Is lone AF inherited?

SHANGHAI, CHINA. Several studies, including our own 2003 LAF Survey, have concluded that there is a strong familial connection in lone atrial fibrillation – in other words, that a significant proportion of lone afibbers owe their condition to a genetic abnormality. Now a team of researchers from the Shanghai Chest Hospital confirms that inherited lone AF is by no means uncommon in China.

Their study included 382 unrelated lone afibbers (probands) and their first- and second-degree relatives for a total study population of 6,856 individuals (2,715 first-degree and 4,141 second-degree relatives). The 382 probands were recruited from consecutive patients admitted to hospital for AF during the period from February 1, 2000 to May 31, 2010. All participants were aged 60 years or below at enrolment and had no evidence of heart disease, hypertension, or any other condition which could predispose them to AF. In other words, they were truly “lone” afibbers. The average age at onset was 44 years, 58% were male, average resting heart rate was 74 bpm, and 90% had paroxysmal AF when first examined. During the duration of the study, 9% progressed to permanent AF. (NOTE: 39% of patients were on digoxin which is known to promote the progression of paroxysmal to permanent AF.)

Forty-one percent of the probands reported a positive family history of AF, with at least one relative having been diagnosed with AF. There were no significant differences between probands with and without relatives with AF; however, probands with no family history of AF were more likely to present initially with paroxysmal AF (93% vs. 86%). The familial prevalence of AF in the study group was compared to that found in an age- and sex-matched group of 15,500 individuals drawn from the general population. Overall, 41% of probands with lone AF had proof of familial evidence. Daughters of a proband with lone AF were 166 times more likely to inherit the disorder than were daughters in the general population. Other risk estimates are given below.

Relationship
Study Group
Control Group
Relative Risk*
Daughter
3.66%
0.02%
166 times higher
Son
4.23%
0.11%
37 times higher
Brother
14.60%
0.53%
27 times higher
Sister
13.50%
0.55%
24 times higher
Mother
12.57%
2.58%
5 times higher
Father
14.40%
3.02%
5 times higher
* Prevalence in study group divided by prevalence in control group

The Chinese researchers conclude that familial aggregation of lone AF is quite common and that it is equally transmitted through paternal and maternal sides of a family. They point out that the prevalence of AF in the “real” world is likely to be substantially higher than reported since many individuals are likely still undiagnosed or suffer from asymptomatic AF.

Yang, YQ, et al. Familial aggregation of lone atrial fibrillation in the Chinese population. Internal Medicine, Vol. 49, 2010, pp. 2385-91

Editor’s comment: Our LAF Survey concluded that 43% of the group of lone afibbers participating in the survey had a close relative with arrhythmia. This number is clearly very close to the 41% reported in the Chinese study. Our survey revealed that 43% of 100 respondents had a close relative with cardiac arrhythmia (54% of mixed afibbers, 44% of permanent, 40% of vagal, and 25% of adrenergic). The most common “carrier” was the mother who accounted for 13 of the relatives (30%), siblings who accounted for 11 (26%), the father who accounted for 10 (23%), and grandparents who accounted for 3 (7%). Permanent afibbers reported the mother to be the “carrier” in 71% of cases. For adrenergic the mother was implicated in 50% of cases. The father was the predominant “carrier” among mixed afibbers (27%) and mothers, fathers and siblings shared the “honours” among vagal afibbers at 28% each.

The estimated overall prevalence of all cardiac arrhythmias in the United States is about 1% with atrial fibrillation accounting for about half of this. Cardiac arrhythmias are generally more common among older people. With only 1% of the general population having arrhythmia is it odd that 43% of the survey respondents had a close relative with arrhythmia? This question can really only be answered definitely by comparing the rate of arrhythmia among close relatives of a group of lone afibbers with the rate in a group of age- and sex-matched controls.

Nevertheless, it is possible to get some idea about the likelihood of a genetic connection. Although we afibbers tend to be an odd bunch, it is probably safe to assume that we each had two biological parents?! This means that there were 23 cases among the 202 parents included in the survey or a rate of 11% - in other words, considerably higher than the 1% that would have been expected. This finding does not prove that LAF can be inherited, but it certainly supports the possibility.

The genetic connection is also supported by work done by Dr. Ramon Brugada and his colleagues at the Baylor College of Medicine and the University of Barcelona. These researchers located three families in Spain in which 21 of 49 family members had lone atrial fibrillation. They mapped their genes and concluded that in these families a mutation in a specific chromosome region (10q22-q24) was the cause of their atrial fibrillation. Dr. Maurits Allessie, MD of the University of Maastricht in the Netherlands makes several very interesting observations concerning these findings:

  • If, as in the three Spanish families, lone atrial fibrillation in the general population is also caused by a genetic mutation, then Brugada’s findings are of paramount importance.
  • The possibility that small molecular defects in DNA can cause changes in the electrophysiologic properties of the atria that, in turn, create a substrate for chronic atrial fibrillation is not unlikely. NOTE: The term chronic in this statement does not mean permanent as opposed to paroxysmal, but rather that LAF is not an acute condition.
  • The genes that encode adrenergic receptors are located at the observed mutation site on chromosome 10q. This means that the basis for familial atrial fibrillation could lie in abnormal atrial triggering mechanisms.

Dr. Allessie concludes, “The anatomical and electrophysiologic features of the atria are such that there is only a narrow margin of safety between normal sinus rhythm and chronic atrial fibrillation.” The above Chinese study, our survey findings of a possible genetic connection and the fascinating discoveries of Dr. Brugada and colleagues together with Dr. Allessie’s profound observations certainly provide much food for thought and will hopefully be followed up by additional research.

The finding that some individuals have a genetic abnormality favouring lone atrial fibrillation does not mean that they are predestined to develop LAF, but it could mean that they need to be more vigilant in avoiding common triggers and known risk factors.