TMAO and Cardiovascular Disease: Potential as a Biomarker
Non-systematic narrative review concludes TMAO associates with cardiovascular risk in observational and animal studies, but Mendelian randomization studies do not support causality.
| Outcome | Grade | Direction | Effect | Studies |
|---|---|---|---|---|
| TMAO–general cardiovascular risk association | C | ▲ Favorable | associação observacional sem OR/RR consolidado com IC 95% reportado nesta revisão | 93 |
| TMAO and hypertension | C | ▲ Favorable | meta-analysis 8 studies n=11750, direction positive, no pooled OR/RR with 95% CI reported in this review | 8 |
| TMAO–CVD causality (Mendelian randomization) | C | — Neutral | MR study n=2076 Europeans, no significant causal association; p not significant in MR-Egger sensitivity analysis | 2 |
| TMAO and atherosclerosis | C | ▲ Favorable | observational/animal data, no pooled effect size with 95% CI | — |
| TMAO and vascular stiffness (animal model) | D | ▲ Favorable | TMAO supplementation increased aortic stiffness in mice; mediated by AGEs and superoxide; no quantitative effect size with 95% CI reported | 1 |
| TMAO and endothelial dysfunction | D | ▲ Favorable | mechanistic/in vitro/animal data: eNOS reduction, NF-kB activation, VCAM-1 upregulation; no clinical effect size | — |
| TMAO and cardiometabolic outcomes (CAD, MI, stroke, AF, T2D) | C | — Neutral | MR study: no significant causal association with CAD, MI, stroke, AF, T2D, CKD; no OR/RR with 95% CI reported | 1 |
Context
TMAO is a gut microbiota-derived metabolite produced from dietary choline and carnitine, with proposed mechanisms involving endothelial dysfunction, atherogenesis, and platelet activation. Identifying accessible cardiovascular risk biomarkers is relevant for preventive strategies. A causal relationship between TMAO and CVD remains unestablished.
What the study showed
Observational and animal studies associate elevated TMAO with higher cardiovascular risk, hypertension, atherosclerosis, and heart failure. A meta-analysis of 8 studies (n=11,750) suggested an association between TMAO and hypertension without mechanistic elucidation. Mendelian randomization studies (including 2,076 European participants) found no significant causal relationship between TMAO and cardiometabolic diseases including CAD, MI, stroke, and AF. No consolidated 95% CI or effect sizes for primary outcomes were reported in the review.
How it was done
Narrative review with searches in PubMed, ScienceDirect, and Google Scholar (2015–2025, extended to 2009 for biochemistry). Screening of 3,793 results; 93 studies included. No formal risk of bias tool applied (no AMSTAR-2 or equivalent). Includes human, animal, and in vitro studies.
Effect magnitude
No pooled effect size with 95% CI was calculated in this review. The cited meta-analysis (n=11,750) suggests an association with hypertension but does not report OR/RR with CI in this review's synthesis.
Limitations
Narrative design without registered protocol, no formal risk of bias assessment (AMSTAR-2 not applied), study selection subject to confirmation bias. Methodological heterogeneity of included studies was not quantified. Available Mendelian randomization studies are scarce, with limited statistical power and potential horizontal pleiotropy. Studied populations are predominantly high cardiovascular risk, limiting generalizability.
In clinical practice
TMAO should not be adopted as a routine clinical biomarker for cardiovascular risk based on this review. Current evidence does not support TMAO-targeted therapeutic interventions outside a research context. Clinicians should await randomized controlled trials and adequately powered Mendelian randomization studies before modifying practice.
What is still missing
Randomized controlled trials evaluating TMAO reduction and hard cardiovascular endpoints are needed. Mendelian randomization studies with greater power, ethnic diversity, and lower-risk populations are a priority.