Intestinal Microbiota‐Generated Metabolite Trimethylamine‐ N‐ Oxide and 5‐Year Mortality Risk in Stable Coronary Artery Disease: The Contributory Role of Intestinal Microbiota in a COURAGE‐Like Patient Cohort
Open accessAbstract
BACKGROUND: Trimethylamine-N-oxide (TMAO), a metabolite derived from gut microbes and dietary phosphatidylcholine, is linked to both coronary artery disease pathogenesis and increased cardiovascular risks. The ability of plasma TMAO to predict 5-year mortality risk in patients with stable coronary artery disease has not been reported. This study examined the clinical prognostic value of TMAO in patients with stable coronary artery disease who met eligibility criteria for a patient cohort similar to that of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial. METHODS AND RESULTS: We examined the relationship between fasting plasma TMAO and all-cause mortality over 5-year follow-up in sequential patients with stable coronary artery disease (n=2235) who underwent elective coronary angiography. We identified the COURAGE-like patient cohort as patients who had evidence of significant coronary artery stenosis and who were managed with optimal medical treatment. Higher plasma TMAO levels were associated with a 4-fold increased mortality risk. Following adjustments for traditional risk factors, high-sensitivity C-reactive protein, and estimated glomerular filtration rate, elevated TMAO levels remained predictive of 5-year all-cause mortality risk (quartile 4 versus 1, adjusted hazard ratio 1.95, 95% CI 1.33-2.86; P=0.003). TMAO remained predictive of incident mortality risk following cardiorenal and inflammatory biomarker adjustments to the model (adjusted hazard ratio 1.71, 95% CI 1.11-2.61; P=0.0138) and provided significant incremental prognostic value for all-cause mortality (net reclassification index 42.37%, P<0.001; improvement in area under receiver operator characteristic curve 70.6-73.76%, P<0.001). CONCLUSIONS: Elevated plasma TMAO levels portended higher long-term mortality risk among patients with stable coronary artery disease managed with optimal medical treatment.
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In 2,235 patients with stable coronary artery disease, elevated plasma TMAO was associated with greater long-term mortality risk.
“The prognostic value of plasma TMAO concentrations was assessed in a cohort of patients (n = 2,235) with stable coronary artery disease, and elevated concentrations were associated with greater long-term mortality risk (101).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [101]
Plasma TMAO was strongly associated with long-term mortality in heart failure patients.
“Plasma TMAO concentrations were strongly associated with long-term mortality in heart failure patients, with advanced left-ventricular diastolic dysfunction, and with atherosclerosis burden in patients with atherosclerotic coronary artery disease (100, 101, 109, 111, 120).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [101]
Multiple human and animal studies support mechanistic and clinical prognostic associations between TMAO formation and cardiometabolic disease risks.
“multiple human and animal studies supporting both mechanistic and clinical prognostic associations between TMAO formation and cardiometabolic disease risks have been reported8–16.”
From Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential (2018) · cites this paper as [16]
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- Authors
- Senthong, V., Wang, Z., Li, X. S., Fan, Y., Wu, Y., Wilson Tang, W. H., & Hazen, S. L.
- Affiliations
- Cleveland Clinic (US)
- Cleveland State University (US)
- Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH
- Corresponding author
- Hazen, Stanley L.
- Venue
- Journal of the American Heart Association
- Published
- 2016-06-13
- Volume
- 5
- Issue
- 6
- ISSN
- 2047-9980 (ISSN-L)
- PMC
- PMC4937244
- OpenAlex
- W2417219077
- Cited by
- 270
- References
- 14
- Citations by year
- 2026: 19 · 2025: 19 · 2024: 28 · 2023: 25 · 2022: 37 · 2021: 33 · 2020: 35 · 2019: 21 · 2018: 22 · 2017: 29 · 2016: 1
- FWCI
- 12.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Journal of the American Heart Association (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- EngagedScholarship @ Cleveland State University (Cleveland State University) (submittedVersion, cc-by-nc)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000439)
- National Heart, Lung, and Blood Institute (R01HL103931, R01HL126827, P20HL113452, P01HL076491, R01HL103866)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK106000)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
- Health Sciences › Medicine › Surgery › Abdominal vascular conditions and treatments
- Keywords
- trimethylamine N-oxide, gut microbiota, stable coronary artery disease, all-cause mortality, prognostic factors, COURAGE trial, phosphatidylcholine, cardiovascular risk, cardiorenal risk, inflammation, net reclassification improvement
- MeSH terms
- Gastrointestinal Microbiome, Aged, Cardiovascular Agents, Coronary Artery Disease, Epidemiologic Methods, Female, Humans, Male, Methylamines, Middle Aged, Myocardial Revascularization, Prognosis, Coronary Stenosis
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