The gut-microbiome derived phenylacetylglutamine predicts adverse events in patients with acute coronary syndromes

Abstract Background and Introduction The gut microbiota-derived metabolite phenylacetylglutamine (PAG) is associated with incident cardiovascular events(1). Acute coronary syndromes (ACS) present a major health challenge, especially as population ages(2). Data from our group show increased PAG levels during aging in humans. However, the predictive potential of PAG for mortality and major adverse cardiovascular events (MACE) in patients (pts) with ACS is unknown. Purpose Here, we investigated the potential of PAG to predict ischemic and fatal events in pts with acute coronary syndromes (ACS). We also compared the predictive potential of PAG to another relevant gut-microbiota derived metabolite involved in CVD, namely Trimethylaminoxyde, (TMAO), and we evaluated their cumulative risk potential. Methods A total of 1’848 patients were enrolled in Cohort I of the SPUM-ACS study – a multi-center prospective ACS cohort study from Switzerland. Overall survival and incident MACE after 1 year follow-up were analyzed using Kaplan-Meier (KM) estimates and compared by log-rank test after patient stratification into PAG tertiles. Uni- and multivariable Cox-regression models were fit to calculate the hazard ratios for 1-year MACE in a crude model and adjusted model (adjusted for established confounders). Healthy controls served as additional controls. PAG plasma levels were quantified using LC-HRMS. Results The median PAG plasma level in the healthy control group was 1.76µM, whereas for the whole ACS patient population it was 1.92µM (Table 1). Pts in the third PAG tertile had a two times higher MACE rate and a four times higher mortality rate compared to pts in the first PAG tertile (p<0.001). (Table 2). PAG levels were significantly higher in pts who presented with MACE (2.63µM) or died (3.1µM) within the 1-year follow-up compared to the healthy control subjects (p<0.0001) (Figure 1A). Spearman correlation analysis revealed that plasma PAG levels were positively associated with age (r=0.43, p<0.0001), while a negative association with eGFR was observed (r=-0.51, p<0.0001) (Figure 1B). KM estimates indicated that pts in the highest PAG tertile had significantly higher 1-year MACE risk relative to those with low levels (Figure 1C; p<0.001 log rank). Following multivariable adjustment, PAG remained an independent predictor for MACE at 1-year follow-up with a hazard ratio (HR) of 1.8 (95% CI, 1.1–3.2, p=0.048) (Figure 1D). KM estimates of both, high levels of PAG and high levels of TMAO together, indicate that the combination of these two detrimental metabolites leads to an even higher risk of 1-year MACE relative to lower levels (Figure 1E). Conclusion PAG is a novel and independent predictor of adverse outcomes in patients with ACS. This study indicates the role of the gut-microbiome and its metabolites in predicting ischemic and fatal outcomes of pts with established CVD.