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American Journal of Kidney Diseases

Fibroblast Growth Factor 23 and Sudden Versus Non-sudden Cardiac Death: The Cardiovascular Health Study

Published:January 05, 2015DOI:https://doi.org/10.1053/j.ajkd.2014.10.025

      Background

      Elevated fibroblast growth factor 23 (FGF-23) concentrations are associated with greater risk of cardiovascular events and mortality, especially among people with chronic kidney disease (CKD). Because individuals with CKD are at an increased risk of sudden cardiac death (SCD), we sought to understand whether FGF-23 level is a stronger risk factor for SCD versus non-SCD.

      Study Design

      Cohort study.

      Setting & Participants

      3,244 participants 65 years or older in the community-based Cardiovascular Health Study.

      Predictor

      Plasma FGF-23 concentrations.

      Outcomes

      We assessed SCD and non-SCD in these analyses. SCD was adjudicated rigorously and was defined as a sudden pulseless condition of cardiac origin in a previously stable person occurring out of hospital or in the emergency department.

      Measurements

      We estimated associations of baseline FGF-23 concentrations with SCD and non-SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, comorbid conditions, and kidney function. We also tested whether associations differed by CKD status.

      Results

      During a median follow-up of 8.1 years, there were 118 adjudicated SCD and 570 non-SCD events. After multivariable adjustment for demographics, cardiovascular risk factors, comorbid conditions, and parameters of kidney function, higher FGF-23 concentrations were an independent risk factor for non-SCD (HR [per doubling], 1.17; 95% CI, 1.06-1.30). However, elevated FGF-23 concentrations were not associated independently with SCD (HR [per doubling], 1.07; 95% CI, 0.85-1.35). In stratified analysis by CKD status (36.5% of cohort), doubling of FGF-23 concentrations was associated independently with non-SCD (adjusted HR, 1.26; 95% CI, 1.10-1.45). A similar magnitude of association was observed between FGF-23 level and SCD in the CKD subgroup; however, it was not significant (HR, 1.20; 95% CI, 0.89-1.62).

      Limitations

      Limited power to detect moderate-sized effects between FGF-23 level and SCD in both the primary and stratified analyses.

      Conclusions

      In this population-based study, FGF-23 level elevations were associated independently with non-SCD. Among individuals with CKD, the associations between FGF-23 level and SCD and non-SCD were similar.

      Index Words

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      References

        • Liu S.
        • Quarles L.D.
        How fibroblast growth factor 23 works.
        J Am Soc Nephrol. 2007; 18: 1637-1647
        • 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
        • 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
        • 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
        • Isakova T.
        • Xie H.
        • Yang W.
        • et al.
        Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease.
        JAMA. 2011; 305: 2432-2439
        • 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
        • Scialla J.J.
        • Xie H.
        • Rahman M.
        • et al.
        Fibroblast growth factor-23 and cardiovascular events in CKD.
        J Am Soc Nephrol. 2013; 25: 349-360
        • Deo R.
        • Sotoodehnia N.
        • Katz R.
        • et al.
        Cystatin C and sudden cardiac death risk in the elderly.
        Circ Cardiovasc Qual Outcomes. 2010; 3: 159-164
        • Whitman I.R.
        • Feldman H.I.
        • Deo R.
        CKD and sudden cardiac death: epidemiology, mechanisms, and therapeutic approaches.
        J Am Soc Nephrol. 2012; 23: 1929-1939
        • Faul C.
        • Amaral A.P.
        • Oskouei B.
        • et al.
        FGF23 induces left ventricular hypertrophy.
        J Clin Invest. 2011; 121: 4393-4408
        • Gutierrez O.M.
        • Januzzi J.L.
        • Isakova T.
        • et al.
        Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease.
        Circulation. 2009; 119: 2545-2552
        • Deo R.
        • Albert C.M.
        Epidemiology and genetics of sudden cardiac death.
        Circulation. 2012; 125: 620-637
        • Fried L.P.
        • Borhani N.O.
        • Enright P.
        • et al.
        The Cardiovascular Health Study: design and rationale.
        Ann Epidemiol. 1991; 1: 263-276
        • Shlipak M.G.
        • Sarnak M.J.
        • Katz R.
        • et al.
        Cystatin C and the risk of death and cardiovascular events among elderly persons.
        N Engl J Med. 2005; 352: 2049-2060
        • Stevens P.E.
        • Levin A.
        Evaluation and management of chronic kidney disease: synopsis of the Kidney Disease: Improving Global Outcomes 2012 clinical practice guideline.
        Ann Intern Med. 2013; 158: 825-830
        • Jonsson K.B.
        • Zahradnik R.
        • Larsson T.
        • et al.
        Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.
        N Engl J Med. 2003; 348: 1656-1663
        • Fishman G.I.
        • Chugh S.S.
        • Dimarco J.P.
        • et al.
        Sudden cardiac death prediction and prevention: report from a National Heart, Lung, and Blood Institute and Heart Rhythm Society Workshop.
        Circulation. 2010; 122: 2335-2348
        • Sotoodehnia N.
        • Siscovick D.S.
        • Vatta M.
        • et al.
        Beta2-adrenergic receptor genetic variants and risk of sudden cardiac death.
        Circulation. 2006; 113: 1842-1848
        • Fine J.P.
        • Gray R.J.
        A proportional hazards model for the subdistribution of a competing risk.
        J Am Stat Assoc. 1999; 94: 496-509
      1. Rebholz CM, Grams ME, Coresh J, et al. Serum fibroblast growth factor-23 is associated with incident kidney disease [published online ahead of print July 24, 2014]. J Am Soc Nephrol. http://dx.doi.org/10.1681/ASN.2014020218.

        • Kawai M.
        • Kinoshita S.
        • Shimba S.
        • Ozono K.
        • Michigami T.
        Sympathetic activation induces skeletal FGF23 expression in a circadian rhythm-dependent manner.
        J Biol Chem. 2014; 289: 1457-1466
        • de Beus E.
        • de Jager R.
        • Joles J.A.
        • Grassi G.
        • Blankestijn P.J.
        Sympathetic activation secondary to chronic kidney disease: therapeutic target for renal denervation?.
        J Hypertens. 2014; 32: 1751-1761
        • Florea V.G.
        • Cohn J.N.
        The autonomic nervous system and heart failure.
        Circ Res. 2014; 114: 1815-1826
        • Babick A.
        • Elimban V.
        • Zieroth S.
        • Dhalla N.S.
        Reversal of cardiac dysfunction and subcellular alterations by metoprolol in heart failure due to myocardial infarction.
        J Cell Physiol. 2013; 228: 2063-2070
        • Colucci W.S.
        The effects of norepinephrine on myocardial biology: implications for the therapy of heart failure.
        Clin Cardiol. 1998; 21: I20-I24
        • Hu M.C.
        • Shi M.
        • Zhang J.
        • et al.
        Klotho deficiency causes vascular calcification in chronic kidney disease.
        J Am Soc Nephrol. 2011; 22: 124-136
        • Galitzer H.
        • Ben-Dov I.Z.
        • Silver J.
        • Naveh-Many T.
        Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease.
        Kidney Int. 2010; 77: 211-218
        • Liu S.
        • Tang W.
        • Zhou J.
        • et al.
        Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D.
        J Am Soc Nephrol. 2006; 17: 1305-1315
        • Thadhani R.
        • Appelbaum E.
        • Pritchett Y.
        • et al.
        Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial.
        JAMA. 2012; 307: 674-684
        • Hinkle Jr., L.E.
        • Thaler H.T.
        Clinical classification of cardiac deaths.
        Circulation. 1982; 65: 457-464