title: Increased p-cresyl sulfate level is independently associated with poor outcomes in patients with heart failure.
abstract: Amino acid-derived metabolites, including protein-bound uremic toxins, may have prognostic value for patients with heart failure (HF). The aim of this study was to investigate whether p-cresyl sulfate (PCS), indoxyl sulfate (IS), and arginine metabolites provided prognostic values in addition to the traditional biomarker, B-type natriuretic peptide (BNP), in patients with HF. Chromatography mass spectrometry was performed to measure tyrosine, tryptophan, arginine, PCS, IS, and asymmetric (ADMA) and symmetric dimethylarginine (SDMA) in the plasma from 51 normal controls and 136 HF patients. Compared to the normal controls, PCS levels significantly increased in HF patients (p = 0.003). During the follow-up (2.3 ± 1.1 years), 35 (25.7 %) patients experienced a composite event of death or HF-related re-hospitalization. In univariable analysis, PCS, estimated glomerular filtration rate (eGFR), BNP, DMA/arginine ratio, and ADMA/arginine ratio were associated with a higher rate of composite events. In the multivariable analysis, PCS was the only independent predictor of composite events [hazard ratio (HR) 1.06 (per 10 μM), 95 % confidence interval (CI) 1.01-1.11, p = 0.02]. Kaplan-Meier curves showed that a PCS level of ≥50 μM was significantly associated with a higher composite event rate than those with a PCS level of <50 μM (Log rank = 5.11, p = 0.024; HR 2.13, 95 % CI 1.09-4.16, p = 0.02). In conclusion, among protein-bound uremic toxins, eGFR, and DMA metabolites, increased PCS is the only independent predictor of HF-related events in patients with HF. A combination of PCS and BNP should better risk-stratify patients with HF.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Heart Failure Research Center, Chang Gung Memorial Hospital, Keelung, Taiwan.|Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Chao-Hung
authors.initials: CH
authors.lastname: Wang
authors.affiliation: Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan. chengm@mail.cgu.edu.tw.|Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan. chengm@mail.cgu.edu.tw.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Cheng
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Heart Failure Research Center, Chang Gung Memorial Hospital, Keelung, Taiwan.|Chang Gung University College of Medicine, Taoyuan, Taiwan.|Department of Nursing, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Min-Hui
authors.initials: MH
authors.lastname: Liu
authors.affiliation: Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan.|Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ming-Shi
authors.initials: MS
authors.lastname: Shiao
authors.affiliation: Laboratory for Epidemiology, Department of Health Care Management, Chang Gung University College, Taoyuan, Taiwan.
authors.forename: Kuang-Hung
authors.initials: KH
authors.lastname: Hsu
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Heart Failure Research Center, Chang Gung Memorial Hospital, Keelung, Taiwan.|Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Yu-Yen
authors.initials: YY
authors.lastname: Huang
authors.affiliation: Graduate Institute of Medical Biotechnology and Laboratory Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Cheng-Cheng
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Jui-Fen
authors.initials: JF
authors.lastname: Lin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000097:blood; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002853:Chromatography, Liquid; D003408:Cresols / Q000097:blood*; D005260:Female; D006333:Heart Failure / Q000097:blood* / Q000175:diagnosis / Q000401:mortality / Q000628:therapy; D006801:Humans; D007200:Indican / Q000097:blood; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020097:Natriuretic Peptide, Brain / Q000097:blood; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D015203:Reproducibility of Results; D012307:Risk Factors; D021241:Spectrometry, Mass, Electrospray Ionization; D013463:Sulfuric Acid Esters / Q000097:blood*; D013997:Time Factors; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D015415:Biomarkers; D003408:Cresols; D013463:Sulfuric Acid Esters; D020097:Natriuretic Peptide, Brain; C408690:4-cresol sulfate; D001120:Arginine; D007200:Indican
keywords: Dimethylarginine; Heart failure; Indoxyl sulfate; Prognosis; p-Cresyl sulfate