Dataset Information

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.

SUBMITTER: Sommakia S

PROVIDER: S-EPMC8930477 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Sommakia Salah S Almaw Naredos H NH Lee Sandra H SH Ramadurai Dinesh K A DKA Taleb Iosif I Kyriakopoulos Christos P CP Stubben Chris J CJ Ling Jing J Campbell Robert A RA Alharethi Rami A RA Caine William T WT Navankasattusas Sutip S Hoareau Guillaume L GL Abraham Anu E AE Fang James C JC Selzman Craig H CH Drakos Stavros G SG Chaudhuri Dipayan D

Circulation. Heart failure 20211206 3

<h4>Background</h4>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.<h4>Methods</h4>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 seru ...[more]

PMID: 34865514

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Project description:UnlabelledIn animals, high fibroblast growth factor 21 (FGF21) states improve insulin resistance but induce bone loss. Whether FGF21 relates to bone mineral density (BMD) is unknown in humans. Contrary to prediction from animal findings, we found higher FGF21 levels associating with greater BMD in women, independent of age and body composition.IntroductionRecent laboratory studies suggest that FGF21 is involved in reciprocal regulation of bone and energy homeostasis. Systemic administration of FGF21 protects animals from obesity and diabetes but causes severe bone loss, smothering the enthusiasm over FGF21 as a potential antiobesity therapeutic. To date, there is no information on whether FGF21 relates to BMD in humans. We thus studied the relationship between plasma FGF21 levels and BMD in healthy adults.MethodsFasting plasma FGF21 levels were measured by enzyme-linked immunosorbent assay and body composition by dual-energy X-ray absorptiometry.ResultsAmong 40 healthy volunteers (age 32 ± 10 year, 16 women), men had significantly higher lean body mass (p < 0.01) and total BMD (p < 0.05), and lower percent body fat than women (p < 0.01). Median plasma FGF21 levels were not different between the sexes. While there was no association between FGF21 concentrations and body composition in men, FGF21 levels correlated positively with fat mass (p < 0.01) in women. In men, no significant correlation between FGF21 with BMD was observed. However, in women, FGF21 correlated positively with total BMD (R (2) = 0.69, p = 0.003) and spine BMD (R (2) = 0.76, p = 0.001); the correlation remained significant after adjusting for age, ethnicity, and body composition.ConclusionsThis study reveals for the first time a strong positive association between plasma FGF21 levels and BMD in healthy women, suggesting the association between bone loss and high FGF21 states in animals may not be directly translated to humans in physiologic states. We hypothesize that FGF21 may increase bone mass particularly in women through paracrine mechanisms in the bone-adipose interface.

Project description:BackgroundRecent studies of fibroblast growth factor 21 (FGF21), first recognized as a regulator of glucose and lipid metabolism, have found that the level of in serum FGF21 is associated with the prognosis of many cardiovascular diseases, but its relationship to acute heart failure (AHF) patients remains unknown. Our study aimed to investigate whether circulating FGF21 could predict the short-term prognosis of AHF patients.MethodsFour hundred and two AHF patients and 19 healthy controls were recruited into the prospective cohort study, and blood samples of participants were collected, in tubes without anticoagulant, within the first 24 h after hospital admission. Serum FGF21 levels were detected by enzyme-linked immunosorbent assay (ELISA). All patients were followed-up at least 6 months after discharge. The primary endpoint was all-cause death, and secondary endpoint was a composite endpoint of death and heart failure readmission. Mortality and composite end point events were analyzed using Kaplan-Meier curves. ROC curves compared the difference between the FGF21 and NT-proBNP in predicting 3- and 6-months mortality. Time-to-event data were evaluated using Kaplan-Meier estimation and Cox proportional hazards models.ResultsIn the present study, the serum FGF21 concentrations were significantly higher in the 402 AHF patients enrolled, compared with the 19 healthy controls (p < 0.001). The average age was 70 (±12) years, and 58% were males. Participants were divided into two groups according to the median FGF21 level (262 pg/ml): a high FGF21 group (n = 201, FGF21 ≥ 262 pg/ml) and low FGF21 group (n = 201, FGF21 <262 pg/ml). FGF21 was positively correlated with NT-proBNP, BUN, AST, creatinine and cholesterol, and negatively correlated with ALB and HDL. After a median follow-up of 193 days, the high FGF21 group had higher mortality and composite endpoint events compared with the low FGF21 group (HR: 3.91, 95% CI 2.21-6.92, p <0.001), even after adjusting for NT-proBNP (HR: 3.17, 95% CI 1.72-5.81, p < 0.001). ROC analysis shows that FGF21 was better than NT-proBNP in predicting death at both 3 (AUC, 0.77 vs. 0.63, p < 0.001) and 6 months (AUC, 0.78 vs. 0.66).ConclusionHigh baseline FGF21 levels are associated with adverse clinical outcomes in AHF patients. Serum FGF21 might be a potential predictive biomarker of AHF patients.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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