Gut microbiota-dependent trimethylamine N-oxide in acute coronary syndromes: a prognostic marker for incident cardiovascular events beyond traditional risk factors

Abstract

Aims: Systemic levels of trimethylamine N-oxide (TMAO), a pro-atherogenic and pro-thrombotic metabolite produced from gut microbiota metabolism of dietary trimethylamine (TMA)-containing nutrients such as choline or carnitine, predict incident cardiovascular event risks in stable primary and secondary prevention subjects. However, the prognostic value of TMAO in the setting of acute coronary syndromes (ACS) remains unknown.

Methods and results: We investigated the relationship of TMAO levels with incident cardiovascular risks among sequential patients presenting with ACS in two independent cohorts. In the Cleveland Cohort, comprised of sequential subjects (n = 530) presenting to the Emergency Department (ED) with chest pain of suspected cardiac origin, an elevated plasma TMAO level at presentation was independently associated with risk of major adverse cardiac events (MACE, including myocardial infarction, stroke, need for revascularization, or death) over the ensuing 30-day (4th quartile (Q4) adjusted odds ratio (OR) 6.30, 95% confidence interval (CI), 1.89-21.0, P < 0.01) and 6-month (Q4 adjusted OR 5.65, 95%CI, 1.91-16.7; P < 0.01) intervals. TMAO levels were also a significant predictor of the long term (7-year) mortality (Q4 adjusted HR 1.81, 95%CI, 1.04-3.15; P < 0.05). Interestingly, TMAO level at initial presentation predicted risk of incident MACE over the near-term (30 days and 6 months) even among subjects who were initially negative for troponin T (< 0.1 ng/mL) (30 days, Q4 adjusted OR 5.83, 95%CI, 1.79-19.03; P < 0.01). The prognostic value of TMAO was also assessed in an independent multicentre Swiss Cohort of ACS patients (n = 1683) who underwent coronary angiography. Trimethylamine N-oxide again predicted enhanced MACE risk (1-year) (adjusted Q4 hazard ratios: 1.57, 95% CI, 1.03-2.41; P <0.05).

Conclusion: Plasma TMAO levels among patients presenting with chest pain predict both near- and long-term risks of incident cardiovascular events, and may thus provide clinical utility in risk stratification among subjects presenting with suspected ACS.

Keywords: Acute coronary syndrome; All-cause mortality; Choline; Gut microbiota; Incident major adverse cardiac events; Risk stratification; Trimethylamine N-oxide.

Figure 1

The association of TMAO levels with clinical outcomes in the Cleveland Cohort. Box-Whisker plots of TMAO levels among patients with complaint of chest pain with (Yes) and without (No) incident major adverse cardiac events (MACE) (MI, stroke, the need for revascularization, or death) and mortality over follow-up periods (A); Kaplan-Meier estimates and the risk of all-cause mortality ranked by quartile of TMAO levels (B); Forest plots indicating the risks of incident major adverse cardiac events (MACE) at 30 days and 6 months (C and D) and all-cause mortality by 7 years (E) according to the quartiles of TMAO levels, multivariable logistic regression model for odds ratio or multivariable Cox model for hazard ratio included adjustments for age, gender, HDL, LDL, smoking, presence or absence of a history of diabetes mellitus, hypertension, hyperlipidaemia, revascularization or coronary artery disease, C-reactive protein level, estimated glomerular filtration rate, initial troponin T level and diagnosis of either STEMI, NSTEMI or unstable angina. The 5–95% confidence interval is indicated by line length.

Figure 2

Risks of incident major adverse cardiac events (MACE) at 30 days (A) and 6 months (B) for patients initially negative for Troponin T test according to TMAO levels ranked by quartiles in the Cleveland Cohort. Multivariable logistic regression model included adjustments for age, gender, HDL, LDL, smoking, presence or absence of a history of diabetes mellitus, hypertension, hyperlipidaemia, revascularization or coronary artery disease, C-reactive protein level, estimated glomerular filtration rate, initial troponin T level and diagnosis of either STEMI, NSTEMI or unstable angina. The 5–95% confidence interval is indicated by line length.

Figure 3

The association of TMAO levels with clinical outcomes in the Swiss ACS Cohort. Box-Whisker plots of TMAO levels in ACS patients with (Yes) and without (No) incident major adverse cardiac events (MACE) (MI, stroke, the need for revascularization, or death) and mortality over follow-up periods (A); Kaplan-Meier estimates and the risk of MACE ranked by quartile of TMAO levels (B); Forest plots indicating the risks of incident major adverse cardiac events (MACE)(C) and all-cause mortality(D) by 1 year according to the quartiles of TMAO levels; The multivariable Cox model included adjustments for age, gender, HDL, LDL, smoking, presence or absence of a history of diabetes mellitus, hypertension, hyperlipidaemia, revascularization or coronary artery disease, C-reactive protein level, estimated glomerular filtration rate, and diagnosis of either STEMI, NSTEMI or unstable angina. The 5–95% confidence interval is indicated by line length.