Serum Trimethylamine N-Oxide Concentration Is Positively Associated With First Stroke in Hypertensive Patients
Open accessAbstract
Background and Purpose—: Trimethylamine N-oxide (TMAO)—a gut derived metabolite—has been shown to be atherogenic. It remains unknown whether TMAO is associated with the risk of first stroke. We aimed to determine the association between serum TMAO levels and first stroke in hypertensive patients without major cardiovascular diseases and examine any possible effect modifiers. Methods—: We used a nested case-control design, using data from the CSPPT (China Stroke Primary Prevention Trial), including 622 patients with first stroke and 622 matched controls. The study was conducted from May 2008 to August 2013. The primary outcome was a first stroke. Results—: After adjusting for choline, L-carnitine, and other important covariates, including baseline systolic blood pressure and time-averaged systolic blood pressure, during the treatment period, the risk of first stroke increased with each increment of TMAO level (per natural log [TMAO] increment: odds ratio, 1.22; 95% CI, 1.02–1.46). Consistently, compared with participants in the lowest tertile (<1.79 μmol/L) of serum TMAO levels, a significantly higher risk of first stroke was found in those in higher TMAO tertiles (≥1.79 μmol/L; odds ratio, 1.34; 95% CI, 1.00–1.81) or in TMAO tertile 3 (≥3.19 μmol/L; odds ratio, 1.43; 95% CI, 1.02–2.01). In the exploratory analysis, we observed an interaction between TMAO and folate levels (≥7.7 [median] versus <7.7 ng/mL) on first stroke ( P for interaction, 0.030). Conclusions—: Higher TMAO levels were associated with increased risk of first stroke in hypertensive patients. Our finding, if further confirmed, calls for a carefully designed clinical trial to further evaluate the role of higher TMAO levels on outcomes in hypertensive patients. Clinical Trial Registration—: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00794885.
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Previous studies have determined an association between TMAO from dietary choline or lecithin and stroke.
“Although, to our knowledge, no trials have examined the effect of α-GPC on stroke, previous studies have determined the association between TMAO from dietary choline or lecithin and stroke.15,16,23”
From Association of L-α Glycerylphosphorylcholine With Subsequent Stroke Risk After 10 Years (2021) · cites this paper as [16]
The introductory passage identifies dietary choline and phosphatidylcholine (lecithin) as precursors of TMAO, and the ‘Association of Baseline TMAO Levels With the Risk of First Stroke’ section reports an association between serum TMAO and first stroke in Chinese hypertensive patients. The paper did not assess dietary intake and, in the Discussion, reports no observed association between choline and either TMAO or stroke in those patients. It therefore does not establish that TMAO specifically derived from dietary choline or lecithin was associated with stroke. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIt is plausible that patients with hypertension were more likely to have a hemorrhagic stroke than an ischemic stroke according to baseline TMAO levels.
“It is plausible that the previous study showed patients with hypertension were more likely to have a hemorrhagic stroke than an ischemic stroke according to baseline TMAO levels.16”
From Association of L-α Glycerylphosphorylcholine With Subsequent Stroke Risk After 10 Years (2021) · cites this paper as [16]
The Discussion says baseline TMAO had a stronger association with hemorrhagic than ischemic stroke, which supports a difference in relative association. It does not show that hypertensive patients were more likely to have a hemorrhagic stroke: the Study Participants and Baseline Characteristics section reports 118 hemorrhagic cases versus 502 ischemic cases. No page numbers are available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHigher TMAO levels appeared to be linked to an increased risk of the first stroke among patients with hypertension.
“A nested case-control study reported that higher TMAO levels appeared to be linked to an increased risk of the first stroke among patients with hypertension.16”
From Association of L-α Glycerylphosphorylcholine With Subsequent Stroke Risk After 10 Years (2021) · cites this paper as [16]
TMAO is associated with stroke as well as cardiovascular disease.
“Some studies suggest that TMAO is associated with stroke as well as cardiovascular disease.”
From Association of L-α Glycerylphosphorylcholine With Subsequent Stroke Risk After 10 Years (2021) · cites this paper as [16]
A high level of TMAO is associated with the risk of hemorrhagic stroke among patients with hypertension.
“A previous study reported that a high level of TMAO is associated with the risk of hemorrhagic stroke among patients with hypertension.16”
From Association of L-α Glycerylphosphorylcholine With Subsequent Stroke Risk After 10 Years (2021) · cites this paper as [16]
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- Authors
- Nie, J., Xie, L., Zhao, B.-X., Li, Y., Qiu, B., Zhu, F., Li, G.-F., He, M., Wang, Y., Wang, B., Liu, S., Zhang, H., Guo, H., Cai, Y., Huo, Y., Hou, F. F., Xu, X., & Qin, X.
- Affiliations
- From the Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease (J.N., L.X., Y.L., B.Q., F.Z., Y.W., B.W., F.F.H., X.X., X.Q.)
- Department of Pharmacy, Rational Medication Evaluation and Drug Delivery Technology Lab, Guangdong Key Laboratory of New Drug Screening (B.-x.Z., G.-f.L.)
- Nanfang Hospital (CN)
- Guangdong Provincial Key Laboratory of Gastroenterology (S.L.)
- Beijing Advanced Innovation Center for Food Nutrition and Human Health (CN)
- Guangdong Provincial Hospital of Chinese Medicine (CN)
- Peking University First Hospital (CN)
- ORCID
- Venue
- Stroke
- Published
- 2018-09
- Volume
- 49
- Issue
- 9
- Pages
- 2021-2028
- ISSN
- 0039-2499 (ISSN-L)
- 1524-4628
- OpenAlex
- W2888466427
- Cited by
- 163
- References
- 38
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 22 · 2023: 20 · 2022: 25 · 2021: 33 · 2020: 24 · 2019: 11 · 2018: 2
- FWCI
- 13.72
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-05-28)
- Open access
- bronze
- doi.org
- Locations
- Stroke (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- Major State Basic Research Development Program of China
- National Key Research and Development Program of China (2016YFC0903100, 81730019, 2016YFC0904900)
- Topics
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- trimethylamine N-oxide, first stroke, hypertension, stroke risk, gut microbiota metabolites, folic acid, choline, L-carnitine, atherogenic lipids, China Stroke Primary Prevention Trial
- MeSH terms
- Gastrointestinal Microbiome, Aged, Carnitine, China, Choline, Female, Folic Acid, Humans, Hypertension, Male, Methylamines, Middle Aged, Odds Ratio, Case-Control Studies, Stroke
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