Cardiac Dysfunction in β-Thalassemia: A Narrative Review
Abstract
Introduction: β-thalassemia, particularly the major form, is associated with significant morbidity, as it requires lifelong maintenance transfusion therapy to manage the condition. This transforms thalassemia from a fatal childhood disease into a chronic disorder. Nonetheless, this therapeutic approach presents challenges due to its pathological adverse effects on cardiac health, including heart failure and arrhythmias.
Discussion: Multiple lifelong transfusions, combined with the pathological effects of thalassemia—such as hemolysis and ineffective erythropoiesis—exacerbate excessive iron deposition, primarily in the liver but most critically in the heart. This creates a vicious cycle between iron overload and cardiac dysfunction. Due to their high dependence on blood transfusions, thalassemia major patients are predisposed to left-sided heart failure, resulting from both dilated and restrictive cardiomyopathy, as well as life-threatening arrhythmias and electrical disturbances. These complications arise from the heart’s overwhelmed capacity to clear free radicals. Cardiac dysfunction represents a critical complication requiring early detection and prompt intervention, underscoring the limitations of conventional echocardiography in diagnosing subclinical and systolic dysfunction—the latter often appearing only in advanced disease. Earlier risk stratification is essential, with recent studies highlighting the role of genetic predisposition, biomarkers, and advanced noninvasive imaging (MRI) in facilitating timely treatment initiation, such as iron-chelating therapy, to improve survival outcomes.
Conclusions: Iron overload is an inevitable consequence for thalassemia major patients requiring transfusions, as the human body lacks mechanisms to eliminate excess iron. These patients require careful observation, monitoring, and timely diagnosis according to standard guidelines to facilitate chelation therapy and prevent its harmful effects. This review examines the complex interplay between symptomatic management of thalassemia, subsequent iron overload, and cardiac dysfunction in treated patients, with the goal of promoting early detection of therapeutic complications and timely intervention.
2. Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis. 2010;5:11. doi:10.1186/1750-1172-5-11
3. Musallam KM, Rivella S, Vichinsky E, Rachmilewitz EA. Non-transfusion-dependent thalassemias and the re-evaluation of the interaction between anemia and vascular disease. Am J Hematol. 2021;96(2):E54-E56. doi:10.1002/ajh.26088
4. Origa R. β-Thalassemia. Genet Med. 2017;19(6):609-619. doi:10.1038/gim.2016.173
5. Rivella S. Ineffective erythropoiesis and thalassemias. Curr Opin Hematol. 2009;16(3):187-194. doi:10.1097/MOH.0b013e32832990a4
6. Borgna-Pignatti C, Cappellini MD, De Stefano P, Del Vecchio GC, Forni GL, Gamberini MR, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica. 2004;89(10):1187-1193.
7. Taksande A, Prabhu S, Venkatesh S. Cardiovascular aspect of Beta-thalassaemia. Cardiovasc Hematol Agents Med Chem. 2012;10(1):25-30. doi:10.2174/187152512799201172
8. Aessopos A, Kati M, Farmakis D. Heart disease in thalassemia intermedia: a review of the underlying pathophysiology. Haematologica. 2007;92(5):658-665. doi:10.3324/haematol.10915
9. Cho JH. Sudden Death and Ventricular Arrhythmias in Heart Failure With Preserved Ejection Fraction. Korean Circ J. 2022;52(4):251-264. doi:10.4070/kcj.2021.0420
10. Motta I, Scaramellini N, Cappellini MD. Management of age-associated medical complications in patients with β-thalassemia. Expert Rev Hematol. 2020;13(1):85-94. doi:10.1080/17474086.2020.1697225
11. Akiki N, Hodroj MH, Bou-Fakhredin R, Matli K, Taher AT. Cardiovascular Complications in β-Thalassemia: Getting to the Heart of It. Thalass Rep. 2023;13(1):38-50. doi:10.3390/thalassrep13010005
12. Koonrungsesomboon N, Chattipakorn SC, Fucharoen S, Chattipakorn N. Early detection of cardiac involvement in thalassemia: From bench to bedside perspective. World J Cardiol. 2013;5(8):270-279. doi:10.4330/wjc.v5.i8.270
13. Walker M, Wood J. Cardiac complications in thalassaemia major. In: Cappellini MD, Cohen A, Porter J, Taher A, editors. Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT). 3rd ed. Nicosia: Thalassaemia International Federation; 2014. p. 47-58.
14. Kremastinos DT, Farmakis D, Aessopos A, Hahalis G, Hamodraka E, Tsiapras D, et al. Beta-thalassemia cardiomyopathy: history, present considerations, and future perspectives. Circ Heart Fail. 2010;3(3):451-458. doi:10.1161/CIRCHEARTFAILURE.109.913863
15. Shariati L, Modaress M, Khanahmad H, Hejazi Z, Nikpour P. Comparison of different methods for erythroid differentiation in the K562 cell line. Biotechnol Lett. 2016;38(8):1243-1250. doi:10.1007/s10529-016-2101-8
16. Ali S, Mumtaz S, Shakir HA, Khan M, Tahir HM, Mumtaz S, et al. Current status of beta-thalassemia and its treatment strategies. Mol Genet Genomic Med. 2021;9(12):e1788. doi:10.1002/mgg3.1788
17. Sangkhae V, Nemeth E. Regulation of the Iron Homeostatic Hormone Hepcidin. Adv Nutr. 2017;8(1):126-136. doi:10.3945/an.116.013961
18. Sanchez-Villalobos M, Blanquer M, Moraleda JM, Salido EJ, Perez-Oliva AB. New Insights into Pathophysiology of β-Thalassemia. Front Med (Lausanne). 2022;9:880752. doi:10.3389/fmed.2022.880752
19. Lee YC, Yen CT, Lee YL, Chen RJ. Thalassemia Intermedia: Chelator or Not? Int J Mol Sci. 2022;23(17):10189. doi:10.3390/ijms231710189
20. Camaschella C, Pagani A, Nai A, Silvestri L. The mutual control of iron and erythropoiesis. Int J Lab Hematol. 2016;38 Suppl 1:20-26. doi:10.1111/ijlh.12505
21. Balci YI, Gurses D. Detection of early cardiac dysfunction in patients with β-thalassemia major and thalassemia trait by tissue Doppler echocardiography. Pediatr Hematol Oncol. 2011;28(6):486-496. doi:10.3109/08880018.2011.568596
22. Wijarnpreecha K, Kumfu S, Chattipakorn SC, Chattipakorn N. Cardiomyopathy associated with iron overload: how does iron enter myocytes and what are the implications for pharmacological therapy? Hemoglobin. 2015;39(1):9-17. doi:10.3109/03630269.2014.987869
23. Oudit GY, Trivieri MG, Khaper N, Liu PP, Backx PH. Role of L-type Ca2+ channels in iron transport and iron-overload cardiomyopathy. J Mol Med (Berl). 2006;84(5):349-364. doi:10.1007/s00109-005-0029-x
24. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):1810-1852. doi:10.1161/CIR.0b013e31829e8807
25. Hahalis G, Alexopoulos D, Kremastinos DT, Zoumbos NC. Heart failure in beta-thalassemia syndromes: a decade of progress. Am J Med. 2005;118(9):957-967. doi:10.1016/j.amjmed.2005.02.021
26. Gujja P, Rosing DR, Tripodi DJ, Shizukuda Y. Iron overload cardiomyopathy: better understanding of an increasing disorder. J Am Coll Cardiol. 2010;56(13):1001-1012. doi:10.1016/j.jacc.2010.03.083
27. Auger D, Pennell DJ. Cardiac complications in thalassemia major. Ann N Y Acad Sci. 2016;1368(1):56-64. doi:10.1111/nyas.13026
28. Raymond I, Pedersen F, Steensgaard-Hansen F, Green A, Busch-Sørensen M, Tuxen C, et al. Prevalence of impaired left ventricular systolic function and heart failure in a middle aged and elderly urban population segment of Copenhagen. Heart. 2003;89(12):1422-1429. doi:10.1136/heart.89.12.1422
29. Kremastinos DT, Tsiapras D, Tsetsos GA, Rentoukas EI, Vretou HP, Toutouzas PK. Heart failure in beta thalassemia: a 5-year follow-up study. Am J Med. 2001;111(5):349-354. doi:10.1016/s0002-9343(01)00827-0
30. Fu DG. Cardiac Arrhythmias: Diagnosis, Symptoms, and Treatments. Cell Biochem Biophys. 2015;73(2):291-296. doi:10.1007/s12013-015-0626-4
31. Shizukuda Y, Rosing DR. Iron overload and arrhythmias: Influence of confounding factors. J Arrhythm. 2019;35(4):575-583. doi:10.1002/joa3.12208
32. Hamed AA, Elguindy W, Elhenawy YI, Ibrahim RH. Early Cardiac Involvement and Risk Factors for the Development of Arrhythmia in Patients With β-Thalassemia Major. J Pediatr Hematol Oncol. 2016;38(1):5-11. doi:10.1097/MPH.0000000000000467
33. Pepe A, Meloni A, Rossi G, Midiri M, Missere M, Valeri G, et al. Prediction of cardiac complications for thalassemia major in the widespread cardiac magnetic resonance era: a prospective multicentre study by a multi-parametric approach. Eur Heart J Cardiovasc Imaging. 2018;19(3):299-309. doi:10.1093/ehjci/jex012
34. Atmakusuma TD, Hasibuan FD, Purnamasari D. The Correlation Between Iron Overload and Endocrine Function in Adult Transfusion-Dependent Beta-Thalassemia Patients with Growth Retardation. J Blood Med. 2021;12:749-753. doi:10.2147/JBM.S325096
35. Lesnefsky EJ. Tissue iron overload and mechanisms of iron-catalyzed oxidative injury. Adv Exp Med Biol. 1994;366:129-146. doi:10.1007/978-1-4615-1833-4_10
36. Bartfay WJ, Bartfay E. Iron-overload cardiomyopathy: evidence for a free radical--mediated mechanism of injury and dysfunction in a murine model. Biol Res Nurs. 2000;2(1):49-59. doi:10.1177/109980040000200106
37. Laurita KR, Chuck ET, Yang T, Dong WQ, Kuryshev YA, Brittenham GM. Optical mapping reveals conduction slowing and impulse block in iron-overload cardiomyopathy. J Lab Clin Med. 2003;142(2):83-89. doi:10.1016/S0022-2143(03)00060-X
38. Lekawanvijit S, Chattipakorn N. Iron overload thalassemic cardiomyopathy: iron status assessment and mechanisms of mechanical and electrical disturbance due to iron toxicity. Can J Cardiol. 2009;25(4):213-218. doi:10.1016/s0828-282x(09)70064-9
39. Sayed SAB, Abd El-Hakim A, El-Sayed MH. The early cardiac involvement in patients with β-thalassemia major. Egypt Heart J. 2013;65(4):307-315. doi:10.1016/j.ehj.2013.07.001
40. Grisaru D, Rachmilewitz EA, Mosseri M, Gotsman M, Lafair JS, Okon E, et al. Cardiopulmonary assessment in beta-thalassemia major. Chest. 1990;98(5):1138-1142. doi:10.1378/chest.98.5.1138
41. Jobanputra M, Paramore C, Laird SG, McGahan M, Telfer P. Co-morbidities and mortality associated with transfusion-dependent beta-thalassaemia in patients in England: a 10-year retrospective cohort analysis. Br J Haematol. 2020;191(5):897-905. doi:10.1111/bjh.17091
42. Russo V, Rago A, Pannone B, Parente E, Cavallaro C, Calabro MP, et al. Atrial Fibrillation and Beta Thalassemia Major: The Predictive Role of the 12-lead Electrocardiogram Analysis. Indian Pacing Electrophysiol J. 2014;14(3):121-132. doi:10.1016/s0972-6292(16)30753-7
43. Ciarambino T, Menna G, Sansone G, Giordano M. Cardiomyopathies: an overview. Int J Mol Sci. 2021;22(14):7722. doi:10.3390/ijms22147722
44. Debonnaire P, Joyce E, Hiemstra Y, Mertens BJ, Atsma DE, Schalij MJ, et al. QRS fragmentation and QTc duration relate to malignant ventricular tachyarrhythmias and sudden cardiac death in patients with hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol. 2015;26(5):547-555. doi:10.1111/jce.12647
45. Ladis V, Chouliaras G, Berdousi H, Kanavakis E, Kattamis C. Longitudinal study of survival and causes of death in patients with thalassemia major in Greece. Ann N Y Acad Sci. 2005;1054:445-450. doi:10.1196/annals.1345.067
46. Barbero U, Fornari F, Gaglioti C, Longo F, Piga A. Atrial fibrillation in β-thalassemia major patients: diagnosis, management and therapeutic options. Hemoglobin. 2018;42(3):189-193. doi:10.1080/03630269.2018.1500449
47. Hahalis G, Manolis AS, Apostolopoulos D, Alexopoulos D, Vagenakis AG, Zoumbos NC. Right ventricular cardiomyopathy in β-thalassaemia major. Eur Heart J. 2002;23(2):147-156. doi:10.1053/euhj.2001.2706
48. Economou-Petersen E, Aessopos A, Kladi A, Flevari P, Karabatsos F, Fragodimitri C, et al. Apolipoprotein E epsilon4 allele as a genetic risk factor for left ventricular failure in homozygous beta-thalassemia. Blood. 1998;92(9):3455-3459.
49. Murphy CJ, Oudit GY. Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment. J Card Fail. 2010;16(11):888-900. doi:10.1016/j.cardfail.2010.05.009
50. Ghanavat M, Ebrahimi M, Shahroukh M, Mirzaei H, Zareifar S, Karimi M. Cardiomyopathy in Thalassemia: Quick Review from Cellular Aspects to Diagnosis and Current Treatments. Lab Med. 2020;51(2):143-150. doi:10.1093/labmed/lmz052
51. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004;351(16):1655-1665. doi:10.1056/NEJMra035488
52. Barnett CF, Hsue PY, Machado RF. Pulmonary hypertension: an increasingly recognized complication of hereditary hemolytic anemias and HIV infection. JAMA. 2008;299(3):324-331. doi:10.1001/jama.299.3.324
53. Farmakis D, Aessopos A. Pulmonary hypertension associated with hemoglobinopathies: prevalent but overlooked. Circulation. 2011;123(11):1227-1232. doi:10.1161/CIRCULATIONAHA.110.988089
54. Aessopos A, Farmakis D, Karagiorga M, Voskaridou E, Loutradi A, Hatziliami A, et al. Cardiac involvement in thalassemia intermedia: a multicenter study. Blood. 2001;97(11):3411-3416. doi:10.1182/blood.v97.11.3411
55. Du ZD, Roguin N, Milgram E, Saab K, Koren A. Pulmonary hypertension in patients with thalassemia major. Am Heart J. 1997;134(3):532-537. doi:10.1016/s0002-8703(97)70091-7
56. Derchi G, Fonti A, Forni GL, Cappellini MD, Turrini F, Galanello R, et al. Pulmonary hypertension in patients with thalassemia major. Am Heart J. 1999;138(2 Pt 1):384. doi:10.1016/s0002-8703(99)70129-8
57. Teawtrakul N, Ungprasert P, Pussadhamma B, Siritanaratkul N, Chuncharunee S, Ruchutrakool T, et al. Effect of genotype on pulmonary hypertension risk in patients with thalassemia. Eur J Haematol. 2014;92(5):429-434. doi:10.1111/ejh.12261
58. Aessopos A, Farmakis D. Pulmonary hypertension in beta-thalassemia. Ann N Y Acad Sci. 2005;1054:342-349. doi:10.1196/annals.1345.041
59. Morris CR, Vichinsky EP. Pulmonary hypertension in thalassemia. Ann N Y Acad Sci. 2010;1202:205-213. doi:10.1111/j.1749-6632.2010.05580.x
60. Haw A, Palevsky HI. Pulmonary hypertension in chronic hemolytic anemias: Pathophysiology and treatment. Respir Med. 2018;137:191-200. doi:10.1016/j.rmed.2018.03.007
61. Modell B, Khan M, Darlison M. Survival in beta-thalassaemia major in the UK: data from the UK Thalassaemia Register. Lancet. 2000;355(9220):2051-2052. doi:10.1016/S0140-6736(00)02357-6
62. Glickstein H, El RB, Shvartsman M, Cabantchik ZI. Intracellular labile iron pools as direct targets of iron chelators: a fluorescence study of chelator action in living cells. Blood. 2005;106(9):3242-3250. doi:10.1182/blood-2005-02-0460
63. Chaosuwannakit N, Makarawate P, Wanitpongpun C. The Importance of Cardiac T2* Magnetic Resonance Imaging for Monitoring Cardiac Siderosis in Thalassemia Major Patients. Tomography. 2021;7(2):130-138. doi:10.3390/tomography7020012
64. Pennell DJ, Udelson JE, Arai AE, Bozkurt B, Cohen AR, Galanello R, et al. Cardiovascular function and treatment in β-thalassemia major: a consensus statement from the American Heart Association. Circulation. 2013;128(3):281-308. doi:10.1161/CIR.0b013e31829b2be6
65. Jessup M, Manno CS. Diagnosis and management of iron-induced heart disease in Cooley's anemia. Ann N Y Acad Sci. 1998;850:242-250. doi:10.1111/j.1749-6632.1998.tb10481.x
66. Silvilairat S, Charoenkwan P, Saekho S, Tantiworawit A, Srichairatanakool S. Early detection of ventricular dysfunction by tissue Doppler echocardiography related to cardiac iron overload in patients with thalassemia. Int J Cardiovasc Imaging. 2021;37(1):91-98. doi:10.1007/s10554-020-01949-8
67. Modell B, Khan M, Darlison M, Westwood MA, Ingram D, Pennell DJ. Improved survival of thalassaemia major in the UK and relation to T2* cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2008;10(1):42. doi:10.1186/1532-429X-10-42
68. Aydinok Y, Porter JB, Piga A, Elalfy M, El-Beshlawy A, Kilinç Y, et al. Prevalence and distribution of iron overload in patients with transfusion-dependent anemias differs across geographic regions: results from the CORDELIA study. Eur J Haematol. 2015;95(3):244-253. doi:10.1111/ejh.12574
69. Wood JC, Noetzli L. Cardiovascular MRI in thalassemia major. Ann N Y Acad Sci. 2010;1202:173-179. doi:10.1111/j.1749-6632.2010.05571.x
70. Kirk P, Roughton M, Porter JB, Walker JM, Tanner MA, Patel J, et al. Cardiac T2* magnetic resonance for prediction of cardiac complications in thalassemia major. Circulation. 2009;120(20):1961-1968. doi:10.1161/CIRCULATIONAHA.109.874487
71. Fischer R, Piga A, Harmatz P, Nielsen P. Monitoring long-term efficacy of iron chelation treatment with biomagnetic liver susceptometry. Ann N Y Acad Sci. 2005;1054:350-357. doi:10.1196/annals.1345.043
72. Triadyaksa P, Oudkerk M, Sijens PE. Cardiac T2* mapping: Techniques and clinical applications. J Magn Reson Imaging. 2020;52(5):1340-1351. doi:10.1002/jmri.27023
73. Ari ME, Ekici F, Çetin İİ, Tavil B, Yarali N, Tunc B. Assessment of left ventricular functions and myocardial iron load with tissue Doppler and speckle tracking echocardiography and T2* MRI in patients with β-thalassemia major. Echocardiography. 2017;34(3):383-389. doi:10.1111/echo.13463
74. Abtahi F, Abdi A, Jamshidi S, Karimi M, Babaei-Beigi MA, Attar A. Global longitudinal strain as an Indicator of cardiac Iron overload in thalassemia patients. Cardiovasc Ultrasound. 2019;17(1):24. doi:10.1186/s12947-019-0174-y
75. Abtahi F, Abdi A, Jamshidi S, Karimi M, Babaei-Beigi MA, Attar A. Tissue Doppler findings in patients with pulmonary arterial hypertension. Int Cardiovasc Res J. 2016;10(3):123-127.
76. Mirzaee F, Abtahi F, Abdi A, Karimi M, Attar A. Speckle tracking echocardiography for detection of early myocardial changes in patients treated with anthracyclines. Int Cardiovasc Res J. 2017;11(2):67-71.
77. Aypar E, Alehan D, Hazirolan T, Gümrük F. The efficacy of tissue Doppler imaging in predicting myocardial iron load in patients with beta-thalassemia major: correlation with T2* cardiovascular magnetic resonance. Int J Cardiovasc Imaging. 2010;26(4):413-421. doi:10.1007/s10554-010-9591-6
78. Magrì D, Sciomer S, Fedele F, Gualdi G, Casciani E, Pugliese P, et al. Early impairment of myocardial function in young patients with beta-thalassemia major. Eur J Haematol. 2008;80(6):515-522. doi:10.1111/j.1600-0609.2008.01054.x
79. Parsaee M, Saedi S, Joghataei P, Azarkeivan A, Alizadeh Sani Z. Value of speckle tracking echocardiography for detection of clinically silent left ventricular dysfunction in patients with β-thalassemia. Hematology. 2017;22(9):554-558. doi:10.1080/10245332.2017.1312206
80. Kolios M, Korantzopoulos P, Vlahos AP, Kapsali E, Briasoulis E, Goudevenos JA. Electrocardiographic abnormalities and arrhythmic risk markers in adult patients with beta thalassemia major. Int J Cardiol. 2016;221:932-936. doi:10.1016/j.ijcard.2016.07.037
81. Sukardi R, Wahidiyat PA, Gultom PA, Sastroasmoro S, Harimurti K, Shatri H, et al. Electrophysiological properties and heart rate variability of patients with thalassemia major in Jakarta, Indonesia. PLoS One. 2023;18(1):e0280401. doi:10.1371/journal.pone.0280401
82. Muncie HL Jr, Campbell J. Alpha and beta thalassemia. Am Fam Physician. 2009;80(4):339-344.
83. Sagnella GA. Measurement and importance of plasma brain natriuretic peptide and related peptides. Ann Clin Biochem. 2001;38(Pt 2):83-93. doi:10.1258/0004563011900317
84. Tschöpe C, Kasner M, Westermann D, Gaub R, Poller WC, Schultheiss HP. The role of NT-proBNP in the diagnostics of isolated diastolic dysfunction: correlation with echocardiographic and invasive measurements. Eur Heart J. 2005;26(21):2277-2284. doi:10.1093/eurheartj/ehi406
85. Delaporta P, Kattamis A, Apostolakou F, Boiu S, Bartzeliotou A, Tsoukas E, et al. Correlation of NT-proBNP levels and cardiac iron concentration in patients with transfusion-dependent thalassemia major. Blood Cells Mol Dis. 2013;50(1):20-24. doi:10.1016/j.bcmd.2012.09.002
86. Beshir M, Hanna D, Khalifa N, Baz E, Elhewala A. Assessment of cystatin C in pediatric sickle cell disease and B-thalassemia as a marker of subclinical cardiovascular dysfunction: A case-control study. HemaSphere. 2022;6(Suppl):2088-2089. doi:10.1097/01.HS9.0000851700.17626.11
87. Kassab-Chekir A, Laradi S, Ferchichi S, Khelil AH, Feki M, Amri F, et al. Oxidant, antioxidant status and metabolic data in patients with beta-thalassemia. Clin Chim Acta. 2003;338(1-2):79-86. doi:10.1016/j.cccn.2003.07.010
88. Sbarouni E, Georgiadou P, Voudris V. Ischemia modified albumin changes - review and clinical implications. Clin Chem Lab Med. 2011;49(2):177-184. doi:10.1515/CCLM.2011.037
89. Adly AAM, ElSherif NHK, Ismail EAR, Ibrahim YA, Niazi G, Elmetwally SH. Ischemia-modified albumin as a marker of vascular dysfunction and subclinical atherosclerosis in β-thalassemia major. Redox Rep. 2017;22(6):430-438. doi:10.1080/13510002.2017.1301624
90. Furuhashi M. Fatty Acid-Binding Protein 4 in Cardiovascular and Metabolic Diseases. J Atheroscler Thromb. 2019;26(3):216-232. doi:10.5551/jat.48710
91. Fuseya T, Furuhashi M, Yuda S, Muranaka A, Kawamukai M, Mita T, et al. Elevation of circulating fatty acid-binding protein 4 is independently associated with left ventricular diastolic dysfunction in a general population. Cardiovasc Diabetol. 2014;13:126. doi:10.1186/s12933-014-0126-7
92. Fianza PI, Rahmawati A, Afifah S, Madiyan M, Putri DC, Soedjatmiko, et al. Correlation between Serum Fatty Acid Binding Protein 4 (FABP4) Levels and Cardiac Function in Patients with Thalassemia Major. Dis Markers. 2021;2021:5130628. doi:10.1155/2021/5130628
93. Singh M, Kumar R, Tewari S, Agarwal S. Determining Nt-proBNP Levels with Diastolic Dysfunction in Thalassemia Major Patients. J Pediatr Genet. 2017;6(4):222-226. doi:10.1055/s-0037-1602138
94. Farmakis D, Porter J, Taher A, Cappellini MD, Angastiniotis M, Eleftheriou A. 2021 Thalassaemia International Federation Guidelines for the Management of Transfusion-dependent Thalassemia. HemaSphere. 2022;6(8):e732. doi:10.1097/HS9.0000000000000732
95. Taher AT, Vichinsky E, Musallam KM, Cappellini MD, Viprakasit V. Guidelines for the Management of Non Transfusion Dependent Thalassaemia (NTDT). 1st ed. Nicosia: Thalassaemia International Federation; 2013.
96. Langer AL. Beta-Thalassemia. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023.
97. Khosravi MA, Abbasalipour M, Concordet JP, Berg JV, Zeinali S, Arashkia A, et al. Targeted deletion of BCL11A gene by CRISPR-Cas9 system for fetal hemoglobin reactivation: A promising approach for gene therapy of beta thalassemia disease. Eur J Pharmacol. 2019;854:398-405. doi:10.1016/j.ejphar.2019.04.042
98. Kountouris P, Lederer CW, Fanis P, Feleki X, Old J, Kleanthous M. IthaGenes: an interactive database for haemoglobin variations and epidemiology. PLoS One. 2014;9(7):e103020. doi:10.1371/journal.pone.0103020
99. Jaing TH, Chang TY, Chen SH, Lin CW, Wen YC, Chiu CC. Molecular genetics of β-thalassemia: A narrative review. Medicine (Baltimore). 2021;100(45):e27522. doi:10.1097/MD.0000000000027522
100. Mettananda S, Gibbons RJ, Higgs DR. α-Globin as a molecular target in the treatment of β-thalassemia. Blood. 2015;125(24):3694-3701. doi:10.1182/blood-2015-03-633594
101. Origa R, Satta S, Matta G, Galanello R. Glutathione S-transferase gene polymorphism and cardiac iron overload in thalassaemia major. Br J Haematol. 2008;142(1):143-145. doi:10.1111/j.1365-2141.2008.07175.x
102. Mokhtar GM, Sherif EM, Habeeb NM, El-Tagui M, Abdel Aziz AM. Glutathione S-transferase gene polymorphism: Relation to cardiac iron overload in Egyptian patients with Beta Thalassemia Major. Hematology. 2016;21(1):46-53. doi:10.1179/1607845415Y.0000000046
103. Allegra S, Cusato J, De Francia S, Longo F, Piga A, Perugini J, et al. Role of CYP1A1, ABCG2, CYP24A1 and VDR gene polymorphisms on the evaluation of cardiac iron overload in thalassaemia patients. Pharmacogenet Genomics. 2018;28(9):199-206. doi:10.1097/FPC.0000000000000348
104. Divanovic S, Dalli J, Jorge-Nebert LF, Flick LM, Gálvez-Peralta M, Boespflug ND, et al. Contributions of the three CYP1 monooxygenases to pro-inflammatory and inflammation-resolution lipid mediator pathways. J Immunol. 2013;191(6):3347-3357. doi:10.4049/jimmunol.1300699
105. Robey RW, To KK, Polgar O, Dohse M, Fetsch P, Dean M, et al. ABCG2: a perspective. Adv Drug Deliv Rev. 2009;61(1):3-13. doi:10.1016/j.addr.2008.11.003
106. Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 2014;21(3):319-329. doi:10.1016/j.chembiol.2013.12.016
107. Gerousi M, Psomopoulos F, Kotta K, Laidou S, Gaitanou A, Fotopoulos D, et al. The Calcitriol/Vitamin D Receptor System Regulates Key Immune Signaling Pathways in Chronic Lymphocytic Leukemia. Cancers (Basel). 2021;13(2):285. doi:10.3390/cancers13020285
108. Patanè S, Marte F. Abnormal troponin I levels in a thalassemia major patient with high ferritin concentration, permanent atrial fibrillation and without acute coronary syndrome. Int J Cardiol. 2010;138(2):e24-e27. doi:10.1016/j.ijcard.2008.06.039
109. Penno G, Solini A, Bonora E, Fondelli C, Orsi E, Zerbini G, et al. Gender differences in cardiovascular disease risk factors, treatments and complications in
patients with type 2 diabetes: the RIACE Italian multicentre study. J Intern Med. 2013;274(2):176-91.
110. Chaikuad A, Thangaratnarajah C, von Delft F, Knapp S. Structural consequences of BMPR2 kinase domain mutations causing pulmonary arterial hypertension. Sci Rep. 2019;9(1):18351.
111. Gardenghi S, Grady RW, Rivella S. Anemia, ineffective erythropoiesis, and hepcidin: interacting factors in abnormal iron metabolism leading to iron overload in β-thalassemia. Hematol Oncol Clin North Am. 2010;24(6):1089-107.
112. Porter J, Viprakasit V. IRON OVERLOAD AND CHELATION. In: Cappellini MD, Cohen A, Porter J, Taher A, editors. Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT) [Internet]. 3rd ed. Nicosia (CY): Thalassaemia International Federation; 2014 [cited 2024 Dec 19]. Chapter 3.
113. Ehteram H, Bavarsad MS, Mokhtari M, Azarkeivan A, Shams S. Prooxidant-antioxidant balance and hs-CRP in patients with beta-thalassemia major. Clin Lab. 2014;60(2):207-15.
114. Cassinerio E, Roghi A, Pedrotti P, Brevi F, Zanaboni L, Graziadei G, et al. Cardiac iron removal and functional cardiac improvement by different iron chelation regimens in thalassemia major patients. Ann Hematol. 2012;91(9):1443-9.
115. Porter JB, Cappellini MD, Taher A, Viprakasit V, Kattamis A, Chuansumrit A, et al. TIF Guidelines for the Management of Transfusion-Dependent β-Thalassemia. 5th ed. Nicosia (CY): Thalassaemia International Federation; 2025.
116. Mobarra N, Shanaki M, Ehteram H, Nasiri H, Sahmani M, Saeidi M, et al. A Review on Iron Chelators in Treatment of Iron Overload Syndromes. Int J Hematol Oncol Stem Cell Res. 2016;10(4):239-47.
117. Xia S, Zhang W, Huang L, Jiang H. Comparative efficacy and safety of deferoxamine, deferiprone and deferasirox on severe thalassemia: a meta-analysis of 16 randomized controlled trials. PLoS One. 2013;8(12):e82662.
118. Davis BA, Porter JB. Long-term outcome of continuous 24-hour deferoxamine infusion via indwelling intravenous catheters in high-risk beta-thalassemia. Blood. 2000;95(4):1229-36.
119. Anderson LJ, Westwood MA, Holden S, Davis B, Porter JB, Wonke B, et al. Myocardial iron clearance during reversal of siderotic cardiomyopathy with intravenous desferrioxamine: a prospective study using T2* cardiovascular magnetic resonance. Br J Haematol. 2004;127(3):348-55.
120. Poggiali E, Cassinerio E, Zanaboni L, Cappellini MD. An update on iron chelation therapy. Blood Transfus. 2012;10(4):411-22.
121. Anderson LJ, Wonke B, Prescott E, Holden S, Walker JM, Pennell DJ. Comparison of effects of oral deferiprone and subcutaneous desferrioxamine on myocardial iron concentrations and ventricular function in beta-thalassaemia. Lancet. 2002;360(9332):516-20.
122. Ladis V, Chouliaras G, Berdoukas V, Moraitis P, Zannikos K, Karabatsos F, et al. Relation of chelation regimes to cardiac mortality and morbidity in patients with thalassaemia major: an observational study from a large Greek Unit. Eur J Haematol. 2010;85(4):335-44.
123. Cianciulli P. Iron chelation therapy in thalassemia syndromes. Mediterr J Hematol Infect Dis. 2009;1(1):e2009034.
124. Pennell DJ, Porter JB, Cappellini MD, El-Beshlawy A, Chan LL, Aydinok Y, et al. Efficacy of deferasirox in reducing and preventing cardiac iron overload in beta-thalassemia. Blood. 2010;115(12):2364-71.
125. Wonke B, Wright C, Hoffbrand AV. Combined therapy with deferiprone and desferrioxamine. Br J Haematol. 1998;103(2):361-4.
126. Tanner MA, Galanello R, Dessi C, Smith GC, Westwood MA, Agus A, et al. A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Circulation. 2007;115(14):1876-84.
127. Galanello R, Piga A, Cappellini MD, Forni GL, Zappu A, Origa R, et al. Effect of food, type of food, and time of food intake on deferasirox bioavailability: recommendations for an optimal deferasirox administration regimen. J Clin Pharmacol. 2008;48(4):428-35.
128. Cappellini MD, Viprakasit V, Taher AT, Georgiev P, Kuo KHM, Coates T, et al. A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent β-Thalassemia. N Engl J Med. 2020;382(13):1219-31.
129. Kwiatkowski JL, Walters MC, Hongeng S, Kwon SY, Rasko JEJ, Soni S, et al. Betibeglogene autotemcel gene therapy in patients with transfusion-dependent, severe genotype β-thalassaemia (HGB-212): a non-randomised, multicentre, single-arm, open-label, single-dose, phase 3 trial. Lancet. 2024;404(10468):2175-86.
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Issue | Vol 20 No 2 (2025) | |
Section | Review Article(s) | |
DOI | https://doi.org/10.18502/jthc.v20i2.19709 | |
Keywords | ||
β-thalassemia Cardiac Dysfunction and Arrhythmias Iron Chelation Treatment and Guidelines Management |
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