The present study is, to our knowledge, the first nationwide study to estimate the familial risk of recurrent hospitalization for LAF. Previous studies have only investigated the familial risk of a first AF event [6–15]. The present study found similar familial risks for first time LAF event to those reported previously [6–15]. The familial risk for recurrent LAF hospitalization was lower than the risk for first time LAF hospitalization, suggesting that familial and possibly genetic factors are more important for first time LAF hospitalization than recurrent LAF hospitalization. Our findings indicate that family history of AF is a new risk factor for recurrent hospitalization for LAF. The higher risk for recurrent LAF hospitalization among multiplex families (i.e. two or more affected relatives) may be genetic although non-genetic familial factors cannot be ruled out. There was an interaction between age and family history, with family history having a weaker effect on AF hospitalization risk in older age groups, which further indicates a genetic contribution. Identifying genetic risk factors for AF may have important prognostic value regarding recurrence risk. The mechanism behind the observed familial recurrent LAF hospitalization risk might be genetic or non-genetic. For instance, patients with familial LAF might have a higher AF awareness and possibly have a lower threshold for seeking health care. However, several genetic variants have been linked to risk of AF [16–25]. It is possible that these variants may also predispose individuals to an increased risk of recurrent hospitalization for LAF. Moreover, the dissected underlying familial risk factors (genetic or nongenetic) are likely to have a magnitude that is stronger than the familial risk itself [40, 41]. For instance, it has been estimated that 10 additive alleles, each with a genotype relative risk of 2.0 and an allele frequency of 0.1, will only explain a familial risk of 1.06 . If multiplicative gene-gene interactions are present, the same 10 alleles will still only explain a familial risk of 1.2 .
Interestingly, there appears to be an interaction between sex and family history, with family history of AF having a greater effect in women than in men in the context of risk of recurrent hospitalization for AF. This suggests that familial and possibly genetic factors might be relatively more important in women than in men regarding recurrent risk of hospitalization for LAF. In individuals without family history of AF, male sex was a risk factor for recurrent LAF. This is opposite to a study that found female sex to be associated with recurrence of AF . However, the patients in that study were older and had cardiovascular comorbidities, which may explain the divergent results. We also investigated whether family history of AF is a risk factor for a third recurrent LAF hospitalization. No such association was found. This may be due to that having a personal history of two or more AF is a strong risk factor in itself for recurrent AF .
The present study has a number of strengths. These include complete nationwide coverage in a country with high medical standards and medical diagnosis of patients by specialists during examinations in hospitals. In addition, the results were not affected by recall bias because both the probands and cases were medically diagnosed. Importantly, the Multigeneration Register is a validated source that has been proved to be reliable in the study of many familial diseases [33–37].
In order to exclude cardiovascular confounders we excluded all LAF patients who developed CVD during the 10 year follow up period after first LAF hospitalization (Table 2, model 1G). The HR for recurrent LAF hospitalization was similar, which suggests that the results are not confounded by other CVD outcomes during follow up.
The present study has also a number of limitations. The most important limitation is that we do not know whether recurrent LAF hospitalization is due to a new episode of paroxysmal AF or to the same persistent episode of AF. Thus, the results could reflect an increased risk of recurrent paroxysmal AF or symptomatic persistent AF in familial cases. The increased risk for recurrent hospitalization persisted during the whole follow up period (10 years after first hospitalization), which suggests that our results mainly reflect an increased risk of recurrent paroxysmal AF. Early recurrence could sometimes be due to admittance for elective cardioversion of persistent AF after at least three weeks of treatment with anticoagulation. However, normally elective cardioversion is performed in outpatients.
Longitudinal registers are subject to missing data before the date the register started. The Swedish Hospital Discharge Register only contains complete data for the period since 1987. However, such losses would be similar for both cases and controls and would not affect the estimates of familial aggregation (i.e. the HR). This is most likely a source of non-differential bias regarding familial risk estimates.
Another potential limitation is that we do not have access to the methods used for objective diagnosis. However, the Swedish Hospital Discharge Register has high validity, especially for cardiovascular disorders such as AF (97%), stroke and myocardial infarction (approximately 95%) [37, 38]. However, hypertension is not specifically validated and it is possible that the prevalence of this diagnoses is underestimated. It is therefore possible that some non-LAF cases have been included in the LAF group. This may have underestimated the familial recurrence of LAF, due to dilution of LAF cases with non-LAF cases.
While not all patients may seek help for AF, affordability of healthcare is probably not a selective factor in Sweden because of equal access to primary and hospital care. However, the likelihood of seeking medical advice might be of importance. It is possible that patients with familial LAF might have a higher AF awareness and possibly have a lower threshold for seeking health care. Thus, familial non-genetic factors might also be of importance.