Gut-Derived Metabolite TMAO Seen to Predict PAD Mortality

Patrice Wendling

October 20, 2016

CLEVELAND, OH — A prospective study reports for the first time that increased plasma levels of trimethylamine N-oxide (TMAO) are a significant prognostic marker for patients with peripheral artery disease (PAD)[1].

At 5 years of follow-up, the upper quartile for TMAO levels was associated with a 2.7-fold higher risk for all-cause mortality that remained significant after full adjustment for traditional risk factors, inflammatory biomarkers, and history of CAD (HR 1.88, 95% CI 1.21–2.92; P<0.01).

"Moreover, mortality risks were not significantly different among all different subtypes of diagnosis of PAD, presence or absence of CAD, or other clinical and laboratory subgroups," principal investigator Dr Vichai Senthong (Cleveland Clinic, OH and Khon Kaen University, Thailand) and his coauthors reported October 19, 2016 in the Journal of the American Heart Association.

The finding supports the growing appreciation for the role of gut microbiota and TMAO, a metabolite produced by gut microbiota metabolism of dietary phosphatidylcholine (PC), in the pathogenesis of atherosclerosis. PC is a major dietary source of choline, which is common in the Western diet of red meats, eggs, and meat products.

Earlier this year, the investigators reported that elevated TMAO levels independently predict high atherosclerotic burden and diffuse atherosclerotic lesions in patients with CAD[2], while Randrianarisoa et al found that elevated TMAO levels are associated with increased carotid intima-media thickness[3].

The present analysis involved 821 consecutive patients (66% male; median TMAO level 4.8 µmol/L) with adjudicated stable PAD. Of these, 70% were on statins, 76% on aspirin, 69% on beta-blockers, and 60% on ACE inhibitor/angiotensin-receptor blockers.

Despite receiving optimal cardioprotective medication, the 5-year mortality rate was high, at 27%. The event rate, however, was 18.1% in the lowest TMAO quartile (<2.94 µmol/L) vs 41.8% in the highest quartile (>8.01 µmol/L).

Notably, TMAO resulted in a significant improvement in all-cause mortality risk estimation over traditional risk factors (net reclassification index 40.22%; P<0.001) and in the area under the receiver-operating characteristic curve (65.7% vs 69.4%; P=0.013).

"An improvement in the understanding of the pathophysiology linking gut microbes, TMAO, and PAD development may serve to help improve selection of high-risk PAD patients who need more aggressive and specific dietary pharmacologic therapy," Senthong wrote.

The research was supported by grants from the National Institutes of Health and the Office of Dietary Supplements. High-sensitivity cardiac troponin-T testing reagents were provided by Roche Diagnostics. Senthong reported no financial relationships. Disclosures for the coauthors are listed in the article.

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