Asymmetric dimethylarginine as a biochemical marker of endothelial dysfunction in major subtypes of ischemic stroke in working-age men

The aim. To determine the level of ADMA in blood plasma and evaluate its role in the development of endothelial dysfunction in various pathogenetic subtypes of stroke in working-age men (18–50 years).

Material and methods. The study was conducted on a sample of 125 men (mean age 42.6 ± 5.3 years) with various subtypes of IS who were admitted to the neurological department before the COVID-19 pandemic. The study included 60 patients with atherothrombotic stroke (ATS), 46 patients with lacunar stroke (LS), and 19 patients with cardioembolic stroke (CES). The IS subtype was determined based on the TOAST classification (Trial of Org 10172 in Acute Stroke Treatment). The patients underwent risk factor assessment, detailed somatic and neurological examinations, neuroimaging of the brain, ultrasound examination of the main arteries of the head, and laboratory tests.

Results. In men aged 18–50 years with various subtypes of IS, the following risk factors were identified: arterial hypertension in 83.2%, dyslipidemia in 50.4%, diabetes mellitus in 8%, smoking in 67.2%, alcohol consumption in 29.6%, obesity in 16.8%, cardiac arrhythmia in 12%, a history of stroke in 16.8%, and a history of acute myocardial infarction in 10.4%. In men aged 18–50, the level of ADMA was higher in patients with ATS and LS compared to patients with CES. Patients with ATS had the highest levels of ADMA. Patients with ATS aged 41–50 had higher levels of ADMA compared to patients aged 31–40. Patients with LS and CES had higher levels of ADMA at the age of 31–40 years compared to patients aged 41–50 years. Significant correlations were found between the level of ADMA and individual risk factors in different subtypes of IS.

Conclusion. The identified changes in the level of ADMA and the obtained correlation relationships reflect the role of ADMA in the development and progression of atherosclerosis and endothelial dysfunction in men aged 18–50 with various subtypes of IS.

1. Wang X, He B. Endothelial dysfunction: molecular mechanisms and clinical implications. MedComm. 2024;5(8):e651. doi: 10.1002/mco2.651.

2. Tuttolomondo A Daidone M Pinto A. Endothelial dysfunction and infl ammation in ischemic stroke pathogenesis. Curr Pharm Des. 2020;26(34):4209–4219. doi: 10.2174/1381612826666200417154126

3. Iadecola C. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron. 2017;96(1):17–42. doi: 10.1016/j.neuron.2017.07.030

4. Madden JA. Role of the vascular endothelium and plaque in acute ischemic stroke. Neurology. 2012;79(13 Suppl1):S58-62. doi: 10.1212/WNL.0b013e3182695836

5. Poggesi A, Pasi M, Pescini F, Pantoni L, Inzitari D. Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: a review. J Cereb Blood Flow Metab. 2016;36(1):72– 94. doi: 10.1038/jcbfm.2015.116.

6. Zhang J. Biomarkers of endothelial activation and dysfunction in cardiovascular diseases. Rev Cardiovasc Med. 2022;23(2):73. doi: 10.31083/j.rcm2302073.

7. Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh 3rd E.E. Classifi cation of subtype of acute ischemic stroke defi nitions for use in a multicenter clinical trial. Stroke. 1993;24(1):35–41. doi: 10.1161/01.str.24.1.35

8. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfi eld JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111–1115. doi: 10.1016/0140-6736(92)93147-F

9. Bokeria LA, Bokeria OL, Bazar-Sadaeva TS, Salia NT, Donakanyan SA, Binia-Shvili MB, Taskina V.Yu. Characteristics of NO-dependent autoregulation of tissue blood fl ow in idiopathic atrial fi brillation. Annaly aritmologii. 2013;10(2):94–101. (In Russ.). https://cyberleninka.ru/article/n/harakteristika-no-zavisimoy-autoregulyatsii-tkanevogo-krovotoka-pri-idiopaticheskoyfibrillyatsii-predserdiy?ysclid=mjr8av6t8f832382920

10. Pribylova NN, Bezzubtseva MV, Pribylov SA, Barbashina TA, Osipova OA. Endothelial Dysfunction in Patients with Arterial Hypertension and AcuteIschemic Stroke. Trudnyi-Patsient. 2016;6-7:14:17–20. (In Russ.). https://cyberleninka.ru/article/n/endotelialnaya-disfunktsiya-u-bolnyh-gipertonicheskoy-boleznyu-v-ostrom-periode-ishemicheskogo-insulta?ysclid=mjr89w8hyu953350724

11. Alexander Y, Osto E, Schmidt-Trucksäss A, Shechter M, Trifunovic D, Duncker DJ, Aboyans V, Bäck M, Badimon L, Cosentino F, De Carlo M, Dorobantu M, Harrison DG, Guzik TJ, Hoefer I, Morris PD, Norata GD, Suades R, Taddei S, Vilahur G, Waltenberger J, Weber C, Wilkinson F, Bochaton-Piallat M-L., Evans PC. Endothelial function in cardiovascular medicine: a consensus paper of the European Society of Cardiology Working Groups on Atherosclerosis and Vascular Biology, Aorta and Peripheral Vascular Diseases, Coronary Pathophysiology and Microcirculation, and Thrombosis. Cardiovasc Res. 2021;117(1):29–42. doi: 10.1093/cvr/cvaa085

12. George MG. Risk Factors for Ischemic Stroke in Younger Adults: A Focused Update. Stroke. 2020;51(3):729–735. doi: 10.1161/STROKEAHA.119.024156

13. Hauer AJ, Ruigrok YM, Algra A, Dijk EJ, Koudstaal PJ, Luijckx GJ, Nederkoorn PJ, Oostenbrugge RJ, Visser MC, Wermer MJ, Kappelle LJ, Klijn CJ.M.; Dutch Parelsnoer Institute‐Cerebrovascular Accident Study Group. Age‐specifi c vascular risk factor profi les according to stroke subtype. J Am Heart Assoc. 2017;6:e005090. doi: 10.1161/JAHA.116.005090

14. Dittrich TD, Schneider T, Katan M, Luft AR, Mono ML, Bolognese M, Nedeltchev K, Kahles T, Arnold M, Heldner M, Michel P, Carrera E, Rodic B, Cereda CW, Peters N, Bonati LH, Renaud S, Humm AM, Medlin F, Albert S, Sturzenegger R, Tarnutzer AA, Siebel P, Baumgärtner M, Berger C, Mordasini P, Vehoff J, De Marchis GM.; Swiss Stroke Registry Investigators. Risk Factors, Treatments, and Outcomes of Adults Aged < 55 Years With Acute Ischemic Stroke With Undetermined Versus Determined Pathogenesis: A Nationwide Swiss Cohort Study. J Am Heart Assoc. 2024;13(23):e036761. doi: 10.1161/JAHA.124.036761

15. Gerdanovics A, Stănescu IC, Mîrza CM, Dogaru GB, Nicula CA, Boarescu PM, Gerdanovics CA, Bulboacă AE. Proinfl ammatory Risk Factors in Patients with Ischemic Stroke: A Systematic Review and Meta-Analysis. Antioxidants (Basel). 2025;14(10):1229. doi: 10.3390/antiox14101229

16. Tohgi H, Tajima T, Konno T, Towada S, Kamata A, Yamazaki M. The risk of cerebral infarction in non-valvular atrial fi brillation: Eff ects of age, hypertension and antihypertensive treatment. Eur. Neurol. 1991;31:126–130. doi: 10.1159/000116661

17. Park JH, Ovbiagele B, Hong KS, Kwon SU. Association of Systolic Blood Pressure with Progression of Symptomatic Intracranial Atherosclerotic Stenosis. J. Stroke. 2017;19:304–311. doi: 10.5853/jos.2017.00136.

18. Kozera GM, Dubaniewicz M, Zdrojewski T, Madej-Dmochowska A, Mielczarek M, Wojczal J, Chwojnicki K, Swierblewska E, Schminke U, Wyrzykowski B, Nyka WM.; SOPKARD Study Group. Cerebral vasomotor reactivity and extent of white matter lesions in middle-aged men with arterial hypertension: A pilot study. Am. J. Hypertens. 2010;23:1198–1203. doi: 10.1038/ajh.2010.152

19. Rundek T, Hundle R, Ratchford E, Ramas R, Sciacca R, Di Tullio MR, Boden-Albala B, Miyake Y, Elkind MS.V., Sacco RL, Homma S. Endothelial dysfunction is associated with carotid plaque: A cross-sectional study from the population based Northern Manhattan Study. BMC Cardiovasc. Disord. 2006;6:35. doi: 10.1186/1471-2261-6-35

20. Knottnerus IL.H., Ten Cate H, Lodder J, Kessels F, van Oostenbrugge RJ. Endothelial dysfunction in lacunar stroke: A systematic review. Cerebrovasc. Dis. 2009;27:519–526. doi: 10.1159/000212672

21. Stevenson SF, Doubal FN, Shuler K, Wardlaw JM. A Systematic Review of Dynamic Cerebral and Peripheral Endothelial Function in Lacunar Stroke Versus Controls. Stroke. 2010;41:e434–e442. doi: 10.1161/STROKEAHA.109.569855

22. Micieli G, Bosone D, Zappoli F, Marcheselli S, Argenteri A, Nappi G. Vasomotor response to CO2 and L-Arginine in patients with severe internal carotid artery stenosis; pre- and postsurgical evaluation with transcranial Doppler. J. Neurol. Sci. 1999;163:153–158. doi: 10.1016/S0022-510X(99)00027-1

23. Wieczór AM, Wieczór R, Kulwas A, Rość D. Asymmetric dimethylarginine and angiogenesis: biological signifi cance. Int Angiol. 2018c;37(6):431–436. doi: 10.23736/S0392-9590.18.04017-8

24. Kielstein JT, Zoccali C. Asymmetric dimethylarginine: a cardiovascular risk factor and a uremic toxin coming of age? Am J Kidney Dis. 2005;46(2):186–202. doi: 10.1053/j.ajkd.2005.05.009

25. Goonasekera CD, Rees DD, Woolard P, Frend A, Shah V, Dillon MJ. Nitric oxide synthase inhibitors and hypertension in children and adolescents. J Hypertens. 1997;15(8):901–9. doi: 10.1097/00004872-199715080-00015

26. Chirinos JA, David R, Bralley JA, Zea-Díaz H, Muñoz-Atahualpa E, Corrales-Medina F, Cuba-Bustinza C, Chirinos-Pacheco J, Medina-Lezama J. Endogenous nitric oxide synthase inhibitors, arterial hemodynamics, and subclinical vascular disease: the PREVENCION study. Hypertension. 2008;52(6):1051–9. doi: 10.1161/HYPERTENSIONAHA.108.120352

27. Schulze F, Lenzen H, Hanefeld C, Bartling A, Osterziel KJ, Goudeva L, Schmidt-Lucke C, Kusus M, Maas R, Schwedhelm E, Strödter D, Simon BC, Mügge A, Daniel WG, Tillmanns H, Maisch D, Streichert T, Böger RH. Asymmetric dimethylarginine is an independent risk factor for coronary heart disease: results from the multicenter Coronary Artery Risk Determination investigating the Infl uence of ADMA Concentration (CARDIAC) study. Am Heart J. 2006;152(3):493.e1-8. doi: 10.1016/j.ahj.2006.06.005

28. Cooke JP. Asymmetrical dimethylarginine: the Uber marker? Circulation. 2004;109(15):1813–8. doi: 10.1161/01.CIR.0000126823.07732.D5

29. Horowitz JD, Heresztyn, T. An overview of plasma concentrations of asymmetric dimethylarginine (ADMA) in health and disease and in clinical studies: methodological considerations. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;851(12):42–50. doi: 10.1016/j.jchromb.2006.09.023

30. Chauhan A, More RS, Mullins PA, Taylor G, Petch C, Schofi eld PM. Aging-associated endothelial dysfunction in humans is reversed by L-arginine. J Am Coll Cardiol. 1996;28(7):1796–804. doi: 10.1016/s0735-1097(96)00394-4

31. Bladowski M, Gawrys J, Gajecki D, Szahidewicz-Krupska E, Sawicz-Bladowska A, Doroszko A. Role of the Platelets and Nitric Oxide Biotransformation in Ischemic Stroke: A Translative Review from Bench to Bedside. Oxid Med Cell Longev. 2020;2020:2979260. doi: 10.1155/2020/2979260

32. Jacobsen JC.B., Hornbech MS, Holstein-Rathlou N.-H. Signifi cance of microvascular remodelling for the vascular fl ow reserve in hypertension. Interface Focus. 2011;1:117–131. doi: 10.1098/rsfs.2010.0003

33. Konukoglu D, Uzun H. Endothelial Dysfunction and Hypertension. Adv. Exp. Med. Biol. 2017;956:511–540. doi: 10.1007/5584_2016_90

34. Li S, Wu Y, Yu G, Xia Q, Xu Y. Angiotensin II Receptor Blockers Improve Peripheral Endothelial Function: A Meta-Analysis of Randomized Controlled Trials. PLoS ONE. 2014;9:e90217. doi: 10.1371/journal.pone.0090217

35. Shahin Y, Alam Khan J, Samuel N, Chetter I. Angiotensin converting enzyme inhibitors eff ect on endothelial dysfunction: A meta-analysis of randomised controlled trials. Atherosclerosis. 2011;216:7–16. doi: 10.1016/j.atherosclerosis.2011.02.044

36. Golbidi S, Edvinsson L, Laher I. Smoking and Endothelial Dysfunction. Curr. Vasc. Pharmacol. 2020;18:1–11. doi: 10.2174/1573403X14666180913120015