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Metabolite from gut microbes predicts mortality risk in patients with PAD
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High levels of the metabolite trimethylamine N-oxide, formed by gut microbes, is a predictor of mortality in patients with peripheral artery disease, according to new findings.
According to the study background, trimethylamine N-oxide (TMAO) is associated with atherosclerotic CAD in humans, but its relationship with PAD was not known.
The researchers analyzed the relationship between TMAO and 5-year mortality rates in 935 patients with PAD who underwent elective coronary angiography at Cleveland Clinic between 2001 and 2007.
“The rationale for the study was to try to understand whether the systemic process of atherogenesis as indicated by this gut flora-derived metabolite affects atherosclerotic processes beyond CAD,” W. H. Wilson Tang, MD, professor of medicine at Cleveland Clinic Lerner College of Medicine and Case Western Reserve University, told Cardiology Today. “In patients with peripheral vascular disease, we see varying levels of severity in the coronary vasculature. The findings mean that this is truly a systemic problem. The dietary-induced gut microbiome-generated metabolic process is a systemic pathway that affects different vascular trees, including those outside the coronary vasculature.”
Patients were stratified into quartiles by TMAO level and were also categorized by type of PAD and presence of CAD.
The median level of plasma TMAO in the cohort was 4.8 µmol/L (interquartile range, 2.9-8), according to Tang and colleagues.
TMAO and mortality
Compared with those in the lowest quartile of plasma TMAO level, those in the highest quartile had increased risk for mortality at 5 years, Tang and colleagues found. This was true before adjustment (HR = 2.86; 95% CI, 1.82-3.97) and after adjustment for traditional risk factors, inflammatory biomarkers and history of CAD (adjusted HR = 2.06; 95% CI, 1.36-3.11).
The results were consistent regardless of whether the patient had carotid artery disease, non-carotid artery disease or lower extremity PAD.
When the researchers added TMAO level to traditional risk factors, there was an improvement in incremental prognostic value for mortality (net reclassification index, 40.22%; P < .001) and an increase in area under receiver operator characteristic curve (65.7% vs. 69.4%; P = .013).
Dietary implications
“This pathway is inducible by what we eat and what is inside us, so the most near-term implication of these findings is that we need to make a lot more emphasis on dietary modifications, particularly with food substances that may not generate the TMAO production,” Tang said in an interview. “We need to continue to tell our patients to avoid red meat, egg yolk and large concentrations of choline and carnitine. We know that vegans and vegetarians have lower TMAO levels compared with their omnivorous counterparts.”
Enzymes in the microbes have been identified that generate TMAO, he said, and research on how to target them with small molecules is needed.
“This means we could actually treat the bacteria that is generating these metabolites without eliminating them,” Tang said. “This could modulate our metabolic activity, thereby reducing our risks.” – by Erik Swain
For more information:
W. H. Wilson Tang, MD, can be reached at Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Ave., Desk J3-4, Cleveland, OH 44195; email: tangw@ccf.org.
Disclosure : Tang reports no relevant financial disclosures. Please see the full study for a list of the other researchers’ relevant financial disclosures.
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