In this large prospective study based on a bi-national cohort, we found that the death of a parent or sibling, both in childhood and in adulthood, was associated with an increased risk of AF. The association was largely similar across all the categories of age at loss and did not differ substantially according to whether the loss concerned a parent or a sibling. Bereavement in childhood was associated with AF only in case of losses due to CVD or other natural causes, while the loss in adulthood was associated with AF in case of unnatural deaths as well.
Comparison with earlier studies
To our knowledge, this is the first study to investigate the association between childhood adversity and the risk of AF. The findings that the death of a parent or sibling, both in childhood and in early adulthood, was associated with an increased risk of AF corroborate the results of earlier studies showing that individuals who lost a partner or child had higher risks of AF than their unexposed counterparts [5, 26]. Similarly, the results were in line with the findings of several [6,7,8,9], though not all [10, 11], previous studies suggesting that job stress, adverse life events, psychological distress, and certain psychiatric disorders are associated with AF, as well as those of several earlier studies reporting an increased risk of cardiovascular mortality or incident ischemic heart diseases, stroke, or heart failure in adulthood after experiencing the death of a parent [15, 27,28,29] or sibling in childhood [30] or after exposure to other childhood adversities [31]. Our study contributes to the existing literature on the role of stress and adverse life events in the etiology of AF by investigating the exposure to death of a close relative in childhood (overall and by subtypes) in a large bi-national cohort study, by comparing the effects of childhood and adult bereavement, and by considering a large number of potential confounders of this association.
We found that the risk of AF was increased when the loss—in childhood or adulthood—was due to CVD or other natural causes. This finding is in line with that of several other studies reporting the highest risks of acute myocardial infarction, ischemic heart disease, stroke, and cardiovascular mortality after the loss of a parent in childhood [15, 28] and of a sibling in childhood and adulthood [32,33,34] if the relative’s death was due to natural, in particular, cardiovascular deaths. One potential explanation for these findings is confounding due to shared familial cardiovascular risk factors, e.g., genetic susceptibility, diet, or living environment. Alternatively, it is possible that childhood adversity may increase the risk of AF only among those with a cardiometabolic vulnerability, which is likely to be more pronounced among those who lost a parent due to CVD or other related diseases. In contrast, unnatural deaths of the relatives—which are less likely to be affected by cardiovascular risk factors clustering in the family—were associated with the risk of AF only if the loss occurred in adulthood, providing stronger support for the hypotheses that stress-related mechanisms may operate.
The association between the parent’s or the sibling’s death in childhood and the risk of AF may differ according to the age of the child at loss. The first few years of life are a sensitive period regarding the loss of a parent as the early interaction with caregivers is critical for the development of the brain architecture and the programming of stress reactivity [35]. Adolescence is another potentially sensitive period, given that adolescents exposed to stress may adopt negative coping strategies in terms of adverse health behaviors [36]. Nevertheless, we found no evidence that the risk of AF differed according to the minor child’s age at loss. Similarly, we expected that the death of parents may have a stronger emotional impact and be more closely related to the adverse health outcomes than the death of a sibling in childhood. Similarly, mothers are often the primary attachment figures and are probably more involved in their children’s upbringing than fathers [37, 38]. However, the associations did not differ substantially when comparing the loss of a sibling to that of a parent, and a link between the death of a parent in childhood and the risk of AF was observed only in the case of deaths of the father, but not of the mother. We speculate that a possible explanation for this latter finding may be related to better statistical power in case of paternal deaths in childhood or a higher proportion of cardiovascular and other natural deaths among the fathers than the mothers during childhood.
Potential linking mechanisms
It is not clear why we did not find an association between bereavement due to unnatural causes in childhood—which are less likely to be affected by cardiovascular risk factors than natural deaths—and the risk of AF. One explanation may be related to the earlier observation in adult samples that the AF risk increase after the loss was more pronounced in the short than in the long term [5]. A similar triggering effect may not apply for pediatric AF, a condition with largely unknown, but potentially different etiology than AF in adulthood, nor for the relation between exposure in childhood and AF in adulthood. Moreover, detecting AF in children may be more difficult than in adults due to the differences in symptom presentation or the lower quality of the information provided by children on their symptoms or because physicians would normally not expect AF in childhood [39]. Though we did not observe an association in the case of unnatural deaths in childhood, it is still possible that stress in childhood may increase the risk of AF if it interacts with cardiometabolic vulnerability.
Bereavement, in childhood or adulthood, may increase the risk of AF through several pathways. An increasing number of studies suggest an elevated autonomic nervous system activity before episodes of paroxysmal AF [40, 41], while others document a higher frequency of stressful life events before paroxysmal AF [42] or first AF diagnoses [5, 26], i.e., a triggering effect. In the longer term, bereavement stress and the associated chronic activation and dysregulation of the hypothalamic-pituitary-adrenal axis and the autonomic nervous system may increase the risk of psychological distress, mental disorders, adverse lifestyle, and unfavorable changes in the autonomic tone and in endocrine, immune, inflammatory, hemodynamic, and cardiovascular activity [17, 18]. These in turn may promote electrical changes and the structural remodeling of the heart [18,19,20,21,22], thereby triggering and sustaining AF [2, 23]. Our findings of a lower AF risk in bereaved individuals who did not develop compared to those who developed ischemic heart diseases, heart failure and hypertension after the loss, may be supportive of these hypotheses, though differences in detection of AF may have also contributed to these findings.
Strengths and limitations
Our study had several strengths. First, we had prospectively collected information on offsprings from birth up to early middle age for both exposure and outcome. Second, the large sample size yielded us the possibility to detect modest associations, to conduct several important sub-analyses according to the characteristics of bereavement, or to relevant sociodemographic factors. Third, the extensive register linkages allowed us to adjust for several important covariates. Nevertheless, our findings need to be interpreted in light of some limitations. First, though we adjusted for several covariates, we did not have information on other potential confounders such as genetic factors, lifestyle, and living environment. Second, our findings may only be generalized to countries comparable to Denmark and Sweden in terms of their welfare system, sociocultural context, and quality and accessibility of healthcare. We could expect that the association between bereavement and AF would be stronger in countries with more limited resources for bereaved children or where adults rely to a larger extent on support from family than the state. Third, though the positive predictive value of the AF diagnoses in the Danish and Swedish patient register has been shown to be very high [24, 25], we may have missed (1) some mild AF cases and (2) AF diagnoses before the coverage of the Danish Hospital Register and the Swedish Patient Register with respect to specialized outpatient care became complete. Similarly, since information on psychiatric disorders was retrieved from specialized outpatient and inpatient care, we may have missed the milder forms of psychiatric diseases in our variables concerning parents’ and family history of psychiatric disorders. Fourth, as information on cardiovascular medications was available only for individuals born after 2005 in Sweden, our possibilities to investigate the importance of antihypertensive or other medication in the studied association were limited.