Biomarker Predicts Mortality Risk for Peripheral Artery Disease Patients

Production of the proatherogenic metabolite, trimethylamine N‐oxide (TMAO), from dietary nutrients by intestinal microbiota enhances atherosclerosis and is associated with atherosclerotic coronary artery disease in humans.

Peripheral artery disease (PAD) is a common manifestation of systemic atherosclerosis and is associated with significantly increased cardiovascular death and mortality and it affects over 27 million people across Europe and North America.

Scientists associated with the Cleveland Clinic (Cleveland, OH, USA) carried out a single‐center prospective cohort study and enrolled 821 sequential consenting patients who underwent elective, non-urgent coronary angiographic evaluation at the Cleveland Clinic between 2001 and 2007. A confirmed diagnosis of PAD was based primarily on the type of PAD, based on reporting evidence of stenosis at the corresponding vasculature. Participants were followed for five years between 2001 and 2007.

The team collected fasting blood samples using EDTA tubes at the time of cardiac catheterization, immediately prior to heparin injection. Creatinine clearance was estimated using the Cockcroft‐Gault equation. Myeloperoxidase was determined by the CardioMPO assay (Cleveland Heart Labs, Cleveland, OH, USA). TMAO, choline, and betaine levels in plasma were determined using stable isotope dilution high‐performance liquid chromatography with online electrospray ionization tandem mass spectrometry on Shimadzu LCMS‐8050 CL Triple Quadrupole mass spectrometer using d9‐(trimethyl)‐labeled internal standards.

In the study cohort, the median TMAO level was 4.8 μmol/L (interquartile range 2.9–8.0 μmol/L), which was similar between patients with extracranial carotid artery stenosis (CAS) and non‐CAS. Subjects with elevated plasma TMAO levels were more likely to be older, with diabetes, with elevated high‐sensitivity C‐reactive protein (hsCRP), as well as with lower estimated glomerular filtration rate (eGFR). In contrast, prior history of CAD, smoking status, myeloperoxidase levels, apolipoprotein B levels, and medication use, were similar across TMAO levels. The incidence of both short- and long-term death progressively increased as blood levels of TMAO rose among patients with PAD. Compared to patients with the lowest levels, those with the highest levels of TMAO were 2.7 times more likely to die of any cause during the course of the five-year study.

W. H. Wilson Tang, MD, the lead author of the study said, “TMAO testing is available for clinical use, and these findings point to the potential for TMAO to help improve selection of high-risk PAD patients. Since people who are vegetarian or vegan or who follow the Mediterranean diet has been reported to have lower TMAO levels, more aggressive dietary counseling in patients with high TMAO levels is warranted.” The study was published on October 19, 2016, in the Journal of the American Heart Association.

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