Plasma Trimethylamine N-Oxide, a Gut Microbe-Generated Phosphatidylcholine Metabolite, Is Associated With Atherosclerotic Burden

Abstract

Background: Trimethylamine N-oxide (TMAO), a gut microbiota metabolite from dietary phosphatidylcholine, has mechanistic links to atherosclerotic coronary artery disease (CAD) pathogenesis and is associated with adverse outcomes.

Objectives: This study sought to examine the relationship between plasma TMAO levels and the complexity and burden of CAD and degree of subclinical myonecrosis.

Methods: We studied 353 consecutive stable patients with evidence of atherosclerotic CAD detected by elective coronary angiography between 2012 and 2014. Their high-sensitivity cardiac troponin T (hs-cTnT) levels were measured. SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) scores and lesion characteristics were used to quantify atherosclerotic burden. Fasting plasma TMAO was measured by mass spectrometry.

Results: In this prospective cohort study, the median TMAO level was 5.5 μM (interquartile range [IQR]: 3.4 to 9.8 μM), the median SYNTAX score was 11.0 (IQR: 4.0 to 18.5), and 289 (81.9%), 40 (11.3%), and 24 (6.8%) patients had low (0 to 22), intermediate (23 to 32), and high (≥33) SYNTAX scores, respectively. Plasma TMAO levels correlated (all p < 0.0001) with the SYNTAX score (r = 0.61), SYNTAX score II (r = 0.62), and hs-cTnT (r = 0.29). Adjusting for traditional risk factors, body mass index, medications, lesion characteristic, renal function, and high-sensitivity C-reactive protein, elevated TMAO levels remained independently associated with a higher SYNTAX score (odds ratio [OR]: 4.82; p < 0.0001), SYNTAX score II (OR: 1.88; p = 0.0001), but were not associated with subclinical myonecrosis (OR: 1.14; p = 0.3147). Elevated TMAO level was an independent predictor of the presence of diffuse lesions, even after adjustments for traditional risk factors and for hs-cTnT (OR: 2.05; 95% confidence interval: 1.45 to 2.90; p = 0.0001).

Conclusions: Fasting plasma TMAO levels are an independent predictor of a high atherosclerotic burden in patients with CAD.

Keywords: SYNTAX score; diffuse; focal; myonecrosis; risk factors; troponin T.

FIGURE 1. CONSORT Diagram

The flow diagram showing the process used to define the study population is depicted. CABG = coronary artery bypass surgery; PAD = peripheral artery disease; PCI = percutaneous coronary intervention; SYNTAX = SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery.

FIGURE 2. TMAO, Atherosclerotic Burden, and Lesion Characteristics

Diffuse, nonfocal and nondiffuse, and focal lesion frequency was compared according to SYNTAX score (A) and SYNTAX score II (B) for PCI tertiles, fasting trimethylamine N-oxide (TMAO) levels were compared according to lesion characteristics (C).

FIGURE 3. CENTRAL ILLUSTRATION Relationship Between TMAO and Measures of CAD Burden and Subclinical Myonecrosis

Trimethylamine N-oxide (TMAO) has links to coronary artery disease (CAD) pathogenesis and is associated with adverse outcomes. One way to measure CAD complexity and burden is via the SYNTAX score that came from the SYNTAX (SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery) trial; the more recent SYNTAX score II has been shown to have improved prognostic ability. In 353 stable patients with evidence of atherosclerotic CAD, concentrations of TMAO were significant higher with increasing SYNTAX score (A), SYNTAX score II (B), and subclinical myonecrosis (quantified by high-sensitivity cardiac troponin T [hs-cTnT]) tertiles (C).