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

Abstract

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...

Novel Biomarkers of Renal Dysfunction and Congestion in Heart Failure

“…Then, some controversies about the differences of FGF-23 impact on prognosis between HFpEF and heart failure with reduced ejection fraction (HFrEF) arose. Several studies revealed that FGF-23 promotes HFpEF but predicts events in HFrEF [ 24 , 89 ]. Higher levels of FGF-23 were associated with volume overload, more frequent failure in reaching optimal doses of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, and increased all-cause mortality and HF hospitalizations [ 23 ].…”