Which of the following is a cardiovascular problem that is a result of chronic stress?

1. Huan Song, postdoctoral fellow1 2,
2. Fang Fang, associate professor2,
3. Filip K Arnberg, associate professor3 4,
4. David Mataix-Cols, professor5 6,
5. Lorena Fernández de la Cruz, assistant professor5 6,
6. Catarina Almqvist, professor2 7,
7. Katja Fall, associate professor2 8,
8. Paul Lichtenstein, professor2,
9. Gudmundur Thorgeirsson, professor1,
10. Unnur A Valdimarsdóttir, professor1 2 9

1. 1Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland
2. 2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
3. 3National Centre for Disaster Psychiatry, Department of Neuroscience, Psychiatry, Uppsala University, Uppsala, Sweden
4. 4Stress Research Institute, Stockholm University, Stockholm, Sweden
5. 5Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
6. 6Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden
7. 7Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden
8. 8Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden
9. 9Department of Epidemiology, Harvard T H Chan School of Public Health, Boston, MA, USA

1. Correspondence to: H Song huan{at}hi.is or huan.song{at}ki.se

• Accepted 12 March 2019

Abstract

Objective To assess the association between stress related disorders and subsequent risk of cardiovascular disease.

Design Population based, sibling controlled cohort study.

Setting Population of Sweden.

Participants 136 637 patients in the Swedish National Patient Register with stress related disorders, including post-traumatic stress disorder [PTSD], acute stress reaction, adjustment disorder, and other stress reactions, from 1987 to 2013; 171 314 unaffected full siblings of these patients; and 1 366 370 matched unexposed people from the general population.

Main outcome measures Primary diagnosis of incident cardiovascular disease—any or specific subtypes [ischaemic heart disease, cerebrovascular disease, emboli/thrombosis, hypertensive diseases, heart failure, arrhythmia/conduction disorder, and fatal cardiovascular disease]—and 16 individual diagnoses of cardiovascular disease. Hazard ratios for cardiovascular disease were derived from Cox models, after controlling for multiple confounders.

Results During up to 27 years of follow-up, the crude incidence rate of any cardiovascular disease was 10.5, 8.4, and 6.9 per 1000 person years among exposed patients, their unaffected full siblings, and the matched unexposed individuals, respectively. In sibling based comparisons, the hazard ratio for any cardiovascular disease was 1.64 [95% confidence interval 1.45 to 1.84], with the highest subtype specific hazard ratio observed for heart failure [6.95, 1.88 to 25.68], during the first year after the diagnosis of any stress related disorder. Beyond one year, the hazard ratios became lower [overall 1.29, 1.24 to 1.34], ranging from 1.12 [1.04 to 1.21] for arrhythmia to 2.02 [1.45 to 2.82] for artery thrombosis/embolus. Stress related disorders were more strongly associated with early onset cardiovascular diseases [hazard ratio 1.40 [1.32 to 1.49] for attained age 80%]. We excluded patients who received a diagnosis before age 5 [n=139],21 had a history of any cardiovascular disease before the diagnosis of a stress related disorder [n=15 899], or had conflicting information [died or emigrated before the diagnosis of a stress related disorder; n=24]. To enable the complete familial links from the Swedish Multi-Generation Register that includes largely complete familial information for people born in Sweden from 1932 onward, we excluded 3838 people born before 1932, leaving 136 637 patients in the analysis. We considered patients with stress related disorders to be exposed from the date of their diagnosis.

Sibling cohort

To control for the familial components,22 we identified 106 180 clusters of full siblings discordant for stress related disorders with a total of 171 314 unaffected full siblings who were alive and free of stress related disorders and cardiovascular disease at the diagnosis date of the affected sibling, through the Multi-Generation Register. We used the date of diagnosis of the affected sibling as the index date for both siblings.

Population matched cohort

We compared the patients with stress related disorders with the general population in a matched cohort. For each exposed patient, we randomly selected 10 people from the Total Population Register who were free of stress related disorders and cardiovascular disease at the diagnosis date of the index patient. Exposed patients and unexposed people were individually matched by birth year and sex. We used the date of diagnosis as the index date for both exposed patients and the matched individuals.

Follow-up

Follow-up of all study participants was from the index date until the first primary diagnosis of cardiovascular disease [any or specific subtype], death, emigration, or the end of follow-up [31 December 2013], whichever occurred first. The follow-up time for the unaffected full siblings or matched unexposed people was additionally censored at the time of their first diagnosis of stress related disorder, if any, during the follow-up.

Definition of stress related disorders

We defined stress related disorders as any first outpatient or inpatient visit with the main diagnosis of the 9th or 10th Swedish revisions of the international classification of diseases [ICD] codes 308 or 309 [ICD-9] or F43 [ICD-10], according to the National Patient Register. We further divided stress related disorders into PTSD [ICD-9: 309B; ICD-10: F43.1], acute stress reaction [ICD-9: 308, 309A; ICD-10: F43.0], and adjustment disorder and other stress reactions [ICD-9: 309X; ICD-10: F43.8, F43.9]. Because PTSD may initially be preceded by acute stress reaction or other stress related disorders,23 we considered all patients who received a diagnosis of PTSD within one year after their first stress related disorder diagnosis to be PTSD patients.

Definition of cardiovascular diseases

We defined an incident cardiovascular disease event [any; specific subtypes including ischaemic heart disease, cerebrovascular disease, emboli/thrombosis, hypertensive disease, heart failure, and arrhythmia/conduction disorder; or individual events] as an outpatient or inpatient visit [according to the National Patient Register] with a main diagnosis of cardiovascular disease or as a death [according to the Cause of Death Register] with cardiovascular disease as the underlying cause, using corresponding ICD codes [see supplementary table B]. We defined a fatal cardiovascular disease as death within 30 days after an incident cardiovascular disease event.24

Covariates

Stress related disorders show substantial comorbidity with other psychiatric disorders, such as mood and anxiety disorders.25 We therefore defined other psychiatric disorders as “history of other psychiatric disorders” if the first diagnosis was made more than three months before the diagnosis of a stress related disorder. We defined other psychiatric disorders that had a first diagnosis made within three months before and one year after the diagnosis of a stress related disorder as “psychiatric comorbidity.” Diagnoses of other psychiatric disorders also came from the National Patient Register [ICD-8: 290-319 except 307, 308.4; ICD-9: 290-319 except 308, 309; and ICD-10: F10-F99 except F43].

We retrieved information about educational level, family income, and marital status from the Longitudinal Integration Database for Health Insurance and Labor Market. History of severe somatic diseases, including chronic pulmonary disease, connective tissue disease, diabetes, renal diseases, liver diseases, ulcer diseases, and HIV infection/AIDS, which are considered to contribute to survival time,26 were collected on the basis of the National Patient Register [ICD codes listed in supplementary table B]. We defined family history of cardiovascular disease as any cardiovascular event among any first degree relatives [that is, biological parents and full siblings] of the participants according to the National Patient Register and the Cause of Death Register. In all analyses, we used the most recent information before the index date for each covariate, except for psychiatric comorbidity [as defined above].

Statistical analysis

We first visualised the time dependent associations of stress related disorders with the risk of cardiovascular disease by using flexible parametric survival models.27 Because of the greatly increased risk of cardiovascular disease during the time period immediately after the diagnosis of stress related disorders, compared with thereafter, we assessed the associations separately during the first year after a diagnosis of stress related disorder and beyond this one year period [