Circulating fibroblast growth factor-23 and the incidence of atrial fibrillation: the Atherosclerosis Risk in Communities study

Abstract

Background: Increased concentrations of circulating fibroblast growth factor 23 (FGF-23) have been associated with higher risk of cardiovascular disease. The association between FGF-23 and the risk of atrial fibrillation (AF), a common arrhythmia, is less defined. Thus, we explored whether FGF-23 concentration was associated with AF incidence in a large community-based cohort.

Methods and results: We studied 12 349 men and women enrolled in the Atherosclerosis Risk in Communities (ARIC) study, without prevalent AF at baseline in 1990-1992. Serum intact FGF-23 concentration was measured with the Kainos 2-site ELISA. Incident AF through 2010 was ascertained from study ECGs and hospital discharge codes. Cox proportional hazards models adjusted for potential confounding factors, including kidney function, were used to estimate the association between FGF-23 and AF risk. We identified 1572 AF events during a mean follow-up of 17 years. In multivariable analysis, a difference of 1 SD (16 pg/mL) in baseline FGF-23 was not associated with the risk of AF (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.99, 1.09). Results were similar when FGF-23 was modeled in quartiles (HR, 1.09; 95% CI, 0.94, 1.26, comparing extreme quartiles). Reduced kidney function was associated with increased AF risk across quartiles of FGF-23 levels.

Conclusion: In this large community-based cohort, baseline FGF-23 levels were not associated with AF risk independently of kidney function. Our results do not support a major role for FGF-23 as a risk factor for AF or as a mediator of the association between chronic kidney disease and AF.

Keywords: atrial fibrillation; epidemiology; kidney; risk factors.

Figure 1.

Inclusion flow chart, Atherosclerosis Risk in Communities Study, 1990–1992. FGF indicates fibroblast growth factor.

Figure 2.

Association of circulating FGF‐23 concentrations with incidence of atrial fibrillation presented as hazard ratio (HR; solid line) and 95% confidence intervals (CI; shaded area). Results from Cox proportional hazards model with FGF‐23 modeled using restricted cubic splines, adjusted for age, sex, and race (top panel) and additionally adjusted for study site, body mass index, smoking, education, height, diabetes, systolic and diastolic blood pressure, use of antihypertensive medication, prevalent coronary heart disease, prevalent heart failure, ECG‐based left ventricular hypertrophy, NT‐proBNP, high‐sensitivity C‐reactive protein, and eGFR (bottom panel). Median value of FGF‐23 was considered the reference (HR=1). The histograms represent the frequency distribution of FGF‐23 in the study sample. Atherosclerosis Risk in Communities Study, 1990–2010. eGFR indicates estimated glomerular filtration rate; FGF, fibroblast growth factor; NT‐proBNP, N‐terminal prohormone of brain natriuretic peptide.

Figure 3.

Hazard ratios (HR) and 95% confidence intervals (CI) of AF by categories of eGFR and FGF‐23 quartile, using participants with eGFR≥90 mL/min per 1.73 m² and FGF‐23 in the first quartile as the reference. Models were adjusted for age, race, sex, study site, body mass index, smoking, education, height, diabetes, systolic and diastolic blood pressure, use of antihypertensive medication, prevalent coronary heart disease, prevalent heart failure, ECG‐based left ventricular hypertrophy, NT‐proBNP, and high‐sensitivity C‐reactive protein, Atherosclerosis Risk in Communities Study, 1990–2010. AF indicates atrial fibrillation; eGFR, estimated glomerular filtration rate; FGF, fibroblast growth factor; NT‐proBNP, N‐terminal prohormone of brain natriuretic peptide.

Figure 4.

Association of circulating FGF‐23 concentrations with incidence of atrial fibrillation presented as hazard ratio (HR; solid line) and 95% confidence intervals (CI; shaded area) by categories of eGFR (<60 (panel C), 60 to 89 (panel B), and 90+ mL/min per 1.73 m² (panel A)). Results from Cox proportional hazards model with FGF‐23 modeled using restricted cubic splines, adjusted for age, sex, race, study site, body mass index, smoking, education, height, diabetes, systolic and diastolic blood pressure, use of antihypertensive medication, prevalent coronary heart disease, prevalent heart failure, ECG‐based left ventricular hypertrophy, NT‐proBNP, high‐sensitivity C‐reactive protein, and eGFR. Median value of FGF‐23 was considered the reference (HR=1). The histograms represent the frequency distribution of FGF‐23 in each category of eGFR. Atherosclerosis Risk in Communities Study, 1990–2010. eGFR indicates estimated glomerular filtration rate; FGF, fibroblast growth factor; NT‐proBNP, N‐terminal prohormone of brain natriuretic peptide.

Figure 5.

Random‐effects meta‐analysis of the association between fibroblast growth factor (FGF)‐23 concentrations and atrial fibrillation incidence in the Multi‐Ethnic Study of Atherosclerosis (MESA), Cardiovascular Health Study (CHS), and Atherosclerosis Risk in Communities (ARIC) cohorts. Study‐specific results correspond to multivariable hazard ratios (HR) and 95% confidence intervals (CI) for 1 unit increment in log₂(FGF‐23) levels. Size of the study‐specific markers is proportional to the meta‐analysis weights.