P2467Gut microbiota-dependent TMAO and risk of cardiovascular events in patients with stroke: relation to pro-inflammatory monocytes

Abstract

Background: In experimental studies gut microbiota-dependent metabolites, in particular trimethylamine N-oxide (TMAO), have recently been reported to promote atherosclerosis. Here, we examined for the first time the relation of TMAO and the risk of incident cardiovascular events (CVE) in patients with recent firstever ischemic stroke in two independent prospective cohorts. Moreover, the link between TMAO and proinflammatory monocytes as a potential contributing factor for increased incidence of cardiovascular risk was studied. Methods and results: The relationship between TMAO concentrations with subsequent (1-year) CVE including myocardial infarction, recurrent stroke and death was examined in a derivation study (n=78), and in a second independent larger validation cohort (n=593). Higher TMAO plasma levels were linked with an increased risk of incident CVE including myocardial infarction, recurrent stroke and death (Quartile (Q) 4 vs Q1; HR: 2.31; 95% CI: 1.25 - 4.23; P<0.01). In the second independent validation cohort, high TMAO levels again heralded marked increased risk of adverse CVE (Q4 vs Q1; HR 5.0; 95% CI: 1.7 - 14.8; P<0.01), and also after adjustments for age, sex, stroke severity, stroke etiology and cardiovascular risk factors including hypertension, diabetes, LDL cholesterol, Lp(a) and history of coronary artery disease (Q4 vs Q1: HR 3.4; 95% CI: 1.1 - 10.1; P=0.02). A significant correlation was also found between TMAO levels and percentage of pro-inflammatory intermediate CD14++CD16+ monocytes (r=0.70, P<0.01). In mice fed a diet enriched with choline to increase TMAO levels, higher levels of pro-inflammatory murine Ly6Chigh monocytes were found as compared to control chow (choline: 23.0±1.0% vs. ctr.: 16.1±1.1%; P<0.01). This increase was abolished in mice with depleted gut-microbiome (13.6±1.7%; P<0.01 vs. choline). Conclusion: This study identifies for the first time a graded relation between TMAO levels and the risk of subsequent CVE in patients with recent prior ischemic stroke. TMAO-related increase of pro-inflammatory monocytes may add to elevated cardiovascular risk in stroke patients.