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  • 1. A. Aessopos, M.DA. Aessopos, M.D.. First Dept. of Internal Medicine,First Dept. of Internal Medicine, University of Athens, MedicalUniversity of Athens, Medical SchoolSchool Cardiovascular involvement in Thalassemia Major and Intermedia 2nd Pan-European Conference on Haemoglobinopathies Berlin, March 12, 2010
  • 2. Thalassemia Major / IntermediaThalassemia Major / Intermedia PathophysiologyPathophysiology  Common basic molecular mechanismCommon basic molecular mechanism impaired synthesis of hemoglobin chainsimpaired synthesis of hemoglobin chains  Common consequencesCommon consequences -- anemia, hemolysis,anemia, hemolysis, - growth retardation, bone marrow expansion, extra-medullar- growth retardation, bone marrow expansion, extra-medullar hematopoiesis,hematopoiesis, hepato-splenomegaly,hepato-splenomegaly, - increased intestinal iron absorption, susceptibility to infections,- increased intestinal iron absorption, susceptibility to infections, hypercoagulability.hypercoagulability.  Diverse clinical severityDiverse clinical severity alpha - beta globin chain balance, gamma globin chain synthesisalpha - beta globin chain balance, gamma globin chain synthesis  Diverse therapeutic approachDiverse therapeutic approach
  • 3. Causes of death inCauses of death in ββ-thalassemia-thalassemia Borgna-Pignatti et al. Haematologica 2004
  • 4. Cardiovascular involvement inCardiovascular involvement in ThalassemiaThalassemia Major and IntermediaMajor and Intermedia PATHOGENETIC MECHANISMSPATHOGENETIC MECHANISMS
  • 5. Mechanisms of heart injury inMechanisms of heart injury in thalassemiathalassemia Major / IntermediaMajor / Intermedia  Two major competing factors:Two major competing factors: 1.1. High cardiac outputHigh cardiac output 2.2. Myocardial iron depositionMyocardial iron deposition  Additional factorsAdditional factors
  • 6. Mechanisms of heart injury inMechanisms of heart injury in thalassemiathalassemia Major / IntermediaMajor / Intermedia 1) High output state1) High output state  Chronic anemiaChronic anemia  ↑↑ HbFHbF  Shunt development:Shunt development: – Bone marrow expansion – extramedullar hematopoiesisBone marrow expansion – extramedullar hematopoiesis  Hepatic injuryHepatic injury  Vascular elastic tissue disorders (dilatation)Vascular elastic tissue disorders (dilatation) Aessopos et al. Blood 2001Aessopos et al. Blood 2001
  • 7. Mechanisms of heart injury inMechanisms of heart injury in thalassemiathalassemia 1.High Cardiac Output State1.High Cardiac Output State in Thal Min Thal Majorajor  Well transfused TM patients, (mean pre transfusionWell transfused TM patients, (mean pre transfusion HbHb level > 9.5 g/dllevel > 9.5 g/dl and mean Hb level between transfusions ofand mean Hb level between transfusions of 11.3gr/dL11.3gr/dL), demonstrate), demonstrate higher resting cardiac outputhigher resting cardiac output ((Cardiac Index 4.3Cardiac Index 4.3±±0.9/3.in TM cf. 3.80.9/3.in TM cf. 3.8±±0.8 P<.01 in normal0.8 P<.01 in normal individuals)individuals) Aessopos A,Aessopos A, et al.et al. .Eur J Haematol. 2004 Nov;73(5):359-66..Eur J Haematol. 2004 Nov;73(5):359-66. ..
  • 8. Mechanisms of heart injury inMechanisms of heart injury in thalassemiathalassemia 1.High Cardiac Output State1.High Cardiac Output State in Thalin Thal IntermediaIntermedia  Aessopos et al. Blood 2001Aessopos et al. Blood 2001 (cardiac index (l/min/m(cardiac index (l/min/m22 ) 5.45) 5.45±±o.33o.33 3.823.82±±0.80 TI/Normals P <.001)0.80 TI/Normals P <.001)  Vaccari et al.Vaccari et al. Chest 2002Chest 2002  Ferrara et alFerrara et al.. HHemoglobin 2004emoglobin 2004  Maggio et al. [MRI study]Maggio et al. [MRI study] :: HemoglobinHemoglobin 20082008..
  • 9. 39 year-old patient Hb: 11gr F:(95%) CO: 11.5 L/Min
  • 10. 1.High Cardiac Output State1.High Cardiac Output State  Increases cardiac loadIncreases cardiac load  Demands increased contractilityDemands increased contractility Mechanisms of heart injury inMechanisms of heart injury in thalassemiathalassemia
  • 11. 22. Iron load. Iron load - Transfusions administration- Transfusions administration (ΤΜ)(ΤΜ) - Increased Iron absorption rate- Increased Iron absorption rate (ΤΙ)(ΤΙ) Mechanisms of heart injury inMechanisms of heart injury in thalassemiathalassemia
  • 12. Histological features from an autopsy from a 29 year old male TM patient who died of CCF. myocyte hypertrophy with multiple deposits of brown granular material within the mytoplasm of the myocytes.
  • 13. OVER 50,000 μg/gm dry weight LIVER BIOPSY IRON
  • 14. Mechanisms of heart injury inMechanisms of heart injury in thalassemiathalassemia 22. Iron load. Iron load  Direct effectDirect effect  Indirect effectsIndirect effects
  • 15. Direct Iron related injuryDirect Iron related injury  Iron is accumulated in cells, including myocytes, inIron is accumulated in cells, including myocytes, in the form ofthe form of haemosiderin,haemosiderin, ferritin and free ironferritin and free iron ((labilelabile cellular iron (LCI)cellular iron (LCI)  There is a significant flux between the three forms,There is a significant flux between the three forms, with haemosiderin being the least accessiblewith haemosiderin being the least accessible  TheThe LCI it is the most toxic formLCI it is the most toxic form as it stimulates theas it stimulates the formation of free radicals and is thought to be theformation of free radicals and is thought to be the most accessible tomost accessible to chelationchelation
  • 16. T2* and LVEF in TMT2* and LVEF in TM Anderson L, et al. Eur Heart J 2001; 22:2171
  • 17. MRI studyMRI study Total number of patients:142Total number of patients:142 Aessopos et al. Haematologica 2007 35,21 16,915,49 32,39 T2*≤ 10ms 10<T2*≤ 15ms 15<T2*≤ 20ms T2*> 20ms % Heart Iron load in TMHeart Iron load in TM
  • 18. Heart Iron load in TIHeart Iron load in TI -- CMR in 26 TI patients:CMR in 26 TI patients: T2 mild depositionT2 mild deposition Voskaridou E, at al,Voskaridou E, at al, BBr Jr J HH20042004 - CMR in 31 TI patients:- CMR in 31 TI patients: T2* value <20 msec in 23%T2* value <20 msec in 23% Pepe A.Pepe A. at al,at al, JACC 2006;47:136AJACC 2006;47:136A - CMR in 20 TI patient :- CMR in 20 TI patient : T2* value <20 msec in noneT2* value <20 msec in none Raffaella OligaRaffaella Oliga at al,at al, Haematologica 2008Haematologica 2008
  • 19. Indirect Iron related injuryIndirect Iron related injury  Infections:Infections: Viral (pericarditis and myocarditis)Viral (pericarditis and myocarditis) – Bacterial– Bacterial infectionsinfections ((siderophore bacteria, such as yersinia and klebsiellasiderophore bacteria, such as yersinia and klebsiella)) ((Immune competence in beta-thalassemia is impaired)Immune competence in beta-thalassemia is impaired)  Vascular Involvement (Afterload):Vascular Involvement (Afterload): Clinical, functional and anatomical changesClinical, functional and anatomical changes  Endocrine abnormalities:Endocrine abnormalities:  Arrhythmias:Arrhythmias:
  • 20. Kremastinos et al, Circulation 1995;91:66-71 Myocarditis in b-thalassaemia majorMyocarditis in b-thalassaemia major A cause of heart failureA cause of heart failure
  • 21. MRI studyMRI study total number of patients:574total number of patients:574
  • 22. Figure 1a.Operative field in a 27 year old male TM patient with a history of recurrent pericarditis and effusive constrictive pericarditis. Figure 1b biopsy from the same patient demonstrating significant pericardial thickening with severe iron deposition and a small amount of muscle in the left hand corner which contains iron (Prussian Blue Stain). 1a. 1b. Mechanisms of heart injury in thalassemia majorMechanisms of heart injury in thalassemia major
  • 23. Indirect Iron related injuryIndirect Iron related injury  Infections:Infections: Viral(pericarditis and myocarditis)Viral(pericarditis and myocarditis) – Bacterial– Bacterial infectionsinfections ((siderophore bacteria, such as yersinia and klebsiellasiderophore bacteria, such as yersinia and klebsiella )) ((Immune competence in beta-thalassemia is impaired)Immune competence in beta-thalassemia is impaired)  Vascular Involvement (Afterload):Vascular Involvement (Afterload): Clinical, functional and anatomical changesClinical, functional and anatomical changes  Endocrine abnormalities:Endocrine abnormalities:  Arrhythmias:Arrhythmias:
  • 24. Indirect Iron related injuryIndirect Iron related injury Vascular InvolvementVascular Involvement Functional changesFunctional changes  IncreasedIncreased aarterialrterial sstiffness andtiffness and eendothelialndothelial dysfdysfunction inunction in ββ--tthalassemiahalassemia CheungCheung et al,et al, Circulation 2002;106:2561-2566.Circulation 2002;106:2561-2566.  A randomized, placebo-controlled, double-blind trial ofA randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine andthe effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia majordeferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance.using cardiovascular magnetic resonance. Tanner MA-Pennell DJ.CirculationTanner MA-Pennell DJ.Circulation. 2007 Apr 10;115(14):1876-84.. 2007 Apr 10;115(14):1876-84.
  • 25. Indirect Iron related injuryIndirect Iron related injury  Infections:Infections: Viral(pericarditis and myocarditis)Viral(pericarditis and myocarditis) – Bacterial– Bacterial infectionsinfections ((siderophore bacteria, such as yersinia and klebsiellasiderophore bacteria, such as yersinia and klebsiella )) ((Immune competence in beta-thalassemia is impaired)Immune competence in beta-thalassemia is impaired)  Vascular Involvement (Afterload)Vascular Involvement (Afterload):: Functional and anatomical changesFunctional and anatomical changes  Endocrine abnormalities:Endocrine abnormalities: [e.g. diabetes[e.g. diabetes M, hypothyroidism, hypoparathyroidism]M, hypothyroidism, hypoparathyroidism]  ArrhythmiasArrhythmias
  • 26. 2. Iron Load:2. Iron Load: direct and indirect effectsdirect and indirect effects  Decreased cardiac contractilityDecreased cardiac contractility Mechanisms of heart injury inMechanisms of heart injury in thalassemiathalassemia
  • 27. Mechanisms of heart injury inMechanisms of heart injury in thalassemiathalassemia Additional factorsAdditional factors 33. Vascular injury. Vascular injury (Functional and Anatomical disorders)(Functional and Anatomical disorders) –– Elastic tissue disordersElastic tissue disorders –– NO deficiencyNO deficiency - Hemolysis- Hemolysis (release of(release of membrane particlesmembrane particles,, hemoglobin, free heme)hemoglobin, free heme) -- IronIron (oxidative stress)(oxidative stress)
  • 28. 1.1. PXE-like elastic tissue disordersPXE-like elastic tissue disorders Skin, ocular and arterial findingSkin, ocular and arterial finding (Hemolysis and Iron load)(Hemolysis and Iron load) Aessopos A, Farmakis D, Loukopoulos D.Aessopos A, Farmakis D, Loukopoulos D. Blood. 2002 Jan 1;99(1):30-5. Review.Blood. 2002 Jan 1;99(1):30-5. Review. 33.. Vascular injuryVascular injury
  • 29. PXE-like elastic tissue disordersPXE-like elastic tissue disorders Aessopos at all Am. J. Hematology 1992Aessopos at all Am. J. Hematology 1992
  • 30. PXE-like elastic tissue disordersPXE-like elastic tissue disorders Angioid streaks in thalassemia majorAngioid streaks in thalassemia major Aessopos at all Am. J. Hematology 1992Aessopos at all Am. J. Hematology 1992
  • 31. ““ Posterior tibial artery calcification: 55% in patientsPosterior tibial artery calcification: 55% in patients over 30 years oldover 30 years old Aessopos et al. Angiology. 1998;49:137-143.Aessopos et al. Angiology. 1998;49:137-143.
  • 32. Elastic tissue abnormalitiesElastic tissue abnormalities Tsomi at all. Eur. J. Haematol 2001Tsomi at all. Eur. J. Haematol 2001 SSplenic hilar artery from a 12 years old with TMplenic hilar artery from a 12 years old with TM
  • 33. PXE-like elastic tissue disordersPXE-like elastic tissue disorders Splenic artery in aSplenic artery in a 6-6-year old HS patientyear old HS patient Tsomi at al, Eur J Haematol 2001Tsomi at al, Eur J Haematol 2001
  • 34. Elastic tissue abnormalitiesElastic tissue abnormalities Tsomi at all. Eur. J. Haematol 2001Tsomi at all. Eur. J. Haematol 2001 Splenic artery in a 9Splenic artery in a 9--year oldyear old ΤΙΤΙ patientpatient Ca deposition (von Kossax2)
  • 35. Posterior and anterior tibial arteryPosterior and anterior tibial artery calcification in a 55year oldcalcification in a 55year old patient with TIpatient with TI - Aessopos at al. Angiology 1998 Elastic tissue abnormalities
  • 36. 2.2. NO deficiencyNO deficiency  NO degradationNO degradation (hemolysis)(hemolysis)  ReducedReduced ΝΟΝΟ synthesis due tosynthesis due to 1) Arginase release (hemolysis)1) Arginase release (hemolysis) 2) Endothelial injury2) Endothelial injury ((oxidative stress)oxidative stress) Vichinsky EPVichinsky EP -- Gladwin M.Gladwin M. N Engl J Med 2004.N Engl J Med 2004. 33.Vascular injury.Vascular injury
  • 37. Mechanisms of heart injury inMechanisms of heart injury in thalassemiathalassemia Additional factorsAdditional factors 4)4) Valvular injuryValvular injury ((inin 110110 patientspatients ΤΙ)ΤΙ)  Leaflet thickeningLeaflet thickening  endocardial calcification (endocardial calcification (21%)21%)  ΜΜVV regurgitation (47%)regurgitation (47%)  AV regurgitation (15%)AV regurgitation (15%)  Moderate AS (3%)Moderate AS (3%) ((Hyperdynamic stateHyperdynamic state –– Elastic tissue disordersElastic tissue disorders)) Aessopos et al. Blood 200Aessopos et al. Blood 20044
  • 38. Cardiac valvular calcifications: a 50-year old thalassemia intermedia patient 4)4) Valvular injuryValvular injury
  • 39. Mechanisms of heart injury inMechanisms of heart injury in thalassemiathalassemia Additional factorsAdditional factors 5)5) HypercoagulabilityHypercoagulability  Thrombocytosis due to splenectomyThrombocytosis due to splenectomy  Platelet activationPlatelet activation  RBC membrane injuryRBC membrane injury  Endothelial dysfunctionEndothelial dysfunction Eldor & Rachmilewitz. Blood 2002Eldor & Rachmilewitz. Blood 2002
  • 40. Cardiovascular involvement inCardiovascular involvement in ThalassemiaThalassemia Major and IntermediaMajor and Intermedia CLINICAL CONSEQUENCESCLINICAL CONSEQUENCES
  • 41. Ophthalmological ConsequencesOphthalmological Consequences Visual acuity impairment – Loss of visionVisual acuity impairment – Loss of vision due to Angioid streaksdue to Angioid streaks
  • 42. Visual loss in Thalassemia intermediaVisual loss in Thalassemia intermedia  a 50-year- old thalassemia intermediaa 50-year- old thalassemia intermedia patientpatient 59-year old thalassemia intermedia patient
  • 43. Cardiovascular consequencesCardiovascular consequences Vascular complications - ArteriesVascular complications - Arteries  Leg ulcersLeg ulcers,, gastrointestinal hemorrhagegastrointestinal hemorrhage AessoposAessopos et al. Haematologica 2007et al. Haematologica 2007  StrokesStrokes ((ischemic, hemorrhagicischemic, hemorrhagic)) AessoposAessopos et alet al.. StrokeStroke.. 19971997 Manfre L. AJR. 1999Manfre L. AJR. 1999 Karimi M…Rachmilewitz EA.Karimi M…Rachmilewitz EA., AJ H. 2008, AJ H. 2008  Increased arterial stiffness – endothelial dysfunctionIncreased arterial stiffness – endothelial dysfunction Cheung YFCheung YF et al. Circulation 2002et al. Circulation 2002 AessoposAessopos etet al.al.Atherosclerosis.Atherosclerosis.20072007 Hahalis GHahalis G Atherosclerosis.Atherosclerosis.20082008  Unstable anginaUnstable angina Farmakis D, …, Aessopos A.Farmakis D, …, Aessopos A. Eur J Haematol 2003Eur J Haematol 2003  Aortic aneurysmsAortic aneurysms Farmakis D, …,Farmakis D, …, Aessopos A,Aessopos A, Ann Hematol 2004Ann Hematol 2004
  • 44. Vascular complications - ArteriesVascular complications - Arteries -E-Endothelialndothelial dysfdysfunctionunction -Elastic tissue disorders-Elastic tissue disorders -NO deficiency-NO deficiency -Valvular injury-Valvular injury -Arrhythmias-Arrhythmias -Hypercoagulability-Hypercoagulability
  • 45. Cardiovascular consequencesCardiovascular consequences Vascular complications - VeinsVascular complications - Veins Thromboembolic complications:Thromboembolic complications: InIn 4.3% and 5.2%4.3% and 5.2% of bothboth TM and TI respectivelyTM and TI respectively andand inin 3030%% of TI pts with splenectomyof TI pts with splenectomy Cappellini MDCappellini MD et alet al.. Br J Haematol 2000Br J Haematol 2000
  • 46. Cardiovascular consequencesCardiovascular consequences HypercoagulabilityHypercoagulability -- ThrombosisThrombosis Dr. Fucharoen’s collectionDr. Fucharoen’s collection
  • 47. Cardiovascular consequencesCardiovascular consequences Right-sided Heart involvementRight-sided Heart involvement 1.Pulmonary hypertension1.Pulmonary hypertension ( It is present in non well treated TM patients and is the( It is present in non well treated TM patients and is the main cause of CHF in TI.main cause of CHF in TI. Aessopos et al. Blood 2001)Aessopos et al. Blood 2001)
  • 48. p <.001 0 20 40 60 80 100 120 0 10 20 30 40 50 60 70 80 Age (years) TricuspidGradient(mmHg) Aessopos et al. Blood 2001Aessopos et al. Blood 2001 PSGPSG >30 mmHg:>30 mmHg: (59.1%)(59.1%) >50 mmHg:>50 mmHg: (7.3%)(7.3%)
  • 49. ““
  • 50. Cardiovascular consequencesCardiovascular consequences Pulmonary hypertension in ThalassemiaPulmonary hypertension in Thalassemia high cardiac output x pulmonary vascular resistancehigh cardiac output x pulmonary vascular resistance => pulmonary hypertension => CHF=> pulmonary hypertension => CHF
  • 51. Pulmonary hypertension inPulmonary hypertension in ThalassemiaThalassemia Increased pulmonary vascular resistanceIncreased pulmonary vascular resistance  Tissue hypoxia -Chronic anemia + HbFTissue hypoxia -Chronic anemia + HbF  Chronic lung injury (infections, iron overload, bone marrowChronic lung injury (infections, iron overload, bone marrow expansion, high CO)expansion, high CO)  Thromboembolic eventsThromboembolic events  Endothelial dysfunction (Endothelial dysfunction (↓↓NO) (Hemolysis – iron overload)NO) (Hemolysis – iron overload)  Elastic tissue disorders (PXE-like)Elastic tissue disorders (PXE-like)  LV dysfunctionLV dysfunction Aessopos et al. Blood 2001Aessopos et al. Blood 2001
  • 52. Cardiovascular consequencesCardiovascular consequences Right-sided Heart involvementRight-sided Heart involvement 2.Iron deposition in TM2.Iron deposition in TM Decreased RV functionDecreased RV function Aessopos et alAessopos et al Eur J Haematol. 2008 Feb;80(2):93-106.Eur J Haematol. 2008 Feb;80(2):93-106.
  • 53. Cardiovascular consequencesCardiovascular consequences Left-sided heart dysfunctionLeft-sided heart dysfunction  High output stateHigh output state  Iron depositionIron deposition  Increased arterial stiffnessIncreased arterial stiffness (Arterio-ventricular disassociation -Coronary artery involvement)(Arterio-ventricular disassociation -Coronary artery involvement)  InfectionsInfections  Endocrine abnormalitiesEndocrine abnormalities  Arrhythmias - Atrio-ventricular conduction abnormalitiesArrhythmias - Atrio-ventricular conduction abnormalities  Valvular disordersValvular disorders ((regurgitation - stenosisregurgitation - stenosis))
  • 54. Dilated cardiomyopathy inDilated cardiomyopathy in Thalassemia MajorThalassemia Major
  • 55. 48-year-old thalassemia intermedia48-year-old thalassemia intermedia patientpatient
  • 56. AoV PSG:68mmHgAoV PSG:68mmHg 48-year-old thalassemia intermedia patient48-year-old thalassemia intermedia patient
  • 57. TVPSG:38mmHgTVPSG:38mmHg 48-year-old thalassemia intermedia patient48-year-old thalassemia intermedia patient
  • 58. ““ Coronary arteryCoronary artery and mitral annularand mitral annular calcification:calcification: a 48-year-olda 48-year-old thalassemiathalassemia intermedia patientintermedia patient
  • 59. 48-year-old thalassemia intermedia patient48-year-old thalassemia intermedia patient
  • 60. The heart in thalasemia intermediaThe heart in thalasemia intermedia PathophysiologyPathophysiology under occasional transfusion therapyunder occasional transfusion therapy Iron overload Tissue hypoxia consequences anemia, hemolysis, growth retardation, bone marrow expansion, extra-medular hematopoiesis, hepato-splenomegaly, increased intestinal iron absorption, susceptibility to infections, hypercoagulability High output state
  • 61. The heart in thalassemia majorThe heart in thalassemia major PathophysiologyPathophysiology under currently accepted therapyunder currently accepted therapy Tissue hypoxia Iron overload LV+RV dysfunction
  • 62. Pathophysiology ofPathophysiology of cardiac injurycardiac injury chronic hypoxia high output state increased PVR PHT poor transfusions hyper transfusions TI pathway TM pathway iron overload LV+RV dysfunction
  • 63. 1st Pan-Middle East Conference on Haemoglobinopathies1st Pan-Middle East Conference on Haemoglobinopathies Damascus, Syria 1st – 2nd May 2009Damascus, Syria 1st – 2nd May 2009
  • 64. Regardless of the road, difficulties will always present!