Increased TMAO levels linked to major CV event risk

Increased levels of trimethylamine-N-oxide are associated with increased risk for incident major adverse CV events, according to new data published in The New England Journal of Medicine.

“Studies in germ-free mice and cross-sectional clinical studies in humans have suggested a role for the intestinal microbiota in the pathogenesis of atherosclerosis in patients with a diet rich in phosphatidylcholine (with major sources including eggs, liver, beef and pork) through the formation of the metabolite trimethylamine and conversion to trimethylamine-N-oxide,” researchers wrote.

Researchers conducted two prospective clinical studies to investigate the relationship between intestinal microbiota-dependent metabolism of dietary phosphatidylcholine, trimethylamine-N-oxide (TMAO) levels and adverse CV events.

In the first study, 40 healthy adults underwent a phosphatidylcholine challenge consisting of two hard-boiled eggs and 250 mg deuterium-labeled phosphatidylcholine as a tracer before and after oral broad-spectrum antibiotics were administered to suppress intestinal microbiota. Serial blood sampling was performed at 1, 2, 3, 4, 6 and 8 hours, in addition to a 24-hour urine sample.

The researchers detected time-dependent increases in levels of TMAO, the d9 isotopologue and other choline metabolites after the phosphatidylcholine challenge. TMAO levels were suppressed following antibiotic administration, but reappeared after antibiotic withdrawal.

In the second study, researchers examined fasting levels of TMAO in 4,007 patients (mean age, 63 years; two-thirds men) at high CV risk who were undergoing elective diagnostic cardiac catheterization.

Patients with a history of major CV events had higher baseline levels of TMAO compared with those who did not have an event (median, 5 mcM vs. 3.5 mcM; P<.001). Patients with TMAO levels in the highest quartile were at significantly increased risk for a major CV event compared with levels in the lowest quartile (HR=2.54; 95% CI, 1.96-3.28). After adjustment, elevated TMAO remained a significant predictor of major CV events.

“We have shown that intestinal microbes participate in phosphatidylcholine metabolism to form circulating and urinary TMAO. We also established a correlation between high plasma levels of TMAO and an increased risk of incident major adverse CV events that is independent of traditional risk factors, even in low-risk cohorts.

“Our findings suggest that pathways that are dependent on the intestinal microbiota may contribute to the pathophysiology of atherosclerotic CAD and suggest potential therapeutic targets,” the researchers wrote.

For more information:

Wilson Tang WH. N Engl J Med. 2013;368:1575-1584.

Disclosure: See the full study for a list of the researchers’ relevant financial disclosures.