Gut Bacteria-Produced Compound May Help Identify Atherosclerotic Burden in Patients With CAD

Plasma levels of trimethylamine N-oxide (TMAO)—which is a product of the breakdown of certain dietary nutrients by gut bacteria—are independently associated with atherosclerotic burden based on the SYNTAX and SYNTAX II scores in patients with CAD, a study shows. Patients with high levels also tend to have more diffuse lesions.

The findings provide more in-depth information about the link between TMAO levels and atherosclerosis, a relationship that has been established in prior animal and human studies, senior author W.H. Wilson Tang, MD (Cleveland Clinic, Cleveland, OH), told TCTMD. 

He said there is currently a lot of excitement in the field about the possibility to both identify individuals who have a heightened risk due to elevated TMAO levels and discover ways to mitigate that risk by targeting the molecule itself or the bacteria that produce it with dietary or pharmacologic interventions, Tang said.

Research is still in the early phase, he noted. He likened the situation to that surrounding the establishment of the relationship between LDL cholesterol and cardiovascular disease, which was well known for some time before effective interventions were developed.

“There are different avenues to continue to explore the pathway to which this may actually impact human health,” Tang said about TMAO research.

The findings of the current study were published online ahead of the June 7, 2016, issue of the Journal of the American College of Cardiology. The lead author is Vichai Senthong, MD (Cleveland Clinic).

Beyond Traditional Risk Factors

TMAO is created through a process that starts with gut bacteria digesting phosphatidylcholine—the primary dietary source of choline—and carnitine, which is found at high levels in red meat. That initially creates trimethylamine, which is eventually oxidized to form TMAO.

The compound has been shown to have direct pro-atherosclerotic effects in animals and has been associated with a higher risk of major adverse cardiac events, prevalence of cardiovascular disease, and number of diseased coronary vessels in humans.

“However, a relationship between plasma TMAO levels and detailed characterization and quantification of atherosclerosis burden has not been investigated,” the authors write.

In a single-center study, the investigators explored the issue in 353 consecutive stable patients who had evidence of significant atherosclerotic CAD detected during elective coronary angiography between 2012 and 2014.

Before multivariate adjustment, plasma TMAO levels correlated with the SYNTAX and SYNTAX II scores and with cardiac troponin T levels (P < 0.0001 for all).

After adjustment for traditional risk factors, body mass index, medications, lesion characteristics, renal function, and high-sensitivity C-reactive protein, elevated TMAO levels remained associated with being in the highest tertile for both the SYNTAX score (OR 4.82; 95% CI 2.43-9.57) and SYNTAX score II (OR 1.88; 95% CI 1.36-2.60), but not with troponin levels (OR 1.14; 95% CI 0.88-1.47).

An elevated TMAO level was also independently associated with about twice the likelihood of having diffuse lesions (OR 2.05; 95% CI 1.45-2.90), with a concomitant decrease in the chances of having focal lesions (OR 0.46; 95% CI 0.31-0.68).

Exploring Mechanisms

Tang said the study “provides some insight [into] a potential dietary and microbial link to a mechanism that leads to coronary artery disease, . . . [and it] actually may explain why different people may have different manifestations of disease with the environment—in this case the food that we eat—because of their different capacity to produce and to eliminate this compound.”

The mechanism through which TMAO could worsen atherosclerosis may be illustrated by the greater atherosclerotic plaque size in the arterial walls and aortic roots of mice with higher plasma levels of TMAO that has been observed in previous studies, the authors note.

“TMAO may have direct biological activity that facilitates the development or propagation of atherosclerosis plaque and suppression of reverse cholesterol transport in in vivo mouse models,” they write. “Moreover, recent studies suggest that flavin monooxygenase 3, the major host enzyme responsible for forming TMAO from gut microbe–generated trimethylamine, is a master regulator of tissue cholesterol and sterol metabolism.”

In addition, mouse studies have suggested that TMAO “may exacerbate impaired glucose tolerance, obstruct hepatic insulin signaling, and promote adipose tissue inflammation, which have been related to the complexity and degree of atherosclerotic burden of CAD,” they write.

In an accompanying editorial, Geert Schmid-Schönbein, PhD (University of California, San Diego, La Jolla, CA), says, “As a clinical index and also a marker for tissue decay, TMAO is an attractive candidate and an alternative to traditional risk factors whose biochemical and biophysical relationship with the actual disease process remains uncertain.

“As a small molecule, TMAO has the advantage that it is rapidly transported from its site of generation into the plasma and may even be detected in the breath by noninvasive methods,” he continues, adding that “for TMAO to become a widely usable risk factor, a new technology needs to be introduced to detect TMAO levels at the point of care with a new biosensor, perhaps even designed along the line of our own sensors in the olfactory epithelium.”