Table 1.

Human studies of TMAO as a potential novel and independent risk factor for predicting clinical risk of atherosclerosis (AS) and prognostic stratification.

	Study	Patient population	Main findings/outcomes
Positive results	Wang et al., 2011	Subjects undergoing selective cardiac evaluations (N = 1,876)	Elevated levels of fasting choline, TMAO and betaine were dose-dependent associated with the risk of CVD
	(Zhong et al., 2019)	302 with CHD and 59 with NCA in southern China	Plasma concentrations of TMAO, creatinine, choline, and carnitine were notably higher in CHD patients than in those with NCA
	(Dong et al., 2018)	132 controls, 243 with CHD, and 175 with CHD and T2DMv	Plasma TMAO levels were remarkably higher in CHD patients than in controls and were significantly elevated in CHD patients with T2DM; TMAO was an independent predictor in CHD patients with or without T2DM
	(Yu et al., 2019)	275 with CHD and 275 controls	Urinary TMAO, but not its precursors, was correlated with a risk of CHD and may accelerate the development of CHD
	(Sheng et al., 2019)	335 with STEMI and 53 healthy controls	TMAO levels were higher in STEMI; elevated plasma TMAO levels predicted both a high SYNTAX score and the presence of multivessel disease and were associated with higher coronary atherosclerotic load
	(Shan et al., 2018)	520 HIV-infected and 217 uninfected (112 incident plaque cases)	In HIV-infected individuals, higher TMAO levels were correlated with an enhanced risk of carotid plaques
	(Randrianarisoa et al., 2016)	220 subjects in the Tübingen lifestyle intervention program	Newly demonstrated that elevated serum TMAO levels had positive correlation with increased cIMT
	Tang et al., 2013	4007 patients undergoing elective coronary angiography	Elevated plasma TMAO levels were associated with an increased risk of incident MACE.
	(Li et al., 2019)	530 with chest pain (suspected ACS) and 1683 with ACS	Elevated TMAO/TML levels were correlated with MACE over both 30 days and 6 months of follow-up and were also relevant to incident long-term (1-year and 7-year) all-cause mortality
	Tang et al., 2014	720 patients with stable heart failure	Elevated plasma TMAO levels were associated with a 3.4-fold enhanced mortality risk and predicted 5-year mortality risk.
	(Senthong et al., 2016)	2235 with stable CAD; 935 with PAD	Higher plasma TMAO levels were respectively associated with a 4-fold and 2.7-fold enhanced mortality risk in a 5-year follow-up period and could predict 5-year all-cause mortality risk.
	(Suzuki et al., 2017)	1079 with acute MI	TMAO independently predicted death/MI at 2 years, but was not able to predict death/MI at 6 months, and was superior to currently used biomarkers
	(Haghikia et al., 2018)	78 and 593 with recent prior ischemic stroke	Both cohorts showed that higher plasma TMAO levels were related to an increased risk of subsequent CV events
Negative results	Yin et al., 2015	322 patients with atherosclerotic ischemic stroke and TIA and 231 asymptomatic AS controls	Stroke and TIA patients had significantly lower TMAO levels than asymptomatic group, rather than higher. And there was no significant change in blood TMAO levels in asymptomatic atherosclerotic controls.
	Meyer et al., 2016	817 participants	TMAO was not associated with cIMT, a measure of AS, during10-year follow-up.
	(Skagen et al., 2016)	264 with carotid artery AS and 62 healthy controls	No remarkable association between TMAO and CV mortality was found
	Kaysen et al., 2015	235 patients receiving hemodialysis	No obvious association between serum TMAO levels and hospitalizations or CV death and all-cause mortality.
	Mueller et al., 2015	339 patients of suspected CAD.	Plasma TMAO or betaine levels were not associated with the presence of CHD or MI history or incident CV events during 8-year follow-up.

CHD, coronary heart disease; NCA, normal coronary arteries; T2DM, type 2 diabetes mellitus; STEMI, ST-segment elevation myocardial infarction; MI, myocardial infarction; cIMT, carotid intima-media thickness; MACE, major adverse cardiovascular events; ACS, acute coronary syndromes; CAD, coronary artery disease; PAD, peripheral artery disease; TIA, transient ischemic attack.