Trimethyllysine, vascular risk factors and outcome in acute ischemic stroke (MARK-STROKE).
Acute ischemic stroke
Coronary artery disease
Major adverse cardiovascular event
Trimethyllysine
Journal
Amino acids
ISSN: 1438-2199
Titre abrégé: Amino Acids
Pays: Austria
ID NLM: 9200312
Informations de publication
Date de publication:
Apr 2021
Apr 2021
Historique:
received:
03
02
2021
accepted:
22
03
2021
pubmed:
1
4
2021
medline:
20
11
2021
entrez:
31
3
2021
Statut:
ppublish
Résumé
Trimethyllysine (TML) is involved in the generation of the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO) by gut microbiota. In clinical studies, elevated TML levels predicted major adverse cardiovascular events (MACE) in patients with acute or stable coronary artery disease (CAD). In contrast to cardiovascular patients, the role of TML in patients with acute cerebral ischemia is unknown. Here, we evaluated circulating TML levels in 374 stroke patients from the prospective biomarkers in stroke (MARK-STROKE) study. Compared with 167 matched healthy controls, acute ischemic stroke patients had lower median TML plasma concentrations, i.e. 0.71 vs. 0.47 µmol/L (p < 0.001) and this difference persisted after adjusting for age and sex. TML plasma concentrations were associated with age, serum creatinine, glucose, cholesterol and lysine. Patients with prevalent arterial hypertension, atrial fibrillation or a history of myocardial infarction had increased TML levels, but this observation was not independent of age, sex and GFR. In 274 patients, follow-up data were available. During a median follow-up of 284 [25th-75th percentile: 198, 431] days, TML was not associated with incident MACE (stroke, myocardial infarction, death). In summary, our data suggests a different role of TML in acute ischemic stroke compared with CAD patients.
Identifiants
pubmed: 33788002
doi: 10.1007/s00726-021-02969-x
pii: 10.1007/s00726-021-02969-x
doi:
Substances chimiques
Biomarkers
0
trimethyllysine
3YGF0495O2
Lysine
K3Z4F929H6
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
555-561Subventions
Organisme : Else Kröner-Fresenius-Stiftung
ID : 2018_EKES.04
Références
Atzler D, Schwedhelm E, Zeller T (2014) Integrated genomics and metabolomics in nephrology. Nephrol Dial Transplant 29:1467–1474
doi: 10.1093/ndt/gft492
Bjornestad EO, Olset H, Dhar I, Loland K, Pedersen EKR, Svingen GFT, Svardal A, Berge RK, Ueland PM, Tell GS, Nilsen DWT, Nordrehaug JE, Nygaard E, Nygard O (2020) Circulating trimethyllysine and risk of acute myocardial infarction in patients with suspected stable coronary heart disease. J Intern Med 288:446–456
doi: 10.1111/joim.13067
Cordts K, Atzler D, Qaderi V, Sydow K, Böger RH, Choe CU, Schwedhelm E (2015) Measurement of homoarginine in human and mouse plasma by LC-MS/MS and ELISA: a comparison and a biological application. Amino Acids 47:2015–2022
doi: 10.1007/s00726-015-2037-7
Cordts K, Grzybowski R, Lezius S, Lüneburg N, Atzler D, Neu A, Hornig S, Böger RH, Gerloff C, Magnus T, Thomalla G, Schwedhelm E, Grant PJ, Choe CU (2019) Guanidino compound ratios are associated with stroke etiology, internal carotid artery stenosis and CHA2DS2-vasc score in three cross-sectional studies. J Neurol Sci 397:156–161
doi: 10.1016/j.jns.2018.12.037
Cox RA, Hoppel CL (1973) Biosynthesis of carnitine and 4-N-trimethylaminobutyrate from 6-N-trimethyl-lysine. Biochem J 136:1083–1090
doi: 10.1042/bj1361083
Daum G, Winkler M, Moritz E, Muller T, Geffken M, von Lucadou M, Haddad M, Peine S, Böger RH, Larena-Avellaneda A, Debus ES, Graler M, Schwedhelm E (2020) Determinants of serum- and plasma sphingosine-1-phosphate concentrations in a healthy study group. TH Open 4:e12–e19
doi: 10.1055/s-0040-1701205
Grosse GM, Schwedhelm E, Worthmann H, Choe CU (2020) Arginine derivatives in cerebrovascular diseases: Mechanisms and clinical implications. Int J Mol Sci 21(5):1798
doi: 10.3390/ijms21051798
Haghikia A, Li XS, Liman TG, Bledau N, Schmidt D, Zimmermann F, Krankel N, Widera C, Sonnenschein K, Haghikia A, Weissenborn K, Fraccarollo D, Heimesaat MM, Bauersachs J, Wang Z, Zhu W, Bavendiek U, Hazen SL, Endres M, Landmesser U (2018) Gut microbiota-dependent trimethylamine n-oxide predicts risk of cardiovascular events in patients with stroke and is related to proinflammatory monocytes. Arterioscler Thromb Vasc Biol 38:2225–2235
doi: 10.1161/ATVBAHA.118.311023
Koeth RA, Lam-Galvez BR, Kirsop J, Wang Z, Levison BS, Gu X, Copeland MF, Bartlett D, Cody DB, Dai HJ, Culley MK, Li XS, Fu X, Wu Y, Li L, DiDonato JA, Tang WHW, Garcia-Garcia JC, Hazen SL (2019) l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans. J Clin Invest 129:373–387
doi: 10.1172/JCI94601
Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL (2013) Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19:576–585
doi: 10.1038/nm.3145
LaBadie J, Dunn WA, Aronson NN Jr (1976) Hepatic synthesis of carnitine from protein-bound trimethyl-lysine. Lysosomal digestion of methyl-lysine-labelled asialo-fetuin. Biochem J 160:85–95
doi: 10.1042/bj1600085
Li XS, Obeid S, Wang Z, Hazen BJ, Li L, Wu Y, Hurd AG, Gu X, Pratt A, Levison BS, Chung YM, Nissen SE, Tang WHW, Mach F, Raber L, Nanchen D, Matter CM, Luscher TF, Hazen SL (2019) Trimethyllysine, a trimethylamine n-oxide precursor, provides near- and long-term prognostic value in patients presenting with acute coronary syndromes. Eur Heart J 40:2700–2709
doi: 10.1093/eurheartj/ehz259
Li XS, Wang Z, Cajka T, Buffa JA, Nemet I, Hurd AG, Gu X, Skye SM, Roberts AB, Wu Y, Li L, Shahen CJ, Wagner MA, Hartiala JA, Kerby RL, Romano KA, Han Y, Obeid S, Luscher TF, Allayee H, Rey FE, DiDonato JA, Fiehn O, Tang WHW, Hazen SL (2018) Untargeted metabolomics identifies trimethyllysine, a TMAO-producing nutrient precursor, as a predictor of incident cardiovascular disease risk. JCI Insight 3(6):e99096
doi: 10.1172/jci.insight.99096
Mueller DM, Allenspach M, Othman A, Saely CH, Muendlein A, Vonbank A, Drexel H, von Eckardstein A (2015) Plasma levels of trimethylamine-n-oxide are confounded by impaired kidney function and poor metabolic control. Atherosclerosis 243:638–644
doi: 10.1016/j.atherosclerosis.2015.10.091
Schiattarella GG, Sannino A, Toscano E, Giugliano G, Gargiulo G, Franzone A, Trimarco B, Esposito G, Perrino C (2017) Gut microbe-generated metabolite trimethylamine-n-oxide as cardiovascular risk biomarker: A systematic review and dose-response meta-analysis. Eur Heart J 38:2948–2956
doi: 10.1093/eurheartj/ehx342
Skagen K, Troseid M, Ueland T, Holm S, Abbas A, Gregersen I, Kummen M, Bjerkeli V, Reier-Nilsen F, Russell D, Svardal A, Karlsen TH, Aukrust P, Berge RK, Hov JE, Halvorsen B, Skjelland M (2016) The carnitine-butyrobetaine-trimethylamine-n-oxide pathway and its association with cardiovascular mortality in patients with carotid atherosclerosis. Atherosclerosis 247:64–69
doi: 10.1016/j.atherosclerosis.2016.01.033
Strand E, Rebnord EW, Flygel MR, Lysne V, Svingen GFT, Tell GS, Loland KH, Berge RK, Svardal A, Nygard O, Pedersen ER (2018) Serum carnitine metabolites and incident type 2 diabetes mellitus in patients with suspected stable angina pectoris. J Clin Endocrinol Metab 103:1033–1041
doi: 10.1210/jc.2017-02139
Szulik MW, Davis K, Bakhtina A, Azarcon P, Bia R, Horiuchi E, Franklin S (2020) Transcriptional regulation by methyltransferases and their role in the heart: highlighting novel emerging functionality. Am J Physiol Heart Circ Physiol 319:H847–H865
doi: 10.1152/ajpheart.00382.2020
Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL (2013) Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 368:1575–1584
doi: 10.1056/NEJMoa1109400
von Eckardstein A (2020) Trimethyllysine and trimethylamine-n-oxide - pathogenic factors or surrogate markers of increased cardiovascular disease risk? J Intern Med 288:484–486
doi: 10.1111/joim.13086
Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL (2011) Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472:57–63
doi: 10.1038/nature09922
Wu C, Xue F, Lian Y, Zhang J, Wu D, Xie N, Chang W, Chen F, Wang L, Wei W, Yang K, Zhao W, Wu L, Song H, Ma Q, Ji X (2020) Relationship between elevated plasma trimethylamine n-oxide levels and increased stroke injury. Neurology 94:e667–e677
doi: 10.1212/WNL.0000000000008862
Yao ME, Liao PD, Zhao XJ, Wang L (2020) Trimethylamine-n-oxide has prognostic value in coronary heart disease: A meta-analysis and dose-response analysis. BMC Cardiovasc Disord 20(1):7
doi: 10.1186/s12872-019-01310-5
Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, Wang Z, Li L, Fu X, Wu Y, Mehrabian M, Sartor RB, McIntyre TM, Silverstein RL, Tang WHW, DiDonato JA, Brown JM, Lusis AJ, Hazen SL (2016) Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165:111–124
doi: 10.1016/j.cell.2016.02.011