Cardiac involvement in hemochromatosis

Cardiology in Review

Volumn 22, Issue 2, 2014, Pages 56-68

  Gulati, Vinay ^a   Harikrishnan, Prakash ^b   Palaniswamy, Chandrasekar ^b   Aronow, Wilbert S ^b   Jain, Diwakar ^b   Frishman, William H ^b  

^a UNIVERSITY OF CONNECTICUT HEALTH CENTER   (United States)

^b NEW YORK MEDICAL COLLEGE   (United States)

Author keywords

cardiomyopathy; hemochromatosis; iron overload

Indexed keywords

BIOPSY; HEART; HEART FAILURE; HEMOCHROMATOSIS; HUMANS; IRON; IRON CHELATING AGENTS; LIVER; PHLEBOTOMY; SURVIVAL RATE; TREATMENT OUTCOME;

EID: 84894098891     PISSN: 10615377     EISSN: 15384683     Source Type: Journal    
DOI: 10.1097/CRD.0b013e3182a67805     Document Type: Review

References (182)

1. Von Recklinghausen FD. Uber Haemochromatose. Heidelberg, Germany: Taggeblatt der (62) Versammlung deutscher Naturforscher and Aerzte; 1889:324-325.
2. Sheldon J. Haemochromatosis. New York, NY: Oxford University Press; 1935.
3. Finch SC, Finch CA. Idiopathic hemochromatosis, an iron storage disease. A. Iron metabolism in hemochromatosis. Medicine (Baltimore). 1955;34:381-430.
4. Andrews NC. Disorders of iron metabolism. N Engl J Med. 1999;341:1986-1995.
5. Olsson KS, Norrby A. Comment to: Hepcidin: from discovery to differential diagnosis. Haematologica 2008;93:90-7. Haematologica. 2008;93:e51.
6. Conrad ME, Umbreit JN. Pathways of iron absorption. Blood Cells Mol Dis. 2002;29:336-355.
7. Ward DM, Kaplan J. Ferroportin-mediated iron transport: expression and regulation. Biochim Biophys Acta. 2012;1823:1426-1433.
8. Yeh KY, Yeh M, Mims L, et al. Iron feeding induces ferroportin 1 and hep-haestin migration and interaction in rat duodenal epithelium. Am J Physiol Gastrointest Liver Physiol. 2009;296:G55-G65.
9. Ponka P, Beaumont C, Richardson DR. Function and regulation of transferrin and ferritin. Semin Hematol. 1998;35:35-54.
10. Ohgami RS, Campagna DR, Greer EL, et al. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet. 2005;37:1264-1269.
11. Richardson DR, Lane DJ, Becker EM, et al. Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol. Proc Natl Acad Sci USA. 2010;107:10775-10782.
12. Shi H, Bencze KZ, Stemmier TL, et al. A cytosolic iron chaperone that delivers iron to ferritin. Science. 2008;320:1207-1210.
13. Nemeth E, Ganz T. The role of hepcidin in iron metabolism. Acta Haematol. 2009;122:78-86.
14. Hentze MW, Muckenthaler MU, Galy B, et al. Two to tango: regulation of mammalian iron metabolism. Cell. 2010;142:24-38.
15. Lin L, Goldberg YP, Ganz T. Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin. Blood. 2005;106:2884-2889.
16. Babitt JL, Huang FW, Wrighting DM, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38:531-539.
17. Silvestri L, Pagani A, Camaschella C. Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis. Blood. 2008;111:924-931.
18. Rouault TA. The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol. 2006;2:406-414.
19. Roetto A, Papanikolaou G, Politou M, et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 2003;33:21-22.
20. Merryweather-Clarke AT, Pointon JJ, Shearman JD, et al. Global prevalence of putative haemochromatosis mutations. J Med Genet. 1997;34:275-278.
21. Adams PC, Reboussin DM, Barton JC, et al; Hemochromatosis and Iron Overload Screening (HEIRS) Study Research Investigators. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med. 2005;352:1769-1778.
22. Acton RT, Barton JC, Passmore LY et al. Accuracy of family history of hemochromatosis or iron overload: the hemochromatosis and iron overload screening study. Clin Gastroenterol Hepatol. 2008;6:934-938.
23. European Association for the Study of the Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010;53:3-22.
24. Camaschella C, Roetto A, Calì A, et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet. 2000;25:14-15.
25. Papanikolaou G, Samuels ME, Ludwig EH, et al. Mutations in HFE2 cause iron overload in chromosome lq-linked juvenile hemochromatosis. Nat Genet. 2004;36:77-82.
26. Sham RL, Phatak PD, West C, et al. Autosomal dominant hereditary hemochromatosis associated with a novel ferroportin mutation and unique clinical features. Blood Cells Mol Dis. 2005;34:157-161.
27. Gordeuk Y Mukiibi J, Hasstedt S J, et al. Iron overload in Africa. Interaction between a gene and dietary iron content. N Engl J Med. 1992;326:95-100.
28. Ali M, Fayemi AO, Rigolosi R, et al. Hemosiderosis in hemodialysis patients. An autopsy study of 50 cases. JAMA. 1980;244:343-345.
29. Kletzmayr J, Horl WH. Iron overload and cardiovascular complications in dialysis patients. Nephrol Dial Transplant. 2002;17(suppl 2):25-29.
30. Sood MM, Oudit GY, Mohammadi H, et al. Effects of parenteral iron on inflammation and the myocardium in hemodialysis patients. Hemodial Int. 2008;12:362-368.
31. Lesnefsky EJ, Moghaddas S, Tandler B, et al. Mitochondrial dysfunction in cardiac disease: ischemia-reperfusion, aging, and heart failure. J Mol Cell Cardiol. 2001;33:1065-1089.
32. Tsushima RG, Wickenden AD, Bouchard RA, et al. Modulation of iron uptake in heart by L-type Ca2+ channel modifiers: possible implications in iron overload. Circ Res. 1999;84:1302-1309.
33. Liu P, Olivieri N. Iron overload cardiomyopathies: new insights into an old disease. Cardiovasc Drugs Ther. 1994;8:101-110.
34. Horwitz LD, Rosenthal EA. Iron-mediated cardiovascular injury. Vase Med. 1999;4:93-99.
35. Miranda CJ, Makui H, Soares RJ, et al. Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin. Blood. 2003;102:2574-2580.
36. Cascales A, Sanchez-Vega B, Navarro N, et al. Clinical and genetic determinants of anthracycline-induced cardiac iron accumulation. Int J Cardiol. 2012;154:282-286.
37. Panjrath GS, Patel Y Valdiviezo CI, et al. Potentiation of Doxorubicin cardiotoxicity by iron loading in a rodent model. J Am Coll Cardiol. 2007;49:2457-2464.
38. Valenti L, Conte D, Piperno A, et al. The mitochondrial superoxide dismutase A16V polymorphism in the cardiomyopathy associated with hereditary haemochromatosis. J Med Genet. 2004;41:946-950.
39. Olson LJ, Edwards WD, Holmes DR Jr, et al. Endomyocardial biopsy in hemochromatosis: clinicopathologic correlates in six cases. J Am Coll Cardiol. 1989;13:116-120.
40. Gaenzer H, Marschang P, Sturm W, et al. Association between increased iron stores and impaired endothelial function in patients with hereditary hemochromatosis. J Am Coll Cardiol. 2002;40:2189-2194.
41. Shizukuda Y, Tripodi DJ, Zalos G, et al. Incidence of cardiac arrhythmias in asymptomatic hereditary hemochromatosis subjects with C282Y homozygosity. Am J Cardiol. 2012;109:856-860.
42. Shizukuda Y, Smith KP, Tripodi DJ, et al. Changes in exercise capacity in subjects with cardiac asymptomatic hereditary hemochromatosis during a follow-up after 5 yrs. Am JPhys Med Rehabil. 2012;91:418-424.
43. Edwards CQ, Griffen LM, Goldgar D, et al. Prevalence of hemochromatosis among 11, 065 presumably healthy blood donors. N Engl J Med. 1988;318:1355-1362.
44. Aldouri MA, Wonke B, Hoffbrand AV, et al. High incidence of cardiomyopathy in beta-thalassaemia patients receiving regular transfusion and iron chelation: reversal by intensified chelation. Acta Haematol. 1990;84:113-117.
45. Buja LM, Roberts WC. Iron in the heart. Etiology and clinical significance. Am JMed. 1971;51:209-221.
46. Hahalis G, Alexopoulos D, Kremastinos DT, et al. Heart failure in beta-thalas-semia syndromes: a decade of progress. Am JMed. 2005;118:957-967.
47. Skinner C, Kenmure AC. Haemochromatosis presenting as congestive cardiomyopathy and responding to venesection. Br Heart J. 1973;35:466-468.
48. Furth PA, Futterweit W, Gorlin R. Refractory biventricular heart failure in secondary hemochromatosis. Am J Med Sci. 1985;290:209-213.
49. Wasserman AJ, Richardson DW, Baird CL, et al. Cardiac hemochromatosis simulating constrictive pericarditis. Am J Med. 1962;32:316-323.
50. Feely J, Counihan TB. Haemochromatosis presenting as angina and responding to venesection. Br Med J. 1977;2:681-682.
51. James TN. Pathology of the cardiac conduction system in hemochromatosis. N Engl JMed. 1964;271:92-94.
52. Aronow WS, Meister L, Kent JR. Atrioventricular block in familial hemochromatosis treated by permanent synchronous pacemaker. Arch Intern Med. 1969;123:433-435.
53. Wu VC, Huang JW, Wu MS, et al. The effect of iron stores on corrected QT dispersion in patients undergoing peritoneal dialysis. Am J Kidney Dis. 2004;44:720-728.
54. Rose RA, Sellan M, Simpson JA, et al. Iron overload decreases CaV1.3-dependent L-type Ca2+ currents leading to bradycardia, altered electrical conduction, and atrial fibrillation. CircArrhythm Electrophysiol. 2011;4:733-742.
55. Klintschar M, Stiller D. Sudden cardiac death in hereditary hemochromatosis: an underestimated cause of death? Int J Legal Med. 2004;118:174-177.
56. Campbell S, George DK, Robb SD, et al. The prevalence of haemochromatosis gene mutations in the West of Scotland and their relation to ischaemic heart disease. Heart. 2003;89:1023-1026.
57. Candore G, Balistreri CR, Lio D, et al. Association between HFE mutations and acute myocardial infarction: a study in patients from Northern and Southern Italy. Blood Cells Mol Dis. 2003;31:57-62.
58. Dunn T, Blankenship D, Beal N, et al. HFE mutations in heart disease. Heart Vessels. 2008;23:348-355.
59. Zacharski LR, Chow BK, Howes PS, et al. Reduction of iron stores and cardiovascular outcomes in patients with peripheral arterial disease: a randomized controlled trial. JAMA. 2007;297:603-610.
60. Schmitt B, Golub RM, Green R. Screening primary care patients for hereditary hemochromatosis with transferrin saturation and serum ferritin level: systematic review for the American College of Physicians. Ann Intern Med. 2005;143:522-536.
61. Qaseem A, Aronson M, Fitterman N, et al; Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Screening for hereditary hemochromatosis: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2005;143:517-521.
62. Beutler E, Felitti VJ, Koziol JA, et al. Penetrance of 845G-> A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet. 2002;359:211-218.
63. Harris EL, McLaren CE, Reboussin DM, et al. Serum ferritin and transferrin saturation in Asians and Pacific Islanders. Arch Intern Med. 2007;167:722-726.
64. Tran TN, Eubanks SK, Schaffer KJ, et al. Secretion of ferritin by rat hepatoma cells and its regulation by inflammatory cytokines and iron. Blood. 1997;90:4979-4986.
65. Chapman RW, Morgan MY, Laulicht M, et al. Hepatic iron stores and markers of iron overload in alcoholics and patients with idiopathic hemochromatosis. Dig Dis Sci. 1982;27:909-916.
66. Brownell A, Lowson S, Brozovic M. Serum ferritin concentration in sickle cell crisis. J Clin Pathol. 1986;39:253-255.
67. Kremastinos DT, Tsiapras DP, Kostopoulou AG, et al. NT-proBNP levels and diastolic dysfunction in beta-thalassaemia major patients. Eur J Heart Fail. 2007;9:531-536.
68. Kremastinos DT, Hamodraka E, Parissis J, et al. Predictive value of B-type natriuretic peptides in detecting latent left ventricular diastolic dysfunction in beta-thalassemia major. Am Heart J. 2010;159:68-74.
69. Aessopos A, Farmakis D, Polonifi A, et al. Plasma B-type natriuretic peptide concentration in beta-thalassaemia patients. Eur J Heart Fail. 2007;9:537-541.
70. Balkan C, Tuluce SY, Basol G, et al. Relation between NT-proBNP levels, iron overload, and early stage of myocardial dysfunction in β-thalassemia major patients. Echocardiography. 2012;29:318-325.
71. Hahalis G, Manolis AS, Apostolopoulos D, et al. Right ventricular cardiomyopathy in beta-thalassaemia major. Eur Heart J. 2002;23:147-156.
72. Aessopos A, Farmakis D, Deftereos S, et al. Thalassemia heart disease: a comparative evaluation of thalassemia major and thalassemia intermedia. Chest. 2005;127:1523-1530.
73. Candell-Riera J, Lu L, Seres L, et al. Cardiac hemochromatosis: beneficial effects of iron removal therapy. An echocardiographic study. Am J Cardiol. 1983;52:824-829.
74. Palka P, Macdonald G, Lange A, et al. The role of Doppler left ventricular filling indexes and Doppler tissue echocardiography in the assessment of cardiac involvement in hereditary hemochromatosis. J Am Soc Echocardiogr. 2002;15:884-890.
75. Davidsen ES, Hervig T, Gmvik P, et al. Left ventricular long-axis function in treated haemochromatosis. Int J Cardiovasc Imaging. 2009;25:237-247.
76. Aypar E, Alehan D, Hazirolan T, et al. 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;26:413-421.
77. Davidsen ES, Omvik P, Hervig T, et al. Left ventricular diastolic function in patients with treated haemochromatosis. Scand Cardiovasc J. 2009;43:32-38.
78. Shizukuda Y, Bolan CD, Tripodi DJ, et al. Significance of left atrial contractile function in asymptomatic subjects with hereditary hemochromatosis. Am J Cardiol. 2006;98:954-959.
79. Aggeli C, Felekos I, Poulidakis E, et al. Quantitative analysis of left atrial function in asymptomatic patients with b-thalassemia major using real-time three-dimensional echocardiography. Cardiovasc Ultrasound. 2011;9:38.
80. Hamdy AM. Use of strain and tissue velocity imaging for early detection of regional myocardial dysfunction in patients with beta thalassemia. Eur J Echocardiogr. 2007;8:102-109.
81. Shizukuda Y, Bolan CD, Tripodi DJ, et al. Does oxidative stress modulate left ventricular diastolic function in asymptomatic subjects with hereditary hemochromatosis? Echocardiography. 2009;26:1153-1158.
82. Monte I, Buccheri S, Bottari V, et al. Left ventricular rotational dynamics in beta thalassemia major: a speckle-tracking echocardiographic study. J Am Soc Echocardiogr. 2012;25:1083-1090.
83. Barbero U, Destefanis P, Pozzi R, et al. Exercise stress echocardiography with tissue doppler imaging (TDI) detects early systolic dysfunction in beta-thalas-semia major patients without cardiac iron overload. Mediterr JHematolInfect Dis. 2012;4:e2012037.
84. Nody AC, Bruno MS, DePasquale NP, et al. Letter: fulminating idiopathic hemochromatosis presenting as constrictive pericarditis. Ann Intern Med. 1975;83:373-374.
85. Cutler DJ, Isner JM, Bracey AW, et al. Hemochromatosis heart disease: an unemphasized cause of potentially reversible restrictive cardiomyopathy. Am J Med. 1980;69:923-928.
86. Hahalis G, Manolis AS, Gerasimidou I, et al. Right ventricular diastolic function in beta-thalassemia major: echocardiographic and clinical correlates. Am Heart J. 2001;141:428-434.
87. Wood JC. Magnetic resonance imaging measurement of iron overload. Curr Opin Hematol. 2007;14:183-190.
88. Mavrogeni SI, Gotsis ED, Markussis V, et al. T2 relaxation time study of iron overload in b-thalassemia. MAGMA. 1998;6:7-12.
89. Anderson LJ, Holden S, Davis B, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J. 2001;22:2171-2179.
90. Wood JC. History and current impact of cardiac magnetic resonance imaging on the management of iron overload. Circulation. 2009;120:1937-1939.
91. Barrera Portillo MC, Uranga Uranga M, Sanchez Gonzalez J, et al. [Liver and heart T2* measurement in secondary haemochromatosis]. Radiologia. 2013;55:331-339.
92. Pepe A, Positano V, Santarelli MF, et al. Multislice multiecho T2* cardiovascular magnetic resonance for detection of the heterogeneous distribution of myocardial iron overload. J Magn Reson Imaging. 2006;23:662-668.
93. Jensen PD. Evaluation of iron overload. Br J Haematol. 2004;124:697-711.
94. Kirk P, Roughton M, Porter JB, et al. Cardiac T2* magnetic resonance for prediction of cardiac complications in thalassemia major. Circulation. 2009;120:1961-1968.
95. Mavrogeni S, Gotsis E, Verganelakis D, et al. Effect of iron overload on exercise capacity in thalassemic patients with heart failure. Int J Cardiovasc Imaging. 2009;25:777-783.
96. Cheong B, Huber S, Muthupillai R, et al. Evaluation of myocardial iron overload by T2* cardiovascular magnetic resonance imaging. Tex Heart Inst J. 2005;32:448-449.
97. Kremastinos DT, Farmakis D. Iron overload cardiomyopathy in clinical practice. Circulation. 2011;124:2253-2263.
98. Gujja P, Rosing DR, Tripodi DJ, et al. Iron overload cardiomyopathy: better understanding of an increasing disorder. J Am Coll Cardiol. 2010;56:1001-1012.
99. Rivers J, Garrahy P, Robinson W, et al. Reversible cardiac dysfunction in hemochromatosis. Am Heart J. 1987;113:216-217.
100. Easley RM Jr, Schreiner BF Jr, Yu PN. Reversible cardiomyopathy associated with hemochromatosis. N Engl J Med. 1972;287:866-867.
101. Niederau C, Fischer R, Sonnenberg A, et al. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl JMed. 1985;313:1256-1262.
102. Rahko PS, Salerni R, Uretsky BF. Successful reversal by chelation therapy of congestive cardiomyopathy due to iron overload. J Am Coll Cardiol. 1986;8:436-440.
103. Jomova K, Valko M. Importance of iron chelation in free radical-induced oxidative stress and human disease. Curr Pharm Des. 2011;17:3460-3473.
104. Crosby WH. Hemochromatosis. Treatment to alleviate injury. Arch Intern Med. 1986;146:1910-1911.
105. Jessup M, Abraham WT, Casey DE, et al. 2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation. 2009;119:1977-2016.
106. Adams PC, Barton JC. How I treat hemochromatosis. Blood. 2010;116:317-325.
107. Pietrangelo A. Non-HFE hemochromatosis. Hepatology. 2004;39:21-29.
108. Bacon BR, Adams PC, Kowdley KY et al; American Association for the Study of Liver Diseases. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:328-343.
109. Adams PC, Kertesz AE, Valberg LS. Rate of iron reaccumulation following iron depletion in hereditary hemochromatosis. Implications for venesection therapy. J Clin Gastroenterol. 1993;16:207-210.
110. Dabestani A, Child JS, Henze E, et al. Primary hemochromatosis: anatomic and physiologic characteristics of the cardiac ventricles and their response to phlebotomy. Am J Cardiol. 1984;54:153-159.
111. Cecchetti G, Binda A, Piperno A, et al. Cardiac alterations in 36 consecutive patients with idiopathic haemochromatosis: polygraphic and echocardiographic evaluation. Eur Heart J. 1991;12:224-230.
112. Fabio G, Minonzio F, Delbini P, et al. Reversal of cardiac complications by deferiprone and deferoxamine combination therapy in a patient affected by a severe type of juvenile hemochromatosis (JH). Blood. 2007;109:362-364.
113. Kontoghiorghes GJ, Eracleous E, Economides C, et al. Advances in iron overload therapies: prospects for effective use of deferiprone (LI), deferoxamine, the new experimental chelators ICL670, GT56-252, L1NA11 and their combinations. Curr Med Chem. 2005;12:2663-2681.
114. Glickstein H, El RB, Link G, et al. Action of chelators in iron-loaded cardiac cells: accessibility to intracellular labile iron and functional consequences. Blood. 2006;108:3195-3203.
115. Kontoghiorghes GJ, Kolnagou A, Peng CT, et al. Safety issues of iron chelation therapy in patients with normal range iron stores including thalassae-mia, neurodegenerative, renal and infectious diseases. Expert Opin Drug Saf. 2010;9:201-206.
116. Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood. 1997;89:739-761.
117. Beris P. Introduction: management of thalassemia. Semin Hematol. 1995;32:243.
118. Cao A, Galanello R, Rosatelli MC, et al. Clinical experience of management of thalassemia: the Sardinian experience. Semin Hematol. 1996;33:66-75.
119. Hershko C, Konijn AM, Nick HP, et al. ICL670A: a new synthetic oral chelator: evaluation in hypertransfused rats with selective radioiron probes of hepatocellular and reticuloendothelial iron stores and in iron-loaded rat heart cells in culture. Blood. 2001;97:1115-1122.
120. Allain P, Mauras Y, Chaleil D, et al. Pharmacokinetics and renal elimination of desferrioxamine and ferrioxamine in healthy subjects and patients with haemochromatosis. Br J Clin Pharmacol. 1987;24:207-212.
121. Prescribing information for deferoxamine. Available at: http://www.access-data. fda.gov/drugsatfda-docs/label/2011/016267s0501bl.pdf. Accessed March2, 2013.
122. Mamtani M, Kulkarni H. Influence of iron chelators on myocardial iron and cardiac function in transfusion-dependent thalassaemia: a systematic review and meta-analysis. Br J Haematol. 2008;141:882-890.
123. Davis BA, O'Sullivan C, Jarritt PH, et al. Value of sequential monitoring of left ventricular ejection fraction in the management of thalassemia major. Blood. 2004;104:263-269.
124. Anderson LJ, Westwood MA, Holden S, 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;127:348-355.
125. Pennell DJ, Carpenter JP, Roughton M, et al. On improvement in ejection fraction with iron chelation in thalassemia major and the risk of future heart failure. J Cardiovasc Magn Resort. 2011;13:45.
126. Davis BA, Porter JB. Long-term outcome of continuous 24-hour deferoxamine infusion via indwelling intravenous catheters in high-risk beta-thalas-semia. Blood. 2000;95:1229-1236.
127. Olivieri NF, Buncic JR, Chew E, et al. Visual and auditory neurotoxicity in patients receiving subcutaneous deferoxamine infusions. N Engl J Med. 1986;314:869-873.
128. Porter JB, Jaswon MS, Huehns ER, et al. Desferrioxamine ototoxicity: evaluation of risk factors in thalassaemic patients and guidelines for safe dosage. Br J Haematol. 1989;73:403-409.
129. Boelaert JR, de Locht M, Van Cutsem J, et al. Mucormycosis during deferoxamine therapy is a siderophore-mediated infection. In vitro and in vivo animal studies. J Clin Invest. 1993;91:1979-1986.
130. Green NS. Yersinia infections in patients with homozygous beta-thalassemia associated with iron overload and its treatment. Pediatr Hematol Oncol. 1992;9:247-254.
131. Neupane GP, Kim DM. Comparison of the effects of deferasirox, deferiprone, and deferoxamine on the growth and virulence of Vibrio vulnificus. Transfusion. 2009;49:1762-1769.
132. Modell B, Khan M, Darlison M. Survival in beta-thalassaemia major in the UK: data from the UKThalassaemia Register. Lancet. 2000;355:2051-2052.
133. Prescribing information for deferiprone. Available at: http://www.access-data.fda.gov/drugsatfda-docs/label/2011/0218251bl.pdf. Accessed March 2, 2013.
134. Hoffbrand AV, AL-Refaie F, Davis B, et al. Long-term trial of deferiprone in 51 transfusion-dependent iron overloaded patients. Blood. 1998;91:295-300.
135. Olivieri NF, Brittenham GM, McLaren CE, et al. Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major. N Engl JMed. 1998;339:417-423.
136. Pepe A, Meloni A, Capra M, et al. Deferasirox, deferiprone and desferrioxamine treatment in thalassemia major patients: cardiac iron and function comparison determined by quantitative magnetic resonance imaging. Haematologica. 2011;96:41-47.
137. Pepe A, Rossi G, Meloni A, et al. A T2* MRI prospective survey on heart and liver iron in thalassemia major patients treated with deferasirox versus deferiprone and desferrioxamine in monotherapy (Abstract 4267). Blood. 2010;116:1731.
138. Farmaki K, Tzoumari I, Pappa C, et al. Normalisation of total body iron load with very intensive combined chelation reverses cardiac and endocrine complications of thalassaemia major. Br J Haematol. 2010;148:466-475.
139. Tanner MA, Galanello R, Dessi C, et al. Combined chelation therapy in thalassemia major for the treatment of severe myocardial siderosis with left ventricular dysfunction. J Cardiovasc Magn Reson. 2008;10:12.
140. Cohen AR, Galanello R, Piga A, et al. Safety and effectiveness of longterm therapy with the oral iron chelator deferiprone. Blood. 2003;102:1583-1587.
141. Ceci A, Baiardi P, Felisi M, et al. The safety and effectiveness of deferiprone in a large-scale, 3-year study in Italian patients. Br J Haematol. 2002;118:330-336.
142. Taher A, Cappellini MD, Vichinsky E, et al. Efficacy and safety of deferasirox doses of >30mg/kg per d in patients with transfusion-dependent anaemia and iron overload. Br J Haematol. 2009;147:752-759.
143. Chirnomas D, Smith AL, Braunstein J, et al. Deferasirox pharmacokinetics in patients with adequate versus inadequate response. Blood. 2009;114:4009-4013.
144. Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood. 2006;107:3455-3462.
145. Pennell DJ, Porter JB, Cappellini MD, et al. Efficacy of deferasirox in reducing and preventing cardiac iron overload in beta-thalassemia. Blood. 2010;115:2364-2371.
146. Cappellini MD, Bejaoui M, Agaoglu L, et al. Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up. Blood. 2011;118:884-893.
147. Pennell DJ, Porter JB, Cappellini MD, et al. Deferasirox for up to 3 years leads to continued improvement of myocardial T2* in patients with β3-thalassemia major. Haematologica. 2012;97:842-848.
148. Wood JC, Kang BP, Thompson A, et al. The effect of deferasirox on cardiac iron in thalassemia major: impact of total body iron stores. Blood. 2010;116:537-543.
149. Borsari M, Gabbi C, Ghelfi F, et al. Silybin, a new iron-chelating agent. J Inorg Biochem. 2001;85:123-129.
150. Barton JC. Drug evaluation: deferitrin (GT-56-252; NaHBED) for iron overload disorders. IDrugs. 2007;10:270-281.
151. Harmatz P, Grady RW, Dragsten P, et al. Phase lb clinical trial of starch-conjugated deferoxamine (40SD02): a novel long-acting iron chelator. Br J Haematol. 2007;138:374-381.
152. Barton JC, McDonnell SM, Adams PC, et al. Management of hemochromatosis. Hemochromatosis Management Working Group. Ann Intern Med. 1998;129:932-939.
153. McLaran CJ, Bett JH, Nye JA, et al. Congestive cardiomyopathy and haemo-chromatosis-rapid progression possibly accelerated by excessive ingestion of ascorbic acid. Aust N Z J Med. 1982;12:187-188.
154. Herbert V. Hemochromatosis and vitamin C. Ann Intern Med. 1999;131:475-476.
155. Milward EA, Baines SK, Knuiman MW, et al. Noncitrus fruits as novel dietary environmental modifiers of iron stores in people with or without HFE gene mutations. Mayo Clin Proc. 2008;83:543-549.
156. Conrad ME, Barton JC. Anemia and iron kinetics in alcoholism. Semin Hematol. 1980;17:149-163.
157. Celada A, Rudolf H, Donath A. Effect of experimental chronic alcohol ingestion and folic acid deficiency on iron absorption. Blood. 1979;54:906-915.
158. Mariani R, Pelucchi S, Perseghin P, et al. Erythrocytapheresis plus erythropoietin: an alternative therapy for selected patients with hemochromatosis and severe organ damage. Haematologica. 2005;90:717-718.
159. Kohan A, Niborski R, Daruich J, et al. Erythrocytapheresis with recombinant human erythropoietin in hereditary hemochromatosis therapy: a new alternative. Vox Sang. 2000;79:40-45.
160. Muncunill J, Vaquer P, Galmés A, et al. In hereditary hemochromatosis, red cell apheresis removes excess iron twice as fast as manual whole blood phlebotomy. J Clin Apher. 2002;17:88-92.
161. Rombout-Sestrienkova E, van Noord PA, van Deursen CT, et al. Therapeutic erythrocytapheresis versus phlebotomy in the initial treatment of hereditary hemochromatosis-a pilot study. Transfus Apher Sci. 2007;36:261-267.
162. Caines AE, Kpodonu J, Massad MG, et al. Cardiac transplantation in patients with iron overload cardiomyopathy. J Heart Lung Transplant. 2005;24:486-488.
163. Raichlin E, Daly RC, Rosen CB, et al. Combined heart and liver transplantation: a single-center experience. Transplantation. 2009;88:219-225.
164. Kuppahally SS, Hunt SA, Valantine HA, et al. Recurrence of iron deposition in the cardiac allograft in a patient with non-HFE hemochromatosis. J Heart Lung Transplant. 2006;25:144-147.
165. Garcia-Manero G. Myelodysplastic syndromes: 2012 update on diagnosis, risk-stratification, and management. Am J Hematol. 2012;87:692-701.
166. Bernaudin F, Socie G, Kuentz M, et al; SFGM-TC. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood. 2007;110:2749-2756.
167. Mugishima H, Ohga S, Ohara A, et al; Aplastic Anemia Committee of the Japanese Society of Pediatric Hematology. Hematopoietic stem cell transplantation for Diamond-Blackfan anemia: a report from the Aplastic Anemia Committee of the Japanese Society of Pediatric Hematology. Pediatr Transplant. 2007;11:601-607.
168. Elborai Y, Uwumugambi A, Lehmann L. Hematopoietic stem cell transplantation for thalassemia. Immunotherapy. 2012;4:947-956.
169. Kumfu S, Chattipakorn S, Srichairatanakool S, et al. T-type calcium channel as a portal of iron uptake into cardiomyocytes of beta-thalassemic mice. Eur J Haematol. 2011;86:156-166.
170. Oudit GY, Sun H, Trivieri MG, et al. L-type Ca2+ channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy. Nat Med. 2003;9:1187-1194.
171. Murphy CJ, Oudit GY. Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment. J Card Fail. 2010;16:888-900.
172. Crowe S, Bartfay WJ. Amlodipine decreases iron uptake and oxygen free radical production in the heart of chronically iron overloaded mice. Biol Res Nurs. 2002;3:189-197.
173. Kumfu S, Chattipakorn S, Chinda K, et al. T-type calcium channel blockade improves survival and cardiovascular function in thalassemic mice. Eur J Haematol. 2012;88:535-548.
174. Brissot P, Bardou-Jacquet E, Jouanolle AM, et al. Iron disorders of genetic origin: a changing world. Trends Mol Med. 2011;17:707-713.
175. Musallam KM, Cappellini MD, Wood JC, et al. Iron overload in non-transfii-sion-dependent thalassemia: a clinical perspective. Blood Rev. 2012;26(suppl 1):S16-S19.
176. Viatte L, Nicolas G, Lou DQ, et al. Chronic hepcidin induction causes hypo-sideremia and alters the pattern of cellular iron accumulation in hemochro-matotic mice. Blood. 2006;107:2952-2958.
177. Gardenghi S, Ramos P, Marongiu MF, et al. Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β3-thalassemic mice. J Clin Invest. 2010;120:4466-4477.
178. Camaschella C: Treating iron overload. N Engl JMed 2013;368:2325-27.
179. Ramos E, Ruchala P, Goodnough JB, et al. Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis. Blood. 2012;120:3829-3836.
180. Payen E, Leboulch P. Advances in stem cell transplantation and gene therapy in the β3-hemoglobinopathies. Hematology Am Soc Hematol Educ Program. 2012;2012:276-283.
181. Townes TM. Gene replacement therapy for sickle cell disease and other blood disorders. Hematology Am Soc Hematol Educ Program. 2008;193-196.
182. Ezquer F, Nún̂ez MT, Rojas A, et al. Hereditary hemochromatosis: an opportunity for gene therapy. Biol Res. 2006;39:113-124.