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

Aim Fibroblast growth factor 23 (FGF23) is an intensively studied biomarker at the crossroads of cardiovascular disease, heart failure (HF) and chronic kidney disease. Independent associations between increasing FGF23 levels and cardiovascular events were found in many, but not all studies. By analysing data from the TIME‐CHF cohort, we sought to investigate the prognostic value of FGF23 in an elderly, multimorbid HF patient cohort. We determined differences between intact (iFGF23) and C‐terminal FGF23 (cFGF23) regarding their prognostic value and their levels over time in different HF subgroups according to left ventricular ejection fraction (LVEF). Methods and results In this multicentre trial of 622 patients with symptomatic HF aged ≥60 years, we determined iFGF23 and cFGF23 at baseline, 3, 6 and 12‐month follow‐up. In unadjusted analyses, cFGF23 significantly predicted all HF‐related outcomes at all time points. The predictive value of iFGF23 was less and not statistically significant at baseline. After multivariable adjustments, the association between both cFGF23 and iFGF23 and outcome lost statistical significance apart from cFGF23 at month 3. Overall, patients with preserved and mid‐range LVEF had higher levels of iFGF23 and cFGF23 than those with reduced LVEF. Levels decreased significantly during the first 3 months in mid‐range and reduced LVEF patients, but did not significantly change over time in those with preserved LVEF. Conclusions Fibroblast growth factor 23 is of limited value regarding risk prediction in this elderly HF population. Potentially heterogeneous roles of FGF23 in different LVEF groups deserve further investigation.

Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Limited role for fibroblast growth factor 23 in assessing prognosis in heart failure patients: data from the TIME‐CHF trial

Stöhr

Brandenburg

Heine

et al. 2020

“…Overall, 100 patients with HF in this study were selected from the EU FP7 funded BIOSTAT‐CHF (A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) project. This was a multicentre clinical study in Europe that aimed to identify poor outcomes in HF patients with standard treatment using a systems biology approach (including demographics, biomarkers, genetics, and proteomics) . This project was conducted according to the Declaration of Helsinki that was approved by national and local ethics committees.…”

Section: Methodsmentioning

confidence: 99%

“…This was a multicentre clinical study in Europe 14 that aimed to identify poor outcomes in HF patients with standard treatment using a systems biology approach (including demographics, biomarkers, genetics, and proteomics). [15][16][17][18][19][20][21][22][23][24][25][26][27] This project was conducted according to the Declaration of Helsinki that was approved by national and local ethics committees. All patients in this study had written informed consent.…”

Section: Patient Populationmentioning

confidence: 99%

Plasma proteomic approach in patients with heart failure: insights into pathogenesis of disease progression and potential novel treatment targets

Cao

Jones

Voors

et al. 2019

Self Cite

Aims To provide insights into pathogenesis of disease progression and potential novel treatment targets for patients with heart failure by investigation of the plasma proteome using network analysis. Methods and results The plasma proteome of 50 patients with heart failure who died or were rehospitalised were compared with 50 patients with heart failure, matched for age and sex, who did not have an event. Peptides were analysed on two‐dimensional liquid chromatography coupled to tandem mass spectrometry (2D LC ESI‐MS/MS) in high definition mode (HDMSE). We identified and quantified 3001 proteins, of which 51 were significantly up‐regulated and 46 down‐regulated with more than two‐fold expression changes in those who experienced death or rehospitalisation. Gene ontology enrichment analysis and protein–protein interaction networks of significant differentially expressed proteins discovered the central role of metabolic processes in clinical outcomes of patients with heart failure. The findings revealed that a cluster of proteins related to glutathione metabolism, arginine and proline metabolism, and pyruvate metabolism in the pathogenesis of poor outcome in patients with heart failure who died or were rehospitalised. Conclusions Our findings show that in patients with heart failure who died or were rehospitalised, the glutathione, arginine and proline, and pyruvate pathways were activated. These pathways might be potential targets for therapies to improve poor outcomes in patients with heart failure.

“…Over a median follow‐up of >12 years, they adjudicated incident HF events (HFrEF, HFpEF) and demonstrated that the association between FGF23 and HF was mainly driven by HFpEF. It complicated straightforward interpretations: if FGF23 promotes HFpEF, how to interpret a selective discriminatory power for hard events in HFrEF? Finally, in BIOSTAT‐CHF, a trial in new‐onset and worsening HF, higher cFGF23 concentrations predicted mortality. However, when added to a prognostic model which already included age, sex, ischaemic aetiology, left ventricular ejection fraction and NT‐proBNP, there was no significant gain anymore for cFGF23 (notwithstanding improvement of the c‐index).…”

mentioning

confidence: 99%

Fibroblast growth factor 23 and the quest for the Holy Grail in heart failure: will the Crusaders be forced to surrender?

Buyzere

Delanghe

2020

This article refers to 'Limited role for fibroblast growth factor 23 in assessing prognosis in heart failure patients: data from the TIME-CHF trial' by R. Stöhr et al., published in this issue on pages 701-709.Fibroblast growth factor 23 (FGF23) is well-known as a phosphaturic hormone (a phosphatonin) primarily secreted by osteocytes to maintain mineral homeostasis, essentially by blocking tubular reabsorption. Of interest, recently expression of FGF23 has been demonstrated in cardiac myocytes and fibroblasts, in coronary artery endothelial cells, in vascular smooth muscle cells and inflammatory macrophages as well as release of FGF23 from the heart. 1 FGF23 has been incriminated to promote pro-hypertrophic, pro-fibrotic, and pro-inflammatory signalling (paracrine effects). Clinical associations with increased FGF23 concentrations in the field of cardiology comprise (acute decompensated) heart failure (HF), ischaemic and dilated cardiomyopathy and myocarditis.While founder fathers of FGF23 research originally focused on hypophosphataemia and rickets not surprisingly the research re-oriented itself rapidly towards kidney disease. Shortly thereafter HF came into the picture through a direct hypertrophic effect on cardiomyocytes and regulation of sodium renal reabsorption/plasma volume bridging kidney disease and the development of HF. However, clinical research has been complicated by intracellular cleavage processes of pre-FGF23 into mature intact FGF23 (mature protein approximately 30 kDa) and N-terminal and C-terminal (cFGF23) fragments (approximately 12 kDa for cFGF23) necessitating the development of more than one analytical assay (e.g. commercial ELISA assays for iFGF23 and cFGF23) to fully characterize the physiology and pathology in kidney and cardiovascular disease. In the earliest clinical studies, cFGF23 data prevailed.About one decade ago the translation from basic physiology of FGF23 to the clinical research has started. Attempts to promote FGF23 as a diagnostic lab parameter were largely unsuccessful The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Heart Failure or of the European Society of Cardiology. FGF23 beyond natriuretic peptides for incident or recurrent episodes of HF was meager. 2 In sharp contrast, the story of FGF23 as a prognostic biomarker at the cross-roads of kidney disease and HF was originally much more successful. In small studies in systolic HF published in 2012, FGF23 predicted outcome and even mortality beyond some classical risk indicators and brain natriuretic peptides. 3,4 One can hardly imagine a greater start for a biomarker in HF. From that time on expectations continuously grew. FGF23 was very rapidly, and maybe prematurely, heralded by the HF society as one of the most promising biomarkers in the field of HF. There was a general belief that FGF23 would offer incremental prognostic information beyond standard of care parameters, natriuretic peptides (and other biomarkers such as troponins and C-reactive protein) for...