Fibroblast growth factor-23 and incident coronary heart disease, heart failure, and cardiovascular mortality: the Atherosclerosis Risk in Communities study

Abstract

Background: Fibroblast growth factor-23 (FGF-23) is a hormone involved in phosphorous regulation and vitamin D metabolism that may be associated with cardiovascular risk, and it is a potential target for intervention. We tested whether elevated FGF-23 is associated with incident coronary heart disease, heart failure, and cardiovascular mortality, even at normal kidney function.

Methods and results: A total of 11 638 Atherosclerosis Risk In Communities study participants, median age 57 at baseline (1990-1992), were followed through 2010. Cox regression was used to evaluate the independent association of baseline serum active FGF-23 with incident outcomes. Models were adjusted for traditional cardiovascular risk factors and estimated glomerular filtration rate. During a median follow-up of 18.6 years, 1125 participants developed coronary heart disease, 1515 developed heart failure, and 802 died of cardiovascular causes. For all 3 outcomes, there was a threshold, whereby FGF-23 was not associated with risk at <40 pg/mL but was positively associated with risk at >40 pg/mL. Compared with those with FGF-23 <40 pg/mL, those in the highest FGF-23 category (≥ 58.8 pg/mL) had a higher risk of incident coronary heart disease (adjusted hazard ratio, 95% CIs: 1.65, 1.40 to 1.94), heart failure (1.75, 1.52 to 2.01), and cardiovascular mortality (1.65, 1.36 to 2.01). Associations were modestly attenuated but remained statistically significant after further adjustment for estimated glomerular filtration rate. In stratified analyses, similar results were observed in African Americans and among persons with normal kidney function.

Conclusions: High levels of serum FGF-23 were associated with increased risk of coronary heart disease, heart failure, and cardiovascular mortality in this large, biracial, population-based cohort. This association was independent of traditional cardiovascular risk factors and kidney function.

Keywords: Atherosclerosis Risk In Communities; cardiovascular mortality; coronary heart disease; epidemiology; fibroblast growth factor 23; heart failure.

Figure 1.

Association of serum FGF‐23 with risk of incident CHD, HF, and cardiovascular mortality: the ARIC Study 1987–2010. Biomarkers modeled as restricted cubic splines with knots at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles and are adjusted for age, sex, and race. Black line represents hazard ratio; gray shaded area, 95% confidence interval. A, FGF‐23 and incident CHD. B, FGF‐23 and incident HF. C, FGF‐23 and incident cardiovascular mortality. ARIC indicates Atherosclerosis Risk In Communities; CHD, coronary heart disease; FGF‐23, fibroblast growth factor‐23; HF, heart failure.