Gut Microbiota–Dependent Trimethylamine N -Oxide Predicts Risk of Cardiovascular Events in Patients With Stroke and Is Related to Proinflammatory Monocytes

Author:

Haghikia Arash12,Li Xinmin S.3,Liman Thomas G.4,Bledau Nils5,Schmidt David1,Zimmermann Friederike1,Kränkel Nicolle12,Widera Christian6,Sonnenschein Kristina5,Haghikia Aiden7,Weissenborn Karin8,Fraccarollo Daniela5,Heimesaat Markus M.910,Bauersachs Johann5,Wang Zeneng3,Zhu Weifei3,Bavendiek Udo5,Hazen Stanley L.311,Endres Matthias41221013,Landmesser Ulf1210

Affiliation:

1. From the Department of Cardiology (A.H., D.S., F.Z., N.K., U.L.)

2. DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Germany (A.H., N.K., M.E., U.L.)

3. Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, OH (X.S.L., Z.W., W.Z., S.L.H.)

4. Department of Neurology (T.G.L., M.E.)

5. Cardiology and Angiology (N.B., K.S., D.F., J.B., U.B.)

6. Department of Cardiology, Heart Center Oldenburg, European Medical School Oldenburg-Groningen, Carl von Ossietzky University Oldenburg, Germany (C.W.)

7. Department of Neurology, Ruhr-University Bochum, Germany (A.H.)

8. Department of Neurology (K.W.), Hannover Medical School, Germany

9. Institute of Microbiology and Infection Immunology (M.M.H.)

10. Berlin Institute of Health (BIH), Germany (M.M.H., M.E., U.L.)

11. Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, OH (S.L.H.)

12. Center for Stroke Research Berlin (M.E.), Charité-Universitätsmedizin Berlin, Germany

13. German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany (M.E.)

Abstract

Objective— 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 TMAO and the risk of incident cardiovascular events in patients with recent first-ever ischemic stroke in 2 independent prospective cohorts. Moreover, the link between TMAO and proinflammatory monocytes as a potential contributing factor for cardiovascular risk in stroke patients was studied. Approach and Results— In a first study (n=78), higher TMAO plasma levels were linked with an increased risk of incident cardiovascular events including myocardial infarction, recurrent stroke, and cardiovascular death (fourth quartile versus first quartile; hazard ratio, 2.31; 95% CI, 1.25–4.23; P <0.01). In the second independent validation cohort (n=593), high TMAO levels again heralded marked increased risk of adverse cardiovascular events (fourth quartile versus first quartile; hazard ratio, 5.0; 95% CI, 1.7–14.8; P <0.01), and also after adjustments for cardiovascular risk factors including hypertension, diabetes mellitus, LDL (low-density lipoprotein) cholesterol, and estimated glomerular filtration rate (hazard ratio, 3.3; 95% CI, 1.2–10.9; P =0.04). A significant correlation was also found between TMAO levels and percentage of proinflammatory intermediate CD14 ++ CD16 + monocytes ( r =0.70; P <0.01). Moreover, in mice fed a diet enriched with choline to increase TMAO synthesis, levels of proinflammatory murine Ly6C high monocytes were higher than in the chow-fed control group (choline: 9.2±0.5×10 3 per mL versus control: 6.5±0.5×10 3 per mL; P <0.01). This increase was abolished in mice with depleted gut microbiota (choline+antibiotics: 5.4±0.7×10 3 per mL; P <0.001 versus choline). Conclusions— The present study demonstrates for the first time a graded relation between TMAO levels and the risk of subsequent cardiovascular events in patients with recent prior ischemic stroke. Our data support the notion that TMAO-related increase of proinflammatory monocytes may add to elevated cardiovascular risk of patients with increased TMAO levels.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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