For the first time, plasma levels of the gut microbe-dependent metabolite TMAO have been correlated with near-term risk of major adverse cardiovascular events (MACE) and long-term mortality in patients with chest pain and suspected acute coronary syndrome (ACS).
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The findings, from a study in two independent cohorts recently published in the European Heart Journal, showed that TMAO predicted near-term MACE even among subjects initially negative for troponin T. “This suggests that TMAO offers prognostic value in the setting of ACS beyond what’s provided by traditional risk factors and laboratory tests,” says the paper’s senior author, Stanley Hazen, MD, PhD, Chair of Cellular and Molecular Medicine and Section Head of Preventive Cardiology and Rehabilitation at Cleveland Clinic.
“These findings are important because of the modifiable nature of TMAO — via diet and potentially via therapies in development — and because they suggest that a rapid, point-of-care TMAO assay is worth pursuing to improve risk stratification of patients presenting with chest pain and suspected ACS,” adds Dr. Hazen.
Expanding TMAO research beyond stable populations
The new research builds on a long string of studies by Dr. Hazen’s research group implicating TMAO in multiple aspects of vulnerability to cardiometabolic disease, including the development of atherosclerotic plaque, alterations in macrophage and endothelial cell phenotype, and promotion of platelet hyperreactivity. Central to this link are the dietary nutrients choline, lecithin and carnitine (all abundant in animal products), which are ultimately metabolized into TMAO (trimethylamine-N-oxide) after they come in contact with microbes in the gut (as explained in detail here).
“The discovery that TMAO impacted platelet function and thrombosis potential made TMAO particularly interesting to study in the setting of chest pain and suspected ACS,” explains Dr. Hazen.
He and colleagues set out to do so in a two-part case-control study across two independent populations in the U.S. and Switzerland.
Findings in the Cleveland cohort
The first portion was a single-center prospective investigation of 530 sequential adults presenting to a Cleveland Clinic emergency department with chest pain of suspected cardiac origin. TMAO and cardiac troponin levels were measured at presentation and serially for several hours thereafter. End points included MACE — a composite of myocardial infarction, stroke, revascularization or all-cause mortality — at 30 days and six months as well as mortality at seven-year follow-up.
Individuals with TMAO levels in the highest quartile (> 7.9 μM) had a 30-day risk for MACE more than six times higher than those with TMAO levels in the lowest quartile (≤ 2.55 μM) (adjusted odds ratio [OR] = 6.30, 95% CI: 1.89 to 21.00; P < .01).
This significant effect continued at six months (adjusted OR = 5.65, 95% CI: 1.91 to 16.7; P < .01).
TMAO also predicted long-term mortality, with levels in the highest quartile conferring nearly twice the risk of death at seven years compared with levels in the lowest quartile (adjusted OR = 1.81, 95% CI: 1.04 to 3.15; P < .05).
Notably, TMAO performed where the established biomarker troponin T failed: Among the 418 patients who were negative for troponin T at baseline or persistently negative, rates of MACE at 30 days and six months increased significantly with increasing quartiles of TMAO — even after adjusting for other risk factors.
Findings in the Swiss cohort
To confirm these results, Dr. Hazen’s group partnered with investigators with the multicenter Swiss ACS Cohort to prospectively study 1,683 patients with angiography-adjudicated ACS followed up at one year.
“Diets are quite different between Switzerland and the U.S.,” says Dr. Hazen. “Since TMAO is influenced by diet, we were interested to see whether our findings from the Cleveland cohort would translate to this setting.”
The researchers found that they did — albeit less dramatically. After adjustment for other variables, the highest quartile of TMAO levels was associated with a 57 percent increase in MACE at one year (P < 0.05) and a 60 percent increase in death at year (borderline nonsignificant) compared with the lowest quartile. As in the U.S. cohort, event rates increased with TMAO levels in a dose-dependent manner.
The researchers speculated that the stronger association between TMAO and events in the U.S. cohort may be related to a higher burden of comorbidities and overall higher plasma TMAO levels in the U.S. cohort relative to the Swiss cohort.
Hypothesis-fueling results with big potential implications
While noting that these findings are hypothesis-generating and further studies are needed before a cause-and-effect relation between TMAO and ACS can be established, Dr. Hazen says this work raises at least two intriguing possibilities.
The first is the potential for plasma TMAO to ultimately be used for point-of-care testing to improve triage and risk stratification of patients presenting with acute chest pain and suspected ACS. If rapid enough, such an assay could address a limitation of cardiac troponin testing. “It can take several hours for cardiac troponin levels to rise in a patient with ACS,” Dr. Hazen explains. While TMAO testing is available and relatively inexpensive, it is not currently rapid enough for use in an emergency setting.
The second is the prospect of studies aimed at reducing TMAO levels through diet and/or experimental TMAO-targeted therapeutics, with the goal of assessing efficacy for primary or secondary prevention of ACS.
“These findings not only broaden the potential clinical utility of TMAO as an independent prognostic marker in suspected ACS, but also suggest a potential basis for a novel therapeutic target in ACS management,” Dr. Hazen notes.