Excess Weight And Transition To Metabolic Dysregulation Increases Atrial Fibrillation Risk

Background: One in three Americans will have atrial fibrillation (AF) during their lifetime. Obesity and metabolic derangements are key risk factors for AF. It is unclear, however, which subset of patients would benefit most from targeted interventions aimed at weight loss and control of metabolic derangements to prevent incident AF. Methods: A landmark analysis to compare time-to-AF after a three-year run-in period was performed among 95,160 subjects from COMMODORE, a cohort with rich longitudinal data obtained from a de-identified copy of the Vanderbilt University Medical Center Electronic Health Record. Included subjects were required to have four height and weight measures collected during a prespecified three-year qualification (i.e., “landmark”) period, with approximately one year (8 to 16 months) between each measure (t 0 -t 3 ), and did not have AF prior to t 3 . We determined the subject weight during the run-in period and metabolic status according to absence, development, or presence at the start of the landmark period, t 0 , of: hypertension (HTN), diabetes mellitus, low high-density lipoprotein, and elevated triglycerides. Results: From the study population of 95,160 adults, incident AF occurred in 9,094 participants (9.6%), over a median follow-up of 6.35 (IQR: 4.40-9.16) years. Participants who developed AF were more likely to be older, heavier, White, males, and have the four metabolic derangements studied. A cox-proportional hazards model was fit using median population values and varying t3 weight to estimate the 10-year AF risk based on weight alone. We observed a U-shaped pattern of risk where participants with a BMI in the range of 18.5 kg/m 2 to 25 kg/m 2 have the lowest 10-year AF risk. Presence of any of the derangements, either chronic or developed, was associated with a decrease in AF-free probability during the outcome period (p<0.001). For HTN and elevated triglycerides, the presence of the abnormality at t 0 resulted in a significant decrease in AF-free probability compared to those who developed the condition (p<0.001). Burden of metabolicabnormalities influenced AF-risk, with increases in adjusted HR of 1.23 (95%, CI, 1.16-1.30), 1.51 (95%, CI, 1.36-1.68), 1.86 (95%, CI, 1.58-2.19), and 2.29 (95%, CI, 1.84-1.2.84), with accumulation of one to four metabolic derangements, respectively. Conclusions and Relevance: In this analysis of a large real-world clinical cohort, both overweight (BMI > 25 kg/m 2 ) and underweight (BMI < 15 kg/m 2 ) participants are at an increased risk for AF development. The presence of metabolic derangements, regardless of diagnostic time, significantly increases AF risk and metabolic burden corresponds to increments in risk. Our findings suggest that prevention of metabolic derangements is critical to AF risk mitigation and that weight loss for AF management should be targeted to overweight patients regardless of metabolic status.