bergen, Clinical Medicine ; Haraldsplass Deaconal Hospital Vollset, Stein Emil; Faculty of Medicine and Dentistry, University of Bergen, Global Public Health and Primary Care; Norwegian Institute of Public Health Tell, Grethe; Universitetet i Bergen Det medisinsk-odontologiske fakultet, Department of Global Public Health and Primary Care Knudsen, Ann Kristin ; Faculty of Medicine and Dentistry, University of Bergen, Global Public Health and Primary Care; Norwegian Institute of Public Health <b>primary Subject Heading</b>: Epidemiology Secondary Subject Heading: Mental health, Cardiovascular medicine Keywords: Health anxiety, Ischemic heart disease, EPIDEMIOLOGY BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

2 Page of BMJ Open Health anxiety and risk of ischemic heart disease: a prospective cohort study linking the Hordaland Health Study (HUSK) with the Cardiovascular Diseases in Norway (CVDNOR) project Line Iden Berge, Jens Christoffer Skogen, Gerhard Sulo, Jannicke Igland, Ingvard Wilhelmsen, Stein Emil Vollset, Grethe S Tell and Ann Kristin Knudsen Division of Psychiatry, Helse-Bergen, Sandviken University Hospital, 0 Bergen, Norway and Faculty of Medicine and Dentistry, University of Bergen, 00 Bergen, Norway Line Iden Berge physician Norwegian Institute of Public Health, 0 Bergen, Norway Jens Christoffer Skogen researcher Faculty of Medicine and Dentistry, University of Bergen, 00 Bergen, Norway Gerhard Sulo post-doc Faculty of Medicine and Dentistry, University of Bergen, 00 Bergen, Norway Janniche Igland statistician Faculty of Medicine and Dentistry, University of Bergen, 00 Bergen, Norway and Haraldsplass Deaconal University Hospital, 00 Bergen, Norway, Ingvard Wilhelmsen professor Faculty of Medicine and Dentistry, University of Bergen, 00 Bergen, Norway and Norwegian Institute of Public Health, 0 Bergen, Stein Emil Vollset professor Faculty of Medicine and Dentistry, University of Bergen, 00 Bergen, Norway Grethe S Tell professor. Faculty of Medicine and Dentistry, University of Bergen, 00 Bergen, Norway and Norwegian Institute of Public Health, 0 Bergen, Norway Ann Kristin Knudsen researcher. Corresponding author: Line Iden Berge, MD, PhD Division of Psychiatry, Sandviken University Hospital, Bergen, Norway. Sandviksleitet 0 Bergen line.iden.berge@gmail.com BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

3 Page of Background: Risk of ischemic heart disease is largely influenced by lifestyle. Interestingly, cohort studies shows that anxiety in general is associated with increased risk of ischemic heart disease, independent of established risk factors for cardiovascular disease. Health anxiety is a specific type of anxiety characterized by preoccupation of having, acquiring or possibly avoiding illness, yet little is known about lifestyle and risk of disease development in this group. Aim: Investigate whether health anxiety is prospectively associated with ischemic heart disease, and whether a potential association can be explained by presence or absence of established risk factors for cardiovascular diseases. Methods: Incident ischemic heart disease was studied among 0 participants in the community based Hordaland Health Study (HUSK) during years follow up by linkage to the Cardiovascular Diseases in Norway (CVDNOR) project. Scores above 0 th percentile of Whiteley Index defined health anxiety cases. Associations were examined with Cox proportional regression models. Results: During follow up,,% of health anxiety cases developed ischemic heart disease compared to.0% of non-cases, yielding a gender adjusted HR of. (% CI:.,.). After adjustments for established cardiovascular risk factors, about 0% increased risk of ischemic heart disease was found among cases with health anxiety. The association followed a dose-response pattern. Conclusions: This finding corroborates and extends the understanding of anxiety in various forms as a risk factor for ischemic heart disease. New evidence of negative consequences over time underlines the importance of proper diagnosis and treatment for health anxiety. BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

4 Page of BMJ Open Strengths and limitations of this study This prospective cohort study ensured complete follow up of participants in a community based health survey due to linkage with a nationwide cardiovascular research project. The exposure health anxiety was assessed by self-report with the Whiteley Index, while the outcome ischemic heart disease was reported by physicians via patient administrative systems in hospitals or at death certificates. Whiteley Index do not discern between imagined illness or more legitimate reasons for concern. To reduce the impact of high levels of health anxiety due to actual illness, participants with prevalent or month s incident ischemic heart disease were excluded. Low participation rate at the community based health survey of %, representing a greater threat to the validity of studies estimating prevalence rather than risks. BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

5 Page of Health anxiety is characterized by persistent preoccupation of having or acquiring a serious illness, misattribution of bodily symptoms and urge to seek medical advice in the absence of physical pathology. As a result, persons with health anxiety stay activated and alert to bodily symptoms in order to detect, or even avoid, illness. Symptoms of health anxiety may range from trivial to severe, and in the most intense form including disease conviction, the diagnostic criteria for hypochondriasis might be met. As the leading cause of premature death in Norway, as well as in many other middle to high income countries, ischemic heart disease (IHD) is reasonably a frequent subject of concern among persons with health anxiety.the risk of IHD is largely influenced by health behaviors, and it has been estimated that close to 0% of the burden of cardiovascular diseases worldwide could be avoided with healthier lifestyle in terms of diet, reduction in tobacco consumption and increased level of physical activity. Anxiety disorders and IHD have several symptoms in common, such as chest discomfort, palpitations, nausea, sweating and tachypnea. Additionally, anxiety disorders in general are associated with increased risk of IHD. Following almost persons for an average of years, a metaanalysis from 00 estimated % increased risk of coronary heart disease among persons with anxiety, independent of demographics, biological factors and health behaviors. This analysis relied on an overall heterogeneous measure of anxiety, counting single studies using instruments assessing generalized anxiety disorders, worry, panic attacks and phobic disorders. The authors concluded that anxiety should be regarded as an independent risk factor for coronary heart disease, and that future research ought to confirm the association using other valid and reliable measures of anxiety. Certainly, the issue of causality between anxiety and IHD has been of great interest, and a recent meta-analysis provided evidence supporting a causal association between anxiety and cardiovascular diseases in general, suggesting anxiety to be targeted in preventive cardiology. Whether an increased risk of IHD also applies to persons suffering from health anxiety has, to the best of our knowledge, not been examined. Safety seeking behavior such as monitoring and frequent check-ups of symptoms associated with heart disease may contribute to a reduced risk of IHD in health anxiety compared with anxiety in general. Further, one could hypothesize that individuals with health anxiety, due to their health concerns, endorse a lifestyle that reduces the risk of IHD. Yet, little is known about health related behaviors such as smoking, physical activity and alcohol consumption in this group. By linking a community based health study with information on hospitalizations and death due to IHD, the aims of the present study were to examine ) whether health anxiety is prospectively associated with incident IHD and ) whether a potential association can be explained by presence or absence of established risk factors for cardiovascular diseases. Methods BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

6 Page of BMJ Open Study population: The Hordaland Health Study The Hordaland Health Study (HUSK) is a community based health survey with baseline examinations conducted during - as a collaboration between the National Health Screening Service, the University of Bergen and local health services 0. All persons born - who resided in Hordaland County on December, (n= 00) received a personal invitation to participate in the study. Data collection encompassed two sets of questionnaires and one brief physical examination at which weight, height and blood pressure were measured and a blood sample was drawn. Questionnaire was included with the mailed invitation to participate in the study and was collected at the health examination, during which participants randomly were given one of two versions of questionnaire to be filled in at home and returned by mail. Participation rate at the health examination was %. Of these, about % returned the second questionnaire. Persons who did not meet at the examination or did not return the second questionnaire received one reminder by mail. Exposure: Health anxiety measured by Whiteley Index (WI) Presence of health anxiety was assessed by the Whiteley Index (WI). Developed by Pilowsky and colleagues in the 0s, this widely used self-report instrument is considered a classic screening tool for health anxiety and hypochondriasis. The index consists of items, each scored from to, aiming to assess the disease dimensions phobia, somatic preoccupation and disease conviction. However, the three-dimensional factor structure has been questioned in later studies, and the use of a one-factor solution summarizing the scores on all items is recommended and widely used. The internal consistency, stability and concurrent validity of WI is considered to be good, both in samples from medical outpatient clinics, general practice and the general population. In the present study, scores for each of the items were summarized and the 0 th percentile was used as a cut-off for cases of health anxiety, corresponding to the highest prevalence estimate of illness anxiety disorder in the general population reported in the DSM-V. In additional analyses, scores on WI was operationalized in quintiles and as a continuous variable. Outcome: IHD The research project Cardiovascular diseases in Norway -00 (CVDNOR) is a collaboration between the University of Bergen and the Norwegian Knowledge Center for the Health Services, and has retrospectively collected data on hospitalizations and deaths due to CVD during -00. In brief, data on hospital stays coded with a CVD diagnosis as main or secondary diagnoses were retrieved from the electronic Patient Administrative System (PAS) in all Norwegian somatic hospitals, while information on persons with a CVD diagnosis on the death certificate, regardless of whether they had been hospitalized for a CVD related diagnosis, was obtained from the Norwegian Cause of Death Registry. Data quality is considered good. The main outcome in the present study was BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

7 Page of incident IHD diagnosed at least one year after participation in HUSK and until December 00, defined as a primary or secondary diagnosis or underlying cause of death with ICD-0 code I0-I. Participants in HUSK were linked with CVDNOR through their personal identification number, unique to each Norwegian resident. Covariates Based on knowledge of established risk factors for IHD, we adjusted the analyses for several covariates assessed at baseline in HUSK. Information on gender and age was obtained from the Norwegian Population Registry. Based on self-reported information we defined persons as cohabiting if they had reported marital status as married or partner, highest achieved education was categorized as college or university, high school or less than high school. Number of alcohol units per days was categorized according to tertiles in 0, - and units, whereas physical activity was categorized as mean hours with hard physical activity per week ranging from 0 to, defined as perspirating and being out of breath. Self-reported information on smoking was categorized as never, former and current. Height and weight were measured at the examination, body mass index (BMI) was calculated as weight (kg)/height (m), and categorized as underweight (.), normal (0.0-.), overweight (.0-.) and obese ( 0). Systolic blood pressure (mmhg), total cholesterol (mg/dl) and HDL (mg/dl) were measured at the examination, and categorized in quintiles. Additionally, we utilized self-reported data on presence of diabetes and first degree relative with acute myocardial infarction (AMI) before 0 years. Study sample and statistical procedures The population eligible for inclusion in this study was participants answering the WI, included in version of questionnaire in HUSK (n=). A total of (.%) participants had missing information on of the items on the WI. In the main analyses, participants responding on to items of the index were given imputed values equal to the mean score of the items with valid responses (n=), while persons with valid responses were excluded from the sample (n=). To reduce the risk of reverse causality due to high levels of health anxiety among persons with prevalent and early onset incident IHD, we excluded persons who had been hospitalized due to IHD from until participation in HUSK (n=0), as well as participants who were hospitalized or died due to IHD during the first months after the HUSK baseline examination (n=0). This yielded a final sample of 0 participants who were followed from baseline until hospitalization or death, or until December, 00, with maximum follow up of years. In a sensitivity analysis of the effect of non-response, only persons with complete responses on all items on the WI were included (n=). A recent confirmatory factor analysis (CFA) and item response theory analysis using baseline data from HUSK argued against the use of the item WI as it did not yield a satisfactory CFA fit, and suggested the BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

8 Page of BMJ Open use of a item one factor solution. Accordingly, a sensitivity analysis summarizing only the recommended items with cut off at score equal to the 0 th percentile was conducted. The distribution of covariates by cases of health anxiety was examined using descriptive statistics. Associations between health anxiety and incident IHD were examined using Cox proportional regression analyses in four models adjusted for ) gender, ) gender, cohabiting and education (sociodemographic factors), ) gender, alcohol consumption, physical activity, diabetes, BMI, st degree relative with AMI before 0 years, smoking, total cholesterol, HDL cholesterol and systolic blood pressure (CVD risk factors) and ) all factors combined. The analyses were repeated stratified by gender. Effect estimates are presented as hazard ratios (HR) with % confidence intervals (CI). To visually explore the association between health anxiety and risk of IHD we used Cox proportional hazards regression model fitting WI scores using restricted cubic splines with three knots 0. Listwise deletion was employed for cases with missing information on the covariates in the multivariate analyses (between 0 and 0 %). All analyses were conducted in SPSS, and figures were constructed in Stata. Ethics The study protocol was approved by the Regional Ethics Committee of Western Norway (REK) (ref 0/) and the Norwegian Data Inspectorate. The linkage between HUSK and CVDNOR was approved by REK. Written informed consent was obtained from all participants at the time of the baseline health examination. Results Participants who scored on WI constituted the 0 th percentile and were defined as cases with health anxiety. Among these, mean WI score was. (standard error (SE) 0.), while mean score among non-cases was 0. (SE 0.0). Health anxiety was positively associated with disadvantageous responses on most of the a priori selected risk factors for IHD, except for lower than usual alcohol consumption. No differences in the distribution of systolic blood pressure were found (table ). (Insert table ) After excluding persons with an ischemic heart event (hospitalization or death) occurring the first year after baseline, (.%) participants had an ischemic heart event during follow up,.% of cases compared to.0% of non-cases. Mean time to event was. years (SE.). Gender adjusted HR for the association between cases of health anxiety and an incident IHD event was. (% CI:.,.) (table ). Established CVD risk factors explained part of the association, however, the fully adjusted model showed % increased risk of incident IHD among cases with health anxiety (table ). Among the included single risk factors, separate adjustments for smoking, HDL cholesterol and BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

9 Page of education attenuated the association most (data not shown). Gender stratified analyses gave slightly higher effect estimates for women than men (table ), however, no significant gender interaction in the association between health anxiety and IHD was found. (Insert table ) Restricting these analyses to participants with complete responses on all the WI items yielded similar results for the association between health anxiety and incident IHD (gender adjusted HR:. (% CI:.,.0), fully adjusted HR:.0 (% CI:.,.)). Although sensitivity analysis including only the items on the WI previously shown to yield the best factor structure slightly attenuated the strength of the association, this analysis also confirmed that high levels of health anxiety was significantly associated with incident IHD (gender adjusted HR:. (% CI:.,.), fully adjusted HR:.0 (% CI:.0,.)). Operationalizing scores on the WI in quintiles and as a continuous variable revealed a dose-response pattern of the association (table and figure ). A significant trend with increased strength of the association by increasing scores on WI was found in all models (table ), while figure revealed a linear association between scores on WI and subsequent risk of IHD, both in the gender adjusted (part A) and fully adjusted models (part B). (Insert table and figure ) Discussion Using self-reported information on health anxiety from a community-based study linked with data on hospitalizations and death, we found a dose-response association between increasing levels of health anxiety and risk of incident IHD. Relative to persons with lower levels of health anxiety, persons with health anxiety defined as scores on the WI equal to or above the 0 th percentile had approximately 0% increased risk of incident IHD events after adjustment for established CVD risk factors. This finding was evident both among men and women, and confirmed in sensitivity analyses. Health anxiety and risk factors for IHD Relative to persons with low levels of health anxiety, persons with high levels reported less hours of hard physical activity per week, higher prevalence of smoking, yet fewer units of alcohol consumed on average per week. With the exception of an Australian population-based study showing approximately twofold odds of current smoking among participants with health anxiety, health behaviors in health anxiety are sparsely examined. Lower levels of hard physical activity could possibly be explained by fear of forcing or putting strain on the body, while the divergent results on substance use in terms of higher levels of smoking yet lower levels of alcohol use are more difficult to explain. One may speculate that smoking can be used as a tranquillizer in attempt to relieve tension, while use of alcohol BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

10 Page of BMJ Open reduces bodily control, and is therefore perhaps more often avoided among persons with health anxiety. Health anxiety and incident IHD Several studies have established a prospective association between anxiety disorders and IHD, and there is evidence of a causal association between anxiety and cardiovascular diseases. Findings from the Norwegian longitudinal Nord-Trøndelag Health Study (HUNT) suggest a possible dose-response pattern between anxiety, measured by the anxiety subscale of the Hospital Anxiety and Depression Scale, and incident myocardial infarction. However, in that study, the association was fully explained by adjusting for gender, age, cohabiting, education, smoking, physical activity, BMI, total cholesterol, diabetes and systolic blood pressure. This contrasts our finding of a dose-response association between increasing levels of health anxiety and IHD persisting after adjustments for a range of established CVD risk factors. The novel finding of an association between health anxiety and incident IHD is in line with, but additionally extends, the current understanding of anxiety as an independent risk factor for incident IHD and cardiac mortality. It further indicates that characteristic behavior among persons with health anxiety, such as monitoring and frequent check-ups of symptoms, does not reduce the risk of IHD events. The persistent and exaggerated attention to symptoms may rather contribute to continuous and high activation of the hypothalamic-pituitary-adrenal (HPA) axis, placing strain on bodily systems and, in turn, increasing the risk of cardiovascular diseases. Reduced heart rate variability and acceleration of the atherosclerotic process has been suggested as mechanisms possibly explaining the increased risk of IHD among persons with anxiety. In a French study investigating over 00 persons free of coronary artery disease at baseline, high levels of anxiety was associated with an almost twofold increase in thickness of the intima media of the carotid arteries, as well as more than threefold increased risk of plaque occurrence during four years of follow up. Limitations Despite a prospective design linking a community based health survey with comprehensive information on subsequent hospitalizations and death ensuring complete follow up of participants, this study is also affected by limitations. First, even though the WI is a validated and frequently used instrument to assess health anxiety, it relies on self-reported symptoms and does not discern between health anxiety due to imagined illness or more legitimate reasons for concern, such as known risk for IHD. We tried to reduce the impact of high levels of health anxiety due to actual illness by excluding participants with prevalent and month s incident IHD. As the CVDNOR project spans the years to 00, we could not exclude participants in HUSK diagnosed with IHD earlier than, however, we argue that this represents a minor bias as the prevalence of IHD among persons BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

11 Page 0 of younger than 0 years of age is very low. Further, if the atherosclerotic process precedes health anxiety, our results might be affected by residual confounding as we lack data in HUSK on subclinical IHD and atherosclerosis. Arguing against this, a Swedish cohort of close to men aged -0 years examined for military service, presumably before start of the atherosclerotic process, confirmed that anxiety present in early adulthood independently predicted subsequent coronary heart disease. Second, low participation rate and nonparticipation always challenges the generalizability of results from population based studies. A previous study of the HUSK population showed higher risk of being awarded disability pension for both neurotic, stress related or somatoform disorders as well as for diseases in the circulatory system among nonparticipants. In general, nonparticipation represents a greater threat to the validity of results from studies estimating prevalence rather than risks, and we argue that this is a minor threat to the internal validity of our results. Third, health anxiety was associated with established risk factors for IHD such as diabetes, lower levels of education and living alone. These covariates may be confounders for the association between health anxiety and IHD, and were therefore adjusted for in the analyses. However, some of them may also be regarded as mediators in the association, as disadvantageous lifestyle, living without a partner and low educational level could be the result of anxiety earlier in life. By adjusting for such possible mediators, our estimates of the association between health anxiety and IHD will represent an underestimation of the true association. Implications Persons with high levels of health anxiety have about 0% increased risk of IHD relative to persons with lower levels after adjustments for established CVD risk factors, including lifestyle factors. This finding is of public health significance as IHD is one of the main causes of morbidity and mortality worldwide. If persons with high levels of health anxiety stay alert with the intention to better control and detect early signs of severe somatic diseases, it might contribute to unintentional harmful effects as the autonomous activation associated with anxiety in general likely is associated with increased risk of IHD. These findings illustrate the dilemma for clinicians between reassuring the patient that current physical symptoms of anxiety do not represent heart disease, contrasted against the emerging knowledge on how anxiety, over time, may be causally associated with increased risk of IHD. At best, this finding might encourage patients to seek treatment for health anxiety and to trust their heart. 0 BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

12 Page of BMJ Open What this paper adds ) What is already known? Risk of ischemic heart disease is largely influenced by lifestyle. Evidence from several cohort studies shows that anxiety in general is associated with increased risk of ischemic heart disease, independent of lifestyle. Health anxiety, a specific type of anxiety, is characterized by preoccupation about having, acquiring or possibly avoiding illness. ) What this study adds? Similar with anxiety in general, health anxiety is associated with increased risk of ischemic heart disease. Established risk factors for cardiovascular diseases explained part of the association, yet, about 0% increased risk of ischemic heart disease was found among cases with health anxiety the fully adjusted model. New evidence of negative consequences of health anxiety over time underlines the importance of proper diagnosis and treatment. BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

13 Page of Contributorship statement Line Iden Berge: MD, PhD. Faculty of Medicine and Dentistry, University of Bergen, Bergen, and Psychiatric Division, Haukeland University Hospital, Bergen. Designed, analyzed and interpreted the data, drafted the article, approved the final version, has agreed to be accountable for all aspects of the work, and is the guarantor of the study. Jens Christoffer Skogen: PhD. Norwegian Institute of Public Health. Designed, analyzed and interpreted the data, revised the manuscript for important intellectual content, approved the final version of the manuscript and has agreed to be accountable for all aspects of the work. Gerhard Sulo: MD, PhD. Faculty of Medicine and Dentistry, University of Bergen, Bergen. Designed, analyzed and interpreted the data, revised the manuscript for important intellectual content, approved the final version of the manuscript and has agreed to be accountable for all aspects of the work. Jannicke Igland: PhD. Faculty of Medicine and Dentistry, University of Bergen, Bergen. Designed, analyzed and interpreted the data, revised the manuscript for important intellectual content, approved the final version of the manuscript and has agreed to be accountable for all aspects of the work. Ingvard Wilhelmsen: MD, Dr. Med. Faculty of Medicine and Dentistry, University of Bergen, Bergen and Haraldsplass Deaconal University Hospital, Bergen. Designed the study, revised the manuscript for important intellectual content, approved the final version of the manuscript and has agreed to be accountable for all aspects of the work. Stein Emil Vollset: MD, DrPH. Faculty of Medicine and Dentistry, University of Bergen, Bergen and Norwegian Institute of Public Health. Designed, analyzed and interpreted the data, revised the manuscript for important intellectual content, approved the final version of the manuscript and has agreed to be accountable for all aspects of the work. Grethe S. Tell: MPH, PhD. Faculty of Medicine and Dentistry, University of Bergen, Bergen. Designed, analyzed and interpreted the data, revised the manuscript for important intellectual content, approved the final version of the manuscript and has agreed to be accountable for all aspects of the work. Ann Kristin Knudsen: PhD. Faculty of Medicine and Dentistry, University of Bergen, Bergen and Norwegian Institute of Public Health. Designed, analyzed and interpreted the data, revised the manuscript for important intellectual content, approved the final version of the manuscript and has agreed to be accountable for all aspects of the work. All authors had full access to all of the data in the study (including statistical reports and tables) and take responsibility for the integrity of the data and the accuracy of the data analysis. BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

14 Page of BMJ Open Copyright statement The Corresponding Author, Line Iden Berge, has the right to grant on behalf of all authors and does grant on behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in all forms, formats and media (whether known now or created in the future), to i) publish, reproduce, distribute, display and store the Contribution, ii) translate the Contribution into other languages, create adaptations, reprints, include within collections and create summaries, extracts and/or, abstracts of the Contribution, iii) create any other derivative work(s) based on the Contribution, iv) to exploit all subsidiary rights in the Contribution, v) the inclusion of electronic links from the Contribution to third party material where-ever it may be located; and, vi) licence any third party to do any or all of the above. Data sharing statement The Norwegian Institute of Public Health owns the data used in the study. According to their legal department, the data cannot be deposited online as the study participants have not explicitly been informed about, nor approved data sharing when signing the informed consent when the study was undertaken in -. Further, the ethical approval for the study obliges us, in general terms, to protect the privacy of the participants. Readers can apply for access and permission to analyze data from the Hordaland Health Study. Application form and general information can be found at and questions may be directed to project coordinator Kari.Juul@igs.uib.no" Declaration of interest "All authors have completed the ICMJE uniform disclosure form at and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work." Transparency declaration The lead author Line Iden Berge affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. Sources of funding Contribution by each of the authors is considered part of their general work as researchers funded by their respective employers, and the study received no additional funding. BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

15 Page of References. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, fifth edition, DSM-V, 0.. Tyrer P, Eilenberg T, Fink P, et al. Health anxiety: the silent, disabling epidemic. BMJ 0;:i0.. Starcevic V. Hypochondriasis and health anxiety: conceptual challenges. Br J Psychiatry 0;0:-.. Institute for Health Metrics and Evaluation. The global burden of disease: Generating Evidence, Guiding Policy, 0:.. Noyes R, Jr., Carney CP, Hillis SL, et al. Prevalence and correlates of illness worry in the general population. Psychosomatics 00;:-.. Global Burden of Disease Risk Factors Collaborators, Forouzanfar MH, Alexander L, et al. Global, regional, and national comparative risk assessment of behavioural, environmental and occupational, and metabolic risks or clusters of risks in countries, 0-0: a systematic analysis for the Global Burden of Disease Study 0. Lancet 0;: -.. Janszky I, Ahnve S, Lundberg I, et al. Early-onset depression, anxiety, and risk of subsequent coronary heart disease: -year follow-up of, young Swedish men. J Am Coll Cardiol 00;:-.. Roest AM, Martens EJ, de Jonge P, et al. Anxiety and risk of incident coronary heart disease: a meta-analysis. J Am Coll Cardiol 00;:-.. Batelaan NM SA, Bot M, Van Balkom AJLM, Penninx BWHH. Anxiety and new onset of cardiovascular disease: critical review and meta-analysis. Br J Psychiatry 0(0):-. 0. The Hordaland Health Study (HUSK). Pilowsky I. Dimensions of hypochondriasis. Br J Psychiatry ;:-.. Hiller W, Rief W, Fichter MM. Dimensional and categorical approaches to hypochondriasis. Psychol Med 00;:0-.. Speckens AE, Spinhoven P, Sloekers PP, et al. A validation study of the Whitely Index, the Illness Attitude Scales, and the Somatosensory Amplification Scale in general medical and general practice patients. J Psychosom Res ;0:-0.. Sulo G IJ, Vollset SE, Nygård O, Øyen N, Tell GS. Cardiovascular diseases and diabetes mellitus in Norway during -00:CVDNOR- a nationwide research project. Norwegian Journal of Epidemiology 0;:0-0.. CVDNOR: Cardiovascular diseases in Norway. Igland J TG, Ebbing M, Nygård O, Vollset SE, Dimoski T. The CVDNOR project: Cardiovascular Diseases in Norway Description of data and data quality, 0.. The World Health Organisation. The ICD-0 classification of mental and behavioural disorders,.. The Framingham Heart Study, a projekct of the National Heart, Lung and Blood Institute and Boston University. Hard Coronary Heart Disease (0 year risk). year-risk.php.. Veddegjaerde KE, Sivertsen B, Wilhelmsen I, et al. Confirmatory factor analysis and item response theory analysis of the Whiteley Index. Results from a large population based study in Norway. The Hordaland Health Study (HUSK). J Psychosom Res 0;:-. 0. Desquilbet L, Mariotti F. Dose-response analyses using restricted cubic spline functions in public health research. Stat Med 00;:0-.. IBM Corp. Released 0. IBM SPSS Statistics for Windows VA, NY: IBM Corp.. StataCorp. 0. Stata Statistical Software: Release. College Station TSL.. Sunderland M, Newby JM, Andrews G. Health anxiety in Australia: prevalence, comorbidity, disability and service use. Br J Psychiatry 0;0:-. BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

16 Page of BMJ Open Gustad LT, Laugsand LE, Janszky I, et al. Symptoms of anxiety and depression and risk of acute myocardial infarction: the HUNT study. Eur Heart J 0;:-0.. Paterniti S, Zureik M, Ducimetiere P, et al. Sustained anxiety and -year progression of carotid atherosclerosis. Arterioscler Thromb Vasc Biol 00;:-.. Chalmers JA, Quintana DS, Abbott MJ, et al. Anxiety Disorders are Associated with Reduced Heart Rate Variability: A Meta-Analysis. Front Psychiatry 0;:0.. Sulo G, Igland J, Nygard O, et al. Favourable trends in incidence of AMI in Norway during do not include younger adults: a CVDNOR project. Eur J Prevent Cardiol 0;:-.. Knudsen AK, Hotopf M, Skogen JC, et al. The health status of nonparticipants in a populationbased health study: the Hordaland Health Study. Am J Epidemiol 00;:0-. BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

17 Page of Age Missing Gender (male) Missing Cohabiting Missing Table : Characteristics of 0 participants in the Hordaland Health Study (HUSK) without prevalent or month incident ischemic heart disease (hospitalization or death with I0-I). Education Less than high school High school College or university Missing Usual alcohol consumption per days (units) 0 - Missing Activity (hours per week) 0 - Missing Diabetes (yes) Missing st degree relative with AMI before 0 years of age (yes) Missing or unknown BMI Missing Total cholesterol quintiles (mg/dl) st (.) nd (., 0.) rd ( 0.,.) th (.,.) th (.) Missing Non-cases health anxiety # N (%). (.) 0 (0) 0 (.) 0 (0) (.0) 0 (0) Cases health anxiety ## N (%). (.) 0 (0) (0.) 0 (0) 0 (.) 0 (0) 0 (.) (.) (.) 0 (0.) (.0) (.) (.) (.) (.) 0 (.) 0 (.) (.) (.) (.) (.0) (0.) (.) (.) (.0) 0 (.) (.0) 0 (.) (0.) (0.0) (.) (.) (0.) (.) (0.) (.) (.) (0.0) (0.) (.) (.) (.) (.) (.) (.) 0 (.) (.) (0.) (.) (.) (.0) (.0) (.) (.) (0.) (0.) 0 (.) (0.) (.) (.) (.) (.) (.) (0.) p-value for difference 0.00^ 0.* <0.00* <0.00* 0.00* 0.00* 0.00* 0.00* 0.0* 0.* BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

18 Page of BMJ Open HDL quintiles (mg/dl) st (.0) nd (.0,.0) rd (.0,.) th (.,.) th (.) Missing Systolic BP quintiles (mmhg) st (.) nd (.,.) rd (., 0.) th ( 0.,.0) th (.0) Missing Smoking Current Former Never Missing (.) (.) 0 (0.) (0.) (.) (0.). (0.) (.) (.) (.0) (0.) (0.) (0.) (.) (.) (.) (.) (.) (0.). (0. (.) (.) (.0) (0.) (.) (0.) (.) (.) 0 (.) (0.) # Score under 0 th percentile (< points) of Whiteley Index ## Score equal to or above 0 th percentile ( points) of Whiteley Index *Pearson chi-square ^Independent samples t-test mean(st.dev) (.0) (.) (.) (0.) <0.00* 0.* <0.00* BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

19 Page of Table : Hazard Ratios (HR) for incident ischemic heart disease (IHD) comparing cases with and without health anxiety. IHD were events occurring to years after baseline participation in the Hordaland Health Study (HUSK). Estimates are adjusted separately for blocks of covariates and all covariates combined. Total sample (n=0) *Score equal to or above 0 th percentile of Whiteley Index ( points) Gender, cohabiting and education Gender, alcohol consumption, physical activity, diabetes, BMI, st degree relative with AMI before 0 years, smoking, total cholesterol, HDL cholesterol, systolic blood pressure. Gender, cohabiting, education, alcohol consumption, physical activity, diabetes, BMI, st degree relative with AMI before 0 years, smoking, total cholesterol, HDL cholesterol, systolic blood pressure. Men (n=) Women (n=) N events (%) (.) (.) (.) HR (% C.I.) HR (% C.I.) HR (% C.I.) Adjusted for gender. (.,.).0 (.,.0). (.,.) Adjusted for sociodemographic.00 (.,.). (.0,.). (.,.0) factors Adjusted for CVD risk factors. (.,.). (.,.). (0.0,.) Adjusted for all covariates. (.,.). (.,.). (0.,.0) BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

20 Page of BMJ Open Table : Hazard Rations (HR) for incident ischemic heart disease events to years after baseline participation in the Hordaland Health Study (HUSK) by quintiles of Whiteley Index. Estimates are adjusted separately for blocks of covariates and all covariates combined. Gender, cohabiting and education N= 0 Quintiles of Whiteley Index (corresponding scores on Whiteley Index) p-value for trend Gender, alcohol consumption, physical activity, diabetes, BMI, st degree relative with AMI before 0 years, smoking, total cholesterol, HDL cholesterol, systolic blood pressure. Gender, cohabiting, education, alcohol consumption, physical activity, diabetes, BMI, st degree relative with AMI before 0 years, smoking, total cholesterol, HDL cholesterol, systolic blood pressure. ^ linear by linear association st (-) nd (-) rd (0-) th (-) th ( ) N events (%) (.) (.) (.0) (.) (.)) <0.00^ HR (% C.I.) HR (% C.I.) HR (% C.I.) HR (% C.I.) HR (% C.I.) Adjusted for gender (ref). (.0,.). (.0,.). (.0,.).0 (.,.) <0.00 Adjusted for gender and (ref). (.0,.). (.0,.). (.,.0). (.,.) <0.00 sociodemographic factors Adjusted for CVD risk factors (ref). (0.,.00).0 (0.,.0). (.,.0). (.,.) 0.00 Adjusted for all covariates (ref). (0.,.). (0.,.). (.0,.). (.,.) 0.00 on January 0 by guest. Protected by copyright. BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from

21 Page 0 of xmm (00 x 00 DPI) BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

22 Page of BMJ Open STROBE Statement Checklist of items that should be included in reports of cohort studies Item No Recommendation Title and abstract (a) Indicate the study s design with a commonly used term in the title or the abstract Introduction Response: The study design is included in the title, page (b) Provide in the abstract an informative and balanced summary of what was done and what was found Response: We argue that the abstract is balanced and informative, page. Background/rationale Explain the scientific background and rationale for the investigation being reported Response: We argue that paragraph - on page explains the scientific background and rationale for the study. Objectives State specific objectives, including any prespecified hypotheses Methods Response: Objective and hypotheses regarding the outcome of the study are presented in paragraph on page. The specific aims of the study are presented in paragraph on page. Study design Present key elements of study design early in the paper Response: Key elements regarding study design are presented in the title of the study om page, in the abstract on page and described in detail on page -. Setting Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection Response: This information is given on page and the first paragraph of page. Participants (a) Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up Response: This information is given on page and on the first paragraph of page. (b) For matched studies, give matching criteria and number of exposed and unexposed Response: Not relevant. Variables Clearly define all outcomes, exposures, predictors, potential confounders, and effect Data sources/ measurement modifiers. Give diagnostic criteria, if applicable Response: This information is given in paragraph and on page, and in paragraph on page. A discussion on whether the covariates represent confounders or mediators for the association between health anxiety and ischemic heart disease are included at the end of paragraph on page. * For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group Response: This information is given in paragraph and on page and in paragraph on page. Bias Describe any efforts to address potential sources of bias Response: Efforts to address bias due to missing data on exposure variable and due to reverse causality are described in paragraph on page. Study size 0 Explain how the study size was arrived at Response: This information is given in paragraph on page. Quantitative variables Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why Response: this information is given in paragraph and on page and in paragraph on page. Statistical methods (a) Describe all statistical methods, including those used to control for confounding BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.

23 Page of Response: Statistical procedures are described under the subheading Study sample and statistical procedures on page and. A discussion on whether the covariates represent confounders or mediators for the association between health anxiety and ischemic heart disease, and whether they should be adjusted for in the Cox proportional regression analysis are included at the end of paragraph on page. (b) Describe any methods used to examine subgroups and interactions Response: Analyses exploring the association between health anxiety and incident ischemic heart disease were stratified on gender, described in paragraph of page. (c) Explain how missing data were addressed Response: Information on how missing data on the exposure was handled is given in paragraph on page. Number and percentage of missing on the covariates are given in table. (d) If applicable, explain how loss to follow-up was addressed Response: Not relevant, no loss to follow up. (e) Describe any sensitivity analyses Response: Information on a sensitivity analysis on the effect of non-response on the exposure is given in paragraph on page. Information on a sensitivity analysis operationalizing the exposure variable according to a recently confirmatory factor and item response theory is given in paragraph on page and paragraph on page. Results Participants * (a) Report numbers of individuals at each stage of study eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed Response: This information is given in paragraph on page and in paragraph on page. (b) Give reasons for non-participation at each stage Response: This information is given in paragraph on page and in paragraph on page. (c) Consider use of a flow diagram Response: We considered using a flow diagram, but argued against it due to limited number of figures. We argue that this information is clearly evident in the text. Descriptive data * (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders Response: This information is given in paragraph on page and in table. (b) Indicate number of participants with missing data for each variable of interest Response: This information is given in table and in section on page. (c) Summarise follow-up time (eg, average and total amount) Response: Information on maximum follow up time is given in the methods section in the abstract on page and information on average follow up time is given in paragraph on page. Outcome data * Report numbers of outcome events or summary measures over time Response: This information is given in table and, and in paragraph on page. Main results (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, % confidence interval). Make clear which confounders were adjusted for and why they were included Response: This information is given in paragraph on page as well as in table and. (b) Report category boundaries when continuous variables were categorized Response: This information is given in table. BMJ Open: first published as 0./bmjopen-0-0 on November 0. Downloaded from on January 0 by guest. Protected by copyright.