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Original Investigation
August 31, 2022

Sex Differences in Atrial Fibrillation Risk: The VITAL Rhythm Study

Author Affiliations
  • 1Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
  • 2Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
  • 3Division of Cardiology, Department of Medicine, Geneva University Hospitals, Geneva, Switzerland
  • 4Institute of Primary Health Care, University of Bern, Bern, Switzerland
  • 5Division of Cardiovascular Medicine, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston
  • 6Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 7Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California
JAMA Cardiol. 2022;7(10):1027-1035. doi:10.1001/jamacardio.2022.2825
Key Points

Question  Are women at lower risk for atrial fibrillation (AF) after accounting for other AF risk factors and do risk factors for AF differ for men vs women?

Findings  In this cohort study of 25 119 participants within the Vitamin D and Omega-3 Trial (VITAL) Rhythm Study, women were at greater risk for developing AF than men when height and weight, rather than body mass index, were controlled for in multivariable models. AF risk factors were similar for women vs men.

Meaning  Results suggest that for a given height and weight, women are at higher risk for incident AF than men, and primary prevention with risk factor modification should be equally effective; these findings emphasize the need for AF prevention in women.


Importance  Women have a lower incidence of atrial fibrillation (AF) compared with men in several studies, but it is unclear whether this sex difference is independent of sex differences in prevalent cardiovascular disease (CVD), body size, and other risk factors.

Objective  To examine sex differences in AF incidence and whether AF risk factors differ by sex in a contemporary cohort of men and women without prevalent CVD.

Design, Setting, and Participants  This was a prospective cohort analysis within the Vitamin D and Omega-3 Trial (VITAL) Rhythm Study, a randomized trial that examined the effect of vitamin D and ω-3 fatty acid supplementation on incident AF among men 50 years or older and women 55 years or older without a prior history of prevalent AF, CVD, or cancer at baseline. Data were analyzed from September 29, 2020, to June 29, 2021.

Exposures  Sex, height, weight, body mass index (BMI), body surface area (BSA), and other AF risk factors at study enrollment.

Main Outcomes and Measures  Incident AF confirmed by medical record review.

Results  A total of 25 119 individuals (mean [SD] age, 67.0 [7.1] years; 12 757 women [51%]) were included in this study. Over a median (IQR) follow-up of 5.3 (5.1-5.7) years, 900 confirmed incident AF events occurred among 12 362 men (495 events, 4.0%) and 12 757 women (405 events, 3.2%). After adjustment for age and treatment assignment, women were at lower risk for incident AF than men (hazard ratio [HR], 0.68; 95% CI, 0.59-0.77; P < .001). The inverse association between female sex and AF persisted after adjustment for race and ethnicity, smoking, alcohol intake, hypertension, diabetes (type 1, type 2, gestational), thyroid disease, exercise, and BMI (HR, 0.73; 95% CI, 0.63-0.85; P <.001). However, female sex was positively associated with AF when height (HR, 1.39; 95% CI, 1.14-1.72; P = .001), height and weight (HR 1.49, 95% CI, 1.21-1.82; P <.001), or BSA (HR, 1.25; 95% CI, 1.06-1.49; P = .009) were substituted for BMI in the multivariate model. In stratified models, risk factor associations with incident AF were similar for women and men.

Conclusions and Relevance  In this cohort study, findings suggest that after controlling for height and/or body size, women without CVD at baseline were at higher risk for AF than men, suggesting that sex differences in body size account for much of the protective association between female sex and AF. These data underscore the importance of AF prevention in women.

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