Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 38, Issue 9, Pages 2225-2235Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.118.311023
Keywords
choline; gut microbiome; myocardial infarction; risk factors; stroke; thrombosis
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Funding
- Deutsche Stiftung fur Herzforschung
- Else Kroner-Fresenius-Stiftung
- Deutsches Zentrum fur Herz-Kreislauf-Forschung (Rotation Grant)
- National Institutes of Health
- Office of Dietary Supplements [R01HL103866, R01DL106000, R01HL130819]
- Shimadzu Corporation
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL103866, R01HL130819] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK106000] Funding Source: NIH RePORTER
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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: 9.20.5x10(3) per mL versus control: 6.5 +/- 0.5x10(3) per mL; P<0.01). This increase was abolished in mice with depleted gut microbiota (choline+antibiotics: 5.4 +/- 0.7x10(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.
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