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Clinical Trial
. 2023 Feb 14;109(5):396-404.
doi: 10.1136/heartjnl-2022-321300.

Trimethylamine-N-oxide is associated with cardiovascular mortality and vascular brain lesions in patients with atrial fibrillation

Marco Luciani  1   2 , Daniel Müller  3   4 , Chiara Vanetta  5 , Thamonwan Diteepeng  2 , Arnold von Eckardstein  3 , Stefanie Aeschbacher  6   7 , Nicolas Rodondi  8   9 , Giorgio Moschovitis  10 , Tobias Reichlin  11 , Tim Sinnecker  12   13 , Jens Wuerfel  13   14 , Leo H Bonati  12   15 , Seyed Soheil Saeedi Saravi  1   2 , Patricia Chocano-Bedoya  8   16 , Michael Coslovsky  7   17 , Giovanni G Camici  2 , Thomas F Lüscher  2   18   19 , Michael Kuehne  6   20 , Stefan Osswald  6   20 , David Conen  21 , Jürg Hans Beer  22   2 ; SWISS-AF Investigators
Collaborators, Affiliations
Free article
Clinical Trial

Trimethylamine-N-oxide is associated with cardiovascular mortality and vascular brain lesions in patients with atrial fibrillation

Marco Luciani et al. Heart. .
Free article

Abstract

Objective: Trimethylamine-N-oxide (TMAO) is a metabolite derived from the microbial processing of dietary phosphatidylcholine and carnitine and the subsequent hepatic oxidation. Due to its prothrombotic and inflammatory mechanisms, we aimed to assess its role in the prediction of adverse events in a susceptible population, namely patients with atrial fibrillation.

Methods: Baseline TMAO plasma levels were measured by liquid chromatography-tandem mass spectrometry in 2379 subjects from the ongoing Swiss Atrial Fibrillation cohort. 1722 underwent brain MRI at baseline. Participants were prospectively followed for 4 years (Q1-Q3: 3.0-5.0) and stratified into baseline TMAO tertiles. Cox proportional hazards and linear and logistic mixed effect models were employed adjusting for risk factors.

Results: Subjects in the highest TMAO tertile were older (75.4±8.1 vs 70.6±8.5 years, p<0.01), had poorer renal function (median glomerular filtration rate: 49.0 mL/min/1.73 m2 (35.6-62.5) vs 67.3 mL/min/1.73 m2 (57.8-78.9), p<0.01), were more likely to have diabetes (26.9% vs 9.1%, p<0.01) and had a higher prevalence of heart failure (37.9% vs 15.8%, p<0.01) compared with patients in the lowest tertile. Oral anticoagulants were taken by 89.1%, 94.0% and 88.2% of participants, respectively (from high to low tertiles). Cox models, adjusting for baseline covariates, showed increased total mortality (HR 1.65, 95% CI 1.17 to 2.32, p<0.01) as well as cardiovascular mortality (HR 1.86, 95% CI 1.21 to 2.88, p<0.01) in the highest compared with the lowest tertile. When present, subjects in the highest tertile had more voluminous, large, non-cortical and cortical infarcts on MRI (log-transformed volumes; exponentiated estimate 1.89, 95% CI 1.11 to 3.21, p=0.02) and a higher chance of small non-cortical infarcts (OR 1.61, 95% CI 1.16 to 2.22, p<0.01).

Conclusions: High levels of TMAO are associated with increased risk of cardiovascular mortality and cerebral infarction in patients with atrial fibrillation.

Trial registration number: NCT02105844.

Keywords: Atrial Fibrillation; Biomarkers; Magnetic Resonance Angiography; Stroke.

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Conflict of interest statement

Competing interests: ML is supported by Forschungskredit from the University of Zurich (FK-19-043) and received honoraria from Boehringer Ingelheim and Pfizer, outside of the current work. DC received consulting fees from Roche Diagnostics and speaker fees from BMS/Pfizer, both outside of the current work. JHB is supported by the Swiss National Foundation of Science (324730_182328), the Swiss Heart Foundation and Kardio Foundation; he has received grant support and consultation fees through the institution from Bayer, Daiichi Sankyo and Sanofi. TFL has received research and educational funding and in part consulting honoraria from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Novartis, Servier, Sanofi and Vifor, outside this work. GM has received consultant fees for taking part in the advisory boards from Novartis, Boehringer Ingelheim, Bayer, AstraZeneca and Daiichi Sankyo, all outside of the presented work.

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