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Licensed Unlicensed Requires Authentication Published by De Gruyter August 31, 2020

Trimethylamine-N-oxide (TMAO) predicts short- and long-term mortality and poor neurological outcome in out-of-hospital cardiac arrest patients

Seraina R. Hochstrasser, Kerstin Metzger, Alessia M. Vincent, Christoph Becker, Annalena K. J. Keller, Katharina Beck, Sebastian Perrig, Kai Tisljar, Raoul Sutter, Philipp Schuetz, Luca Bernasconi, Peter Neyer, Stephan Marsch and Sabina Hunziker

Abstract

Objectives

Prior research found the gut microbiota-dependent and pro-atherogenic molecule trimethylamine-N-oxide (TMAO) to be associated with cardiovascular events as well as all-cause mortality in different patient populations with cardiovascular disease. Our aim was to investigate the prognostic value of TMAO regarding clinical outcomes in patients after out-of-hospital cardiac arrest (OHCA).

Methods

We included consecutive OHCA patients upon intensive care unit admission into this prospective observational study between October 2012 and May 2016. We studied associations of admission serum TMAO with in-hospital mortality (primary endpoint), 90-day mortality and neurological outcome defined by the Cerebral Performance Category (CPC) scale.

Results

We included 258 OHCA patients of which 44.6% died during hospitalization. Hospital non-survivors showed significantly higher admission TMAO levels (μmol L−1) compared to hospital survivors (median interquartile range (IQR) 13.2 (6.6–34.9) vs. 6.4 (2.9–15.9), p<0.001). After multivariate adjustment for other prognostic factors, TMAO levels were significantly associated with in-hospital mortality (adjusted odds ratios (OR) 2.1, 95%CI 1.1–4.2, p=0.026). Results for secondary outcomes were similar with significant associations with 90-day mortality and neurological outcome in univariate analyses.

Conclusions

In patients after OHCA, TMAO levels were independently associated with in-hospital mortality and other adverse clinical outcomes and may help to improve prognostication for these patients in the future. Whether TMAO levels can be influenced by nutritional interventions should be addressed in future studies.


Corresponding author: Prof. Sabina Hunziker, MD, MPH, Department of Medical Communication and Psychosomatic Medicine, University Hospital Basel, Basel, Switzerland; and Faculty of Medicine, University of Basel, Basel, Switzerland, E-mail:
Seraina Rahel Hochstrasser and Kerstin Metzger contributed equally to this article and are considered equally first authors.

Funding source: Gottfried und Julia Bangerter-Rhyner-Stiftung

Award Identifier / Grant number: 8472/HEG-DSV

  1. Research funding: Gottfried und Julia Bangerter-Rhyner-Stiftung, 8472/HEG-DSV.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: The study was conducted in accordance with the Declaration of Helsinki and was approved by the local Ethics Committee (Ethics Committee of Northwest and Central Switzerland, Ethikkommission Nordwest- und Zentralschweiz, EKNZ).

References

1. Koeth, RA, Wang, Z, Levison, BS, Buffa, JA, Org, E, Sheehy, BT, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013;19:576–85. https://doi.org/10.1038/nm.3145.Search in Google Scholar

2. Tang, WH, Wang, Z, Levison, BS, Koeth, RA, Britt, EB, Fu, X, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 2013;368:1575–84. https://doi.org/10.1056/nejmoa1109400.Search in Google Scholar

3. Wang, Z, Klipfell, E, Bennett, BJ, Koeth, R, Levison, BS, Dugar, B, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011;472:57–63. https://doi.org/10.1038/nature09922.Search in Google Scholar

4. Ottiger, M, Nickler, M, Steuer, C, Bernasconi, L, Huber, A, Christ-Crain, M, et al. Gut, microbiota-dependent trimethylamine-N-oxide is associated with long-term all-cause mortality in patients with exacerbated chronic obstructive pulmonary disease. Nutrition 2018;45:135–41.e1. https://doi.org/10.1016/j.nut.2017.07.001.Search in Google Scholar

5. Ottiger, M, Nickler, M, Steuer, C, Odermatt, J, Huber, A, Christ-Crain, M, et al. Trimethylamine-N-oxide (TMAO) predicts fatal outcomes in community-acquired pneumonia patients without evident coronary artery disease. Eur J Intern Med 2016;36:67–73. https://doi.org/10.1016/j.ejim.2016.08.017.Search in Google Scholar

6. Tang, WH, Wang, Z, Fan, Y, Levison, B, Hazen, JE, Donahue, LM, et al. Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis. J Am Coll Cardiol 2014;64:1908–14. https://doi.org/10.1016/j.jacc.2014.02.617.Search in Google Scholar

7. Troseid, M, Ueland, T, Hov, JR, Svardal, A, Gregersen, I, Dahl, CP, et al. Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure. J Intern Med 2015;277:717–26. https://doi.org/10.1111/joim.12328.Search in Google Scholar

8. Tang, WH, Wang, Z, Kennedy, DJ, Wu, Y, Buffa, JA, Agatisa-Boyle, B, et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res 2015;116:448–55. https://doi.org/10.1161/circresaha.116.305360.Search in Google Scholar

9. Ottiger, M, Nickler, M, Steuer, C, Odermatt, J, Huber, A, Christ-Crain, M, et al. Trimethylamine-N-oxide (TMAO) predicts fatal outcomes in community-acquired pneumonia patients without evident coronary artery disease. Eur J Intern Med 2016;36:67–73. https://doi.org/10.1016/j.ejim.2016.08.017.Search in Google Scholar

10. Zeisel, SH, Blusztajn, JK. Choline and human nutrition. Annu Rev Nutr 1994;14:269–96. https://doi.org/10.1146/annurev.nu.14.070194.001413.Search in Google Scholar

11. Zhang, AQ, Mitchell, SC, Smith, RL. Dietary precursors of trimethylamine in man: a pilot study. Food Chem Toxicol 1999;37:515–20. https://doi.org/10.1016/s0278-6915(99)00028-9.Search in Google Scholar

12. Zeisel, SH. Choline: critical role during fetal development and dietary requirements in adults. Annu Rev Nutr 2006;26:229–50. https://doi.org/10.1146/annurev.nutr.26.061505.111156.Search in Google Scholar

13. Zeisel, SH. Choline: an essential nutrient for humans. Nutrition 2000;16:669–71. https://doi.org/10.1016/s0899-9007(00)00349-x.Search in Google Scholar

14. Ussher, JR, Lopaschuk, GD, Arduini, A. Gut microbiota metabolism of L-carnitine and cardiovascular risk. Atherosclerosis 2013;231:456–61. https://doi.org/10.1016/j.atherosclerosis.2013.10.013.Search in Google Scholar

15. al-Waiz, M, Mikov, M, Mitchell, SC, Smith, RL. The exogenous origin of trimethylamine in the mouse. Metabolism 1992;41:135–6. https://doi.org/10.1016/0026-0495(92)90140-6.Search in Google Scholar

16. Barrett, EL, Kwan, HS. Bacterial reduction of trimethylamine oxide. Annu Rev Microbiol 1985;39:131–49. https://doi.org/10.1146/annurev.mi.39.100185.001023.Search in Google Scholar

17. Romano, KA, Vivas, EI, Amador-Noguez, D, Rey, FE. Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. mBio 2015;6:e02481. https://doi.org/10.1128/mbio.02481-14.Search in Google Scholar

18. Lang, DH, Yeung, CK, Peter, RM, Ibarra, C, Gasser, R, Itagaki, K, et al. Isoform specificity of trimethylamine N-oxygenation by human flavin-containing monooxygenase (FMO) and P450 enzymes: selective catalysis by FMO3. Biochem Pharmacol 1998;56:1005–12. https://doi.org/10.1016/s0006-2952(98)00218-4.Search in Google Scholar

19. Zeisel, SH, Wishnok, JS, Blusztajn, JK. Formation of methylamines from ingested choline and lecithin. J Pharmacol Exp Ther 1983;225:320–4.Search in Google Scholar

20. Miller, CA, Corbin, KD, da Costa, KA, Zhang, S, Zhao, X, Galanko, JA, et al. Effect of egg ingestion on trimethylamine-N-oxide production in humans: a randomized, controlled, dose-response study. Am J Clin Nutr 2014;100:778–86. https://doi.org/10.3945/ajcn.114.087692.Search in Google Scholar

21. Monsieurs, KG, Nolan, JP, Bossaert, LL, Greif, R, Maconochie, IK, Nikolaou, NI, et al. European resuscitation council guidelines for resuscitation 2015 section 1. Executive summary. Resuscitation 2015;95:1–80. https://doi.org/10.1016/j.resuscitation.2015.07.038.Search in Google Scholar

22. Young, GB. Clinical practice. Neurologic prognosis after cardiac arrest. N Engl J Med 2009;361:605–11. https://doi.org/10.1056/nejmcp0903466.Search in Google Scholar

23. Garza, EG, Rumbak, MJ. Prediction of mortality from out-of-hospital cardiac arrest is key to decrease morbidity and mortality from cardiac, neurologic, and other major organ damage*. Crit Care Med 2015;43:503. https://doi.org/10.1097/ccm.0000000000000829.Search in Google Scholar

24. Annborn, M, Nilsson, F, Dankiewicz, J, Rundgren, M, Hertel, S, Struck, J, et al. The combination of biomarkers for prognostication of long-term outcome in patients treated with mild hypothermia after out-of-hospital cardiac arrest-A pilot study. Ther Hypothermia Temp Manag 2016;6:85–90. https://doi.org/10.1089/ther.2015.0033.Search in Google Scholar

25. Shinozaki, K, Oda, S, Sadahiro, T, Nakamura, M, Hirayama, Y, Watanabe, E, et al. Blood ammonia and lactate levels on hospital arrival as a predictive biomarker in patients with out-of-hospital cardiac arrest. Resuscitation 2011;82:404–9. https://doi.org/10.1016/j.resuscitation.2010.10.026.Search in Google Scholar

26. Williams, TA, Martin, R, Celenza, A, Bremner, A, Fatovich, D, Krause, J, et al. Use of serum lactate levels to predict survival for patients with out-of-hospital cardiac arrest: a cohort study. Emerg Med Australasia 2016;28:171–8. https://doi.org/10.1111/1742-6723.12560.Search in Google Scholar

27. Donnino, MW, Andersen, LW, Giberson, T, Gaieski, DF, Abella, BS, Peberdy, MA, et al. Initial lactate and lactate change in post-cardiac arrest: a multicenter validation study. Crit Care Med 2014;42:1804–11. https://doi.org/10.1097/ccm.0000000000000332.Search in Google Scholar

28. Schuetz, P, Affolter, B, Hunziker, S, Winterhalder, C, Fischer, M, Balestra, GM, et al. Serum procalcitonin, C-reactive protein and white blood cell levels following hypothermia after cardiac arrest: a retrospective cohort study. Eur J Clin Invest 2010;40:376–81. https://doi.org/10.1111/j.1365-2362.2010.02259.x.Search in Google Scholar

29. Frydland, M, Kjaergaard, J, Erlinge, D, Stammet, P, Nielsen, N, Wanscher, M, et al. Usefulness of serum B-type natriuretic peptide levels in comatose patients resuscitated from out-of-hospital cardiac arrest to predict outcome. Am J Cardiol 2016;118:998–1005. https://doi.org/10.1016/j.amjcard.2016.07.006.Search in Google Scholar

30. Rosjo, H, Vaahersalo, J, Hagve, TA, Pettila, V, Kurola, J, Omland, T, et al. Prognostic value of high-sensitivity troponin T levels in patients with ventricular arrhythmias and out-of-hospital cardiac arrest: data from the prospective FINNRESUSCI study. Crit Care 2014;18:605. https://doi.org/10.1186/s13054-014-0605-y.Search in Google Scholar

31. Geri, G, Mongardon, N, Dumas, F, Chenevier-Gobeaux, C, Varenne, O, Jouven, X, et al. Diagnosis performance of high sensitivity troponin assay in out-of-hospital cardiac arrest patients. Int J Cardiol 2013;169:449–54. https://doi.org/10.1016/j.ijcard.2013.10.011.Search in Google Scholar

32. Luescher, T, Mueller, J, Isenschmid, C, Kalt, J, Rasiah, R, Tondorf, T, et al. Neuron-specific enolase (NSE) improves clinical risk scores for prediction of neurological outcome and death in cardiac arrest patients: results from a prospective trial. Resuscitation 2019;142:50–60. https://doi.org/10.1016/j.resuscitation.2019.07.003.Search in Google Scholar

33. Isenschmid, C, Luescher, T, Rasiah, R, Kalt, J, Tondorf, T, Gamp, M, et al. Performance of clinical risk scores to predict mortality and neurological outcome in cardiac arrest patients. Resuscitation 2019;136:21–9. https://doi.org/10.1016/j.resuscitation.2018.10.022.Search in Google Scholar

34. Isenschmid, C, Kalt, J, Gamp, M, Tondorf, T, Becker, C, Tisljar, K, et al. Routine blood markers from different biological pathways improve early risk stratification in cardiac arrest patients: results from the prospective, observational COMMUNICATE study. Resuscitation 2018;130:138–45. https://doi.org/10.1016/j.resuscitation.2018.07.021.Search in Google Scholar

35. Steuer, C, Schutz, P, Bernasconi, L, Huber, AR. Simultaneous determination of phosphatidylcholine-derived quaternary ammonium compounds by a LC-MS/MS method in human blood plasma, serum and urine samples. J Chromatogr B Analyt Technol Biomed Life Sci 2016;1008:206–11. https://doi.org/10.1016/j.jchromb.2015.12.002.Search in Google Scholar

36. Adrie, C, Cariou, A, Mourvillier, B, Laurent, I, Dabbane, H, Hantala, F, et al. Predicting survival with good neurological recovery at hospital admission after successful resuscitation of out-of-hospital cardiac arrest: the OHCA score. Eur Heart J 2006;27:2840–5. https://doi.org/10.1093/eurheartj/ehl335.Search in Google Scholar

37. Nickler, M, Ottiger, M, Steuer, C, Huber, A, Anderson, JB, Muller, B, et al. Systematic review regarding metabolic profiling for improved pathophysiological understanding of disease and outcome prediction in respiratory infections. Respir Res 2015;16:125. https://doi.org/10.1186/s12931-015-0283-6.Search in Google Scholar

38. Suzuki, T, Heaney, LM, Bhandari, SS, Jones, DJ, Ng, LL. Trimethylamine N-oxide and prognosis in acute heart failure. Heart 2016;102:841–8. https://doi.org/10.1136/heartjnl-2015-308826.Search in Google Scholar

39. Li, XS, Obeid, S, Klingenberg, R, Gencer, B, Mach, F, Raber, L, et al. Gut microbiota-dependent trimethylamine N-oxide in acute coronary syndromes: a prognostic marker for incident cardiovascular events beyond traditional risk factors. Eur Heart J 2017;38:814–24. https://doi.org/10.1093/eurheartj/ehw582.Search in Google Scholar

40. Kim, RB, Morse, BL, Djurdjev, O, Tang, M, Muirhead, N, Barrett, B, et al. Advanced chronic kidney disease populations have elevated trimethylamine N-oxide levels associated with increased cardiovascular events. Kidney Int 2016;89:1144–52. https://doi.org/10.1016/j.kint.2016.01.014.Search in Google Scholar

41. Jaworska, K, Huc, T, Samborowska, E, Dobrowolski, L, Bielinska, K, Gawlak, M, et al. Hypertension in rats is associated with an increased permeability of the colon to TMA, a gut bacteria metabolite. PLoS One 2017;12:e0189310. https://doi.org/10.1371/journal.pone.0189310.Search in Google Scholar

42. Yu, W, Xu, C, Li, G, Hong, W, Zhou, Z, Xiao, C, et al. Simultaneous determination of trimethylamine N-oxide, choline, betaine by UPLC-MS/MS in human plasma: an application in acute stroke patients. J Pharmaceut Biomed Anal 2018;152:179–87. https://doi.org/10.1016/j.jpba.2018.01.049.Search in Google Scholar

43. Yin, J, Liao, SX, He, Y, Wang, S, Xia, GH, Liu, FT, et al. Dysbiosis of gut microbiota with reduced trimethylamine-N-oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack. J Am Heart Assoc 2015;4:e002699. https://doi.org/10.1161/jaha.115.002699.Search in Google Scholar

44. Estruch, R, Ros, E, Salas-Salvado, J, Covas, MI, Corella, D, Aros, F, et al. Primary prevention of cardiovascular disease with a mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med 2018;378:e34. https://doi.org/10.1056/nejmc1806491.Search in Google Scholar


Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/ijcre-2019-0226).


Received: 2020-02-15
Accepted: 2020-08-06
Published Online: 2020-08-31
Published in Print: 2021-02-23

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