Background Atrial fibrillation (AF) is a common arrhythmia. Application of metabolomic approaches, which may identify novel pathways and biomarkers of disease risk, to a longitudinal epidemiologic study of AF has been limited. Methods We determined the prospective association of 118 serum metabolites identified through untargeted metabolomics profiling with the incidence of newly-diagnosed AF in 1919 African- American men and women from the Atherosclerosis Risk in Communities study without AF at baseline (1987-1989). Incident AF cases through 2011 were ascertained from study electrocardiograms, hospital discharge codes, and death certificates. Results During a median follow-up of 22 years, we identified 183 incident AF cases. In Cox proportional hazards models adjusted for age, sex, smoking, body mass index, systolic blood pressure, use of antihypertensive medication, diabetes, prevalent heart failure, prevalent coronary heart disease, and kidney function, two conjugated bile acids (glycolithocholate sulfate and glycocholenate sulfate) were significantly associated with AF risk after correcting for multiple comparisons (p<0.0004). Multivariable-adjusted hazard ratios (95% confidence intervals) of AF were 1.22 (1.12-1.32) for glycolithocholate sulfate and 1.22 (1.10- 1.35) for glycocholenate sulfate per 1-standard deviation higher levels. Associations were not appreciably different after additional adjustment for alcohol consumption or concentrations of circulating albumin and liver enzymes. Conclusion We found an association of higher levels of two bile acids with an increased risk of AF, pointing to a potential novel pathway in AF pathogenesis. Replication of results in independent studies is warranted.
Bibliographical noteFunding Information:
The authors thank the staff and participants of the ARIC study for their important contributions The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HSN268201100012C). The metabolomics research was sponsored by the National Human Genome Research Institute (3U01HG004402-02S1). This work was additionally supported by National Heart, Lung, and Blood Institute grant RC1HL099452 to Dr. Alonso and by National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK089174 and K24DK106414 to Dr. Selvin. The metabolomics measurements were sponsored by National Human Genome Research Institute (3U01HG004402-02S1). Reagents for the ALT, AST, and GGTassays were donated by Roche Diagnostics. Author DA is employed by Metabolon, Inc., a commercial entity. Metabolon, Inc. provided support in the form of salaries for this author [DA], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the ''author contribution'' section. Similarly, the remaining funders did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.