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Fibroblast growth factor 23 is related to profiles indicating volume overload, poor therapy optimization and prognosis in patients with new-onset and worsening heart failure

      Abstract

      Background

      Fibroblast growth factor (FGF) 23 is a hormone that increases urinary phosphate excretion and regulates renal sodium reabsorption and plasma volume. We studied the role of plasma FGF23 in therapy optimization and outcomes in patients with new-onset and worsening heart failure (HF).

      Methods

      We measured plasma C-terminal FGF23 levels at baseline in 2399 of the 2516 patients included in the BIOlogy Study to Tailored Treatment in Chronic HF (BIOSTAT-CHF) trial. The association between FGF23 and outcome was evaluated by Cox regression analysis adjusted for potential confounders.

      Results

      Median FGF23 was 218.0 [IQR: 117.1–579.3] RU/ml; patients with higher FGF23 levels had a worse NYHA class, more signs of congestion, and were less likely to use an ACE-inhibitor (ACEi) or angiotensin receptor blocker (ARBs) at baseline (all P < 0.01). Higher FGF23 levels were independently associated with higher BNP, lower eGFR, the presence of oedema and atrial fibrillation (all P< 0.001). In addition, higher FGF23 was independently associated with impaired uptitration of ACEi/ARBs after 3 months, but not of beta-blockers. In multivariable Cox regression analysis, FGF23 was independently associated with all-cause mortality (hazard ratio: 1.17 (1.09–1.26) per log increase, P < 0.001), and the combined endpoint of all-cause mortality and HF hospitalization (1.15 (1.08–1.22) per log increase, P < 0.001).

      Conclusions

      In patients with new-onset and worsening HF, higher plasma FGF23 levels were independently associated with volume overload, less successful uptitration of ACEi/ARBs and an increased risk of all-cause mortality and HF hospitalization.

      Abbreviations:

      ACEi (angiotensin converting enzyme inhibitor), ARB (angiotensin receptor blocker), BNP (Brain Natriuretic Peptide), BIOSTAT-CHF (BIOlogy Study to Tailored Treatment in Chronic Heart Failure), CKD (chronic kidney disease), eGFR (estimated Glomerular Filtration Rate), FGF23 (fibroblast growth factor 23), HF (heart failure), JVP (jugular venous pressure), NT-pro BNP (N terminal pro Brain Natriuretic Peptide), RAAS (Renin Angiotensin Aldosterone System)

      Keywords

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      References

        • Kovesdy C.P.
        • Quarles L.D.
        Fibroblast growth factor-23: what we know, what we don't know, and what we need to know.
        Nephrol. Dial. Transplant. 2013; 28: 2228-2236
        • 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. 2014; 25: 349-360
        • Faul C.
        • Amaral A.P.
        • Oskouei B.
        • et al.
        FGF23 induces left ventricular hypertrophy.
        J. Clin. Invest. 2011; 121: 4393-4408
        • Andrukhova O.
        • Slavic S.
        • Smorodchenko A.
        • et al.
        FGF23 regulates renal sodium handling and blood pressure.
        EMBO Mol. Med. 2014; 6: 744-759
        • de Borst M.H.
        • Vervloet M.G.
        • ter Wee P.M.
        • Navis G.
        Cross talk between the renin-angiotensin-aldosterone system and vitamin D-FGF-23-klotho in chronic kidney disease.
        J Am Soc Nephrol. 2011; 22: 1603-1609
        • Humalda J.K.
        • Lambers Heerspink H.J.
        • Kwakernaak A.J.
        • et al.
        Fibroblast growth factor 23 and the antiproteinuric response to dietary sodium restriction during renin-angiotensin-aldosterone system blockade.
        Am. J. Kidney Dis. 2015; 65: 259-266
        • Udell J.A.
        • Morrow D.A.
        • Jarolim P.
        • et al.
        Fibroblast growth factor-23, cardiovascular prognosis, and benefit of angiotensin-converting enzyme inhibition in stable ischemic heart disease.
        J. Am. Coll. Cardiol. 2014; 63: 2421-2428
        • Gruson D.
        • Lepoutre T.
        • Ketelslegers J.M.
        • Cumps J.
        • Ahn S.A.
        • Rousseau M.F.
        C-terminal FGF23 is a strong predictor of survival in systolic heart failure.
        Peptides. 2012; 37: 258-262
        • Poelzl G.
        • Trenkler C.
        • Kliebhan J.
        • et al.
        FGF23 is associated with disease severity and prognosis in chronic heart failure.
        Eur. J. Clin. Investig. 2014; 44: 1150-1158
        • Plischke M.
        • Neuhold S.
        • Adlbrecht C.
        • et al.
        Inorganic phosphate and FGF-23 predict outcome in stable systolic heart failure.
        Eur. J. Clin. Investig. 2012; 42: 649-656
        • Wohlfahrt P.
        • Melenovsky V.
        • Kotrc M.
        • et al.
        Association of fibroblast growth factor-23 levels and angiotensin-converting enzyme inhibition in chronic systolic heart failure.
        JACC Heart Fail. 2015; 3: 829-839
        • Voors A.A.
        • Anker S.D.
        • Cleland J.G.
        • et al.
        A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure: rationale, design, and baseline characteristics of BIOSTAT-CHF.
        Eur. J. Heart Fail. 2016; 18: 716-726
        • Ouwerkerk W.
        • Voors A.A.
        • Anker S.D.
        • et al.
        Determinants and clinical outcome of uptitration of ACE-inhibitor and beta-blocker in patients with heart failure: a prospective European study.
        Eur. Heart J. 2016; 38: 1883-1890
        • McMurray J.J.
        • Adamopoulos S.
        • Anker S.D.
        • et al.
        ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC.
        Eur. Heart J. 2012; 33: 1787-1847
        • Ponikowski P.
        • Voors A.A.
        • Anker S.D.
        • et al.
        ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
        Eur. Heart J. 2016; 18: 891-975
        • Heijboer A.C.
        • Levitus M.
        • Vervloet M.G.
        • et al.
        Determination of fibroblast growth factor 23.
        Ann. Clin. Biochem. 2009; 46: 338-340
        • 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
        • Levey A.S.
        • Stevens L.A.
        • Schmid C.H.
        • et al.
        A new equation to estimate glomerular filtration rate.
        Ann. Intern. Med. 2009; 150: 604-612
        • Voors A.A.
        • Ouwerkerk W.
        • Zannad F.
        • et al.
        Development and validation of multivariate models to predict mortality and hospitalization in patients with heart failure.
        Eur. J. Heart Fail. 2017; 19: 627-634
        • 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
        • Isakova T.
        • Wahl P.
        • Vargas G.S.
        • et al.
        Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease.
        Kidney Int. 2011; 79: 1370-1378
        • Scialla J.J.
        • Wolf M.
        Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease.
        Nat. Rev. Nephrol. 2014; 10: 268-278
        • Baia L.C.
        • Humalda J.K.
        • Vervloet M.G.
        • et al.
        Fibroblast growth factor 23 and cardiovascular mortality after kidney transplantation.
        Clin. J. Am. Soc. Nephrol. 2013; 8: 1968-1978
        • Scialla J.J.
        • Lau W.L.
        • Reilly M.P.
        • et al.
        Fibroblast growth factor 23 is not associated with and does not induce arterial calcification.
        Kidney Int. 2013; 83: 1159-1168
        • Reindl M.
        • Reinstadler S.J.
        • Feistritzer H.J.
        • et al.
        Fibroblast growth factor 23 as novel biomarker for early risk stratification after ST-elevation myocardial infarction.
        Heart. 2016; 103: 856-862
        • Humalda J.K.
        • Seiler-Muler S.
        • Kwakernaak A.J.
        • et al.
        Response of fibroblast growth factor 23 to volume interventions in arterial hypertension and diabetic nephropathy.
        Medicine (Baltimore). 2016; 95e5003
        • Ix J.H.
        • Shlipak M.G.
        • Wassel C.L.
        • Whooley M.A.
        Fibroblast growth factor-23 and early decrements in kidney function: the Heart and Soul Study.
        Nephrol. Dial. Transplant. 2010; 25: 993-997
        • 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
        • Li Y.C.
        • Kong J.
        • Wei M.
        • Chen Z.F.
        • Liu S.Q.
        • Cao L.P.
        1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system.
        J. Clin. Invest. 2002; 110: 229-238
        • Koller L.
        • Kleber M.E.
        • Brandenburg V.M.
        • et al.
        Fibroblast growth factor 23 is an independent and specific predictor of mortality in patients with heart failure and reduced ejection fraction.
        Circ. Heart Fail. 2015; 8: 1059-1067
        • 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
        • Poletti R.
        • Vergaro G.
        • Zyw L.
        • Prontera C.
        • Passino C.
        • Emdin M.
        Prognostic value of plasma renin activity in heart failure patients with chronic kidney disease.
        Int. J. Cardiol. 2013; 167: 711-715
        • Moe S.M.
        • Chertow G.M.
        • Parfrey P.S.
        • et al.
        Cinacalcet, fibroblast growth factor-23, and cardiovascular disease in hemodialysis: the evaluation of cinacalcet HCl therapy to lower cardiovascular events (EVOLVE) trial.
        Circulation. 2015; 132: 27-39

      Linked Article

      • Heart, kidney and FGF23: Les liaisons dangereuses
        International Journal of CardiologyVol. 253
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          Heart failure (HF) is a complex clinical syndrome accompanied by increased mortality and sustained by a very complex pathophysiology, characterized by abnormal cardiac function, altered hemodynamics, maladaptive neurohormonal derangement, eventual immune and inflammatory activation and target organ damage/dysfunction.
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