Plasma levels of trimethylamine-N-oxide are confounded by impaired kidney function and poor metabolic control
Abstract
Background After ingestion of phosphatidylcholine, l-carnitine or betaine, trimethylamine-N-oxide (TMAO) is formed by gut microbiota and liver enzymes. Elevated TMAO plasma levels were associated with increased cardiovascular risk and other diseases. Also betaine and choline itself were recently associated with increased cardiovascular risk.Methods A newly developed LC-HRMS method was applied to measure the plasma concentrations of TMAO, betaine and choline in a cohort of 339 patients undergoing coronary angiography for the evaluation of suspected coronary artery disease.Results Betaine concentrations in males were significantly higher than in females (42.0 vs. 35.9 μmol/L; p < 0.001). Plasma concentrations of TMAO but not of betaine or choline were higher in patients with diabetes compared to euglycemic patients (2.39 vs. 0.980 μmol/L; p = 0.001) as well as in patients with metabolic syndrome as compared to patients without metabolic syndrome (2.37 vs. 1.43 μmol/L; p = 0.002). Plasma concentrations of TMAO or choline increased significantly with decreasing renal function (Spearman's rho: -0.281; p < 0.001). However, plasma levels of TMAO or betaine were associated with neither a history of myocardial infarction nor the angiographically assessed presence of coronary heart disease, nor incident cardiovascular events during 8 years of follow-up. Plasma levels of choline were significantly lower in patients with a history of acute myocardial infarction as compared to those without such history (10.0 vs. 10.8 μmol/L; p = 0.045).Conclusions Plasma levels of TMAO are confounded by impaired kidney function and poor metabolic control but are not associated with the history, presence or incidence of symptoms or events of coronary heart disease.
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In an 8-year follow-up study, plasma TMAO, betaine or choline levels were confounded by impaired kidney function or poor metabolic control and were not associated with presence, incidence or events of coronary heart disease.
“Mueller et al., (2015) [47] did an 8 years follow-up study trying to relate plasma TMAO, betaine or choline levels with cardiovascular disease (CVD), but the results showed that the levels were confounded by impaired kidney function or poor metabolic control and they were not associated with presence, incidence or events of coronary heart disease.”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [47]
Differences in characteristics and disease status of participants across studies might affect TMAO levels and therefore partly explain inconsistency in associations.
“Differences in characteristics and disease status of participants across studies might affect TMAO levels14, 27, 28 and therefore partly explain such inconsistency.”
From Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies (2017) · cites this paper as [14]
Another 3 studies did not show a significantly elevated RR when TMAO was analyzed as a continuous variable in model.
“Also, another 3 studies did not show a significantly elevated RR when TMAO was analyzed as a continuous variable in model.10, 14, 17”
From Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies (2017) · cites this paper as [14]
Excluding the study with a newly developed TMAO measurement method, the pooled adjusted RR per 1-μmol/L increment in TMAO was 1.02 (95% CI, 1.01, 1.04).
“One study14 introduced a newly developed method for the measurement of TMAO, and their IQRs of TMAO were lower than other studies, so that we calculated a RR without data from the study. Results of the analysis showed a similar pooled adjusted RR per 1‐μmol/L increment in TMAO of 1.02 (1.01, 1.04).”
From Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies (2017) · cites this paper as [14]
In 339 patients who had coronary angiography, plasma TMAO or choline increased significantly as renal function decreased.
“In a cohort of 339 patients who underwent coronary angiography, plasma concentrations of TMAO or choline were significantly increased with decreasing renal function, but TMAO concentrations were not associated with incidence or symptoms of coronary heart disease.”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [85]
In that cohort, TMAO concentrations were not associated with incidence or symptoms of coronary heart disease.
“In a cohort of 339 patients who underwent coronary angiography, plasma concentrations of TMAO or choline were significantly increased with decreasing renal function, but TMAO concentrations were not associated with incidence or symptoms of coronary heart disease.”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [85]
That study concluded plasma TMAO was confounded by impaired kidney function because it increased with declining GFR.
“The study concluded that plasma concentrations of TMAO were confounded by impaired kidney function because it was increased with declining GFR (85).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [85]
In 339 patients undergoing coronary angiography, plasma levels of TMAO or betaine were not associated with a history of myocardial infarction, angiographically-assessed presence of coronary heart disease, or incident cardiovascular events during 8 years of follow-up.
“The plasma levels of TMAO or betaine were not found to be associated with a history of myocardial infarction, the angiographically-assessed presence of coronary heart disease, or the incident cardiovascular events during 8 years of follow-up.”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [35]
In 339 patients undergoing coronary angiography, plasma TMAO concentrations were higher in diabetics compared to euglycemic patients.
“Mueller et al. measured plasma concentrations of TMAO, betaine and choline in a cohort of 339 patients undergoing coronary angiography and noted that plasma concentrations of TMAO were higher in diabetics compared to euglycemic patients [35].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [35]
TMAO and choline levels increase with decreasing renal function.
“TMAO and choline levels increase with decreasing renal function [35].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [35]
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“, (2015) [47] did an 8 years follow-up study trying to relate plasma TMAO, betaine or choline levels with cardiovascular disease (CVD), but the results showed that the levels were confounded by impaired kidney function or poor metabolic control and they were not associated with presence, incidence or events of coronar…”
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- Authors
- Mueller, D. M., Allenspach, M., Othman, A., Saely, C. H., Muendlein, A., Vonbank, A., Drexel, H., & von Eckardstein, A.
- Affiliations
- University of Zurich (CH)
- Landeskrankenhaus Feldkirch (AT)
- ORCID
- Venue
- Atherosclerosis
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 243
- Issue
- 2
- Pages
- 638-644
- ISSN
- 0021-9150 (ISSN-L)
- OpenAlex
- W1751395982
- Cited by
- 217
- References
- 46
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 18 · 2023: 21 · 2022: 30 · 2021: 19 · 2020: 36 · 2019: 18 · 2018: 20 · 2017: 20 · 2016: 18 · 2015: 1
- FWCI
- 8.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Atherosclerosis (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- trimethylamine N-oxide, betaine, choline, plasma biomarkers, renal function, renal dysfunction, metabolic control, diabetes mellitus, metabolic syndrome, coronary artery disease, myocardial infarction, cardiovascular risk, gut microbiota
- MeSH terms
- Aged, Betaine, Blood Glucose, Choline, Chromatography, Liquid, Coronary Disease, Diabetes Mellitus, Female, Glomerular Filtration Rate, Humans, Kidney, Male, Methylamines, Middle Aged, Predictive Value of Tests, Prognosis, Time Factors, Reproducibility of Results, Biomarkers, Coronary Angiography, Spectrometry, Mass, Electrospray Ionization, Metabolic Syndrome
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