High Level of Gut Metabolite Predicts Worse Outcomes in ACS Patients

In patients presenting to the emergency department with acute coronary syndromes, high levels of plasma trimethylamine N-oxide (TMAO) are associated with a significantly increased risk of major adverse cardiac events at 30 days and 6 months, according to the results of a new study.

Additionally, elevated plasma concentrations of TMAO are associated with an increased MACE risk among patients with initially negative cardiac troponin T (cTnT) levels, with the frequency of adverse events at 30 days and 6 months increasing with higher levels of TMAO.

“We looked at more than 500 subjects here in Cleveland as they presented to the emergency department with chest pain and the baseline level of TMAO predicted thrombotic events and adverse prognosis, even in the subjects with the very first [cardiac troponin] test collected within minutes of their arrival,” said senior investigator Stanley Hazen (Cleveland Clinic, OH). “Of course, a lot of time, that turned out be before the cardiac enzymes were even positive.”

The study results were published January 11, 2017, in the European Heart Journal.

Metabolite a Gut Byproduct of Red Meat, High-Fat Dairy

TMAO is a proatherogenic metabolite produced after the breakdown of dietary nutrients by gut bacteria. Phosphatidylcholine, or lecithin, is a major source of choline in the Western diet and can be found in red meat, eggs, high-fat dairy products, and other meats. After the gut microbiota metabolizes phosphatidylcholine, as well as L-carnitine found in red meat, trimethylamine (TMA) is created and eventually oxidized to for TMAO.

High levels of TMAO have been shown to be associated with an increased risk of death in patients with peripheral artery disease as well as in patients with heart failure and/or renal insufficiency. The byproduct has also been linked with atherosclerotic disease burden in patients with coronary artery disease. When the metabolism of choline is blocked, and TMAO levels subsequently reduced, researchers showed they could reduce the formation of cholesterol-laded macrophage foam cells and atherosclerosis in an animal model.

Hazen, who has been at the forefront of TMAO research along with W.H. Wilson Tang, MD (Cleveland Clinic, OH), told TCTMD that their 2016 study in Cell showed in more than 4,000 subjects that the gut metabolite enhanced platelet hyperreactivity and thrombosis risk.

“Based on that, it suggested that if we were to look at people presenting with chest pain, a high TMAO should predict who would be more likely to have a thrombotic event, like a heart attack,” said Hazen. “While it wouldn’t necessarily be a diagnostic test for a heart attack, if you knew the TMAO number, you should be able to get clinical value in terms of identifying who is at heightened risk for thrombotic events amongst patients who present with ACS.”

In the Cleveland Clinic cohort, 530 subjects presented to the emergency department with chest pain of suspected cardiac origin. In addition to baseline and serial cTnT testing, TMAO levels were also measured. Overall, the risk of MACE at 30 days was more than sixfold higher among those with the highest TMAO concentrations (> 7.91 µM) when compared with those with the lowest levels (0.12-2.55 µM). At 6 months, the risk was more than fivefold higher for the highest versus lowest TMAO groups. For those with a negative baseline cTnT test, those with the highest TMAO levels also had a more than fivefold increased risk of MACE at 30 days and 6 months. 

The researchers confirmed the findings in an independent multicenter Swiss cohort study of 1,683 ACS patients who underwent coronary angiography. In this sample, the risk of MACE at 1 year was not as large among individuals with elevated TMAO levels, but it was statistically higher than what was seen in individuals with low levels of TMAO (HR 1.57 for Q4 vs Q1; 95% CI 1.03-2.41).

Role for TMAO in Practice

To TCTMD, Hazen said to test for TMAO would require a full mass spectrometry assay, but the study in ACS patients suggests a potential need for developing a rapid point-of-care test, one that might be used to stratify patients into higher-risk categories. He noted that another study published this week, in Clinical Chemistry, found TMAO levels also improved risk stratification for death/MI in acute MI patients. In that study, which was led by Toru Suzuki (University of Leicester, England), TMAO was used to rule out risk when added to the Global Registry of Acute Coronary Events (GRACE) score.

“These sets of papers kind of argue there is a need for high-throughput TMAO [screening],” said Hazen.  

Brent Muhlestein, MD (Intermountain Medical Center Heart Institute, Salt Lake City, UT), who was not involved in the research by Hazen and colleagues, told TCTMD there are now a number of studies showing a relationship between TMAO concentrations and cardiovascular risk in various settings, so the next question is understanding the mechanism of action. “So far the major way not to increase TMAO levels is to not eat any meat,” he said.

At present, it appears that TMAO plays a predominant role in the thrombotic complications that occur after plaque rupture in ACS patients. “If everybody has ruptured plaque, who does worse?” asked Muhlestein. “It’s the patients with more thrombus complications, and TMAO appears to be correlated with that.”

Muhlestein noted that if a chest pain patient has negative troponin test, they will often be sent for stress testing to rule out evidence of ischemia. He also said that while cTnT-negative patients with high TMAO levels were more likely to have worse outcomes at 30 days and 6 months, the study showed only a statistical association. There were also patients with high TMAO levels who fared just fine, Muhlestein pointed out.

“The sensitivity and specificity of TMAO will need to be evaluated if TMAO is to become a new marker that can manage care,” he said. There is no different management strategy for patients based on TMAO levels, he added, although the concept of different dietary strategies based on the microbiome remains very exciting.  

Muhlestein said they are currently studying the effects of fasting on various cardiovascular risk factors, with published papers showing that people who fast at least once per month have fewer cardiovascular complications. When fasting, TMAO levels also declined significantly, he noted, and it is a marker they are studying in ongoing trials.