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Background  Gut microbial metabolites have been implicated as novel risk factors for cardiovascular events and premature death. The strength and consistency of associations between blood concentrations of the gut microbial metabolites, trimethylamine‐N‐oxide ( TMAO ) and its precursors, with major adverse cardiovascular events ( MACE ) or death have not been comprehensively assessed. We quantified associations of blood concentrations of  TMAO  and its precursors with risks of  MACE  and mortality.    Methods and Results  PubMed and Embase databases were searched up, and a total of 19 prospective studies from 16 publications (n=19 256, including 3315 incident cases) with quantitative estimates of the associations of  TMAO  with the development of  MACE  or death were included in our main analysis. Multivariate‐adjusted relative risks ( RR s) were used when these were available. Elevated concentrations of  TMAO  were associated with a pooled  RR  of 1.62 (95%  CI,  1.45, 1.80;  P  heterogeneity =0.2; I 2 =23.5%) for  MACE  compared with low  TMAO  levels, and 1 study of black participants influenced the heterogeneity of the association. After excluding the data of blacks, the  RR s were not different according to body mass index, prevalence of diabetes mellitus, history of cardiovascular diseases, and kidney dysfunction. Furthermore, elevated  TMAO  concentrations were associated with a pooled  RR  of 1.63 (1.36, 1.95) for all‐cause mortality. Individuals with elevated concentrations of  TMAO  precursors ( l ‐carnitine, choline, or betaine) had an approximately 1.3 to 1.4 times higher risk for  MACE  compared to those with low concentrations.    Conclusions  Elevated concentrations of  TMAO  and its precursors were associated with increased risks of  MACE  and all‐cause mortality independently of traditional risk factors.

journal of the american heart association

Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies