Discussion
In this large population-based study, the severely stressful life event of losing a partner was associated with a transiently increased risk of AF, which lasted for about 1 year. The elevated risk was especially high for those who were young and those who lost a relatively healthy partner.
To the best of our knowledge, our study is the first to examine the risk of AF after stressful life events, but an association has been suggested by case reports.9 A few studies have examined the relationship between psychological distress and AF, but the association remains unclear. The Women's Health Study from the US24 followed 30 746 women for a median of 125 months and identified 771 patients with AF. The study used the Mental Health Inventory-5 to measure global psychological distress, but no association with AF was revealed. As the American study included only few severely distressed study participants and did not take timing into account, an acute effect of severe stress may have been overlooked. In our study, the association between bereavement and AF was weak 1 year after the bereavement if at all present. A cohort study from Australia25 followed 226 patients for a median of 6 days after cardiac surgery and identified 56 patients who developed AF. They used the Depression Anxiety Stress Scales to measure self-reported postoperative stress, depression, and anxiety symptoms. Their findings showed that only anxiety was associated with higher risk of AF. The Australian study was, however, limited by small sample size. In addition, the results may not apply to the general population as the study was based on a highly selected group of individuals who had just undergone cardiac surgery.
Our study indicated that one of the most severe types of stress is associated with an increased risk of AF. We used the ACCI scores of the deceased partner 1 month before the death as a proxy for the expectedness of the death because we presume that the stress associated with bereavement is more severe if the loss is unexpected.26 We found that the highest risk was associated with the least predicted losses, while no association was found for more expected losses (ie, the partners with the highest ACCI scores). A long-lasting disease with great suffering and considerable care may be stressful and place high demands on the partner, and death may sometimes even be a relief. Cardiovascular disease, diabetes and male sex are well-known risk factors for AF.1 However, in our study, the OR of AF after bereavement did not differ much in the investigated subgroups during the 30-day period.
Bereavement is a major life event, which is known to increase the risk of cardiovascular disease,7 mental illness27 and death.28 The underlying causal mechanisms for the association between the loss of a partner and AF is unclear, but acute stress may possess direct arrhythmogenic properties by alternating autonomic control, influencing heart rate variability and enhancing proinflammatory cytokines.10–12 Animal studies have substantiated the importance of the neural component surrounding AF when manipulation of the autonomic pathways either promotes or eliminates AF.29 In addition, patients with paroxysmal AF often claim that emotional stress is a common triggering factor8 and increasing levels of perceived stress are associated with prevalent AF.30
The main strengths of our study include the population-based design and the large sample size, which allowed us to consider timing and study the association in high-risk populations. The case–control study was nested in a nationwide cohort and included all persons treated for inpatient incident AF in any Danish hospital during the study period. Denmark provides free access (tax-funded) to healthcare services for all residents, and the registration of AF is known to be valid (positive predictive value 92.6%).17 Controls were randomly selected from the underlying cohort using risk-set sampling. Thus, bias due to selection of study participants is an unlikely explanation for our findings. Since a precise day of onset is important in timing analysis, we only included persons with new onset of AF who were treated in hospitals as inpatients. We expect that the vast majority of these cases had an acute onset. Unfortunately, we do not have information on the diagnoses made in primary care in Denmark. However, the results were virtually unchanged when we excluded cases and corresponding controls who had redeemed a prescription of an antithrombotic agent before the index date. Information on the death of a partner was collected prospectively and did not rely on the memory of the study participants. Registration of death in the Danish Civil Registration System has a high validity and a completeness close to 100%, which implies that our assessment of death is accurate.15 In our study, the participants had to be married or cohabiting in order to be categorised as exposed to bereavement. This procedure is, however, unlikely to have introduced any bias as the results did not change much if we used only non-bereaved cohabitants as controls.
We adjusted for several confounding factors, such as medication and comorbid conditions, and found only little change in the estimates. However, residual confounding cannot be ruled out because we had no information on potential confounding factors such as lifestyle factors, physical activities and family history of AF. We believe that the risk of residual confounding is likely to be small as we cannot think of any possible confounder that could cause a transiently increased risk of AF shortly after bereavement. Adverse lifestyle factors (such as increased alcohol consumption, decreased sleep quality, poor diet and less physical activity)31 caused by the bereavement may be steps on the causal pathway from bereavement to AF1 and, therefore, should not be adjusted for.23
In conclusion, we found a transiently increased risk of AF after partner bereavement, especially if the loss was unpredicted according to the Charlson comorbidity index. Our results call for further studies aiming at evaluating whether the association also applies to more common, but less severe, stressors and at identifying causal mechanisms and treatment possibilities.