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TMAO as a biomarker of cardiovascular events: a systematic review and meta-analysis

Internal and Emergency Medicine volume 16, pages 201–207 (2021)Cite this article

Abstract

Background

Unmasking the residual cardiovascular risk is a major research challenge in the attempt to reduce cardiovascular disease (CVD) morbidity and mortality. Mounting evidence suggests that a high circulating level of trimethylamine N-oxide is a new potential CVD risk factor. We performed a systematic review of the published studies to clarify the association between circulating high levels of TMAO and cardiovascular events.

Methods

Studies evaluating the association between TMAO and CVD events were searched by electronic databases up to December 2018. Pooled results were expressed as risk ratio (RR) with 95% pertinent confidence interval (CI).

Results

Three studies for a total of 923 patients at high/very high CVD risk were included in our analysis. Overall, a high TMAO level was associated with both major adverse cardiovascular events (RR = 2.05; 95% CI 1.61–2.61) and all-cause mortality (RR = 3.42; 95% CI 2.27–5.15).

Conclusions

Our findings support a role of high TMAO levels in predicting CVD events. High levels of TMAO may be a new CVD risk factor, potentially useful to better plan personalized CVD prevention strategies.

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References

  1. De Carlo M, Mazzolai L, Bossone E, Brodmann M, Micari A, Muiesan ML et al (2017) Eur Heart J 38:1028–1033

    PubMed  Google Scholar 

  2. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ et al (2008) Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 359:2195–2207

    CAS  Article  Google Scholar 

  3. Libby P (2005) The forgotten majority: unfinished business in cardiovascular risk reduction. J Am Coll Cardiol 46:1225–1228

    Article  Google Scholar 

  4. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B et al (2011) Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472:57–63

    CAS  Article  Google Scholar 

  5. van Mens TE, Büller HR, Nieuwdorp M (2019) Targeted inhibition of gut microbiota proteins involved in TMAO production to reduce platelet aggregation and arterial thrombosis: a blueprint for drugging the microbiota in the treatment of cardiometabolic disease? J Thromb Haemost 17:3–5

    Article  Google Scholar 

  6. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62:1006–1012

    Article  Google Scholar 

  7. Kip KE, Hollabaugh K, Marroquin OC, Williams DO (2008) The problem with composite end points in cardiovascular studies: the story of major adverse cardiac events and percutaneous coronary intervention. J Am Coll Cardiol 51:701–707

    Article  Google Scholar 

  8. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    CAS  Article  Google Scholar 

  9. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560

    Article  Google Scholar 

  10. Stubbs JR, House JA, Ocque AJ, Zhang S, Johnson C, Kimber C et al (2016) Serum trimethylamine-N-oxide is elevated in CKD and correlates with coronary atherosclerosis burden. J Am Soc Nephrol 27:305–313

    CAS  Article  Google Scholar 

  11. Kaysen GA, Johansen KL, Chertow GM, Dalrymple LS, Kornak J, Grimes B et al (2015) Associations of trimethylamine N-oxide with nutritional and inflammatory biomarkers and cardiovascular outcomes in patients new to dialysis. J Ren Nutr 25:351–356

    CAS  Article  Google Scholar 

  12. Missailidis C, Hällqvist J, Qureshi AR, Barany P, Heimbürger O, Lindholm B et al (2016) Serum trimethylamine-N-oxide is strongly related to renal function and predicts outcome in chronic kidney disease. PLoS ONE 11:e0141738

    Article  Google Scholar 

  13. Kim RB, Morse BL, Djurdjev O, Tang M, Muirhead N, Barrett B et al (2016) Advanced chronic kidney disease populations have elevated trimethylamine N-oxide levels associated with increased cardiovascular events. Kidney Int 89:1144–1152

    CAS  Article  Google Scholar 

  14. Robinson-Cohen C, Newitt R, Shen DD, Rettie AE, Kestenbaum BR, Himmelfarb J et al (2016) Association of FMO3 variants and trimethylamine N-oxide concentration, disease progression, and mortality in CKD patients. PLoS ONE 11:e0161074

    Article  Google Scholar 

  15. Ottiger M, Nickler M, Steuer C, Odermatt J, Huber A, Christ-Crain M et al (2016) Trimethylamine-N-oxide (TMAO) predicts fatal outcomes in community-acquired pneumonia patients without evident coronary artery disease. Eur J Intern Med 36:67–73

    CAS  Article  Google Scholar 

  16. Tang WH, Topol EJ, Fan Y, Wu Y, Cho L, Stevenson C et al (2014) Prognostic value of estimated functional capacity incremental to cardiac biomarkers in stable cardiac patients. J Am Heart Assoc 3(5):e000960

    Article  Google Scholar 

  17. Tang WH, Wang Z, Kennedy DJ, Wu Y, Buffa JA, Agatisa-Boyle B et al (2015) Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res 116:448–455

    CAS  Article  Google Scholar 

  18. Tang WH, Wang Z, Li XS, Fan Y, Li DS, Wu Y et al (2017) Increased trimethylamine N-oxide portends high mortality risk independent of glycemic control in patients with type 2 diabetes mellitus. Clin Chem 63:297–306

    CAS  Article  Google Scholar 

  19. Suzuki T, Heaney LM, Bhandari SS, Jones DJ, Ng LL (2016) Trimethylamine N-oxide and prognosis in acute heart failure. Heart 102:841–848

    CAS  Article  Google Scholar 

  20. Senthong V, Wang Z, Fan Y, Wu Y, Hazen SL, Tang WH (2016) Trimethylamine N-oxide and mortality risk in patients with peripheral artery disease. J Am Heart Assoc 5:e004237

    PubMed  PubMed Central  Google Scholar 

  21. Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X et al (2013) Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 368:1575–1584

    CAS  Article  Google Scholar 

  22. Li XS, Obeid S, Klingenberg R, Gencer B, Mach F, Räber L et al (2017) Gut microbiota-dependent trimethylamine N-oxide in acute coronary syndromes: a prognostic marker for incident cardiovascular events beyond traditional risk factors. Eur Heart J 38:814–824

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Suzuki T, Heaney LM, Jones DJ, Ng LL (2017) Trimethylamine N-oxide and risk stratification after acute myocardial infarction. Clin Chem 63:420–428

    CAS  Article  Google Scholar 

  24. Piepoli FM (2017) European Guidelines on cardiovascular disease prevention in clinical practice: the sixth joint task force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts). Int J Behav Med. 24:321–419

    Article  Google Scholar 

  25. Wang Z, Zhao Y (2018) Gut microbiota derived metabolites in cardiovascular health and disease. Protein Cell 9:416–431

    CAS  Article  Google Scholar 

  26. Seldin MM, Meng Y, Qi H, Zhu W, Wang Z, Hazen SL et al (2016) Trimethylamine N-oxide promotes vascular inflammation through signalling of mitogen-activated protein kinase and nuclear factor-κB. J Am Heart Assoc 5(2):e002767

    Article  Google Scholar 

  27. Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, Wang Z et al (2016) Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165:111–124

    CAS  Article  Google Scholar 

  28. Zhu W, Wang Z, Tang WHW, Hazen SL (2017) Gut microbe-generated trimethylamine N-oxide from dietary choline is prothrombotic in subjects. Circulation 135:1671–1673

    Article  Google Scholar 

  29. Loscalzo J (2013) Gut microbiota, the genome, and diet in atherogenesis. N Engl J Med 368:1647–1649

    CAS  Article  Google Scholar 

  30. Abbasi J (2019) TMAO and heart disease: the new red meat risk? JAMA 321:2149–2151

    Article  Google Scholar 

  31. Bogiatzi C, Gloor G, Allen-Vercoe E, Reid G, Wong RG, Urquhart BL et al (2018) Metabolic products of the intestinal microbiome and extremes of atherosclerosis. Atherosclerosis 273:91–97

    CAS  Article  Google Scholar 

  32. Roberts AB, Gu X, Buffa JA, Hurd AG, Wang Z, Zhu W et al (2018) Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat Med 24:1407–1417

    CAS  Article  Google Scholar 

  33. Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J et al (2013) Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab 17:49–60

    CAS  Article  Google Scholar 

  34. Shih DM, Wang Z, Lee R, Meng Y, Che N, Charugundla S et al (2015) Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis. J Lipid Res 56:22–37

    CAS  Article  Google Scholar 

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Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

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Affiliations

  1. Department of Medicine and Surgery, University of Insubria, Varese, Como, Italy

    Luigina Guasti, Eleonora Visconti, Benedetta Pennella, Giovanni Vincenzo Gaudio, Alessandro Lupi, Anna Maria Grandi & Alessandro Squizzato

  2. Internal Medicine Unit, Ospedale S.Valentino, Montebelluna, Treviso, Italy

    Silvia Galliazzo

  3. Ospedale Metropolitano Niguarda, Milan, Italy

    Marta Molaro

  4. U.O.C Medicina Generale, ASST Lariana-Ospedale S.Anna,, Via Ravona, 20, 22042, San Fermo della Battaglia, Como, Italy

    Alessandro Squizzato

Authors
  1. Luigina Guasti
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  2. Silvia Galliazzo
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  3. Marta Molaro
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  4. Eleonora Visconti
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  9. Alessandro Squizzato
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Correspondence to Alessandro Squizzato.

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Guasti, L., Galliazzo, S., Molaro, M. et al. TMAO as a biomarker of cardiovascular events: a systematic review and meta-analysis. Intern Emerg Med 16, 201–207 (2021). https://doi.org/10.1007/s11739-020-02470-5

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  • DOI: https://doi.org/10.1007/s11739-020-02470-5

Keywords

  • Trimethylamine oxide
  • Cardiovascular events
  • Gut microbiota