Advertisement

Fibroblast growth factor 23 predicts carotid atherosclerosis in individuals without kidney disease. The CORDIOPREV study

  • Author Footnotes
    1 These authors contributed equally to this work.
    Maria E. Rodríguez-Ortiz
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Reina Sofia University Hospital/University of Cordoba, Spain
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
    Juan F. Alcalá-Díaz
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Lipid and Atherosclerosis Unit, Department of Internal Medicine (IMIBIC), Reina Sofia University Hospital/University of Cordoba, Avda. Menéndez Pidal s/n. C.P., 14004 Cordoba, Spain

    CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
    Search for articles by this author
  • Antonio Canalejo
    Affiliations
    Department of Integrated Sciences/Centro de investigacion RENSMA, University of Huelva, Spain
    Search for articles by this author
  • José D. Torres-Peña
    Affiliations
    Lipid and Atherosclerosis Unit, Department of Internal Medicine (IMIBIC), Reina Sofia University Hospital/University of Cordoba, Avda. Menéndez Pidal s/n. C.P., 14004 Cordoba, Spain

    CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
    Search for articles by this author
  • Francisco Gómez-Delgado
    Affiliations
    Lipid and Atherosclerosis Unit, Department of Internal Medicine (IMIBIC), Reina Sofia University Hospital/University of Cordoba, Avda. Menéndez Pidal s/n. C.P., 14004 Cordoba, Spain

    CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
    Search for articles by this author
  • Juan R. Muñoz-Castañeda
    Affiliations
    Unidad de Gestión Clinica Nefrología, Instituto Maimonides de Investigacion Biomédica de Córdoba (IMIBIC), Reina Sofia University Hospital/University of Cordoba, Spain
    Search for articles by this author
  • Javier Delgado-Lista
    Affiliations
    Lipid and Atherosclerosis Unit, Department of Internal Medicine (IMIBIC), Reina Sofia University Hospital/University of Cordoba, Avda. Menéndez Pidal s/n. C.P., 14004 Cordoba, Spain

    CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
    Search for articles by this author
  • Mariano Rodríguez
    Affiliations
    Unidad de Gestión Clinica Nefrología, Instituto Maimonides de Investigacion Biomédica de Córdoba (IMIBIC), Reina Sofia University Hospital/University of Cordoba, Spain
    Search for articles by this author
  • Author Footnotes
    2 These authors share senior authorship.
    José López-Miranda
    Correspondence
    Corresponding author at: Lipid and Atherosclerosis Unit, Department of Internal Medicine, Reina Sofia University Hospital/IMIBIC/University of Cordoba, Spain.
    Footnotes
    2 These authors share senior authorship.
    Affiliations
    Lipid and Atherosclerosis Unit, Department of Internal Medicine (IMIBIC), Reina Sofia University Hospital/University of Cordoba, Avda. Menéndez Pidal s/n. C.P., 14004 Cordoba, Spain

    CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
    Search for articles by this author
  • Author Footnotes
    2 These authors share senior authorship.
    Yolanda Almadén
    Correspondence
    Corresponding author at: Unidad de Gestión Clinica Medicina Interna, Instituto de Biomedicina de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba/Universidad de Córdoba, Spain.
    Footnotes
    2 These authors share senior authorship.
    Affiliations
    Unidad de Gestión Clinica Medicina Interna, Instituto de Biomedicina de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba/Universidad de Córdoba, Spain

    CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
    2 These authors share senior authorship.
Published:December 30, 2019DOI:https://doi.org/10.1016/j.ejim.2019.12.008

      Highlights

      • • In preserved renal function, FGF23 can turn up minute variations in phosphate.
      • • Higher FGF23 levels associated independently with carotid atherosclerosis.
      • • FGF23 might be a predictor of cardiovascular risk independent of renal failure.

      Abstract

      Background

      Fibroblast growth factor 23 (FGF23) is a major determinant of mineral metabolism derangements and emerges as a possible risk factor underlying the negative cardiovascular outcome in CKD patients. However, its contribution in non-CKD individuals is less clear. This cross-sectional study investigated the associations between FGF23 and mineral metabolism parameters and with carotid atherosclerosis in a population at high cardiovascular risk with preserved renal function.

      Methods

      We employed 939 subjects with coronary heart disease enrolled in the CORDIOPREV study (mean eGFR=93.0 ± 0.7 ml/min/1.73 m2 and median FGF23=44.9 (IQR=13.1) pg/ml), in which intima-media thickness of both common carotid arteries (IMT-CC) was measured.

      Results

      Adjusted for anthropometric factors, FGF23 associated positively with creatinine, phosphate, calcium and 25(OH)-vitaminD and negatively with eGFR and calcitriol. In multivariable-adjusted models all of them were independent contributors to FGF23 levels. FGF23 showed a positive relationship with IMT-CC; both the higher third and fourth quartiles associated significantly with IMT-CC (Beta= 0.135 and 0.187, respectively) and after additional adjustment for established cardiovascular risk factors and morbidities FGF23 remained as a significant contributor to IMT-CC. Logistic regression analysis confirmed its predictive ability to differentiate patients at higher atherosclerotic risk defined by an IMT-CC≥0.7 mm (OR for FGF23 quartiles 3 and 4 vs. 1: 1.860; 95%CI 1.209–2.862 and 2.114; 95%CI 1.339–3.337, respectively).

      Conclusion

      Even in the setting of a normally functioning phosphate-FGF23-calcitriol system, FGF23 independently associated with IMT-CC, a surrogate of atherosclerotic vascular dysfunction. This supports the notion of FGF23 as a predictor of cardiovascular risk independent of renal failure.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Shimada T.
        • Kakitani M.
        • Yamazaki Y.
        • et al.
        Targeted ablation of FGF23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism.
        J Clin Invest. 2004; 113: 561-568
        • Kurosu H.
        • Ogawa Y.
        • Miyoshi M.
        • et al.
        Regulation of fibroblast growth factor-23 signaling by KLOTHO.
        J Biol Chem. 2006; 281: 6120-6123
        • Urakawa I.
        • Yamazaki Y.
        • Shimada T.
        • et al.
        Klotho converts canonical FGF receptor into a specific receptor for FGF23.
        Nature. 2006; 444: 770-774
        • Gutierrez O.
        • Isakova T.
        • Rhee E.
        • et al.
        Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease.
        J Am Soc Nephrol. 2005; 16: 2205-2215
        • Dhayat N.A.
        • Ackermann D.
        • Pruijm M.
        • et al.
        Fibroblast growth factor 23 and markers of mineral metabolism in individuals with preserved renal function.
        Kidney Int. 2016; 90: 648-657
        • Robinson-Cohen C.
        • Bartz T.M.
        • Lai D.
        • et al.
        Genetic variants associated with circulating fibroblast growth factor 23.
        J Am Soc Nephrol. 2018; 29: 2583-2592
        • Gutierrez O.M.
        • Mannstadt M.
        • Isakova T.
        • et al.
        Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis.
        N Engl J Med. 2008; 359: 584-592
        • Mirza M.A.
        • Larsson A.
        • Lind L.
        • Larsson T.E.
        Circulating fibroblast growth factor-23 is associated with vascular dysfunction in the community.
        Atherosclerosis. 2009; 205: 385-399
        • Parker B.D.
        • Schurgers L.J.
        • Brandenburg V.M.
        • et al.
        The associations of fibroblast growth factor 23 and uncarboxylated matrix GLA protein with mortality in coronary artery disease: the heart and soul study.
        Ann Intern Med. 2010; 152: 640-648
        • Pichler G.
        • Haller M.C.
        • Kainz A.
        • Wolf M.
        • Redon J.
        • Oberbauer R.
        Prognostic value of bone- and vascular-derived molecular biomarkers in hemodialysis and renal transplant patients: a systematic review and meta-analysis.
        Nephrol Dial Transp. 2017; 32: 1566-1578
        • Isakova T.
        • Cai X.
        • Lee J.
        • Xie D.
        • Wang X.
        • et al.
        Longitudinal FGF23 trajectories and mortality in patients with CKD.
        J Am Soc Nephrol. 2018; 29: 579-590
        • Biscetti F.
        • Straface G.
        • Porreca C.F.
        • et al.
        Increased FGF23 serum level is associated with unstable carotid plaque in type 2 diabetic subjects with internal carotid stenosis.
        Cardiovasc Diabetol. 2015; 14: 139
        • Kestenbaum B.
        • Sachs M.C.
        • Hoofnagle A.N.
        • et al.
        Fibroblast growth factor-23 and cardiovascular disease in the general population: the multi-ethnic study of atherosclerosis.
        Circ Heart Fail. 2014; 7: 409-417
        • Masson S.
        • Agabiti N.
        • Vago T.
        • et al.
        The fibroblast growth factor-23 and Vitamin D emerge as nontraditional risk factors and may affect cardiovascular risk.
        J Intern Med. 2015; 277: 318-330
        • Zhou C.
        • Mei C.
        • Dai B.
        • Xue C.
        Fibroblast growth factor-23 may follow cardiovascular disease rather than causing it in chronic kidney disease.
        J Am Soc Nephrol. 2018; 29: 2602
        • Rodelo-Haad C.
        • Santamaria R.
        • Muñoz-Castañeda J.R.
        • et al.
        FGF23, biomarker or target?.
        Toxins (Basel). 2019; 11 (pii: E175)
        • Shah N.H.
        • Dong C.
        • Elkind M.S.
        • et al.
        Fibroblast growth factor 23 is associated with carotid plaque presence and area: the Northern Manhattan study.
        Arterioscler Thromb Vasc Biol. 2015; 35: 2048-2053
        • Tartière J.M.
        • Henry O.F.
        • Safar H.
        • et al.
        Carotid intima-media thickness and carotid and/or iliofemoral plaques: comparison of two markers of cardiovascular risk in hypertensive patients.
        J Hypertens. 2003; 21: 739-746
        • O'Leary D.H.
        • Polak J.F.
        • Kronmal R.A.
        • Manolio T.A.
        • Burke G.L.
        • Wolfson Jr., S.K.
        Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. cardiovascular health study collaborative research group.
        N Engl J Med. 1999; 340: 14-22
        • Lorenz M.W.
        • Markus H.S.
        • Bots M.L.
        • Rosvall M.
        • Sitzer M.
        Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis.
        Circulation. 2007; 115: 459-467
        • Silva A.P.
        • Gundlach K.
        • Büchel J.
        • et al.
        Low magnesium levels and FGF-23 dysregulation predict mitral valve calcification as well as intima media thickness in predialysis diabetic patients.
        Int J Endocrinol. 2015; 2015308190
        • Delgado-Lista J.
        • Perez-Martinez P.
        • Garcia-Rios A.
        • Alcala-Diaz J.F.
        • Perez-Caballero A.I.
        • Gomez-Delgado F.
        CORonary diet intervention with Olive oil and cardiovascular PREVention study (the Cordioprev study): rationale, methods, and baseline characteristics: a clinical trial comparing the efficacy of a Mediterranean diet rich in olive oil versus a low-fat diet on cardiovascular disease in coronary patients.
        Am Heart J. 2016; 177: 42-50
        • Stein J.H.
        • Korcarz C.E.
        • Hurst R.T.
        • et al.
        American society of echocardiography carotid intima-media thickness task force. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American society of echocardiography carotid intima-media thickness task force. Endorsed by the society for vascular medicine.
        J Am Soc Echocardiogr. 2008; 21: 93-111
        • Rohde L.E.
        • Lee R.T.
        • Rivero J.
        • et al.
        Circulating cell adhesion molecules are correlated with ultrasound-based assessment of carotid atherosclerosis.
        Arterioscler Thromb Vasc Biol. 1988; 18: 1765-1770
        • O'Leary D.H.
        • Bots M.L.
        Imaging of atherosclerosis: carotid intima-media thickness.
        Eur Heart J. 2010; 31: 1682-1689
        • González-Molero I.
        • Morcillo S.
        • Valdés S.
        • et al.
        Vitamin D deficiency in Spain: a population-based cohort study.
        Eur J Clin Nutr. 2011; 65: 321-328
        • Pilz S.
        • Tomaschitz A.
        • Drechsler C.
        • Dekker J.M.
        • März W.
        Vitamin D deficiency and myocardial diseases.
        Mol Nutr Food Res. 2010; 54: 1103-1113
        • Gattineni J.
        • Twombley K.
        • Goetz R.
        • Mohammadi M.
        • Baum M.
        Regulation of serum 1,25(OH)2 vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4.
        Am J Physiol Renal Physiol. 2011; 301: F371-F377
        • Gattineni J.
        • Alphonse P.
        • Zhang Q.
        • Mathews N.
        • Bates C.M.
        • Baum M.
        Regulation of renal phosphate transport by FGF23 is mediated by FGFR1 and FGFR4.
        Am J Physiol RenalPhysiol. 2014; 306: F351-F358
        • Jean G.
        • Terrat J.C.
        • Vanel T.
        • et al.
        High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients.
        Nephrol Dial Transpl. 2009; 24: 2792-2796
        • Qin Z.
        • Liu X.
        • Song M.
        • et al.
        Fibroblast growth factor 23 as a predictor of cardiovascular and all-cause mortality in prospective studies.
        Atherosclerosis. 2017; 261: 1-11
        • Ix J.H.
        • Katz R.
        • Kestenbaum B.R.
        • et al.
        Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (cardiovascular health study).
        J Am Coll Cardiol. 2012; 60: 200-207
        • Ärnlöv J.
        • Carlsson A.C.
        • Sundström J.
        • et al.
        Serum FGF23 and risk of cardiovascular events in relation to mineral metabolism and cardiovascular pathology.
        Clin J Am Soc Nephrol. 2013; 8: 781-786
        • Roos M.
        • Lutz J.
        • Salmhofer H.
        • et al.
        Relation between plasma fibroblast growth factor-23, serum fetuin-A levels and coronary artery calcification evaluated by multislice computed tomography in patients with normal kidney function.
        Clin Endocrinol (Oxf). 2008; 68: 660-665
        • Pastor-Arroyo E.M.
        • Gehring N.
        • Krudewig C.
        • et al.
        The elevation of circulating fibroblast growth factor 23 without kidney disease does not increase cardiovascular disease risk.
        Kidney Int. 2018; 94: 49-59
        • Mirza M.A.
        • Hansen T.
        • Johansson L.
        • et al.
        Relationship between circulating FGF23 and total body atherosclerosis in the community.
        Nephrol Dial Transpl. 2009; 24: 3125-3131
        • Garimella P.S.
        • Ix J.H.
        • Katz R.
        • et al.
        Fibroblast growth factor 23, the ankle-brachial index, and incident peripheral artery disease in the cardiovascular health study.
        Atherosclerosis. 2014; 233: 91-96
        • Faul C.
        • Amaral A.P.
        • Oskouei B.
        • et al.
        FGF23 induces left ventricular hypertrophy.
        J Clin Invest. 2011; 121: 4393-4408
        • Faul C.
        FGF23 effects on the heart-levels, time, source, and context matter.
        Kidney Int. 2018; 94: 7-11
        • Singh S.
        • Grabner A.
        • Yanucil C.
        • et al.
        Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease.
        Kidney Int. 2016; 90: 985-996
        • Donate-Correa J.
        • Mora-Fernández C.
        • Martínez-Sanz R.
        • et al.
        Expression of FGF23/KLOTHO system in human vascular tissue.
        Int J Cardiol. 2013; 165: 179-183
        • Jimbo R.
        • Kawakami-Mori F.
        • Mu S.
        • et al.
        Fibroblast growth factor 23 accelerates phosphate-induced vascular calcification in the absence of KLOTHO deficiency.
        Kidney Int. 2014; 85: 1103-1111
        • Nasrallah M.M.
        • El-Shehaby A.R.
        • Salem M.M.
        • et al.
        Fibroblast growth factor-23 (FGF-23) is independently correlated to aortic calcification in haemodialysis patients.
        Nephrol Dial Transp. 2010; 25: 2679-2685
        • Kendrick J.
        • Cheung A.K.
        • Kaufman J.S.
        • et al.
        FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis.
        J Am Soc Nephrol. 2011; 22: 1913-1922
        • Marthi A.
        • Donovan K.
        • Haynes R.
        • et al.
        Fibroblast growth factor-23 and risks of cardiovascular and noncardiovascular diseases: a meta-analysis.
        J Am Soc Nephrol. 2018; 29: 579-590
        • Panwar B.
        • Judd S.E.
        • Wadley V.G.
        • et al.
        Association of fibroblast growth factor 23 with risk of incident coronary heart disease in community-living adults.
        JAMA Cardiol. 2018; 3: 318-325
        • Lutsey P.L.
        • Alonso A.
        • Selvin E.
        • et al.
        Fibroblast growth factor-23 and incident coronary heart disease, heart failure, and cardiovascular mortality: the atherosclerosis risk in communities study.
        J Am Heart Assoc. 2014; 10e000936