Phenylacetylglutamine as a risk factor and prognostic indicator of heart failure

Abstract

AimsTo explore the associations between serum phenylacetylglutamine (PAGln) and chronic heart failure (HF). Methods and resultsTotally 956 subjects were enrolled consecutively from the Department of Cardiovascular Medicine, Ruijin Hospital. Baseline data were obtained from all participants, and 471 stable chronic HF subjects were followed up. Serum PAGln was analysed by liquid chromatography-tandem mass spectrometry. The association between PAGln and basic renal indicators was assessed by simple correlation analysis. Logistic regression analysis was conducted to measure the association between PAGln and HF risk. Event-free survival was determined by Kaplan-Meier curves, and differences in survival were assessed using log-rank tests. Cox proportional hazards analysis was used to assess the prognostic value of PAGln in HF. Serum PAGln levels were increased in patients with chronic HF (3.322 ± 8.220 μM vs. 1.249 ± 1.168 μM, P < 0.001) and were associated with HF after full adjustment [odds ratio (OR), 1.507; 95% confidence interval (CI): 1.213-1.873; P < 0.001]. PAGln levels were correlated with the levels of basic renal indicators. High PAGln levels indicated a high risk of renal dysfunction in HF (OR: 1.853; 95% CI: 1.344-2.556; P < 0.001), and elevated PAGln levels were associated with a high risk of cardiovascular death in patients with chronic HF (HR: 2.049; 95% CI: 1.042-4.029; P = 0.038). Conclusions Elevated PAGln levels are an independent risk factor for HF and are associated with a higher risk of cardiovascular death. High PAGln levels could indicate renal dysfunction in HF patients. PAGln can be a valuable indicator of HF.

Increased circulating phenylacetylglutamine concentration elevates the predictive value of cardiovascular event risk in heart failure patients

“…In recent years, the link between gut microbiota and circulating PAGln has been elucidated in several studies [35,36], especially by Nemet et al, which validates a major role for gut microbiota in PAGln generation in humans [20]. Notably, some literature regarding CVD seems to uncover the destructive role of circulating PAGln [18,19,23,25,[37][38][39]. For instance, PAGln is reportedly associated with the degree of coronary atherosclerotic severity in patients with coronary artery disease, and similar results were obtained in patients with carotid atherosclerosis [18,39].…”

“…This suggests that the association between PAGln and HF is robust across different races. For the predictive value of PAGln for cardiovascular events, a small cohort study including 471 patients with HFrEF with a short follow‐up period also showed that elevated PAGln levels are associated with a higher risk of cardiovascular death [25]. Nonetheless, this study did not consider patients with HFpEF, and a detailed dose‐response relationship was not examined (Figs.…”

“…Notably, plasma PAGln is associated with HF in the US and European Cohorts [23,24]. Elevated PAGln levels are also associated with a higher risk of cardiovascular death in heart failure with reduced ejection fraction (HFrEF); however, the study's sample size was rather small and followup was short [25]. Whether the types of HF and the use of beta-adrenergic receptor blocking agents (β-blocker) could modify the association of interest remains unclear.…”

Dysregulated amino acid metabolism in heart failure: role of gut microbiome

“…In patients with chronic kidney disease, serum PAGln levels were associated with all-cause mortality and cardiovascular disease independent of other risk factors [34]. Two recent Chinese studies also highlighted the association between elevated PAGln levels and adverse cardiovascular outcomes in patients with heart failure [35 ▪ ,36]. In cell models, PAGln increased apoptosis, reactive oxygen species production, calcium/calmodulin-dependent protein kinase II, and ryanodine receptor 2 activation but decreased cell viability [37].…”

‘Debugging’ heart failure

“…Elevated PAGln levels have also been associated with a higher risk of cardiovascular death in HF with reduced ejection fraction (HFrEF); however, these studies were limited in size and follow‐up period [8]. Additionally, the association between PAGln and the classical biomarker NT‐proBNP remained to be fully addressed.…”