Gut Metabolite TMAO Linked to Worse Prognosis

Trimethylamine N-oxide in blood tied to more severe disease

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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People with pulmonary hypertension (PH) who had elevated blood levels of the trimethylamine N-oxide (TMAO) molecule were at a five times greater risk of a poor prognosis than patients who didn’t have high levels, according to a recent study.

High levels of this gut-derived metabolite were generally linked to more severe disease, with a higher chance of hospitalizations due to heart failure, functional declines, or death, among PH patients in China.

“TMAO possesses the potential to be an effective plasma [blood] biomarker and a surrogate in PH, highlighting the need for a collaborative research effort over the next decade to improve and develop strategies for managing PH,” the study’s researchers wrote.

The study, “Higher circulating Trimethylamine N-oxide levels are associated with worse severity and prognosis in pulmonary hypertension: a cohort study,” was published in the journal Respiratory Research

TMAO is found in the blood that’s generated when its dietary precursors are broken down in the intestines by microorganisms that live in the gut.

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An accumulating body of evidence has linked TMAO to several diseases, including cardiovascular conditions such as heart failure. Generally, higher TMAO levels are associated with more severe disease and worse prognosis.

PH is characterized by high blood pressure affecting the pulmonary arteries that supply blood to the lungs. Consequently, it is marked by a number of cardiovascular complications, including heart failure.

But whether TMAO may be a valuable biomarker of disease severity or prognosis in PH hadn’t been evaluated before this study.

Accordingly, the research team investigated the relationship between TMAO blood levels and clinical features of PH among 163 patients (63.8% females), with a mean age of 36.3, treated at Fuwai Hospital, Beijing — site of the largest PH center in China.

Among them, 36 had idiopathic or heritable pulmonary arterial hypertension (PAH), 76 had PAH associated with congenital heart disease,  and 51 had chronic thromboembolic PH (CTEPH).

All participants were hospitalized at least twice over the course of the study, and TMAO levels were measured during both visits. After their second hospital stay, patients were followed via clinical visits or telephone calls for a mean 1.3 years of follow-up.

The mean TMAO level across all patients was 2 micromoles per liter (mcmol/L). Patients with TMAO levels above a cutoff of 1.69 umol/L were considered to have “high” TMAO, whereas those with levels below that cutoff had “low” TMAO.

Patients in the high TMAO group showed evidence of more severe disease than those in the low TMAO group.

Specifically, these patients had more significant functional limitations, reflected by a higher World Health Organization functional class, as well as signs of more impaired heart function and blood flow. High TMAO patients had greater levels of NT-proBNP, a biomarker of heart failure, than low TMAO patients.

High TMAO was associated with generally more severe disease even after adjusting for potentially influential factors, including sex, body mass index, heart size, and high blood pressure.

Classifying the PH patients

The COMPERA risk stratification tool, which accounts for a range of clinical measures of disease severity, was used to group patients into low, intermediate, or high risk of severe disease.

At the study’s start, higher TMAO levels were associated with a higher risk status. After initiating PH treatment, 154 people experienced improvements or stabilizations in risk status, which was associated with a decrease in TMAO levels.

Among the nine people who experienced a worsening risk status, TMAO levels generally increased.

Over the course of follow-up, 45 patients were re-hospitalized due to heart failure or reduced exercise capacity, and six patients died.

Overall, high TMAO levels were associated with a worse prognosis in PH, including a higher risk of death, re-hospitalization due to heart failure, or at least a 15% functional decline, as assessed by the six-minute walk test.

In an adjusted statistical model, levels of the metabolite were an independent predictor of pulmonary hypertension prognosis. Specifically, having high TMAO was associated with a more than five times greater risk of poor prognosis.

Overall, “PH patients with elevated TMAO concentrations exhibited more severe disease conditions and worse prognosis than those with low plasma [blood] TMAO levels,” the researchers wrote.

They noted, however, that whether elevated TMAO is a product of severe PH, or whether high levels of the metabolite itself drives more severe outcomes, isn’t yet known.

“A further study determined to investigate the ’cause’ or ‘effect’ role of TMAO in PH is warranted,” the team wrote.


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