TMAO, formed by gut microbiota, associates with incident MACE and mortality
Gut microbiota-dependent trimethylamine N-oxide in acute coronary syndromes: a prognostic marker for incident cardiovascular events beyond traditional risk factors
Recent studies emphasise the role of gut microbes in the development of atherosclerotic heart disease and adverse thrombotic events [1-5]. Trimethylamine N-oxide (TMAO) is a plasma metabolite that is formed by nutrient precursors abundant in a Western diet, such as choline, and gut microbiota . TMAO levels have been shown to associate with cardiovascular risk [1-3, 5].
Its relationship with incident risk in individuals with acute coronary syndrome (ACS) has not been studied yet. Therefore, this study explored the relationship between systemic levels of TMAO and incident major adverse cardiovascular events (MACE) and mortality among individuals with ACS, using the single centre Cleveland cohort (n=530) and the multi-site Swiss ACS cohort (n=1683) that is part of the special program university medicine (SPUM). Cleveland patients presented in the emergency department with chest pain of suspected cardiac origin within 24hrs of onset, whereas Swiss patients include all patients who underwent coronary angiography for ACS.
- Within the first 30 days and 6 months, Cleveland patients with higher average plasma TMAO levels at presentation experienced incident MACE more often. Also after 7 years, TMAO levels were on average higher in patients that died (all P<0.001). This was a dose-dependent relationship as patients with the lowest quartile TMAO levels had the highest survival rates, whereas patients of the highest TMAO quartile had the lowest survival rates (log rank all quartiles P<0.001).
- The frequency of experiencing MACE at 30 days and 6 months following presentation increased with increasing quartiles of TMAO levels as follows: 30-day and 6-month frequency of 30.1% and 31.6% in quartile 1, 32.6% and 37.1% in quartile 2, 40.2% and 43.9% in quartile 3, and 49.6% and 53.4% in quartile 4 (P< 0.01 for trend).
- After multivariable correction, TMAO levels predicted risk of MACE at 30 days (OR 4th vs. lowest quartile 6.30, 95% CI: 1.89-21.00, P<0.01) and 6 months (OR 4th quartile 5.65, 95% CI: 1.91-16.74, P<0.01) and 7-years mortality (HR 4th quartile 1.81, 95% CI: 1.04-3.15, P<0.05).
- Among patients who were initially cTnT-negative at presentation, TMAO levels were higher amongst those who had subsequently experienced an incident MACE at 30 days (median IQR 5.5 µM (3.5-9.9) vs. 3.7 µM (3.4-6.9), P<0.001) and 6 months (median IQR 5.3 µM (3.3-9.6) vs 3.7 µM (2.4-6.8), P<0.0001), compared with those who did not. Also for cTnT negative patients the frequency of MACE at 30 days and 6 months increased with TMAO quartiles (P trend < 0.05) and remained a significant predictor for MACE at 30 days (OR 4th quartile 5.83, 95% CI: 1.79-19.03, P<0.01) and 6 months (OR 4th quartile 5.51, 95% CI: 1.90-16.01, P<0.001) in a multivariate analysis.
- The Swiss cohort showed similar results; higher average TMAO levels amongst patients who experienced adverse outcomes, including 1-year MACE (3.75 mM (2.14–7.04), n= 190, vs. 2.80 µM (1.91–4.55), n= 1493; P<0.001), and 1-year mortality (5.95 mM (2.79–13.08), n= 71, vs. 2.82 mM (1.92–4.61), n= 1612; P<0.001). Also quartile levels of TMAO associated with long-term incident MACE risk (log rank P<0.001) and elevated levels of TMAO remained a significant predictor of MACE (HR 4th quartile [adjusted] 1.57, 95% CI: 1.03-2.41, P<0.05).
TMAO levels were associated with short-term risk of MACE and long-term mortality in two independent ACS cohorts comprising sequential patients who presented with complaint of chest pain and suspected ACS. The relationship with risk of incident MACE was dose-dependent. Therefore, gut microbiota-dependent metabolite, TMAO, may serve as a clinically useful and potentially modifiable prognostic marker.