Trimethylamine-N-Oxide (TMAO) Predicts Cardiovascular Mortality in Peripheral Artery Disease

Abstract

Peripheral artery disease (PAD) is a major cause of acute and chronic illness, with extremely poor prognosis that remains underdiagnosed and undertreated. Trimethylamine-N-Oxide (TMAO), a gut derived metabolite, has been associated with atherosclerotic burden. We determined plasma levels of TMAO by mass spectrometry and evaluated their association with PAD severity and prognosis. 262 symptomatic PAD patients (mean age 70 years, 87% men) categorized in intermittent claudication (IC, n = 147) and critical limb ischemia (CLI, n = 115) were followed-up for a mean average of 4 years (min 1-max 102 months). TMAO levels were increased in CLI compared to IC (P < 0.001). Receiver operating characteristic (ROC) curves for severity (CLI) rendered a cutoff of 2.26 µmol/L for TMAO (62% sensitivity, 76% specificity). Patients with TMAO > 2.26 µmol/L exhibited higher risk of cardiovascular death (subhazard ratios ≥2, P < 0.05) that remained significant after adjustment for confounding factors. TMAO levels were associated to disease severity and CV-mortality in our cohort, suggesting an improvement of PAD prognosis with the measurement of TMAO. Overall, our results indicate that the intestinal bacterial function, together with the activity of key hepatic enzymes for TMA oxidation (FMO3) and renal function, should be considered when designing therapeutic strategies to control gut-derived metabolites in vascular patients.

NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications

“…Furthermore, some meta-analyses have also confirmed a strong association between circulating TMAO levels and risk of fatal and non-fatal CVD events [92,93]. Patients with ischaemic stroke also exhibit higher TMAO levels than healthy controls [94], and increased TMAO levels also predict CVD mortality in patients with existing peripheral arterial disease [95]. Interestingly, so far only a very few reports exist investigating circulating TMAO levels in NAFLD cohorts.…”

Carnitine Traffic in Cells. Link With Cancer

“…Furthermore, the role of carnitine in mediating TMAO synthesis has relevance to human health. Indeed, TMAO was suggested as one of the factors promoting atherosclerosis and increased cardiovascular risk (Koeth et al, 2013;Gao et al, 2017;Roncal et al, 2019). Later on, it has been shown that more than 200 variants exist in the coding region of TMAO producing enzyme, with different outcomes on the cardiovascular risk (Phillips and Shephard, 2020).…”

Trimethylamine N-oxide and the reverse cholesterol transport in cardiovascular disease: a cross-sectional study

“…However, in ApoE -/- mice transfected with human CETP, an increase in plasma TMAO was associated with a significantly reduced area of aortic lesions 19 . Nevertheless, recent clinical studies have shown a positive correlation between elevated plasma TMAO and an increased risk for major adverse cardiovascular events defined as death, myocardial infarction, or stroke 20 , 21 .…”