Comparison And Identification of Serum Metabolomic Profiles in Stage B And Stage C Ejection Fraction Preserved Heart Failure

Song Zou^1,2Liwei Zhang^1,2Ting Wang^1,2Yuhao Wan^1,2Ke Chai³Si-Ming Wang⁴Chen Meng^3,5Jian-Ping Cai^6*Hua Wang^1,2*Jie-Fu Yang^1,2*

• ¹Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
• ²Graduate School of Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China
• ³Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
• ⁴Beijing Institute of Geriatrics of the National Health Commission, Beijing, China
• ⁵Peking University Fifth School of Clinical Medicine, Beijing, China
• ⁶Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China

Background: Disturbed metabolism correlates with the progression of heart failure with preserved ejection fraction (HFpEF). However, the discrepancy in metabolism between asymptomatic (stage B) and symptomatic (stage C) HFpEF patients remain unclear. This study aimed to explore the metabolic differences between stages B and C HFpEF patients, and to screen metabolites to distinguish between the two groups of patients. Methods: 97 stage B and 31 stage C HFpEF patients were included from a previous cohort, named Frailty and Comprehensive Geriatric Assessment in Hospitalized Elderly Patients (registration number: ChiCTR1800017204). Serum metabolites of the participants were identified and quantified using targeted metabolomics (Biocrates MxP® Quant 500 kit). Results: Differential analysis identified 208 metabolites of 19 categories, of which lipids (n=168), amino acids (n=7) and related metabolites (n=18) accounted for the top 3 differential metabolites. Additionally, the differential metabolites were significantly enriched in 15 metabolic pathways encompassing amino acid metabolism (10 pathways), lipid metabolism (2 pathways), carbohydrate metabolism (1 pathway), energy metabolism (1 pathway) and protein translation (1 pathway). Metabolite set enrichment analysis demonstrated that the differential metabolites most likely originated from muscles and were most significantly enriched in renal disease states (continuous ambulatory peritoneal dialysis and chronic renal failure). Three non-heart-specific metabolites, cystine (AUC=0.919), stearic acid (FA (18:0), (AUC=0.913), and N-palmitoyl-sphingomyelin (SM C 16:0, (AUC=0.898), displayed higher accuracy than N-terminal pro-B-type brain natriuretic peptide (AUC=0.838) in differentiating stage B and stage C patients. Conclusion: Compared with stage B control, stage C patients suffer from extensive metabolic disorders, of which lipid metabolism and amino acid metabolism are mostly significantly impaired. The alterations of metabolites are largely attributed to renal dysfunction and muscle proteolysis. Moreover, non-heart-specific metabolites display potential diagnostic value in differentiating subgroups of patients with HFpEF.