TMAO Implicated in PAD Mortality Risk

Elevated plasma levels of the proatherogenic gut microbial metabolite TMAO are a significant predictor of five-year all-cause mortality in patients with stable peripheral artery disease (PAD). So finds a prospective cohort study from Cleveland Clinic published in the October 2016 issue of Journal of the American Heart Association.

“These findings point to the potential for TMAO to help improve selection of high-risk PAD patients who require more aggressive and specific interventions,” says Cleveland Clinic cardiologist W.H. Wilson Tang, MD, the study’s primary author.

A role for TMAO in yet another disease?

TMAO, or trimethylamine-N-oxide, is a byproduct of metabolism of the dietary nutrients choline, lecithin and carnitine — all abundant in animal products — by microbes in the gut. Increased plasma levels of TMAO have been associated with the development of atherosclerosis and heightened risk of related disorders in humans — including heart failure, chronic kidney disease and thrombosis — in a series of studies by Dr. Tang and the Cleveland Clinic lab of Stanley Hazen, MD, PhD, who is a co-author of the current study.

Since their milestone discovery of TMAO’s mechanistic role in these cardiometabolic diseases, the Cleveland Clinic team has been steadily expanding its inquiries into how broadly this role extends. PAD was a natural candidate for exploration, as it’s a common manifestation of systemic atherosclerosis with a considerable clinical burden. “Moreover, predictors of mortality and underlying pathophysiology in patients with PAD are not well-defined,” Dr. Tang notes.

Five-year follow-up in 821 PAD patients

So he and his colleagues examined the relationship between fasting plasma TMAO and all-cause mortality over five years among 821 consecutive patients with adjudicated PAD who underwent elective angiography for cardiac evaluation at Cleveland Clinic during a recent six-year period.

Mean patient age was 66 years, and 66 percent of patients were men. The median plasma TMAO level was 4.8 μmol/L.

Over five years of follow-up, 222 deaths occurred in the cohort, for a mortality rate of 27 percent. When patients were stratified into quartiles based on plasma TMAO levels, a statistically significant graded increase in all-cause mortality risk was observed with increasing TMAO levels across the cohort (P < .001).

A TMAO level in the highest quartile was associated with a 2.7-fold increase in mortality risk relative to a level in the lowest quartile (hazard ratio = 2.69; 95% CI, 1.82-3.97).

After adjustment for traditional cardiovascular risk factors, inflammatory biomarkers and history of coronary artery disease, elevated TMAO levels remained significantly predictive of mortality, with a hazard ratio for the fourth versus first quartiles of 2.06 (95% CI, 1.36-3.11). The association remained statistically significant following additional adjustment models.

The researchers found that mortality risk did not differ significantly among patients with different subtypes of PAD (carotid artery vs. noncarotid artery vs. lower extremity) or according to the presence or absence of coronary artery disease.

Incremental prognostic value in PAD

“This is the first known report of elevated plasma TMAO levels as a significant prognostic marker in patients with PAD,” says Dr. Tang. “Notably, we found that TMAO provided significant improvement in estimating mortality risk over traditional cardiovascular risk factors.”

Noting that TMAO testing is already available for clinical use, he says the study suggests plasma TMAO measurements could be used to identify patients in whom more detailed PAD surveillance efforts are needed.

“TMAO levels could help us improve the selection of high-risk PAD patients, with or without significant coronary artery disease, who are likely to need more aggressive and specific dietary and medical therapy,” he says. Given that intestinal TMAO production correlates with consumption of red meat and other animal products, he adds, dietary counseling holds particular potential.