BACKGROUND: Phenylacetylglutamine (PAGln) is a phenylalanine-derived metabolite produced by gut microbiota with mechanistic links to hear failure (HF)-relevant phenotypes. We sought to investigate the prognostic value of PAGln in patients with stable HF.

METHODS AND RESULTS: Fasting plasma PAGln levels were measured by stable-isotope-dilution LC-MS/MS in patients with stable HF from two large cohorts. All-cause mortality was assessed at 5-year follow up in the Cleveland Cohort, and HF, hospitalization, or mortality were assessed at 3-year follow up in the Berlin Cohort. Fasting PAGln levels were measured by stable-isotope-dilution LC-MS/MS. Within the Cleveland cohort, median PAGln levels were 4.2[IQR 2.4-6.9] μM. Highest quartile of PAGln was associated with 3.09-fold increased mortality risk compared to lowest quartile. Following adjustments for traditional risk factors, as well as race, eGFR, NT-proBNP, hsCRP, LV ejection fraction, ischemic etiology, and heart failure drug treatment, elevated PAGln levels remained predictive of 5-year mortality in quartile comparisons (adjusted Hazard Ratio [95%CI] for Q4vQ1: 1.64 [1.07-2.53]). In the Berlin cohort, a similar distribution of PAGln levels was observed (median 3.2 μM [IQR 2.0-4.8] μM), and PAGln levels were associated with a 1.94-fold increase in 3-year HF hospitalization or all-cause mortality risk (adjusted HR [95%CI] for Q4vQ1: 1.94 [1.14-3.28]). Prognostic value of PAGln appears to be independent of trimethylamine N-oxide levels.

CONCLUSION: High levels of PAGln are associated with adverse outcomes independent of traditional cardiac risk factors and cardio-renal risk markers. This article is protected by copyright. All rights reserved.