W H Wilson Tang1, Xinmin S Li2, Yuping Wu3, Zeneng Wang2, Kay-Tee Khaw4, Nicholas J Wareham5, Max Nieuwdorp6, S Matthijs Boekholdt7, Stanley L Hazen8. 1. Center for Microbiome and Human Health, Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland, OH; Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland, OH. Electronic address: tangw@ccf.org. 2. Center for Microbiome and Human Health, Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland, OH. 3. Department of Mathematics & Statistics, Cleveland State University, Cleveland, OH. 4. Institute of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. 5. MRC Epidemiology Unit, Cambridge, United Kingdom. 6. Amsterdam Diabetes Center, Department of Internal Medicine at Amsterdam UMCs, Academic Medical Center-VU Medical Center, Amsterdam, The Netherlands; Department of (Experimental) Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. 7. Amsterdam UMC, University of Amsterdam, Department of Cardiology, Amsterdam, the Netherlands. 8. Center for Microbiome and Human Health, Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland, OH; Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland, OH.
Abstract
BACKGROUND: Recent studies show a mechanistic link between gut microbiota-dependent formation of the atherosclerosis- and thrombosis-promoting metabolite trimethylamine N-oxide (TMAO) and cardiovascular disease (CVD). The clinical utility of TMAO in apparently healthy subjects for predicting incident CVD risks is unclear. METHODS AND RESULTS: In the EPIC-Norfolk community-based study, we examined baseline fasting levels of TMAO and two of its nutrient precursors, choline and betaine, in a case:control design study comparing apparently European healthy middle-aged participants who subsequently develop CVD (Cases, n = 908) vs those who did not (Controls, n = 1,273) over an ensuing average follow-up period of 8 years. In participants who developed CVD vs controls, higher plasma TMAO (3.70 [IQR 2.50-6.41]μM vs 3.25 [IQR 2.19-52,1.15]μM; P < .001) and choline levels (9.09 [IQR 7.87-10.53]μM vs 8.89 [IQR 7.66-10.13]μM; P = .001) were observed. Following adjustments for traditional risk factors, elevated TMAO (adjusted odds ratio (OR) 1.58 [95% confidence interval (CI) 1.21-2.06], P < .001) and choline levels (adjusted OR 1.31 [95%CI 1.00-1.72], P < .05) remained predictive of incident CVD development. The clinical prognostic utility of TMAO remained significant and essentially unchanged regardless of the level of cutoff chosen between 1.5 uM (10%ile) to 10.5 uM (90%ile). CONCLUSION: In apparently healthy participants of the community-based middle-aged EPIC-Norfolk population, elevated plasma levels of the gut microbe-dependent metabolite TMAO, and its nutrient precursor choline, predict incident risk for CVD development independent of traditional risk factors.
BACKGROUND: Recent studies show a mechanistic link between gut microbiota-dependent formation of the atherosclerosis- and thrombosis-promoting metabolite trimethylamine N-oxide (TMAO) and cardiovascular disease (CVD). The clinical utility of TMAO in apparently healthy subjects for predicting incident CVD risks is unclear. METHODS AND RESULTS: In the EPIC-Norfolk community-based study, we examined baseline fasting levels of TMAO and two of its nutrient precursors, choline and betaine, in a case:control design study comparing apparently European healthy middle-aged participants who subsequently develop CVD (Cases, n = 908) vs those who did not (Controls, n = 1,273) over an ensuing average follow-up period of 8 years. In participants who developed CVD vs controls, higher plasma TMAO (3.70 [IQR 2.50-6.41]μM vs 3.25 [IQR 2.19-52,1.15]μM; P < .001) and choline levels (9.09 [IQR 7.87-10.53]μM vs 8.89 [IQR 7.66-10.13]μM; P = .001) were observed. Following adjustments for traditional risk factors, elevated TMAO (adjusted odds ratio (OR) 1.58 [95% confidence interval (CI) 1.21-2.06], P < .001) and choline levels (adjusted OR 1.31 [95%CI 1.00-1.72], P < .05) remained predictive of incident CVD development. The clinical prognostic utility of TMAO remained significant and essentially unchanged regardless of the level of cutoff chosen between 1.5 uM (10%ile) to 10.5 uM (90%ile). CONCLUSION: In apparently healthy participants of the community-based middle-aged EPIC-Norfolk population, elevated plasma levels of the gut microbe-dependent metabolite TMAO, and its nutrient precursor choline, predict incident risk for CVD development independent of traditional risk factors.
Authors: W H Wilson Tang; Zeneng Wang; Yiying Fan; Bruce Levison; Jennie E Hazen; Lillian M Donahue; Yuping Wu; Stanley L Hazen Journal: J Am Coll Cardiol Date: 2014-10-27 Impact factor: 24.094
Authors: Andrew Mente; Kenneth Chalcraft; Handan Ak; A Darlene Davis; Eva Lonn; Ruby Miller; Murray A Potter; Salim Yusuf; Sonia S Anand; Matthew J McQueen Journal: Can J Cardiol Date: 2015-06-25 Impact factor: 5.223
Authors: Yoriko Heianza; Wenjie Ma; Joseph A DiDonato; Qi Sun; Eric B Rimm; Frank B Hu; Kathryn M Rexrode; JoAnn E Manson; Lu Qi Journal: J Am Coll Cardiol Date: 2020-02-25 Impact factor: 24.094
Authors: Zeneng Wang; Bruce S Levison; Jennie E Hazen; Lillian Donahue; Xin-Min Li; Stanley L Hazen Journal: Anal Biochem Date: 2014-04-01 Impact factor: 3.365
Authors: Daniel M Mueller; Martina Allenspach; Alaa Othman; Christoph H Saely; Axel Muendlein; Alexander Vonbank; Heinz Drexel; Arnold von Eckardstein Journal: Atherosclerosis Date: 2015-10-24 Impact factor: 5.162
Authors: Zeneng Wang; Nathalie Bergeron; Bruce S Levison; Xinmin S Li; Sally Chiu; Xun Jia; Robert A Koeth; Lin Li; Yuping Wu; W H Wilson Tang; Ronald M Krauss; Stanley L Hazen Journal: Eur Heart J Date: 2019-02-14 Impact factor: 35.855
Authors: Melissa L Erickson; Steven K Malin; Zeneng Wang; J Mark Brown; Stanley L Hazen; John P Kirwan Journal: Nutrients Date: 2019-01-16 Impact factor: 5.717
Authors: Gabriele Giacomo Schiattarella; Anna Sannino; Evelina Toscano; Giuseppe Giugliano; Giuseppe Gargiulo; Anna Franzone; Bruno Trimarco; Giovanni Esposito; Cinzia Perrino Journal: Eur Heart J Date: 2017-10-14 Impact factor: 29.983
Authors: Kristen L James; Erik R Gertz; Eduardo Cervantes; Ellen L Bonnel; Charles B Stephensen; Mary E Kable; Brian J Bennett Journal: Nutrients Date: 2022-03-25 Impact factor: 5.717
Authors: Natalia Andújar-Tenorio; Isabel Prieto; Antonio Cobo; Ana M Martínez-Rodríguez; Marina Hidalgo; Ana Belén Segarra; Manuel Ramírez; Antonio Gálvez; Magdalena Martínez-Cañamero Journal: PLoS One Date: 2022-08-16 Impact factor: 3.752