FGF21 defines a potential cardio-hepatic signaling circuit in human heart failure

ABSTRACT Background Extrinsic control of cardiac contractility and ultrastructure via neurohormonal signaling is well established, but how other organs regulate cardiomyocyte metabolism is less well understood. Fibroblast growth factor-21 (FGF21) a hormonal regulator of metabolism mainly produced 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 heart failure with reduced ejection fraction (HFrEF) at the time of left ventricular assist device (LVAD) implantation, and correlated serum FGF21 levels with cardiac gene expression, immunohistochemistry, and clinical parameters. Results Circulating FGF21 levels were substantially elevated in HFrEF, compared to healthy subjects (HFrEF: 834.4 ± 101.8 pg/mL, n = 40; controls: 145.9 ± 28.6 pg/mL, n = 20, p = 5.5 × 10 −8 ). 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 low in failing and non-failing hearts, suggesting at least partial extracardiac production of the circulating hormone. Circulating FGF21 levels were correlated with BNP and total bilirubin, markers of chronic cardiac and hepatic congestion. Conclusions Circulating FGF21 levels are elevated in HFrEF. The liver is likely the main extracardiac source, and congestive hepatopathy, common in HFrEF, was likely the proximate signal leading to FGF21 elevations. This supports a model of venous congestion from cardiomyopathy driving hepatic FGF21 communication to diseased cardiomyocytes, defining a potential cardio-hepatic signaling circuit in human heart failure.