Red Meat and Dairy Gut Metabolite Linked to Higher Mortality in PAD Patients

High levels of a digestive metabolite produced following the consumption of red meat, eggs, high-fat dairy products, and other meats is associated with an increased risk of death in patients with peripheral artery disease, a new study shows.

For PAD patients with the highest levels of trimethylamine N-oxide (TMAO), which is an oxidized form of a metabolite generated by the intestinal microbiota, there was nearly a two-fold increased risk of all-cause mortality at 5 years when compared with those with the lowest plasma levels of TMAO.

“These findings, while associative, point to the potential for TMAO to help improve selection of high-risk PAD patients with or without significant coronary artery disease, [patients] who likely need more aggressive and specific dietary and pharmacologic therapy,” senior investigator W.H. Wilson Tang, MD (Cleveland Clinic, OH), told TCTMD.

The study, published online October 19, 2016, in the Journal of the American Heart Association, is the latest in a series of reports linking TMAO, a proatherogenic metabolite produced when the gut microbiota metabolizes phosphatidylcholine, to adverse clinical outcomes. Phosphatidylcholine, or lecithin, is a major source of choline in the Western diet and can be found in red meat, eggs, dairy, and other meat products. When gut bacteria digest and metabolize phosphatidylcholine, as well as L-carnitine, which is abundant in red meat, trimethylamine (TMA) is created and eventually oxidized to form TMAO.   

The researchers, including Tang and Stanley Hazen, MD (Cleveland Clinic), have published a series of studies investigating the intestinal microbiota metabolism of phosphatidylcholine, choline, and L-carnitine and the association with atherosclerosis and cardiovascular disease. To TCTMD, Tang noted that they identified higher mortality risks associated with higher TMAO levels in the setting of heart failure and/or renal insufficiency. In a 2013 study, the researchers showed that increased plasma levels of TMAO were associated with an increased risk of major adverse cardiac events. 

The investigators have also shown that when they blocked the metabolism of choline and subsequently reduced TMAO levels, they could inhibit the formation of cholesterol-laden macrophage foam cells and atherosclerosis in an animal model. In June, the same researchers showed that plasma levels of TMAO were independently associated with high SYNTAX and SYNTAX II scores as well as with increased likelihood of having diffuse lesions in CAD patients.

In the latest study, the group, including first author Vichal Senthong, MD (Cleveland Clinic), examined the relationship between plasma TMAO levels and all-cause mortality in 935 patients with PAD who underwent elective angiography as part of a cardiac evaluation. Patients were stratified into quartiles based on their TMAO levels: the median TMAO levels in the four groups were 2.2 µmol/L, 4.7 µmol/L, 6.1 µmol/L, and 13 µmol/L, respectively.

Over the 5-year follow-up, 222 patients died. Compared with individuals with lowest plasma TMAO levels (quartile 1), those with the highest levels had an 88% increase in risk of death at 5 years after adjustment for traditional risk factors, history of coronary artery disease, and multiple inflammatory biomarkers. When levels of TMAO were analyzed as a continuous variable, each 1-standard deviation increase was associated with a 26% increase in risk of all-cause mortality.

Tang said mortality risks were not significantly different when patients were stratified PAD subtype—carotid artery, non-carotid artery, or lower-extremity PAD—and by the presence of coronary artery disease. When TMAO levels were added as a variable to risk-prediction models, there was a significant improvement in risk estimation over traditional risk factors, with the digestive byproduct providing incremental prognostic value for all-cause mortality (net reclassification index 40.22%; P < 0.001).

An improved understanding of pathophysiology linking gut microbes, TMAO, and the development of PAD may identify compounds that can modulate TMA-lyase activity to reduce generation of TMA/TMAO without eliminating the essential microbes, Tang suggested. He added that that vegans and vegetarians have lower TMAO levels compared with omnivores and future studies will involve modifying diets to determine if doing so impacts TMAO levels.