FGF21 (Fibroblast Growth Factor 21) Defines a Potential Cardiohepatic Signaling Circuit in End-Stage Heart Failure

Abstract

Background: Extrinsic control of cardiomyocyte metabolism is poorly understood in heart failure (HF). FGF21 (Fibroblast growth factor 21), a hormonal regulator of metabolism produced mainly in the liver and adipose tissue, is a prime candidate for such signaling.

Methods: To investigate this further, we examined blood and tissue obtained from human subjects with end-stage HF with reduced ejection fraction at the time of left ventricular assist device implantation and correlated serum FGF21 levels with cardiac gene expression, immunohistochemistry, and clinical parameters.

Results: Circulating FGF21 levels were substantially elevated in HF with reduced ejection fraction, compared with healthy subjects (HF with reduced ejection fraction: 834.4 [95% CI, 628.4-1040.3] pg/mL, n=40; controls: 146.0 [86.3-205.7] pg/mL, n=20, P=1.9×10^-5). There was clear FGF21 staining in diseased cardiomyocytes, and circulating FGF21 levels negatively correlated with the expression of cardiac genes involved in ketone metabolism, consistent with cardiac FGF21 signaling. FGF21 gene expression was very low in failing and nonfailing hearts, suggesting extracardiac production of the circulating hormone. Circulating FGF21 levels were correlated with BNP (B-type natriuretic peptide) and total bilirubin, markers of chronic cardiac and hepatic congestion.

Conclusions: Circulating FGF21 levels are elevated in HF with reduced ejection fraction and appear to bind to the heart. The liver is likely the main extracardiac source. This supports a model of hepatic FGF21 communication to diseased cardiomyocytes, defining a potential cardiohepatic signaling circuit in human HF.

Keywords: bilirubin; fibroblast growth factor; ketones; metabolism; natriuretic peptides.

Figure 1.. Circulating FGF21 levels are elevated in HFrEF.

A. FGF21 levels in healthy controls (n=20) versus patients with heart failure with reduced ejection fraction (HFrEF, n=40) displayed as Tukey boxplots, with mean shown as white circle. Note logarithmic scales. Student’s t-test used for two-sample comparisons. B. No significant difference in FGF21 levels across gender in HFrEF patients (female = 15, male = 25). C. No significant difference in FGF21 levels between ischemic (n=12) and non-ischemic (n=28) HFrEF. D. No correlation with age of patient. Black line represents linear regression fit to the data, with shaded area representing 95% confidence bands. E. No significant difference in FGF21 between responders (n=18) and non-responders (n=22). Coefficient of determination (r²) and corresponding p value are shown.

Figure 2.. FGF21 is present in cardiomyocytes from HFrEF patients.

Immunostaining for FGF21 in human heart slices reveals little FGF21 present in donor hearts but robust staining in HFrEF hearts. Nuclei are labelled in blue and FGF21 immunostaining is brown. Each panel is from a different patient.

Figure 3.. Correlations between serum FGF21 and cardiac gene expression.

For each gene listed above, the left panel is the relative gene expression between normal donor (DON, n=4–6) and HFrEF hearts (HF, n=9–17). The right panel for each gene shows the linear regression for the HFrEF hearts against serum FGF21 (sFGF21) levels. The black line is the linear regression, with shaded area corresponding to 95% confidence bands. Coefficient of determination (r²) and corresponding Benjamini-Hochberg corrected p value (q) for a false discovery rate of 0.05 are shown.

Figure 4.. Correlations between serum FGF21 and clinical parameters.

Correlation of serum FGF21 values with clinical index via linear regression (n=34–40). The black line is the linear regression, with shaded area corresponding to 95% confidence bands. Coefficient of determination (r²) and corresponding Benjamini-Hochberg corrected p value (q) for a false discovery rate of 0.05 are shown. Note logarithmic scale for FGF21, BNP, AST, and total bilirubin.