Coexistence of low vitamin D and high fibroblast growth factor-23 plasma levels predicts an adverse outcome in patients with coronary artery disease.

José Tuñón,Jesús Egido,Nieves Tarín,Fernando Rodríguez-Artalejo,Rocío Carda,Emilio González-Parra,Álvaro Aceña,Óscar Lorenzo,María Luisa González-Casaus,Ana María Pello,Joaquín Alonso,Carmen Cristóbal,Ignacio Mahíllo-Fernández,Jerónimo Farré,Lorenzo López-Bescós,Ana Huelmos

doi:10.1371/journal.pone.0095402

Abstract

ObjectiveVitamin D and fibroblast growth factor-23 (FGF-23) are related with cardiovascular disorders. We have investigated the relationship of calcidiol (vitamin D metabolite) and FGF-23 plasma levels with the incidence of adverse outcomes in patients with coronary artery disease.MethodsProspective follow-up study of 704 outpatients, attending the departments of Cardiology of four hospitals in Spain, 6–12 months after an acute coronary event. Baseline calcidiol, FGF-23, parathormone, and phosphate plasma levels were assessed. The outcome was the development of acute ischemic events (any acute coronary syndrome, stroke, or transient ischemic attack), heart failure, or death. Cox regression adjusted for the main confounders was performed.ResultsCalcidiol levels showed a moderate-severe decrease in 57.3% of cases. Parathormone, FGF-23, and phosphate levels were increased in 30.0%, 11.5% and 0.9% of patients, respectively. Only 22.4% of patients had glomerular filtration rate<60 ml/min1.73 m2. After a mean follow-up was 2.15±0.99 years, 77 patients developed the outcome. Calcidiol (hazard ratio [HR] = 0.67; 95% confidence interval [CI] = 0.48–0.94; p = 0.021) and FGF-23 (HR = 1.13; 95% CI = 1.04–1.23; p = 0.005) plasma levels predicted independently the outcome. There was a significant interaction between calcidiol and FGF-23 levels (p = 0.025). When the population was divided according to FGF-23 levels, calcidiol still predicted the outcome independently in patients with FGF-23 levels higher than the median (HR = 0.50; 95% CI = 0.31–0.80; p = 0.003) but not in those with FGF-23 levels below this value (HR = 1.03; 95% CI = 0.62–1.71; p = 0.904).ConclusionsAbnormalities in mineral metabolism are frequent in patients with stable coronary artery disease. In this population, low calcidiol plasma levels predict an adverse prognosis in the presence of high FGF-23 levels.

Highlights

Renal disease is associated with increased cardiovascular risk
We have studied 704 patients with coronary artery disease (CAD) in order to assess whether plasma levels of calcidiol and fibroblast growth-23 (FGF-23) are related to the incidence of adverse outcomes, and the potential influence of their relationship on the prognosis
By multivariate linear regression analysis we investigated how much of calcidiol (Table 5) and FGF-23 plasma levels (Table 6) were explained by age, sex, glomerular filtration rate, and parathormone, phosphate, and high sensitivity C-reactive protein plasma levels

Summary

Introduction

Renal disease is associated with increased cardiovascular risk. High phosphate serum levels have been associated with increased mortality and cardiovascular events even in the absence of renal disease [1]. FGF-23 promotes phosphaturia and diminishes vitamin D plasma levels, downregulating its synthesis and enhancing its degradation [2]. Adaptive mechanisms appear before serum phosphate levels are increased. These mechanisms have been related to vascular damage [3,4]. High FGF-23 plasma levels are independently associated with endothelial dysfunction, arterial stiffness, left ventricular hypertrophy, progression of renal disease, incidence of mortality and cardiovascular events [3,4]. Vitamin D deficiency has been associated with hypertension, coronary artery disease (CAD) and stroke [5,6].

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