Circulating fibroblast growth factor‐23 plasma levels predict adverse cardiovascular outcomes in patients with diabetes mellitus with coronary artery disease

Tuñón, José; Fernández-Fernández, Beatriz; Carda, Rocío; Pello, Ana; Cristóbal, Carmen; Tarín, Nieves; Aceña, Álvaro; González-Casaús, María Luisa; Huelmos, Ana; Alonso, Joaquín; Lorenzo, Óscar; González‐Parra, Emilio; Hernández-González, Ignacio; Mahíllo‐Fernández, Ignacio; López-Bescós, Lorenzo; Egido, Jesús

doi:10.1002/dmrr.2787

Cited by 31 publications

(22 citation statements)

References 38 publications

(48 reference statements)

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“…We identified eight circulating biomarkers, including four novel ones, for incident cardiovascular events after adjustment for established risk factors. Our results replicate previous findings in individuals with type 2 diabetes of associations of increased levels of MMP-12 [ 17 ], FGF-23 [ 28 ], TNFR-1 and TNFR-2 [ 29 ] with incident MACE. For the other four biomarkers, we found no previous studies of prospective associations with MACE in type 2 diabetes, although all have been implicated in cardiometabolic disease in other settings.…”

Section: Discussionsupporting

confidence: 91%

Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes

et al. 2018

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Aims/hypothesisMultiplex proteomics could improve understanding and risk prediction of major adverse cardiovascular events (MACE) in type 2 diabetes. This study assessed 80 cardiovascular and inflammatory proteins for biomarker discovery and prediction of MACE in type 2 diabetes.MethodsWe combined data from six prospective epidemiological studies of 30–77-year-old individuals with type 2 diabetes in whom 80 circulating proteins were measured by proximity extension assay. Multivariable-adjusted Cox regression was used in a discovery/replication design to identify biomarkers for incident MACE. We used gradient-boosted machine learning and lasso regularised Cox regression in a random 75% training subsample to assess whether adding proteins to risk factors included in the Swedish National Diabetes Register risk model would improve the prediction of MACE in the separate 25% test subsample.ResultsOf 1211 adults with type 2 diabetes (32% women), 211 experienced a MACE over a mean (±SD) of 6.4 ± 2.3 years. We replicated associations (<5% false discovery rate) between risk of MACE and eight proteins: matrix metalloproteinase (MMP)-12, IL-27 subunit α (IL-27a), kidney injury molecule (KIM)-1, fibroblast growth factor (FGF)-23, protein S100-A12, TNF receptor (TNFR)-1, TNFR-2 and TNF-related apoptosis-inducing ligand receptor (TRAIL-R)2. Addition of the 80-protein assay to established risk factors improved discrimination in the separate test sample from 0.686 (95% CI 0.682, 0.689) to 0.748 (95% CI 0.746, 0.751). A sparse model of 20 added proteins achieved a C statistic of 0.747 (95% CI 0.653, 0.842) in the test sample.Conclusions/interpretationWe identified eight protein biomarkers, four of which are novel, for risk of MACE in community residents with type 2 diabetes, and found improved risk prediction by combining multiplex proteomics with an established risk model. Multiprotein arrays could be useful in identifying individuals with type 2 diabetes who are at highest risk of a cardiovascular event.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4641-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Section: Discussionsupporting

confidence: 91%

Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes

et al. 2018

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“…In contrast, a large community based study also with FGF-23 concentration within normal range followed for 19 years, demonstrated an association between higher FGF-23 and increased risk of incident ESRD independent of kidney function[ 8 ]. In a mixed diabetic and non-diabetic cohort of patients with coronary heart disease, higher FGF-23 predicted CV outcomes in the diabetic but not in the non-diabetic patients suggesting potential biological differences in the FGF-23 response between patients with and without diabetes[ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Growth differentiation factor-15 and fibroblast growth factor-23 are associated with mortality in type 2 diabetes – An observational follow-up study

et al. 2018

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ObjectivesTwo biomarkers, growth differentiation factor 15 (GDF-15) and fibroblast growth factor 23 (FGF-23)), reflecting different aspects of renal pathophysiology, were evaluated as determinants of decline in estimated glomerular filtration rate (eGFR), incident cardiovascular disease (CVD) and all-cause mortality in patients with type 2 diabetes (T2D) and microalbuminuria, but without clinical cardiac disease.Materials and methodsProspective study including 200 T2D patients. The predefined endpoint of chronic kidney disease (CKD) progression: A decline in eGFR of >30% at any time point during follow-up. Hazard ratios (HR) are provided per 1 SD increment of log2-transformed values.ResultsMean (± SD) age was 59 ± 9 years, eGFR 91.1 ± 18.3 ml/min/1.73m2 and median (IQR) UAER 103 (39–230) mg/24-h. During a median 6.1 years follow-up, 40 incident CVD events, 26 deaths and 42 patients reached the CKD endpoint after median 4.9 years. Higher GDF-15 was a determinant of decline in eGFR >30% and all-cause mortality in adjusted models (HR 1.7 (1.1–2.5); p = 0.018 and HR 1.9 (1.2–2.9); p = 0.003, respectively). Adding GDF-15 to traditional risk factors improved risk prediction of decline in renal function (relative integrated discrimination improvement (rIDI) = 30%; p = 0.037). Higher FGF-23 was associated with all-cause mortality in adjusted models (HR 1.6 (1.1–2.2); p = 0.011) with a rIDI of 30% (p = 0.024).ConclusionsIn patients with T2D and microalbuminuria, higher GDF-15 and FGF-23 were independently associated with all-cause mortality and higher GDF-15 improved risk prediction of decline in kidney function and higher FGF-23 of all-cause mortality, beyond traditional risk factors, but not independently of GDF-15.

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“…Serum FGF23 levels are also markedly elevated in patients with acute decompensated heart failure (ADHF), which is a sudden worsening of the signs and symptoms of heart failure, including difficulty breathing, leg or feet swelling, and fatigue (Andersen et al, 2016 ), with heart failure and a reduced ejection fraction (Koller et al, 2015 ), incident atrial fibrillation (Mathew et al, 2014 ), coronary heart disease, heart failure, and cardiovascular mortality (Lutsey et al, 2014 ), non-ischemic cardiac disease (Imazu et al, 2014 ), chronic systolic heart failure (Wohlfahrt et al, 2015 ), and CAD (Tuñón et al, 2016 ). However, myocardial FGF23 gene expression levels and FGF23 immunostaining are not increased in ADHF patients, suggesting that the myocardium does not contribute to elevated circulating FGF23 levels in ADHF and that FGF23 plays roles in heart failure in an endocrine manner (Andersen et al, 2016 ).…”

Section: Pathophysiological Roles Of Fgfs Indicated By Human Diseasesmentioning

confidence: 99%

Roles of FGF Signals in Heart Development, Health, and Disease

Itoh

Ohta

Nakayama

et al. 2016

Front. Cell Dev. Biol.

105

103

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The heart provides the body with oxygen and nutrients and assists in the removal of metabolic waste through the blood vessels of the circulatory system. It is the first organ to form during embryonic morphogenesis. FGFs with diverse functions in development, health, and disease are signaling proteins, mostly as paracrine growth factors or endocrine hormones. The human/mouse FGF family comprises 22 members. Findings obtained from mouse models and human diseases with FGF signaling disorders have indicated that several FGFs are involved in heart development, health, and disease. Paracrine FGFs including FGF8, FGF9, FGF10, and FGF16 act as paracrine signals in embryonic heart development. In addition, paracrine FGFs including FGF2, FGF9, FGF10, and FGF16 play roles as paracrine signals in postnatal heart pathophysiology. Although FGF15/19, FGF21, and FGF23 are typical endocrine FGFs, they mainly function as paracrine signals in heart development or pathophysiology. In heart diseases, serum FGF15/19 levels or FGF21 and FGF23 levels decrease or increase, respectively, indicating their possible roles in heart pathophysiology. FGF2 and FGF10 also stimulate the cardiac differentiation of cultured stem cells and cardiac reprogramming of cultured fibroblasts. These findings provide new insights into the roles of FGF signaling in the heart and potential therapeutic strategies for cardiac disorders.

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Circulating fibroblast growth factor‐23 plasma levels predict adverse cardiovascular outcomes in patients with diabetes mellitus with coronary artery disease

Abstract: FGF-23 plasma levels predict adverse cardiovascular outcomes in coronary artery disease patients who have T2D but not in those without T2D. This finding should be confirmed in larger studies. Copyright © 2016 John Wiley & Sons, Ltd.

Cited by 31 publications

References 38 publications

Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes

Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes

Growth differentiation factor-15 and fibroblast growth factor-23 are associated with mortality in type 2 diabetes – An observational follow-up study

Roles of FGF Signals in Heart Development, Health, and Disease

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