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

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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.

Key Words

diffuse
focal
myonecrosis
risk factors
SYNTAX score
troponin T

Abbreviations and Acronyms

AUC
area under the receiver-operating curve
BMI
body mass index
CABG
coronary artery bypass graft
CAD
coronary artery disease
CI
confidence interval
CVD
cardiovascular disease
eGFR
estimated glomerular filtration rate
hs-CRP
high-sensitivity C-reactive protein
hs-cTnT
high-sensitivity cardiac troponin T
MACE
major adverse cardiac events
NRI
net reclassification index
OR
odds ratio
PAD
peripheral arterial disease
PCI
percutaneous coronary intervention
SYNTAX score
Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery score
TMAO
trimethylamine N-oxide

Cited by (0)

This research was supported by grants from the National Institutes of Health (NIH) and the Office of Dietary Supplements (R01HL103866, P20HL113452, R01DK106000). The BioBank study has been supported by NIH grants P01HL076491, P01HL098055, R01HL103931, and the Cleveland Clinic Clinical Research Unit of the Case Western Reserve University CTSA (UL1TR 000439). Mass spectrometry studies were performed on instruments housed in a facility supported in part by a Center of Innovations Award by AB SCIEX. High-sensitivity cardiac troponin T testing reagents were provided by Roche Diagnostics. Dr. Wang was partially supported by NIH grant R01HL130819. Dr. Hazen was partially supported by a gift from the Leonard Krieger endowment.

Drs. Wang, Levison, and Hazen are named as co-inventors on pending patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. Drs. Levison and Wang have received royalty payment for inventions or discoveries related to cardiovascular diagnostics from Cleveland Heart Lab. Dr. Hazen is a paid consultant for Esperion and P&G; has received research funds from Abbott, P&G, Pfizer Inc., Roche Diagnostics, and Takeda; and has received royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland Heart Lab, Siemens, Esperion, and Frantz Biomarkers, LLC. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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