Risk Factors for Atrial Fibrillation

By Michael H. Crawford, MD

Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco

SYNOPSIS: A United Kingdom Biobank study of new onset atrial fibrillation (AF) has shown strong associations with hypertension and obesity at all ages and acute illnesses/surgery in older individuals. Genetics was less important, but in those at low genetic risk, obesity and hypertension were strong predictors of AF.

SOURCE: Wang N, Yu Y, Sun Y, et al. Acquired risk factors and incident atrial fibrillation according to age and genetic predisposition. Eur Heart J 2023;44:4982-4993.

Prior studies have identified 46 risk factors for atrial fibrillation (AF), which can be aggregated into five aspects: social, such as education level and socioeconomic level; health behaviors, such as alcohol consumption or smoking; cardiometabolic factors, such as hypertension and obesity; comorbidities, such as sleep disordered breathing and an acute illness; and genetics. Also, AF becomes more prevalent with increasing age. However, the interaction between the five aspects and their relative importance with age is unclear. Thus, this study from the UK Biobank (UKB) is of interest.

The UKB includes more than 500,000 individuals aged 40-69 years at baseline recruited between 2006 and 2010. For this analysis, 409,661 without AF at baseline and with data on all AF risk factors were included. Genome-wide association studies (GWAS) revealed 104 single nucleotide polymorphisms (SNPs) associated with AF. The strength of these associations was used to determine a genetic risk score (GRS), which was divided into low-, moderate-, and high-risk GRS. In addition, the subjects were grouped into three age groups: 40-49 years, 50-59 years, and 60-69 years at baseline. The primary endpoint was the occurrence of AF determined by medical records that the subjects made available to the investigators. The mean age of the cohort was 56 years and 46% were men.

After a median follow-up of 12 years, 5.8% developed AF and more of them were in the older age strata. Of the 46 known risk factors for AF, there were no data in the UKB on nine. The remaining 34 were condensed into 23, all of which were significantly associated with AF except air pollution, physical inactivity, extreme physical activity, and no coffee intake. The risk factors were ranked by determining their percent population associated risk (PAR) for AF.

Cardiometabolic factors accounted for most of the incident AF across all age groups (PAR range, 36% to 40%) and GRS groups (34% to 42%). Of these, hypertension and obesity were the leading modifiable factors. Health behaviors were associated with more AF in the lowest age group and GRS group vs. the highest groups (PAR 12% vs. 9% and GRS 19% vs. 14%, respectively). The association of comorbidities with AF was relatively stable across the age groups (PAR 21% to 24%) but decreased significantly with increased GRS. Genetics was more important in the lower two age groups (PAR 18% to 19% vs. 14% in the oldest group). The association of social factors was relatively low across the age groups (PAR 5.5% to 6%) and GRS groups (PAR 5% to 7%). The authors concluded that cardiometabolic factors had the strongest association with AF among all age and GRS groups, with hypertension and obesity being the leading modifiable factors. Health behaviors and genetics were stronger risk factors in the age 40-49 years group compared to the age 60-69 years group, while the AF risk of comorbidities and social factors was relatively stable across the age groups. Finally, the AF risk associated with cardiometabolic factors and comorbidities decreased significantly with increasing GRS.

COMMENTARY

The incidence of AF is increasing as the result of the aging population, increased surveillance, and higher prevalence of lifestyle factors, such as obesity. AF is associated with increased strokes and mortality. In planning a public health approach to reducing AF, two factors have a continuous relationship with AF: age and genetics. AF is more common in older individuals and those of Northern European ancestry. The UKB AF study was organized to understand the relationship between these two overriding variables and other clinical characteristics. The aim was to develop data useful for targeting the prevention and management of AF.

Clinical characteristics were aggregated into five categories, and age and genetics were divided into three levels each, from young age/low GRS to older age/high GRS. The researchers found that the cardiometabolic category had the strongest association with AF in all three age groups and GRS groups but was less important in the high GRS group. In this category, hypertension and obesity emerged as the most important modifiable risk factors. The effect of comorbidities was less than cardiometabolic factors and was similar across the age spectrum but decreased in importance as the GRS increased. Genetics was next in importance but was more important in the younger age groups. Health behaviors and social factors were least important and trended downward with older age. Considering these findings, genetics do not play a big role in the risk of AF. Cardiometabolic factors and comorbidities play the biggest role, especially in those with low genetic risk. In the cardiometabolic group, hypertension and obesity are the low-hanging fruit. Interestingly, in the comorbidity group, acute illnesses, including surgery, had the highest PARs and are a challenge for AF prevention.

This highly informative study does have limitations to consider. There were no subjects ≥ 70 years of age at baseline. Much of the baseline data was self-reported, and data were not collected on any changes in the baseline risk factors over time. No electrocardiogram monitoring was done to detect AF, so asymptomatic AF is not included. Also, these were mainly white British subjects who volunteered for the UKB study and may be a relatively healthy group. In addition, those recruited may have underrepresented subjects of lower socioeconomic level. Finally, their analysis did not segregate by sex.

The take-home message here is that genetics is not as important as lifestyle factors that contribute to hypertension and obesity, such as alcohol consumption and overeating. Exercise and coffee consumption did not seem to be important in the UKB. Especially in older individuals, the management of acute illnesses and surgery to reduce the incidence of AF is a challenge.