Elevated plasma phenylacetylglutamine is independently associated with heart failure: A cross-sectional biomarker study

Phenylacetylglutamine (PAGln), a microbial metabolite generated from dietary phenylalanine, has emerged as a candidate mediator in cardiovascular disease, but whether it holds diagnostic value for heart failure (HF) is unclear. We designed a cross-sectional case-control study at Xiangya Hospital, enrolling 104 participants (65 stable HF patients and 39 non-HF controls), to address this question. Plasma PAGln was quantified by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Concentrations were significantly higher in the HF group than in controls (median 1.7 vs. 1.2 μM, P = 0.001). After multivariable adjustment for age, sex, body mass index, lifestyle factors, comorbidities, and low-density lipoprotein cholesterol, every 1-SD increase in log-transformed PAGln raised HF odds by 95% (odds ratio [OR] 1.95, 95% confidence interval [CI] 1.07-3.56, P = 0.030). The top tertile carried 4.57-fold greater odds than the bottom tertile (OR 4.57, 95% CI 1.08-19.45, P = 0.040). On receiver operating characteristic (ROC) analysis, PAGln achieved an area under the curve (AUC) of 0.658 (95% CI 0.551-0.764) with 46.2% sensitivity and 84.6% specificity. PAGln tracked positively with LDL-C, total cholesterol, and fasting glucose, and inversely with estimated glomerular filtration rate. Notably, the highest PAGln levels were seen in HF with reduced ejection fraction (HFrEF), with a significant difference between non-HF and HFrEF subgroups (P = 0.01). Collectively, our results indicate that elevated plasma PAGln is independently linked to HF and may reflect disease severity, supporting its potential as a complementary metabolic biomarker for HF evaluation.