Abstract 567: Fgf21 as a Biomarker for Metabolic Stress in Heart Failure

Abstract

FGF21, an important metabolic regulator, has recently been suggested as a biomarker for heart failure (HF). FGF21 is involved in the integrated mitochondrial stress response, and has been shown to be upregulated with mitochondrial DNA damage, which occurs more frequently in dilated cardiomyopathy. In this study, we investigated whether FGF21 can be used as a biomarker for metabolic stress in HF. We collected blood and cardiac tissue samples from ischemic and non-ischemic HF patients who have undergone VAD transplantation. We also collected blood and tissue from mice with HF due to 1) combination of transverse aortic constriction and coronary artery ligation (TAC+Lig) or 2) cardiac-specific knockout of the mitochondrial transcription factor A (Tfam). Serum FGF21 levels were measured using Enzyme-linked immunosorbent assay (ELISA). Messenger RNA was extracted from the tissue and FGF21 gene expression was measured using real-time quantitative PCR (qPCR). Immunohistochemical staining was performed on tissue sections (either paraffin embedded or frozen) to observe FGF21 levels. Serum FGF21 was elevated in human HF patients compared to healthy controls, as well as in both mouse models of HF. In human patients, cardiac FGF21 gene expression was upregulated 2.2-fold compared to donors. In the TAC+Lig mouse model we observed a 3.37-fold increase, while the Tfam knockout model which has severe mitochondrial damage exhibited a 218-fold increase in cardiac FGF21 gene expression. Further qPCR assays revealed changes in FGF21 gene expression in the liver and white fat of TFAM-KO, indicating metabolic stress on other organs resulting from HF. In conclusion, serum FGF21 is elevated in multiple models of HF, and appears to have both cardiac and extra cardiac sources. Future work will investigate 1) whether there is a correlation between FGF21 levels and mitochondrial damage, and 2) the signaling pathway resulting in metabolic stress to other organs in HF.