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Research ArticleArticle

Increased Trimethylamine N-Oxide Portends High Mortality Risk Independent of Glycemic Control in Patients with Type 2 Diabetes Mellitus

W. H. Wilson Tang, Zeneng Wang, Xinmin S. Li, Yiying Fan, Daniel S. Li, Yuping Wu, Stanley L. Hazen
DOI: 10.1373/clinchem.2016.263640 Published December 2016
W. H. Wilson Tang
Center for Cardiovascular Diagnostics & Prevention, Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH; Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH;
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Zeneng Wang
Center for Cardiovascular Diagnostics & Prevention, Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH;
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Xinmin S. Li
Center for Cardiovascular Diagnostics & Prevention, Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH;
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Yiying Fan
Department of Mathematics, Cleveland State University, Cleveland, OH;
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Daniel S. Li
Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH.
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Yuping Wu
Department of Mathematics, Cleveland State University, Cleveland, OH;
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Stanley L. Hazen
Center for Cardiovascular Diagnostics & Prevention, Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH; Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH;
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  • For correspondence: hazens@ccf.org
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Abstract

BACKGROUND: Recent studies show a mechanistic link between intestinal microbial metabolism of dietary phosphatidylcholine and coronary artery disease pathogenesis. Concentrations of a proatherogenic gut microbe-generated metabolite, trimethylamine N-oxide (TMAO), predict increased incident cardiovascular disease risks in multiple cohorts. TMAO concentrations are increased in patients with type 2 diabetes mellitus (T2DM), but their prognostic value and relation to glycemic control are unclear.

METHODS: We examined the relationship between fasting TMAO and 2 of its nutrient precursors, choline and betaine, vs 3-year major adverse cardiac events and 5-year mortality in 1216 stable patients with T2DM who underwent elective diagnostic coronary angiography.

RESULTS: TMAO [4.4 μmol/L (interquartile range 2.8–7.7 μmol/L) vs 3.6 (2.3–5.7 μmol/L); P < 0.001] and choline concentrations were higher in individuals with T2DM vs healthy controls. Within T2DM patients, higher plasma TMAO was associated with a significant 3.0-fold increased 3-year major adverse cardiac event risk (P < 0.001) and a 3.6-fold increased 5-year mortality risk (P < 0.001). Following adjustments for traditional risk factors and high-sensitivity C-reactive protein, glycohemoglobin, and estimated glomerular filtration rate, increased TMAO concentrations remained predictive of both major adverse cardiac events and mortality risks in T2DM patients [e.g., quartiles 4 vs 1, hazard ratio 2.05 (95% CI, 1.31–3.20), P < 0.001; and 2.07 (95% CI, 1.37–3.14), P < 0.001, respectively].

CONCLUSIONS: Fasting plasma concentrations of the proatherogenic gut microbe-generated metabolite TMAO are higher in diabetic patients and portend higher major adverse cardiac events and mortality risks independent of traditional risk factors, renal function, and relationship to glycemic control.

  • Received for publication July 7, 2016.
  • Accepted for publication October 27, 2016.
  • © 2016 American Association for Clinical Chemistry
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Clinical Chemistry: 63 (1)
Vol. 63, Issue 1
January 2017
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Increased Trimethylamine N-Oxide Portends High Mortality Risk Independent of Glycemic Control in Patients with Type 2 Diabetes Mellitus
W. H. Wilson Tang, Zeneng Wang, Xinmin S. Li, Yiying Fan, Daniel S. Li, Yuping Wu, Stanley L. Hazen
Clinical Chemistry Jan 2017, 63 (1) 297-306; DOI: 10.1373/clinchem.2016.263640
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Increased Trimethylamine N-Oxide Portends High Mortality Risk Independent of Glycemic Control in Patients with Type 2 Diabetes Mellitus
W. H. Wilson Tang, Zeneng Wang, Xinmin S. Li, Yiying Fan, Daniel S. Li, Yuping Wu, Stanley L. Hazen
Clinical Chemistry Jan 2017, 63 (1) 297-306; DOI: 10.1373/clinchem.2016.263640

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