Scientific Online Resource System

Varna Medical Forum

Endothelial dysfunction in beta-thalassemia

Kristina Petrova


The vascular endothelium is a dynamic endocrine structure that actively contributes to the maintenance of vascular homeostasis. Endothelial dysfunction, which serves as a marker of vascular damage, often precedes and initiates cardiovascular disease. The identification of endothelial dysfunction holds significant clinical importance and can be achieved through the examination of various cell markers or functional tests.

Endothelial damage leads to arterial stiffness, which aids in the diagnosis of atherosclerosis and cardiovascular diseases, while also acting as a marker for increased cardiovascular morbidity and mortality. Pulse wave velocity measurement is one of the primary methods used to assess arterial stiffness, serving as an independent risk factor for future cardiovascular events and overall mortality.

In patients with beta-thalassemia major (BTM), free iron-related peroxidative tissue damage is associated with a high risk of developing endothelial dysfunction and arterial stiffness. Increased life expectancy and the alarming prevalence of classic cardiovascular risk factors such as diabetes, arterial hypertension, and smoking lead to an increased risk of accelerated atherosclerosis and cardiovascular disease in BTM patients.

Multicenter studies focusing on the evaluation of vascular damage and oxidative stress in BTM patients continue to be conducted in order to enhance early diagnosis, secondary prevention, and timely therapeutic interventions.


endothelial dysfunction, oxidative stress, β-thalassaemia major, atherosclerosis, arterial stiffness

Full Text


Pries AR, Secomb TW, Gaehtgens P. The endothelial surface layer. Pflugers Arch Eur J Physiol. 2000;440(5):653–66.

Николов ПФ. Ендотелна дисфункция и коронарна болест. Пловдив: Лакс Бук; 2019.

Higashi Y, Yoshizumi M. Exercise and endothelial function: Role of endothelium-derived nitric oxide and oxidative stress in healthy subjects and hypertensive patients. Pharmacol Ther. 2004;102(1):87–96.

Benjamin EJ, Larson MG, Keyes MJ, Mitchell GF, Vasan RS, Keaney JF, et al. Clinical Correlates and Heritability of Flow-Mediated Dilation in the Community: The Framingham Heart Study. Circulation. 2004;109(5):613–9.

Feher A, Broskova Z, Bagi Z. Age-related impairment of conducted dilation in human coronary arterioles. Am J Physiol - Hear Circ Physiol. 2014;306(12).

Lerman A, Zeiher AM. Endothelial function: Cardiac events. Circulation. 2005;111(3):363–8.

Gao J, Pan X, Li G, Chatterjee E, Xiao J. Physical Exercise Protects Against Endothelial Dysfunction in Cardiovascular and Metabolic Diseases. J Cardiovasc Transl Res. 2022;15(3):604–20.

Krüger-Genge A, Blocki A, Franke RP, Jung F. Vascular endothelial cell biology: An update. Int J Mol Sci. 2019;20(18).

Денева Т. Серумни маркери за ендотелна дисфункция при атерсклероза. Пловдив, 2022: Лакс Бук;

Moncada S, Higgs EA. The discovery of nitric oxide and its role in vascular biology. Br J Pharmacol. 2006;147(SUPPL. 1):193–201.

Ignarro LJ. Nitric oxide is not just blowing in the wind. Br J Pharmacol. 2019;176(2):131–4.

Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327(6122):524–6.

Dulce RA, Kulandavelu S, Schulman IH, Fritsch J, Hare JM. Nitric Oxide Regulation of Cardiovascular Physiology and Pathophysiology. Third Edit. Nitric Oxide: Biology and Pathobiology: Third Edition. Elsevier Inc.; 2017. 313–338 p.

Förstermann U, Sessa WC. Nitric oxide synthases: Regulation and function. Eur Heart J. 2012;33(7):1–13.

Adams MR, Kinlay S, Blake GJ, Orford JL, Ganz P, Selwyn AP. Atherogenic lipids and endothelial dysfunction: Mechanisms in the genesis of ischemic syndromes. Annu Rev Med. 2000;51:149–67.

Jebari-Benslaiman S, Galicia-García U, Larrea-Sebal A, Olaetxea JR, Alloza I, Vandenbroeck K, et al. Pathophysiology of Atherosclerosis. Int J Mol Sci. 2022;23(6):1–38.

Saenz-Medina J, Muñoz M, Rodriguez C, Sanchez A, Contreras C, Carballido-Rodríguez J, et al. Endothelial Dysfunction: An Intermediate Clinical Feature between Urolithiasis and Cardiovascular Diseases. Int J Mol Sci. 2022;23(2):1–19.

Stohs SJ, Bagchi D. Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med. 1995;18(2):321–36.

Martemucci G, Costagliola C, Mariano M, D’andrea L, Napolitano P, D’Alessandro AG. Free Radical Properties, Source and Targets, Antioxidant Consumption and Health. Oxygen. 2022;2(2):48–78.

Khalid M, Hassani S, Abdollahi M. Metal-induced oxidative stress: an evidence-based update of advantages and disadvantages. Curr Opin Toxicol. 2020;20–21:55–68.

Yuji T and. What is oxidative stress ? 2002;124(11):271–6.

Sies H. Oxidative stress: Concept and some practical aspects. Antioxidants. 2020;9(9):1–6.

Liebert MA, Jones DP. Redefining Oxidative Stress. 2006;8.

Helmut Sies, Carsten Berndt DPJ. Oxidative stress. Vitiligo. 2010;(April):231–7.

Mohammed NA, Rasoul HFA. Evaluation of Oxidative Stress and Antioxidant Status in Beta Thalassemia Major Patients: A Single-Center Study. Med J Cairo Univ. 2020;88(12):2147–55.

Shazia Q, Mohammad ZH, Rahman T, Shekhar HU. Correlation of oxidative stress with serum trace element levels and antioxidant enzyme status in beta thalassemia major patients: A review of the literature. Anemia. 2012;2012.

Hershko C. Pathogenesis and management of iron toxicity in thalassemia. Ann N Y Acad Sci. 2010;1202:1–9.

Desai SN, Farris FF, Ray SD. Lipid Peroxidation. Third Edit. Vol. 2, Encyclopedia of Toxicology: Third Edition. Elsevier; 2014. 89–93 p.

Maria Sposi N. Oxidative Stress and Iron Overload in β-Thalassemia: An Overview. Beta Thalass. 2020;

Cunningham MJ, Macklin EA, Neufeld EJ, Cohen AR. Complications of β-thalassemia major in North America. Blood. 2004;104(1):34–9.

Detchaporn P, Kukongviriyapan U. Altered Vascular Function , Arterial Stiffness , and Antioxidant Gene Responses in Pediatric Thalassemia Patients. 2012;1054–60.

Verma S, Buchanan MR, Anderson TJ. Endothelial Function Testing as a Biomarker of Vascular Disease. Circulation. 2003;108(17):2054–9.

Halcox JPJ, Donald AE, Ellins E, Witte DR, Shipley MJ, Brunner EJ, et al. Endothelial function predicts progression of carotid intima-media thickness. Circulation. 2009;119(7):1005–12.

Kattoor AJ, Pothineni NVK, Palagiri D, Mehta JL. Oxidative Stress in Atherosclerosis. Curr Atheroscler Rep. 2017;19(11).

Tsutsui H, Kinugawa S, Matsushima S. Oxidative stress and heart failure. Am J Physiol - Hear Circ Physiol. 2011;301(6):2181–90.

Cighetti G, Duca L, Bortone L, S.Sala, Nava I. Oxidative status andmalondialdehyde in.pdf. 2002;32:55–60.

Manios E, Tsivgoulis G, Koroboki E, Stamatelopoulos K, Papamichael C, Toumanidis S, et al. Impact of prehypertension on common carotid artery intima-media thickness and left ventricular mass. Stroke. 2009;40(4):1515–8.

Jeffrey A Switzer, David C Hess FTN. Pathophysiology and treatment of stroke in sickle-cell disease: present and future. Lancet Neurol. 2006;5(6):501–12.

Hahalis G, Kremastinos DT, Terzis G, Kalogeropoulos AP, Chrysanthopoulou A, Karakantza M, et al. Global vasomotor dysfunction and accelerated vascular aging in β-thalassemia major. Atherosclerosis. 2008;198(2):448–57.

Cheung YF, Chow PC, Chan GC. Carotid intima-media thickness is increased and related to arterial stiffening in patients with beta-thalassaemia major. 2006;732–4.

Tantawy AAG, Adly AAM, El Maaty MGA, Amin SAG. Subclinical atherosclerosis in young β-thalassemia major patients. Hemoglobin. 2009;33(6):463–74.

Borgna-Pignatti C, Cappellini MD, De Stefano P, Del Vecchio GC, Forni GL, Gamberini MR, et al. Survival and complications in thalassemia. Ann N Y Acad Sci. 2005;1054:40–7.

Soltani M, Hassanipour S, Veisani Y, Darbandi M, Rezaiean S. Global survival rate of patients with beta thalassemia major: a systematic review and meta-analysis. J Contemp Med Sci. 2021;7(2):80–5.

Farmakis D, Giakoumis A, Angastiniotis M, Eleftheriou A. The changing epidemiology of the ageing thalassaemia populations: A position statement of the Thalassaemia International Federation. Eur J Haematol. 2020;105(1):16–23.

Zurlo MG, De Stefano P, Borgna-Pignatti C, Di Palma A, Melevendi C, Piga A, et al. Survival and Causes of Death in Thalassaemia Major. Lancet. 1989;334(8653):27–30.

Kremastinos DT, Farmakis D. Iron overload cardiomyopathy in clinical practice. Circulation. 2011;124(20):2253–63.

Kraml P. The role of iron in the pathogenesis of atherosclerosis. Physiol Res. 2017;66:S55–67.

Knuiman MW, Divitini ML, Olynyk JK, Cullen DJ, Bartholomew HC. Serum ferritin and cardiovascular disease: A 17-year follow-up study in Busselton, Western Australia. Am J Epidemiol. 2003;158(2):144–9.

Stefan Kiechl, Johann Willeit, Georg Egger, Werner Poewe, Friedrich Oberhollenzer and 1 for the BSG. Body Iron Stores are Associated, 1997.

Salonen JT, Tuomainen TP, Salonen R, Lakka TA, Nyyssönen K. Donation of blood is associated with reduced risk of myocardial infarction: The Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Epidemiol. 1998;148(5):445–51.

Манолов В, Петрова Ю ВВ. Роля на хепсидина в патогенезата на атеросклерозата. 2017;16–23.

Georgieva V, Dimitrova A. Applanation Arterial Tonometry Assesment Of Arterial Stiffness. Varna Med Forum. 2021;10(3):14.

Nichols WW. Clinical measurement of arterial stiffness obtained from noninvasive pressure waveforms. Am J Hypertens. 2005;18(1 SUPPL.):3–10.

Chemla D, Nitenberg A, Teboul JL, Richard C, Monnet X, Le Clesiau H, et al. Subendocardial viability index is related to the diastolic/systolic time ratio and left ventricular filling pressure, not to aortic pressure: An invasive study in resting humans. Clin Exp Pharmacol Physiol. 2009;36(4):413–8.

Duprez DA, Cohn JN. Arterial stiffness as a risk factor for coronary atherosclerosis. Curr Atheroscler Rep. 2007;9(2):139–44.

Vriz O, Aboyans V, Minisini R, Magne J, Bertin N, Pirisi M, et al. Reference values of one-point carotid stiffness parameters determined by carotid echo-tracking and brachial pulse pressure in a large population of healthy subjects. Hypertens Res. 2017;40(7):685–95.

Kocabay G, Hasdemir H, Yildiz M. Evaluation of pulse wave velocity in systemic lupus erythematosus, rheumatoid arthritis and Behçet’s disease. J Cardiol [Internet]. 2012;59(1):72–7. Available from:

Fried R. Measuring and Evaluating Function, Impairment, and Change with Intervention [Internet]. Erectile Dysfunction As a Cardiovascular Impairment. Elsevier Inc.; 2014. 27–75 p. Available from:

Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et al. Expert consensus document on arterial stiffness: Methodological issues and clinical applications. Eur Heart J. 2006;27(21):2588–605.

Vriz O, Driussi C, La Carrubba S, Di Bello V, Zito C, Carerj S, et al. Comparison of sequentially measured Aloka echo-tracking one-point pulse wave velocity with SphygmoCor carotid–femoral pulse wave velocity. SAGE Open Med. 2013;1:205031211350756.

Visseren FLJ, MacH F, Smulders YM, Carballo D, Koskinas KC, Bäck M, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021;42(34):3227–337.

Chirinos JA, Zambrano JP, Chakko S, Veerani A, Schob A, Willens HJ, et al. Aortic pressure augmentation predicts adverse cardiovascular events in patients with established coronary artery disease. Hypertension. 2005;45(5):980–5.

В.Минчева. Артериална ригидност и артериално налягане Възможности за оценка и клинично значение. Мединфо. 2008;(09):1–2.

Marinova E. Ultrasound measument of local arterial stiffness through one-point echo-tracking technique. Varna Med Forum. 2020;9(1):41.

Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: Principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006;113(9):1213–25.

E.Lukich, Z.Matas, M.Boaz. Increasing derangement of glucose homeostasis is associated with increased arterial stiffness in patients with diabetes, impaired fasting glucose and normal controls. Diabetes Metab Res Rev [Internet]. 2014;32(30):13–23. Available from:

Corretti MC, Anderson TJ, Benjamin EJ, Ms C, Celermajer D, Charbonneau F, et al. Guidelines for the Ultrasound Assessment of Endothelial-Dependent Flow-Mediated Vasodilation of the Brachial Artery A Report of the International Brachial Artery Reactivity Task Force. 2002;39(2).

Richardson CJ, Maki-Petaja KM, McDonnell BJ, Hickson SS, Wilkinson IB, McEniery CM. Comparison of estimates of central systolic blood pressure and peripheral augmentation index obtained from the Omron HEM-9000AI and SphygmoCor systems. Artery Res [Internet]. 2009;3(1):24–31. Available from:

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).

Hamburg NM, Keyes MJ, Larson MG, Vasan RS, Schnabel R, Pryde MM, et al. Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham heart study. Circulation. 2008;117(19):2467–74.



Font Size