Gut Flora Metabolite Seen to Predict Cardiac Events in Patients With ACS

Patrice Wendling

January 20, 2017

CLEVELAND, OH and ZURICH, SWITZERLAND — High plasma levels of trimethylamine-N-oxide (TMAO) in US patients with acute coronary syndromes independently predict major adverse cardiac events (MACE) at 30 days and 6 months and mortality at 7 years. The prognostic value of the gut-derived metabolite was confirmed, this time using 1-year MACE risk, in a large Swiss ACS cohort undergoing coronary angiography, investigators report[1].

The study, published in the European Heart Journal, comes on the heels of another paper, in Clinical Chemistry[2], in which TMAO independently predicted death/MI at 2 years after hospitalization for acute MI.

The new findings broaden the evidence base for TMAO beyond stable patients, including those with heart failure or peripheral artery disease, and call further attention to the prospect of TMAO as a potentially modifiable risk marker for cardiovascular events.

"There are a lot of perspectives here in terms of intervention that of course need additional research, but an interesting way to go about it is to influence TMAO levels directly either by dietary intervention or also in the future with compounds that inhibit the enzyme in the bacteria that produces TMAO," co–senior investigator of the US/Swiss study Dr Thomas Lüscher (University Hospital Zurich, Switzerland) told heartwire from Medscape.

He added that fellow co–senior investigator Dr Stanley Hazen (Cleveland Clinic, OH) and his team are already developing such compounds, and "we have experimental studies that should soon have results on whether this works in mice."

Hazen's team has been a leader in TMAO research and previously reported[3] that targeting trimethylamine (TMA), the first step in TMAO formation, with 3,3-dimethyl-1-butanol inhibits foam-cell formation and aortic atherosclerotic plaque formation in mice, without altering normal gut flora.

TMAO is produced after gut bacteria break down dietary nutrients such as phosphatidylcholine, choline, and L-carnitine, found in red meat, eggs, and high-fat dairy products, all common in the Western diet.

Cleveland ACS Cohort

To study the role of TMAO in the ACS setting, the investigators evaluated 530 consecutive patients who presented to the Cleveland Clinic emergency department with chest pain of suspected cardiac origin. TMAO levels were measured at baseline along with baseline and serial cardiac troponin.

Patients with the highest TMAO levels (>7.9 μM) had more than six times increased risk for MACE at 30 days (odds ratio [OR] 6.30, 95% CI 1.89–21.00; P<0.01) than those with the lowest TMAO levels (<2.56 μM) and more than five times increased MACE risk at 6 months (OR 5.65, 95% CI 1.91–16.74; P<0.01) after multivariable adjustment.

Strikingly, patients with the highest TMAO levels faced a nearly twofold increased hazard of 7-year mortality when compared with those with the lowest level (OR 1.81, 95% CI 1.04–3.15; P<0.05).

Point-of-Care Testing?

Notably, in adjusted analyses of patients with initially negative cardiac troponin, elevated TMAO levels maintained prognostic significance for MACE at 30 days (OR 5.83, 95% CI 1.79–19.03; P<0.01) and 6 months (OR 5.51, 95% CI 1.90–16.01; P<0.001) beyond traditional risk factors, biomarkers, and ECG data, including C-reactive protein (CRP), hypertension, hyperlipidemia, and diagnosis of STEMI, non-STEMI, or unstable angina.

"It is therefore tempting to speculate that the ability to generate rapid and accurate TMAO results through point-of-care testing could significantly improve rapid triaging and risk stratification among subjects presenting with complaint of chest pain and suspected ACS," the investigators, led by Dr Xinmin S Li (Cleveland Clinic, OH) and Dr Slayman Obeid (University Hospital Zurich, Switzerland), write.

Commenting to heartwire , lead investigator of the acute-MI study Dr Toru Suzuki (University of Leicester, UK) said while the idea is attractive, the technology isn't there yet.

"I'm really invested in a point-of-care test, but this requires mass spectrometry. If we run it in our lab it will probably be ready the next morning, but not in 10 minutes. Also, whether TMAO is elevated or not doesn't change the management on the spot. What it changes is down the line, it's informative," he said.

Suzuki also observed there is intraindividual variation in TMAO, spiking, for example, in patients after simply eating a steak dinner.

"It's true that TMAO can vary quite a bit like CRP as well, and we have to further understand why there are these changes that occur even from one day to another," Lüscher agreed.

He noted that research in his department looking at TMAO changes throughout the day has also shown "it's not as stable as troponin. So I would think it [TMAO] is not so useful as a diagnostic marker but as a prognostic marker."

Swiss ACS Cohort

To strengthen the Cleveland Cohort findings, the investigators went on to examine 1683 patients in the multicenter Swiss Acute Coronary Syndrome Cohort who underwent coronary angiography.

"Swiss patients have quite a different diet, and this is of interest because TMAO [values] are influenced by what you ingest, in particular meat, shellfish, and eggs, and so were much higher in patients in the US. Cardiovascular complications were also more common in these patients. So we were quite excited about what we found," Lüscher said.

As in the Cleveland Cohort, TMAO levels were associated with a graded increase in incident MACE risk.

The adjusted risk of MACE at 1 year was 1.5 times higher in patients with the highest TMAO levels (>4.85 μM) than in those with the lowest levels of TMAO (0.08-1.93 μM) (hazard ratio [HR] 1.57, 95% CI 1.03–2.41; P<0.05).

Finally, adding TMAO to the model significantly improved risk estimation for 1-year MACE over traditional risk factors (net reclassification index [NRI] 0.3, P< 0.001) but did not significantly improve the C statistic.

In contrast, inclusion of TMAO in the Cleveland Clinic's model significantly improved risk estimation for MACE at 30 days and 6 months, with significant improvement in C statistics for both time points.

"What you could see from our work is that those who are at risk have substantially higher values than those who are not at risk. So you need quite an elevation of TMAO in the human to consider it a cardiovascular risk factor," Lüscher said.

Acute MI Study

Suzuki and his colleagues turned their attention to TMAO in 1079 acute MI patients admitted to the University Hospitals of Leicester between August 2004 and April 2007.

Multivariable analyses revealed TMAO was an independent predictor of death/MI at 2 years (HR 1.21, 95% CI 1.03–1.43; P=0.023) but not at 6 months (P=0.119).

In a fully adjusted model for death/MI at 2 years, TMAO was the only biomarker that significantly predicted outcome, despite inclusion of such contemporary markers as cardiac troponin, N-terminal probrain natriuretic peptide (NT-proBNP), and copeptin.

Finally, when used with the Global Registry of Acute Coronary Events (GRACE) score for calculating death/MI at 6 months, TMAO was able to down-classify patients with low risk (NRI 29.0, 95% CI 19.8–38.3; P<0.0005) but unable to reclassify those at high risk (NRI −9.1, 95% CI −30.0 to 11.8).

Mechanistic Mystery

While TMAO appears to be a toxic agent for the cardiovascular-renal system, Suzuki and Lüscher both observed that it remains unclear exactly how TMAO exerts its effects.

Experiments in mice suggest there may be a prothrombotic effect of TMAO in the circulation in vivo, but whether or not it also stimulates macrophages and plaque formation is currently under investigation.

"I think this is very important," Lüscher said. "The molecular mechanisms in the plaque in the vessel wall have not been fully elucidated."

He added, "I think there's a lot of excitement and projects that are ahead of us, but I wouldn't rush into the clinical use before we understand the whole story."

Lüscher is editor in chief of European Heart Journal, which published the study, and reports grants from AstraZeneca, Biotronik, Boston Scientific, Eli Lilly, and St Jude Medical. Disclosures for the coauthors are listed in the paper. Suzuki reports his study was supported by the Japan Agency for Medical Research and Development, the University of Tokyo, the John and Lucille van Geest Foundation, and the National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit. The coauthors report no relevant financial relationships.

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org, follow us on Twitter and Facebook.

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