Fibroblast Growth Factor 23 Is an Independent and Specific Predictor of Mortality in Patients With Heart Failure and Reduced Ejection Fraction.
BACKGROUND
Strategies to improve risk prediction are of major importance in patients with heart failure (HF). Fibroblast growth factor 23 (FGF-23) is an endocrine regulator of phosphate and vitamin D homeostasis associated with an increased cardiovascular risk. We aimed to assess the prognostic effect of FGF-23 on mortality in HF patients with a particular focus on differences between patients with HF with preserved ejection fraction and patients with HF with reduced ejection fraction (HFrEF).


RESULTS
FGF-23 levels were measured in 980 patients with HF enrolled in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study including 511 patients with HFrEF and 469 patients with HF with preserved ejection fraction and a median follow-up time of 8.6 years. FGF-23 was additionally measured in a second cohort comprising 320 patients with advanced HFrEF. FGF-23 was independently associated with mortality with an adjusted hazard ratio per 1-SD increase of 1.30 (95% confidence interval, 1.14-1.48; P<0.001) in patients with HFrEF, whereas no such association was found in patients with HF with preserved ejection fraction (for interaction, P=0.043). External validation confirmed the significant association with mortality with an adjusted hazard ratio per 1 SD of 1.23 (95% confidence interval, 1.02-1.60; P=0.027). FGF-23 demonstrated an increased discriminatory power for mortality in addition to N-terminal pro-B-type natriuretic peptide (C-statistic: 0.59 versus 0.63) and an improvement in net reclassification index (39.6%; P<0.001).


CONCLUSIONS
FGF-23 is independently associated with an increased risk of mortality in patients with HFrEF but not in those with HF with preserved ejection fraction, suggesting a different pathophysiologic role for both entities.
From the Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria (L.K., G.G., B.R., P.S., R.B., D.M., M.H., R.P., A.N.); Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology) (M.E.K., T.B.G., G.D., W.M.) and Mannheim Institute of Public Health, Social and Preventive Medicine (T.B.G.), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany (V.M.B.); Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.S.), Division of Cardiology (A.T.) and Division of Endocrinology and Metabolism (S.P.), Department of Internal Medicine, Medical University of Graz, Graz, Austria (H.S., W.M.); Department of Angiology, Inselspital, Bern, Switzerland; Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee: Specialist Clinic for Rehabilitation, PV Bad Aussee, Austria (A.T.); and Synlab Academy, Synlab Services GmbH, Mannheim, Germany (W.M.).
Lorenz
L
Koller
From the Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria (L.K., G.G., B.R., P.S., R.B., D.M., M.H., R.P., A.N.); Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology) (M.E.K., T.B.G., G.D., W.M.) and Mannheim Institute of Public Health, Social and Preventive Medicine (T.B.G.), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany (V.M.B.); Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.S.), Division of Cardiology (A.T.) and Division of Endocrinology and Metabolism (S.P.), Department of Internal Medicine, Medical University of Graz, Graz, Austria (H.S., W.M.); Department of Angiology, Inselspital, Bern, Switzerland; Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee: Specialist Clinic for Rehabilitation, PV Bad Aussee, Austria (A.T.); and Synlab Academy, Synlab Services GmbH, Mannheim, Germany (W.M.).
Marcus E
ME
Kleber
From the Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria (L.K., G.G., B.R., P.S., R.B., D.M., M.H., R.P., A.N.); Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology) (M.E.K., T.B.G., G.D., W.M.) and Mannheim Institute of Public Health, Social and Preventive Medicine (T.B.G.), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany (V.M.B.); Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.S.), Division of Cardiology (A.T.) and Division of Endocrinology and Metabolism (S.P.), Department of Internal Medicine, Medical University of Graz, Graz, Austria (H.S., W.M.); Department of Angiology, Inselspital, Bern, Switzerland; Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee: Specialist Clinic for Rehabilitation, PV Bad Aussee, Austria (A.T.); and Synlab Academy, Synlab Services GmbH, Mannheim, Germany (W.M.).
Vincent M
VM
Brandenburg
From the Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria (L.K., G.G., B.R., P.S., R.B., D.M., M.H., R.P., A.N.); Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology) (M.E.K., T.B.G., G.D., W.M.) and Mannheim Institute of Public Health, Social and Preventive Medicine (T.B.G.), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany (V.M.B.); Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.S.), Division of Cardiology (A.T.) and Division of Endocrinology and Metabolism (S.P.), Department of Internal Medicine, Medical University of Graz, Graz, Austria (H.S., W.M.); Department of Angiology, Inselspital, Bern, Switzerland; Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee: Specialist Clinic for Rehabilitation, PV Bad Aussee, Austria (A.T.); and Synlab Academy, Synlab Services GmbH, Mannheim, Germany (W.M.).
Georg
G
Goliasch
From the Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria (L.K., G.G., B.R., P.S., R.B., D.M., M.H., R.P., A.N.); Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology) (M.E.K., T.B.G., G.D., W.M.) and Mannheim Institute of Public Health, Social and Preventive Medicine (T.B.G.), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany (V.M.B.); Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.S.), Division of Cardiology (A.T.) and Division of Endocrinology and Metabolism (S.P.), Department of Internal Medicine, Medical University of Graz, Graz, Austria (H.S., W.M.); Department of Angiology, Inselspital, Bern, Switzerland; Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee: Specialist Clinic for Rehabilitation, PV Bad Aussee, Austria (A.T.); and Synlab Academy, Synlab Services GmbH, Mannheim, Germany (W.M.).
Bernhard
B
Richter
From the Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria (L.K., G.G., B.R., P.S., R.B., D.M., M.H., R.P., A.N.); Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology) (M.E.K., T.B.G., G.D., W.M.) and Mannheim Institute of Public Health, Social and Preventive Medicine (T.B.G.), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany (V.M.B.); Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.S.), Division of Cardiology (A.T.) and Division of Endocrinology and Metabolism (S.P.), Department of Internal Medicine, Medical University of Graz, Graz, Austria (H.S., W.M.); Department of Angiology, Inselspital, Bern, Switzerland; Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee: Specialist Clinic for Rehabilitation, PV Bad Aussee, Austria (A.T.); and Synlab Academy, Synlab Services GmbH, Mannheim, Germany (W.M.).
Patrick
P
Sulzgruber
From the Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria (L.K., G.G., B.R., P.S., R.B., D.M., M.H., R.P., A.N.); Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology) (M.E.K., T.B.G., G.D., W.M.) and Mannheim Institute of Public Health, Social and Preventive Medicine (T.B.G.), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany (V.M.B.); Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.S.), Division of Cardiology (A.T.) and Division of Endocrinology and Metabolism (S.P.), Department of Internal Medicine, Medical University of Graz, Graz, Austria (H.S., W.M.); Department of Angiology, Inselspital, Bern, Switzerland; Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee: Specialist Clinic for Rehabilitation, PV Bad Aussee, Austria (A.T.); and Synlab Academy, Synlab Services GmbH, Mannheim, Germany (W.M.).
Hubert
H
Scharnagl
From the Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria (L.K., G.G., B.R., P.S., R.B., D.M., M.H., R.P., A.N.); Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology) (M.E.K., T.B.G., G.D., W.M.) and Mannheim Institute of Public Health, Social and Preventive Medicine (T.B.G.), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany (V.M.B.); Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.S.), Division of Cardiology (A.T.) and Division of Endocrinology and Metabolism (S.P.), Department of Internal Medicine, Medical University of Graz, Graz, Austria (H.S., W.M.); Department of Angiology, Inselspital, Bern, Switzerland; Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee: Specialist Clinic for Rehabilitation, PV Bad Aussee, Austria (A.T.); and Synlab Academy, Synlab Services GmbH, Mannheim, Germany (W.M.).
Günther
G
Silbernagel
From the Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria (L.K., G.G., B.R., P.S., R.B., D.M., M.H., R.P., A.N.); Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology) (M.E.K., T.B.G., G.D., W.M.) and Mannheim Institute of Public Health, Social and Preventive Medicine (T.B.G.), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany (V.M.B.); Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.S.), Division of Cardiology (A.T.) and Division of Endocrinology and Metabolism (S.P.), Department of Internal Medicine, Medical University of Graz, Graz, Austria (H.S., W.M.); Department of Angiology, Inselspital, Bern, Switzerland; Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee: Specialist Clinic for Rehabilitation, PV Bad Aussee, Austria (A.T.); and Synlab Academy, Synlab Services GmbH, Mannheim, Germany (W.M.).
Tanja B
TB
Grammer
From the Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria (L.K., G.G., B.R., P.S., R.B., D.M., M.H., R.P., A.N.); Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology) (M.E.K., T.B.G., G.D., W.M.) and Mannheim Institute of Public Health, Social and Preventive Medicine (T.B.G.), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany (V.M.B.); Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.S.), Division of Cardiology (A.T.) and Division of Endocrinology and Metabolism (S.P.), Department of Internal Medicine, Medical University of Graz, Graz, Austria (H.S., W.M.); Department of Angiology, Inselspital, Bern, Switzerland; Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee: Specialist Clinic for Rehabilitation, PV Bad Aussee, Austria (A.T.); and Synlab Academy, Synlab Services GmbH, Mannheim, Germany (W.M.).
Graciela
G
Delgado
From the Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria (L.K., G.G., B.R., P.S., R.B., D.M., M.H., R.P., A.N.); Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology) (M.E.K., T.B.G., G.D., W.M.) and Mannheim Institute of Public Health, Social and Preventive Medicine (T.B.G.), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany (V.M.B.); Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.S.), Division of Cardiology (A.T.) and Division of Endocrinology and Metabolism (S.P.), Department of Internal Medicine, Medical University of Graz, Graz, Austria (H.S., W.M.); Department of Angiology, Inselspital, Bern, Switzerland; Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee: Specialist Clinic for Rehabilitation, PV Bad Aussee, Austria (A.T.); and Synlab Academy, Synlab Services GmbH, Mannheim, Germany (W.M.).
Andreas
A
Tomaschitz
From the Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria (L.K., G.G., B.R., P.S., R.B., D.M., M.H., R.P., A.N.); Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology) (M.E.K., T.B.G., G.D., W.M.) and Mannheim Institute of Public Health, Social and Preventive Medicine (T.B.G.), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany (V.M.B.); Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.S.), Division of Cardiology (A.T.) and Division of Endocrinology and Metabolism (S.P.), Department of Internal Medicine, Medical University of Graz, Graz, Austria (H.S., W.M.); Department of Angiology, Inselspital, Bern, Switzerland; Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee: Specialist Clinic for Rehabilitation, PV Bad Aussee, Austria (A.T.); and Synlab Academy, Synlab Services GmbH, Mannheim, Germany (W.M.).
Stefan
S
Pilz
From the Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria (L.K., G.G., B.R., P.S., R.B., D.M., M.H., R.P., A.N.); Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology) (M.E.K., T.B.G., G.D., W.M.) and Mannheim Institute of Public Health, Social and Preventive Medicine (T.B.G.), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany (V.M.B.); Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.S.), Division of Cardiology (A.T.) and Division of Endocrinology and Metabolism (S.P.), Department of Internal Medicine, Medical University of Graz, Graz, Austria (H.S., W.M.); Department of Angiology, Inselspital, Bern, Switzerland; Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee: Specialist Clinic for Rehabilitation, PV Bad Aussee, Austria (A.T.); and Synlab Academy, Synlab Services GmbH, Mannheim, Germany (W.M.).
Rudolf
R
Berger
From the Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria (L.K., G.G., B.R., P.S., R.B., D.M., M.H., R.P., A.N.); Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology) (M.E.K., T.B.G., G.D., W.M.) and Mannheim Institute of Public Health, Social and Preventive Medicine (T.B.G.), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany (V.M.B.); Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.S.), Division of Cardiology (A.T.) and Division of Endocrinology and Metabolism (S.P.), Department of Internal Medicine, Medical University of Graz, Graz, Austria (H.S., W.M.); Department of Angiology, Inselspital, Bern, Switzerland; Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee: Specialist Clinic for Rehabilitation, PV Bad Aussee, Austria (A.T.); and Synlab Academy, Synlab Services GmbH, Mannheim, Germany (W.M.).
Deddo
D
Mörtl
From the Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria (L.K., G.G., B.R., P.S., R.B., D.M., M.H., R.P., A.N.); Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology) (M.E.K., T.B.G., G.D., W.M.) and Mannheim Institute of Public Health, Social and Preventive Medicine (T.B.G.), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany (V.M.B.); Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.S.), Division of Cardiology (A.T.) and Division of Endocrinology and Metabolism (S.P.), Department of Internal Medicine, Medical University of Graz, Graz, Austria (H.S., W.M.); Department of Angiology, Inselspital, Bern, Switzerland; Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee: Specialist Clinic for Rehabilitation, PV Bad Aussee, Austria (A.T.); and Synlab Academy, Synlab Services GmbH, Mannheim, Germany (W.M.).
Martin
M
Hülsmann
From the Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria (L.K., G.G., B.R., P.S., R.B., D.M., M.H., R.P., A.N.); Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology) (M.E.K., T.B.G., G.D., W.M.) and Mannheim Institute of Public Health, Social and Preventive Medicine (T.B.G.), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany (V.M.B.); Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.S.), Division of Cardiology (A.T.) and Division of Endocrinology and Metabolism (S.P.), Department of Internal Medicine, Medical University of Graz, Graz, Austria (H.S., W.M.); Department of Angiology, Inselspital, Bern, Switzerland; Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee: Specialist Clinic for Rehabilitation, PV Bad Aussee, Austria (A.T.); and Synlab Academy, Synlab Services GmbH, Mannheim, Germany (W.M.).
Richard
R
Pacher
From the Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria (L.K., G.G., B.R., P.S., R.B., D.M., M.H., R.P., A.N.); Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology) (M.E.K., T.B.G., G.D., W.M.) and Mannheim Institute of Public Health, Social and Preventive Medicine (T.B.G.), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany (V.M.B.); Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.S.), Division of Cardiology (A.T.) and Division of Endocrinology and Metabolism (S.P.), Department of Internal Medicine, Medical University of Graz, Graz, Austria (H.S., W.M.); Department of Angiology, Inselspital, Bern, Switzerland; Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee: Specialist Clinic for Rehabilitation, PV Bad Aussee, Austria (A.T.); and Synlab Academy, Synlab Services GmbH, Mannheim, Germany (W.M.).
Winfried
W
März
From the Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria (L.K., G.G., B.R., P.S., R.B., D.M., M.H., R.P., A.N.); Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology) (M.E.K., T.B.G., G.D., W.M.) and Mannheim Institute of Public Health, Social and Preventive Medicine (T.B.G.), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany (V.M.B.); Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.S.), Division of Cardiology (A.T.) and Division of Endocrinology and Metabolism (S.P.), Department of Internal Medicine, Medical University of Graz, Graz, Austria (H.S., W.M.); Department of Angiology, Inselspital, Bern, Switzerland; Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee: Specialist Clinic for Rehabilitation, PV Bad Aussee, Austria (A.T.); and Synlab Academy, Synlab Services GmbH, Mannheim, Germany (W.M.). alexander.niessner@meduniwien.ac.at.
Alexander
A
Niessner
D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood*; D006333:Heart Failure / Q000097:blood* / Q000401:mortality* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D011237:Predictive Value of Tests; D012307:Risk Factors; D013318:Stroke Volume / Q000502:physiology*; D016019:Survival Analysis
D015415:Biomarkers; C000717427:FGF23 protein, human; D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23
biological markers; fibroblast growth factors; heart failure; mortality; risk assessment