Sex Differences and Body Size in Incident Atrial Fibrillation Risk

A patient’s body size may affect risk for developing incident atrial fibrillation more than a patient’s sex.

Women have a lower risk than men for developing incident atrial fibrillation (AF) and female sex associates with a higher risk for AF when controlling for height, suggesting previously described protective associations between female sex and AF are related to body size sex differences. These are among the analysis findings published in the Journal of the American Medical Association Cardiology.

Investigators sought to evaluate sex differences in AF and if AF risk factors differ by sex among individuals without prevalent cardiovascular disease (CVD). Considered exposures included height, weight, sex, body mass index (BMI), and body surface area (BSA) measured at enrollment. The primary outcome was incident atrial fibrillation.

They initiated a cohort analysis using data from the VITAL (Vitamin D and Omega-3 Trial) Rhythm Study, a randomized trial evaluating the effect of vitamin D and ω-3 fatty acid supplementation on incident AF among women 55 years or older and men 50 years or older without history of prevalent CVD, cancer, or AF at baseline. The VITAL Rhythm Study was conducted between November 2011 and March 2014 in the United States and included 25,871 participants. The study analysis was performed between September 2020 and the end of June 2021.

The study population (69% White, 20% Black, 4% Hispanic) was aged an average of 67 years at randomization and 74 years at the time of incident AF. Women were older (68.1 vs 66.0 years), more often Black (25% vs 16%), and had higher prevalence of thyroid disorders (19% vs 5%) and hypertension (54% vs 49%). Women drank less alcohol (48% vs 30%), exercised less (37% vs 29%), and were less likely to have ever smoked cigarettes (55% vs 49%). They reported lower income (<$50,000 annual; 46% vs 28%).

…women had a lower risk of developing incident AF; however, after controlling for height, female sex was associated with a higher risk for AF.

The investigators noted that women had higher mean BMI (28.4 vs 27.8), lower mean weight (167.5 vs 194.8 lbs), and lower mean height (64.4 vs 70.2 inches). Height and weight were self-reported values.  

Of the VITAL participants, 25,119 were included in the analysis (51% women). The investigators noted 405 incident confirmed AF events (3.2%) among the women and 495 incident confirmed AF events (4.0% of 12,362) among the men over a median follow-up of 5.3 years (IQR, 5.1-5.7). They found women were at a lower risk for incident AF than men (hazard ratio [HR], 0.68; 95% CI, 0.59-0.77; P <.001) after adjustment for age and treatment assignment.

Following adjustment for smoking cigarettes, alcohol, hypertension, thyroid disease, exercise, diabetes (type 1, type 2, gestational), BMI, and ethnicity and race, the inverse relationship between female sex and AF endured (HR, 0.73; 95% CI, 0.63-0.85; P <.001). Conversely, 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 in the multivariate model for BMI, the investigators noted female sex positively associated with AF.

They found risk factor associations with incident AF similar for men and women in stratified models.

Significant analysis limitations include the study design as secondary analysis and limited generalizability to younger individuals. There is also limited generalizability to patients with established CVD. There may also be misclassification from self-reported height and weight.

“…women had a lower risk of developing incident AF; however, after controlling for height, female sex was associated with a higher risk for AF,” the study authors wrote. “These data suggest that sex differences in body size account for much of the previously reported protective association between female sex and AF and underscore the importance of AF prevention in women.”

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Siddiqi HK, Vinayagamoorthy M, Gencer B, et al. Sex differences in atrial fibrillation risk: The VITAL Rhythm Study. JAMA Cardiol. Published online August 31, 2022. doi:10.1001/jamacardio.2022.2825