TMAO’s Prognostic Value Extends to Incident Coronary Artery Disease in Healthy Adults

For the first time, the gut microbe-dependent metabolite TMAO has been shown to predict incident coronary artery disease (CAD) in a large prospective population study of apparently healthy adults.

The finding, published in American Heart Journal (2021;236:80-86) by a Cleveland Clinic-led research team, adds to mounting evidence linking the TMAO pathway to elevated risk of cardiometabolic disease.

“CAD risk increased with plasma TMAO levels in a dose-dependent fashion among our study population of middle-aged individuals with no history of cardiovascular disease,” observes the study’s lead and corresponding author, Cleveland Clinic cardiologist W.H. Wilson Tang, MD. “This increase was independent of traditional risk factors.”

Assessing TMAO in a primary prevention context

TMAO (trimethylamine N-oxide) is produced when gut bacteria digest choline, carnitine and lecithin — nutrients that are abundant in animal products, particularly red meat. This metabolite has been mechanistically linked to atherosclerosis, thrombosis and various forms of cardiometabolic disease through a series of animal model and clinical association studies over the past decade — many of them conducted by a Cleveland Clinic team including Dr. Tang and led by Stanley Hazen, MD, PhD.

Despite this growing body of evidence linking TMAO and cardiometabolic disease, virtually all the clinical studies have been in people with a high risk factor burden or prevalent cardiovascular disease, particularly CAD.

To explore TMAO’s impact in the general population, the Cleveland Clinic researchers teamed with European investigators to conduct a nested case-control study among participants in the EPIC-Norfolk prospective population study. This community-based cohort study had recruited over 25,000 apparently healthy men and women between ages 40 and 79 years in the mid-1990s, all of them from Norfolk in the United Kingdom. The purpose of EPIC-Norfolk was to evaluate determinants of cancer and other diseases through long-term follow-up.

The present investigation identified the 908 EPIC-Norfolk participants who developed CAD during an average follow-up period of 8 years and individually matched them to 1,273 control EPIC-Norfolk participants by sex, age, enrollment site and date of visit. All participants had nonfasting blood samples taken at enrollment in EPIC-Norfolk, which were used to determine baseline plasma levels of TMAO and other metabolites.

Key findings

Analysis of the 2,181 participants’ outcomes by baseline plasma TMAO revealed the following:

• TMAO levels were higher in participants who developed CAD than in those who did not, 3.70 µM (interquartile range [IQR], 2.50-6.41) vs. 3.25 µM (IQR, 2.19-5.21) (P < 0.001).
• When the overall cohort was stratified into quartiles by TMAO level, elevated TMAO was predictive of CAD development, with an odds ratio of 1.86 for the highest versus lowest TMAO quartiles (95% CI, 1.46-2.37) (P < 0.001). After adjustment for traditional risk factors, elevated TMAO remained predictive of incident CAD (odds ratio = 1.58; 95% CI, 1.21-2.06) (P < 0.001).

Analysis of associations for other metabolites showed plasma choline levels to be predictive of CAD development (although less strongly than TMAO), whereas betaine conferred no significant prognostic value.

Additionally, the researchers found that TMAO’s predictive utility maintained its statistical significance for all TMAO threshold levels from 1.5 µM (10th percentile) to 10.5 µM (90th percentile), underscoring the dose-dependent relationship between TMAO and incident risks, as well as the concept that “lower is better” across a broad range of TMAO levels. In contrast, choline’s prognostic value was less consistent across the cohort, particularly at lower concentration thresholds.

Further support for a TMAO pathway role

“This long-term study of apparently healthy adults found that TMAO levels were higher among those who went on to develop CAD than in those who did not, even after adjustment for other risk factors,” says Dr. Tang.

He notes that these findings are consistent with the one previously published prospective study of TMAO levels in a primary prevention context, which was conducted in a much smaller cohort and with shorter follow-up (Atherosclerosis. 2019;280:126-131).

“Our study and this small earlier study support the prognostic value of TMAO in the general population and bolster the growing data that link the TMAO pathway to elevated cardiovascular risk,” adds Dr. Hazen, Co-Section Head of Preventive Cardiology and Rehabilitation at Cleveland Clinic. “These findings suggest that keeping TMAO levels lower may help reduce incident risk of cardiovascular disease, even in apparently healthy middle-aged adults.”

That suggests a potential role for TMAO-lowering strategies within the cardiovascular therapeutic landscape. Clinical studies by this Cleveland Clinic group and others have shown that certain dietary interventions can reduce TMAO levels, and novel pharmacologic interventions that target TMAO production have slowed atherosclerosis progression in mouse studies.

But further study is clearly needed, Dr. Tang notes. “These promising findings warrant further investigation,” he says. “The next step is seeing whether TMAO-lowering interventions in patients show the same promising effects seen in animal studies, and if they will actually reduce cardiovascular risks in the clinical setting, whether for primary or secondary prevention.”

“We know that eating a healthy diet can have a dramatic impact on the risk of developing cardiovascular disease,” observes Leslie Cho, MD, Co-Section Head of Preventive Cardiology and Rehabilitation at Cleveland Clinic. “This noteworthy study helps us understand the important role of the gut microbiome in development of cardiovascular disease.”

Disclosure: Dr. Tang reports no commercial interests relevant to the work discussed above. Dr. Hazen reports being named as co-inventor on pending and issued patents held by Cleveland Clinic relating to cardiovascular diagnostics and therapeutics, as well as having received royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland Heart Lab, a fully owned subsidiary of Quest Diagnostics, and Procter & Gamble.