Gut microbiota-derived imidazole propionate is a novel marker of cardiometabolic risk in patients with coronary artery disease

Abstract Background Circulating imidazole propionate (ImP) is a gut-derived amino acid metabolite with adverse effects on glucometabolic function. Upcoming targeted treatment approaches aim at inhibiting microbial ImP production. Purpose This study examined the prognostic value of ImP in patients with coronary artery disease (CAD). Methods Circulating ImP levels were measured in a prospective multicentre cohort of patients with acute coronary syndrome (ACS) from Switzerland (n=4787), in a cohort of patients with chronic coronary syndrome (CCS, n=883), and in individuals without CAD (n=254) from Germany. All-cause mortality and major adverse cardiovascular events (MACE), defined as the first occurrence of death, myocardial infraction, and cerebrovascular events, were assessed at 1-year in patients with ACS and at a median follow-up of 2.95 years in patients with CCS. Multivariable-adjusted Cox models, accounting for a broad range of established risk factors, were used to evaluate the incremental predictive value of ImP. In patients with ACS, we additionally adjusted for various gut-derived metabolites including trimethylaminoxid (TMAO). Results ImP levels were higher in patients with ACS and CCS compared to individuals without CAD. ImP was strongly associated with cardiometabolic traits including high haemoglobin A1c, presence of type 2 diabetes, impaired renal function, a higher number of affected coronary arteries, and decreased left ventricular function in both clinical entities. ImP was associated with increased mortality on crude (ACS hazard ratio [HR] per log2 increase: 1.68, 95% confidence interval [CI] 1.53–1.85, P<0.001; CCS HR: 1.46, 95% CI 1.23–1.74, P<0.001) and on multivariable-adjusted analysis (ACS HR: 1.28, 95% CI 1.12–1.48, P=0.001, CCS HR: 1.25, 95% CI 1.03–1.52, P=0.027) in both entities. Similar results were observed for MACE (ACS HR: 1.24, 95% CI 1.10–1.38, P<0.001; CCS HR: 1.21, 95% CI 1.09–1.36, P=0.001). In patients with ACS, ImP provided predictive value beyond TMAO (HR 1.64, 95% CI 1.18–2.28, P=0.003) and beyond the Global Registry of Acute Coronary Events (GRACE) 2.0 score (HR 1.24, 95% CI 1.05–1.45, P=0.010). Conclusions Circulating ImP reflects the cardiometabolic risk of patients with CAD beyond established gut-derived metabolites holding promise as a therapeutic target. ImP may refine risk stratification for personalised secondary prevention strategies.ImP is linked to cardiometabolic traits ImP independently predicts mortality