FGF-23 is a biomarker of RV dysfunction and congestion in patients with HFrEF

Abstract

There is no biomarker reflecting right ventricular dysfunction in HFrEF patients used in clinical practice. We have aimed to look for a circulating marker of RV dysfunction employing a quantitative proteomic strategy. The Olink Proteomics Multiplex panels (Cardiovascular Disease II, III, Cardiometabolic, and Inflammation Target Panels) identified FGF-23 to be the most differentially abundant (more than 2.5-fold) in blood plasma of HF patients with severe RV dysfunction (n = 30) compared to those with preserved RV function (n = 31). A subsequent ELISA-based confirmatory analysis of circulating FGF-23 in a large cohort of patients (n = 344, 72.7% NYHA III/IV, LVEF 22.5%, 54.1% with moderate/severe RV dysfunction), followed by multivariable regression analysis, revealed that the plasma FGF-23 level was most significantly associated with RV dysfunction grade (p = 0.0004) and congestion in the systemic circulation (p = 0.03), but not with LV-ejection fraction (p = 0.69) or estimated glomerular filtration rate (eGFR, p = 0.08). FGF-23 was associated with the degree of RV dysfunction in both sub-cohorts (i.e. in patients with and without congestion, p < 0.0001). The association between FGF-23 and RV-dysfunction remained significant after the adjustment for BNP (p = 0.01). In contrast, when adjusted for BNP, FGF-23 was no longer associated with LV dysfunction (p = 0.59). The Cox proportional hazard model revealed that circulating FGF-23 was significantly associated with adverse outcomes even after adjusting for BNP, LVEF, RV dysfunction grade and eGFR. Circulating FGF-23 is thus a biomarker of right ventricular dysfunction in HFrEF patients regardless of congestion status.

Figure 1

Olink proteomic analysis—Volcano plots showing relative abundances of plasmatic proteins. (A) A comparison between HFrEF patients and controls. NT-proBNP, BNP and FGF-23 were among the most markedly and significantly upregulated proteins in HFrEF patients while PON-3 (Serum paraoxonase/lactonase 3) was the most significantly downregulated (B) A comparison between HFrEF patients with and without RV dysfunction. FGF-23 was the most markedly upregulated in patients with HFrEF and severe RV dysfunction compared with those with HFrEF and preserved RV function.

Figure 2

FGF-23 plasma levels determined by ELISA with respect to RV dysfunction grade. (A) the whole cohort, (B) patients without objective signs of congestion, (C) patients with objective signs of congestion Data are presented as mean ± SEM. noRVD—preserved RV function (n = 72), RVD1-mild RV dysfunction (n = 86), RVD2-moderate RV dysfunction (n = 131), RVD3-severe RV dysfunction (n = 55).

Figure 3

ROC curve analysis. AUC of the numerical product of BNP and FGF-23-0.75 (95%, CI 0.70–0.79) was significantly higher that the AUC of BNP alone − 0.69, (95% CI 0.64–0.74), p = 0.02.