Background: Previous clinical studies have suggested that trimethylamine-N-oxide (TMAO) could contribute to the development of atherosclerosis cardiovascular disease. However, the synthetic analysis in coronary heart disease (CHD) was not yet performed. We aimed to clarify the relationship between elevated plasma concentrations of TMAO and the incidence of major adverse cardiovascular events (MACE) in CHD patients. Methods: Meta-analysis and dose-response analysis of hazard ratio data from prospective observational studies reporting on the association between TMAO plasma concentrations and the incidence of MACE in patients with CHD were conducted. Results: Of the 2369 published articles identified in the search, seven papers, with data from nine cohort studies (10,301 patients), were included in the meta-analysis. Combined data showed that elevated plasma TMAO concentrations could increase 58% higher risk of MACE in patients with CHD (hazard ratios [HR]: 1.58; 95% confidence interval [CI] = 1.35-1.84, P = 0.000). For follow-up ≥ 1 year, it was associated with 62% higher risk of MACE in patients with longer-term than shorter-term (HR for follow-up ≥ 4 years: 1.96; 95% CI = 1.52-2.52 vs one to 3 years: 1.34; 95% CI = 1.26-1.43, P = 0.004). The dose-response analysis revealed a 'J' shaped association between TMAO concentration and the incidence of MACE (P = 0.033), with the concentration above 5.1 μmol/L being associated with HR of > 1. Conclusions: Elevated levels of TMAO are associated with an increased incidence of MACE in patients with CHD. TMAO concentration of 5.1 μmol/L may be a cutoff value for prognosis.

Cardiovascular disease (CVD) is one of the three major threats to human health identified by WHO. Dyslipidemia, hypertension, diabetes, and obesity are well established as common CVD risk factors. However, controversies exist on the effects of gut flora on cardiovascular disease (CVD). Current evidence suggests that gut microbiota is a double-edged sword for CVD risk, and its effects are largely determined by the metabolites of the gut microbiota. Trimethylamine N-oxide (TMAO), as one of the metabolites of gut flora, is consistently associated with higher CVD risk. A few studies have emerged providing early evidence about the safety and efficacy of traditional Chinese medicine (TCM) in treating cardiovascular diseases by regulating gut flora. In this article, we review and interpret the existing evidence as well as explore the potential of intestinal flora as novel therapeutic targets of traditional Chinese medicine for the prevention of cardiovascular disease (CVD).

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