Family history as a risk factor for recurrent hospitalization for lone atrial fibrillation: a nationwide family study in Sweden
BMC Cardiovascular Disorders
Family history as a risk factor for recurrent hospitalization for lone atrial fibrillation: a nationwide family study in Sweden
Bengt Zller 0 2
Henrik Ohlsson 0 2
Jan Sundquist 0 1 2
Kristina Sundquist 0 1 2
0 Center for Primary Health Care Research, CRC, Skane University Hospital , Building 28, Floor 11, Jan Waldenstroms gata 35, Malmo S-205 02 , Sweden
1 Stanford Prevention Research Center, Stanford University School of Medicine , Stanford, California , USA
2 Center for Primary Health Care Research, CRC, Skane University Hospital , Building 28, Floor 11, Jan Waldenstroms gata 35, Malmo S-205 02 , Sweden
Background: Although the heritability of atrial fibrillation (AF) has been determined, the relevance of family history of AF for the likelihood of recurrent hospitalization for AF is unknown. The aim of this nationwide study was to determine whether family history of AF is a risk factor of recurrent hospitalization for lone AF (LAF), i.e., AF with unknown etiology. The familial risk for first time LAF hospitalization was also determined and compared to the risk of recurrent hospitalization for LAF. Methods: We examined whether family history of AF is a risk factor for recurrent hospitalization for LAF in the whole Swedish population. We linked Multigeneration Register data on individuals aged 0-60 years to Hospital Discharge Register data for the period 1987-2009 to compare LAF recurrent hospitalization risk among individuals with and without parental or sibling history of AF. We calculated hazard ratios (HRs) to determine the familial HR of recurrent hospitalization for LAF. Odds ratios (OR) were calculated for familial risk of first time LAF hospitalization. Results: The risk of recurrent LAF hospitalization was 1.23 (95% CI 1.17-1.30) for individuals with affected parents compared to 1.30 (95% CI 1.22-1.38) for those with affected siblings. After 10 years of follow up 50% of those without and 60% of those with family history had recurrent hospitalization for LAF. The risk of recurrent LAF hospitalization in individuals with two affected parents was 1.65 (95% CI 1.44-1.90). There was an interaction between age and family history, with family history having a weaker effect on LAF hospitalization risk in older age groups. The OR for first time LAF hospitalization was 2.08 (95% CI 2.02-2.15) for offspring with affected parents and 3.23 (95% CI 3.08-3.39) for individuals with affected siblings. Conclusions: Family history of AF is a novel risk factor for recurrent LAF hospitalization. The higher recurrence hospitalization risk in multiplex families and younger individuals suggests a genetic contribution. However, the familial risk for recurrent LAF hospitalization was much 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.
Atrial fibrillation; Family history; Risk factors; Genetics
Atrial fibrillation (AF) is a major public health problem
because of its increasing prevalence and because it is
associated with increased morbidity and mortality [1,2].
Many risk factors for AF have been described and they
include, e.g., old age, cardiomyopathy, valvular disease,
ischemic heart disease, heart failure, thyroid disease,
hypertension and diabetes mellitus [1-3]. In some
patients, its etiology remains unknown. AF occurring
before the age of 60 years without any evidence of
associated cardiopulmonary or other comorbid disease has
been termed lone AF (LAF) [4,5]. Familial AF was first
reported in 1943 , and familial clustering of AF has
been repeatedly demonstrated [7-15]. The first
chromosomal location of an AF susceptibility gene was reported
in 1997 based on genetic mapping studies in three
families . Several genetic variants have since then been
linked to risk of AF [17-25]. The importance of family
history for LAF has been determined in several studies
Despite the use of antiarrhythmic agents for sinus
rhythm maintenance in cardioverted AF patients, a
considerable proportion of patients relapse to AF . It is
generally believed that these recurrences are associated
with older age, atrial dilatation, and long duration of AF
. Studies have also suggested that female sex, obesity,
personal history of two or more AF events, decreased
renal function, increased circulating markers of
cardiomyocyte injury/strain (high-sensitivity troponin T,
Nterminal probrain natriuretic peptide and mid-regional
proatrial natriuretic peptide) and endothelin, and
increased C-reactive protein to be risk factors for relapse
to AF [26-32]. The tendency of AF to become sustained
over time is not easily managed, and represents a
challenging therapeutic problem. Although family history is
a risk factor for first event of AF [6-15], the risk of AF
recurrence in patients with a family history of AF has
not yet been determined.
In this nationwide study, we investigated the
relationship between family history of AF and the risk of
recurrent hospitalization for LAF. The familial risk for first
LAF hospitalization was also determined and compared
to the risk of recurrent hospitalization for LAF.
To assess LAF among individuals in Sweden,
comprehensive register and health care data from multiple
nationwide sources were linked [33-37]. This linking was
based on the unique 10-digit personal ID numbers
assigned at birth or immigration to all Swedish residents
for life, information on which is nearly 100% complete.
These numbers were replaced with serial numbers to
preserve anonymity. Our database contains data from
1. The Swedish Multigeneration Register, which
contains information on family relationships (siblings,
parent-offspring). The register contains information
on index persons registered in Sweden between
January 1, 1961 and December 31, 2008 and born
between January 1, 1932 and December 31, 2008.
2. The Swedish Hospital Discharge Register, which
contains information on all hospital diagnoses for all
people in Sweden for the period 19872009. Each
record includes the main discharge diagnosis.
3. The Swedish Cause of Death Register, which contains
data on date of death for the period 19612010.
4. The Total Population Register, which includes data
on year of birth, gender, country of birth and
This study was approved by the Ethics Committee of
Lund University, Sweden.
Cases of LAF were identified in the Swedish Hospital
Discharge Register by the use of the ICD (International
Classification of Diseases) codes 427D (ICD-9) and I48
(ICD-10) and age 60 years at the first diagnosis of AF.
Individuals with one or more of the following discharge
diagnoses within the 5-year period prior to the first
diagnosis of AF were excluded: Hypertension (401405
(ICD-9) and (I10-I15 (ICD-10)); Heart failure (428
(ICD9) and I50 (ICD-9)); Coronary heart disease (410414
(ICD-9) and I20-I25 (ICD-9)); Morbi rheumatici cordis
and Valvular disease (390398, 421 and 424 (ICD-9) and
I00-I09 and I33-I39 (ICD-10)); Cardiomyopathy (425
(ICD-9) and I42 and I43 (ICD-10)); Myocarditis (422
(ICD-9) and I40 and I41 (ICD-9)); Pericarditis (420
(ICD-9) and I30-I32 (ICD-10)); Other heart disease (429
(ICD-9) and I51 (ICD-10)); Thyrotoxicosis (242 (ICD-9)
and E05 (ICD-10)); and Diabetes mellitus (250 (ICD-9)
and (E10-E14 (ICD-10)). These diagnoses, together with
the same diagnoses from the Cause of Death Register,
were also used to define cardiovascular disease (CVD)
outcome in model 1.G (see below).
AF in parents and siblings was defined by the ICD
codes 427D (ICD-9) and I48 (ICD-10). Parental history
of AF was defined as AF in at least one parent during
the study period. Sibling history of AF was defined as
AF in at least one sibling sometime during the study
The validity of the diagnosis of AF has been evaluated,
and diagnoses were found to be correct in 97% of cases
in the Hospital Discharge Register [37,38]. Diagnoses of
other cardiovascular disorders such as stroke and
myocardial infarction have an approximate 95% validity .
Generally, the validity in the Hospital Discharge Register
is approximately 85-95% .
The analyses were based on a database containing
information on all cases of LAF during the period 19872009
(n=29,660, mean age=50.1 years (SD=9.6), 74% men, AF
We used Cox proportional hazards models in order to
investigate recurrence of AF within 10 years. Cases were
followed from date of LAF diagnosis during the study
period until AF recurrence, death, emigration or the end
of the follow-up period (December 31, 2009 or a
maximum of 10 years) (whichever came first). In the first
analysis, a parent-offspring analysis, we investigated all
LAF proband cases whose parents both lived in Sweden
sometime between 1987 and 2009 (n=16,160). In model
1.A, parental history of AF was included as a covariate
(yes/no), and in model 1.B we also included sex, age at
diagnosis of LAF (centered at the mean value), and
terms for the interaction between parental history of AF
and age/sex. The interaction terms were only included
in the model if the p-values were <0.05. In model 1.C
the variable parental history was categorized as no
parental history of AF, one parent with AF and two parents
with AF. In model 1.D, we investigated the association
of parental history of LAF with time to first recurrence
of AF in proband cases.
In order to further evaluate the results, we also
investigated time from first until second recurrence of AF
(model 1.E), as well as time from diagnosis of LAF until
second recurrence of AF (model 1.F, n=7,370). We
additionally investigated time to first recurrence of AF in
individuals who did not experience any other CVD
outcome during the 10-year follow-up period (model 1.G,
In the second analysis, a sibling analysis, we examined
all LAF proband cases with at least one sibling living in
Sweden sometime between 1987 and 2009 (n=20,373).
In model 2.A, sibling history of AF was included as a
covariate (yes/no), and in model 2.B we also included
sex, age at diagnosis of LAF (centered at the mean
value), and terms for the interactions between sibling
history of AF and age/sex. The interaction terms were
only included in the model if the p-values were <0.05.
We also adjusted both models for number of siblings to
the proband case (not reported in the tables).
In the third analysis, we merged datasets I and II and
only analyzed individuals who were included in both
datasets (13,525 cases). In model 3.A, sibling history of
AF and parental history of AF were included as
covariates (yes/no), and in model 3.B we also included sex, age
at diagnosis of LAF (age at LAF), terms for the
interactions between sibling history of AF and parental history
of AF and terms for the interactions between sibling
history of AF/parental history of AF and age/sex. The
interaction terms were only included in the model if the
p-values were <0.05.
In order to take into account the non-independence of
observations from the same family, we used a robust
sandwich estimator in all models [34,35]. We present
hazard ratios (HRs) and the corresponding 95% CIs .
The proportional hazards assumption was fulfilled for
the variables of interest.
In order to investigate familial transmission of first
time LAF hospitalization we used a case-cohort
approach to determine familial risks with odds ratios
(ORs) [34,35]. We conducted two main analyses:
proband-sibling and proband-parent. In these analyses,
we studied all LAF proband-relative pairs that could be
matched to five control pairs in the Swedish population.
For example, in the proband-sibling analysis we selected
all sibling pairs for which at least one sibling was
diagnosed with LAF and matched each of them to five
control pairs. The control pairs were chosen randomly from
individuals who lived in Sweden at the time of the
probands diagnosis of LAF and comprised pairs of
individuals who were not diagnosed with LAF or AF prior to
the time of the probands diagnosis of LAF. Furthermore,
both individuals in the control pair also had to have
lived in Sweden sometime during the period 19872009.
Control pairs were matched based on year of birth, sex,
country of birth and level of education (the year before
the date of diagnosis). Analyses were conducted by
conditional logistic regression [34,35]. As an example, in the
proband-sibling analysis, AF in sibling (yes/no) was used
as the independent variable. We present odds ratios
(ORs) and the corresponding 95% CIs, according to
previous studies of familial risks [34,35]. As a proband
could be included several times, we adjusted for
nonindependence by using a robust sandwich estimator
[34,35]. In all analyses, less than 1% of the proband pairs
could not be matched to five controls and were excluded
from the analysis.
All calculations were performed using SAS version 9.3.
There were 16,160 individuals with LAF in families in
which both parents were alive sometime during the
study period (Table 1). 45.6% of them had recurrent
hospitalization for AF. 26.9% of individuals with
recurrence had a parent with AF, compared to 21.6% of those
without recurrence. There were 20,373 individuals with
LAF in families in which at least one sibling was alive
sometime during the study period. 48.6% of them had
recurrent hospitalization for AF. 11.6% of the individuals
with recurrence had at least one sibling diagnosed with
AF during the study period. The corresponding number
for non-recurrent cases was 7.7%.
Table 1 Descriptive statistics for individuals with lone atrial fibrillation (LAF) in the Swedish population (19872009)
Table 2, model 1.A shows that proband cases with
parents diagnosed with AF had a 1.23 times higher hazard
(95% CI 1.17-1.30) for recurrent AF hospitalization than
proband cases without parental history. This number
was not attenuated when age and sex were included in
the model (Table 2, model 1B). However, there seemed
to be an interaction between age at diagnosis of AF
among parents (HR 0.99, 95% CI 0.99-0.99), indicating a
decreased association of parental AF on recurrent AF
the older the case. Model 1.C indicates that the HR was
higher for proband cases with two affected parents (HR
1.65, 95% CI 1.44-1.90) than for proband cases with only
one affected parent (HR 1.16, 95% CI 1.10-1.23). Model
1.D shows that proband cases with parents diagnosed
with LAF had a 1.42-fold higher hazard rate for
recurrent AF hospitalization. While model 1.E shows that
parental history is less important when investigating time
between second and third episodes of AF, model 1.F
shows that the HR for parental history is similar when
investigating time from first to second episode of AF
and time from first to third episode of AF. The HR in
model 1.G (in which all cases with a CVD diagnosis in
the 10 years after first AF hospitalization were excluded)
is similar to the HR in model 1.A. This indicates that the
results in model 1.A are not confounded by other CVD
outcomes. Figure 1A shows that at the end of the
follow-up period, approximately 60% of proband cases
with parental history of AF had recurrent hospitalization
for AF; the corresponding number for proband cases
without parental history was 50%.
Table 3, model 2.A shows that proband cases with at
least one sibling diagnosed with AF had a 1.30-fold
higher hazard rate (95% CI 1.22-1.38) for recurrent AF
hospitalization than proband cases without sibling
history. However, model 2.B shows that the risk of LAF
associated with sibling history differed between men and
Table 2 Results from Cox proportional hazard models for individuals with LAF in the Swedish population (19872009):
parent-offspring analysis (n=16,160)
Model 1.A: HR of parental history of AF. Model 1B: also included sex, age at diagnosis of LAF (centered at the mean value), and terms for the interaction between
parental history of AF and age/sex. The interaction terms were only included in the model if the p-values were <0.05. Model 1C: the variable parental history was
categorized as no parental history of AF, one parent with AF and two parents with AF. Model 1D: the association of parental history of LAF with time to first
recurrence of AF in proband cases in proband cases was determined. Model 1E: time from first until second recurrence of AF was used to calculate the familial
HR. Model 1F: time from diagnosis of LAF until second recurrence of AF was used. Model 1G: time to first recurrence of AF in individuals who did not experience
any other CVD outcome during the 10-year follow-up period was used to calculate HR.
Figure 1 A (left) Survivorship function for model 1.A, i.e. parental history of AF (yes/no). B (right) Survivorship function for model 2.A, ie.
sibling history of AF (yes/no). Note that the survivorship function for men with sibling history of AF overlaps with the survivorship function for
women with sibling history of AF.
women (HR for interaction term 0.83, 95% CI
0.720.95). This indicates that even though men had a higher
risk of recurrent AF hospitalization (HR 1.21), the effect
of AF among siblings was more important for women
than for men. Figure 1B shows the survivorship function
from model 2.B, indicating that at the end of the
followup period 65% of individuals with at least one sibling
with AF had recurrent hospitalization for AF. This
number was the same for both men and women. Model 3.A
shows that the HR was similar for parental and sibling
history of AF (HR 1.21 and 1.28, respectively).
Familial risk of first time LAF hospitalization was
determined for comparison with recurrent risk only.
Table 4 shows the results of the case-cohort analysis.
Table 3 Results from Cox proportional hazard models for individuals with LAF in the Swedish population (19872009):
sibling analysis (n=20,373) and parent-sibling analysis (n=13,525)
AF in sibling(s) (yes/no)
Sex (Reference: females)
Age at diagnosis of AF (yearly increase)
AF in Sibling (age at diagnosis of AF)
AF in parent(s) (age at diagnosis of AF)
Model 2.A: sibling history of AF was included as a covariate (yes/no). Model 2.B: we also included sex, age at diagnosis of LAF (centered at the mean value), and
terms for the interactions between sibling history of AF and age/sex. The interaction terms were only included in the model if the p-values were <0.05. Both
model 2A and 2B were adjusted for the number of siblings to the proband case. Model 3.A, sibling history of AF and parental history of AF were included as
covariates (yes/no). Model 3.B: included sex, age at diagnosis of LAF (age at LAF), terms for the interactions between sibling history of AF and parental history of
AF and terms for the interactions between sibling history of AF/parental history of AF and age/sex. The interaction terms were only included in the model if the
p-values were <0.05.
14.2% of the proband cases had a parent diagnosed with
AF. The OR for the parent-offspring analysis was 2.08
(95% CI 2.02-2.15), which can be interpreted as a 2-fold
increase in the odds of AF in the parents of proband
cases diagnosed with LAF compared to the parents to
controls. The sibling analysis revealed that 5.3% of the
proband cases had a sibling diagnosed with AF. The OR
was 3.23 (95% CI 3.08-3.39), indicating more than 3-fold
higher odds of AF siblings of individuals diagnosed with
LAF compared to the siblings of controls.
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
Table 4 Familial risk of first time LAF hospitalization in
individuals with parental or sibling history of AF
OR (95% CI)* 3.23 (3.08-3.39) 2.08 (2.02-2.15)
LAF hospitalization among multiplex families (i.e. two
or more affected relatives) may be genetic although
nongenetic 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 hos
pitalization was similar, which suggests that the results
are not confounded by other CVD outcomes during
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
The present study demonstrates that family history of
AF is a risk factor for recurrent hospitalization for LAF
in Swedish patients. Risk of recurrent hospitalization for
LAF was especially high in multiplex families and
younger individuals, which suggests a genetic
contribution. However, the familial risk for recurrent LAF
hospitalization was lower than the risk for first time
LAF hospitalization, suggesting that familial factors are
more important for first time LAF hospitalization than
recurrent LAF hospitalization.
AF: Atrial fibrillation; LAF: Lone atrial fibrillation; CI: Confidence interval;
HR: Hazard ratio; OR: Odds ratio; ICD: International Classification of Diseases.
All authors contributed to the conception and design of the study; JS and KS
contributed to the acquisition of data; all authors contributed to the analysis
and interpretation of data; BZ drafted the manuscript; and all authors revised
it critically and approved the final version. All authors had full access to all of
the data (including statistical reports and tables) and take responsibility for
the integrity of the data and the accuracy of their analysis.
The authors wish to thank the CPFs Science Editor Stephen Gilliver for his
useful comments on the text. The registers used in the present study are
maintained by Statistics Sweden and the National Board of Health and
This work was supported by grants to Dr Bengt Zller from the Swedish
Heart-Lung Foundation and Region Skne (REGSKANE-124611), to Dr Kristina
Sundquist from the Swedish Research Council (K2009-70X-15428-05-3;
K2012-70X-15428-08-3), to Dr Jan Sundquist from the Swedish Council for
Working Life and Social Research (20071754) and the Swedish Freemasons
Foundation as well as ALF funding from Region Skne awarded to Jan
Sundquist and Kristina Sundquist.
The funding sources had no role in the design, conduct, or analysis of the
study or in the decision to submit the manuscript for publication.
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