5761Relation of gut microbiota-dependent TMAO with aortic atherosclerosis: prognostic implication for patients with stroke

Abstract

Background: In experimental studies gut microbiota-dependent metabolites, in particular trimethylamine N-oxide (TMAO), have recently been reported to promote atherosclerosis and thrombosis. Here, we examined for the first time the relation of the gut microbe-dependent metabolite TMAO with the severity of aortic atherosclerosis. Moreover, the relation between choline and TMAO and the risk of cardiovascular events and recurrent stoke was determined in a derivation and a validation cohort of patients with first-ever ischemic stroke. Method: In a derivation study, the relationship of plasma TMAO levels with the severity of aortic atherosclerosis as assessed by transesophageal echocardiography was characterized in patients admitted with ischemic stroke (n=79). The relation between TMAO and choline with subsequent (1-year) cardiovascular events including myocardial infarction, recurrent stroke and death was examined in the derivation, and in a second independent validation cohort (n=593). Results: A close correlation was observed between TMAO levels and the severity of aortic atherosclerosis (r=0.39, P<0.01). In the initial study higher TMAO plasma levels were linked with an increased incident risk of cardiovascular events over a 1-year follow-up (HR: 2.31; 95% CI: 1.25-4.23; P<0.01). In the validation cohort, a markedly increased risk of cardiovascular events over a 1-year follow-up was observed in patients with high TMAO ((Quartile (Q) 4 vs Q1; HR: 5.0, 95% CI: 1.7 - 14.8; P<0.01), but not choline levels. This was also observed after adjustment for sex, age, stroke severity, stroke etiology and cardiovascular risk factors including hypertension, diabetes and history of peripheral or coronary artery disease or myocardial infarction (Q4 vs Q1: HR 3.5; 95% CI: 1.1. - 11.2; P=0.03). Moreover, patients with high TMAO levels were at greater risk of recurrent stroke (Q4 vs Q4: HR 2.7; 95% CI: 1.1.-6.1; P<0.01). Conclusion: These results suggest a close relation between the gut microbiotadependent metabolite TMAO and severity of aortic atherosclerosis in humans. The findings demonstrate for the first time a graded relation between TMAO levels and the risk of subsequent combined cardiovascular events and also recurrent stroke alone in patients with recent prior ischemic stroke.