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

Abstract

BackgroundPhenylacetylglutamine (PAGln)—a newly discovered microbial metabolite produced by phenylalanine metabolism—is reportedly associated with cardiovascular events via adrenergic receptors. Nonetheless, its association with cardiovascular outcomes in heart failure (HF) patients remains unknown.ObjectivesThis study aimed to prospectively investigate the prognostic value of PAGln for HF.MethodsPlasma PAGln levels were quantified by liquid chromatography‐tandem mass spectrometry. We first assessed the association between plasma PAGln levels and the incidence of adverse cardiovascular events in 3152 HF patients (including HF with preserved and reduced ejection fraction) over a median follow‐up period of 2 years. The primary endpoint was the composite of cardiovascular death or heart transplantation. We then assessed the prognostic role of PAGln in addition to the classic biomarker N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP). The correlation between PAGln levels and β‐blocker use was also investigated.ResultsIn total, 520 cardiovascular deaths or heart transplantations occurred in the HF cohort. Elevated PAGln levels were independently associated with a higher risk of the primary endpoint in a dose‐response manner, regardless of HF subtype. Concurrent assessment of PAGln and NT‐proBNP levels enhanced risk stratification among HF patients. PAGln further showed prognostic value at low NT‐proBNP levels. Additionally, the interaction effects between PAGln and β‐blocker use were not significant.ConclusionsPlasma PAGln levels are an independent predictor of an increased risk of adverse cardiovascular events in HF. Our work could provide joint and complementary prognostic value to NT‐proBNP levels in HF patients.

Prognostic value of gut microbe‐generated metabolite phenylacetylglutamine in patients with heart failure

“…15,28 Three recent Chinese studies also highlighted the association between elevated PAGln levels and adverse cardiovascular outcomes. 16,29,30 However, both were smaller in sample size and with shorter follow-up duration compared to our present analysis, and neither of them adjusted for renal function in their multivariate analysis for all-cause mortality.…”

‘Debugging’ heart failure

“…A range of microbiota-derived metabolites, including trimethylamine (and its derivative trimethylamine N-oxide (TMAO)), short-chain fatty acids, indole derivatives, bile acids, branched-chain amino acids and tryptophan have already been implicated in the pathogenesis of a range of metabolic disorders. The present study from Wei et al [1] adds to this body of evidence and shows clinically that PAGln levels can track HF risk.…”

“…Patients typically have poor prognoses, hence identifying individuals at a higher risk of adverse outcomes and novel targets for interventions are much desired. The paper from Wei et al [1] adds to a growing evidence base that increased circulating levels of phenylacetylglutamine (PAGln), a microbial metabolite, can be used as a predictive risk measure for cardiovascular events in HF patients.…”

Unravelling the gut hypothesis of heart failure with gut microbiota‐derived metabolites

“…3 In a recent large Chinese study on PAGln and prognosis in HF patients, also referenced by the authors, the interaction between PAGln and creatinine levels on endpoints was more clearly demonstrated. 10 The prognostic value of PAGln in the study by Wei et al 10 was considerably adjusted by kidney function but still retained its predictive value for 2-year all-cause mortality. TMAO has been previously studied and also has a clear correlation coefficient of 0.55 with estimated glomerular filtration rate as a measure of kidney function.…”

“…5 For PAGln this question could not be addressed for non-ischaemic HF patients in the present study, but in an in vitro study from the Cleveland Clinic investigators, it was forwarded that PAGln had an inhibitory effect on myocytes stimulated by epinephrine, and a BNP gene activating effect. 13 In the study of Wei et al, 10 the question was addressed in patients with HF who did not have a history of ischaemic heart disease (43% of the population); here PAGln levels were also predictive of cardiovascular death or heart transplant similarly to patients with an ischaemic heart disease history. Whether the findings in non-ischaemic HF patients would reflect the presence of intestinal permeability, indicating its severity and thus make TMAO or PAGln substitute biomarkers for intestinal permeability, or that outcomes are specifically linked to the metabolites, remains an interesting study subject.…”