Early biomarkers of endothelial dysfunction: clinical implications for the diagnosis and management of cardiovascular disease
Abstract
This review synthesizes current evidence on early biomarkers of endothelial dysfunction (ED) in cardiovascular disease (CVD), emphasizing their role in diagnosis, prognosis, and management. ED, characterized by reduced nitric oxide bioavailability and increased inflammation, serves as a reversible precursor to atherosclerosis, thrombosis, and events like myocardial infarction. Established biomarkers, including adhesion molecules, cytokines, and inflammatory markers, reflect endothelial activation and predict CVD risk, with recent studies confirming their utility in hypertension. Emerging focus on L-arginine derivatives, particularly asymmetric dimethylarginine (ADMA), highlights its specificity as an endogenous nitric oxide synthase inhibitor, associated with vascular impairment in hypertension, diabetes, and CVD. Clinical trials, such as the AtheroGene and Framingham Offspring studies, demonstrate ADMA’s prognostic value for major adverse events. Future directions advocate integrating ADMA into multi-biomarker panels with AI and omics for personalized medicine, addressing gaps in standardization and early detection. Non-invasive techniques like flow-mediated dilation and ultrasound-derived markers complement biomarkers for subclinical CVD assessment. Overall, biomarker-driven strategies promise enhanced CVD prevention and tailored therapies.
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List of references
Alexander Y, Osto E, Schmidt-Trucksäss A, Shechter M, Trifunovic D, Duncker DJ, et al. 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. https://doi.org/10.1093/cvr/cvaa085.
Bokhari SFH, Umais M, Faizan Sattar SM, Mehboob U, Iqbal A, Amir M, et al. Novel cardiac biomarkers and multiple-marker approach in the early detection, prognosis, and risk stratification of cardiac diseases. World J Cardiol. 2025;17(7):106561. https://doi.org/10.4330/wjc.v17.i7.106561.
Brown K, et al. ICAM-1 and plaque instability in atherosclerosis: a systematic review. Atherosclerosis. 2023;370:12-20.
Chong B, Jayabaskaran J, Jauhari SM, Chan SP, Goh R, Kueh MTW, et al. Global burden of cardiovascular diseases: projections from 2025 to 2050. Eur J Prev Cardiol. 2024; zwae281. https://doi.org/10.1093/ eurjpc/zwae281.
Climente-González H, Oh M, Chajewska U, et al. Interpretable machine learning leverages proteomics to improve cardiovascular disease risk prediction and biomarker identification. Commun Med. 2025;5(1):170. https://doi.org/10.1038/s43856-025-00872-0.
Filipovic MG, Luedi MM. Cardiovascular biomarkers: current status and future directions. Cells. 2023;12(22):2647. https://doi.org/10.3390/cells12222647.
Flammer AJ, Anderson T, Celermajer DS, Creager MA, Deanfield J, Ganz P, et al. The assessment of endothelial function: from research into clinical practice. Circulation. 2012;126(6):753-67. https://doi.org/10.1161/CIRCULATIONAHA.112.093245.
Fortini F, et al. Focus on biomarkers of endothelial function in COVID-19. Biomedicines. 2021;9(8):997.
Fortini F, Vieceli Dalla Sega F, Marracino L, Severi P, Rapezzi C, Rizzo P, et al. Well-Known and Novel Players in Endothelial Dysfunction: Updates on a Notch(ed) Landscape. Biomedicines. 2021;9(8):997. https://doi.org/10.3390/biomedicines9080997.
Garcia S, et al. von Willebrand factor as a predictor of adverse outcomes in CAD: a cohort study. J Am Coll Cardiol. 2024;83(2):234-242.
Hadi HA, Carr CS, Al Suwaidi J. Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag. 2005;1(3):183-98. PMID: 17319104; PMCID: PMC1993955.
Naderi-Meshkin H, Setyaningsih WAW. Endothelial cell dysfunction: onset, progression, and conse- quences. Front Biosci (Landmark Ed). 2024;29(6):223. https://doi.org/10.31083/j.fbl2906223.
Jawalekar SL, Karnik A, Bhutey A. Risk of cardiovascular diseases in diabetes mellitus and serum concentration of asymmetrical dimethylarginine. Biochem Res Int. 2013;2013:189430. https://doi.org/10.1155/2013/189430.
Suraj-Prażmowska J, Marczyk B, Śmierciak N, Szwajca M, Kurpińska A, Kij A, et al. Young first- episode psychosis patients exhibit impaired microvascular function in the skin and low systemic nitric oxide availability, independent of classical cardiovascular risk factors. Schizophr Res. 2025;283:188-99. https://doi.org/10.1016/j.schres.2025.07.002.
Kalucka J, Bierhansl L, Conchinha NV, Missiaen R, Elia I, Bruning U, et al. Quiescent endothelial cells upregulate fatty acid β-oxidation for vasculoprotection via redox homeostasis. Cell Metab. 2018;28(6):881- 94.e13.
Kim H, et al. High-sensitivity CRP and cardiovascular events: a meta-analysis. Am J Cardiol. 2022;170:45- 53.
Kobayashi S, Ohtake T, Mochida Y, Ishioka K, Oka M, Maesato K, et al. Asymmetric dimethylarginine (ADMA) as a novel risk factor for progression of coronary artery calcification in patients with chronic kidney disease. J Clin Med. 2025;14(4):1051. https://doi.org/10.3390/jcm14041051.
Kovacic JC, Dimmeler S, Harvey RP, Finkel T, Aikawa E, Krenning G, et al. Endothelial-to-mesenchymal transition in cardiovascular disease: JACC state-of-the-art review. J Am Coll Cardiol. 2019;73(2):190-209.
Lee M, et al. E-selectin as a marker of subclinical endothelial dysfunction in chronic kidney disease. Nephrol Dial Transplant. 2024;39(3):456-64.
Makhkamova M.M., Nurillayeva N.M. Relationship between metabolical associated steatotic liver disease and ischemic heart disease: clinical aspects of comorbidity. (2024). CARDIOLOGY OF UZBEKISTAN, 1(4), 221-227. https://doi.org/10.70626/cardiouz-2024-1-00025
Mućka S, Miodońska M, Jakubiak GK, Starzak M, Cieślar G, Stanek A. Endothelial function assessment by flow-mediated dilation method: a valuable tool in the evaluation of the cardiovascular system. Int J Environ Res Public Health. 2022;19(18):11242. https://doi.org/10.3390/ijerph191811242.
Nazir A, Nazir A, Afzaal U, Aman S, Sadiq SUR, Akah OZ, et al. Advancements in biomarkers for early detection and risk stratification of cardiovascular diseases: a literature review. Health Sci Rep. 2025;8(5):e70878. https://doi.org/10.1002/hsr2.70878.
Papageorgiou N, Theofilis P, Oikonomou E, Lazaros G, Sagris M, Tousoulis D. Asymmetric dimethy- larginine as a biomarker in coronary artery disease. Curr Top Med Chem. 2023;23(6):470-80. https://doi.org/10.2174/1568026623666221213085917.
Patel R, et al. TNF-α in post-COVID-19 cardiovascular sequelae: implications for endothelial dysfunction. Cardiovasc Res. 2025;121(1):88-96.
Shah AV, Birdsey GM, Peghaire C, Pitulescu ME, Dufton NP, Yang Y, et al. The endothelial transcription factor ERG mediates angiopoietin-1-dependent control of Notch signalling and vascular stability. Nat Commun. 2017;8:16002. https://doi.org/10.1038/ncomms16002.
Smith J, et al. Meta-analysis of VCAM-1 as a biomarker for endothelial dysfunction in metabolic syndrome. J Clin Endocrinol Metab. 2023;108(4):876-85.
Thijssen DH, Black MA, Pyke KE, Padilla J, Atkinson G, Harris RA, et al. Assessment of flow-mediated dilation in humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol. 2011;300(1):H2-12. https://doi.org/10.1152/ajpheart.00471.2010.
Thompson D, et al. Canakinumab reduces endothelial dysfunction markers in post-MI patients: a random- ized controlled trial. Circulation. 2023;147(5):401-10.
Tica O, Tica O. Molecular diagnostics in heart failure: from biomarkers to personalized medicine. Diagnostics. 2025;15(14):1807. https://doi.org/10.3390/diagnostics15141807.
Vaduganathan M, Mensah G, Turco J, et al. The global burden of cardiovascular diseases and risk: a compass for future health. J Am Coll Cardiol. 2022;80(25):2361-71. https://doi.org/10.1016/j.jacc.2022.1 1.005.
Vilcea A, Borta SM, Popet,iu RO, Alexandra RL, Pilat L, Nica DV, et al. High ADMA is associated with worse health profile in heart failure patients hospitalized for episodes of acute decompensation. Medicina (Kaunas). 2024;60(5):813. https://doi.org/10.3390/medicina60050813.
Wang T, et al. Multi-marker panels for endothelial dysfunction: integration with imaging modalities. Cardiovasc Diabetol. 2024;23(1):67-75.
Zhang L, et al. IL-6 and cardiovascular risk in coronary artery disease: a prospective cohort study. Eur Heart J. 2022;43(7):620-9.
Copyright (c) 2025 Н.М. Нуриллаева, Н.З. Срожидинова, М.А. Махкамова, Л. Хафизова (Автор)
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