cardiovascular involvement in thalassemia major and intermedia

A. Aessopos, M.DA. Aessopos, M.D..

First Dept. of Internal First Dept. of Internal Medicine, University of Medicine, University of Athens, Medical SchoolAthens, Medical School

Cardiovascular involvement in Thalassemia Major and

Intermedia2nd Pan-European Conference on Haemoglobinopathies

Berlin, March 12, 2010

Thalassemia Major / Intermedia Thalassemia Major / Intermedia Pathophysiology Pathophysiology

Common basic molecular mechanismCommon basic molecular mechanismimpaired 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 - increased intestinal iron absorption, susceptibility to

infections, hypercoagulability.infections, hypercoagulability.

Diverse clinical severityDiverse clinical severity alpha - beta globin chain balance, gamma globin chain alpha - beta globin chain balance, gamma globin chain synthesissynthesis

Diverse therapeutic approachDiverse therapeutic approach

Causes of death in Causes of death in ββ-thalassemia-thalassemia

Borgna-Pignatti et al. Haematologica 2004

Cardiovascular involvement in Cardiovascular involvement in Thalassemia Thalassemia

Major and IntermediaMajor and Intermedia

PATHOGENETIC MECHANISMSPATHOGENETIC MECHANISMS

Mechanisms of heart injury in Mechanisms of heart injury in thalassemia thalassemia

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

Mechanisms of heart injury in Mechanisms of heart injury in thalassemia thalassemia

Major / IntermediaMajor / Intermedia

1) High output state1) High output state

Chronic anemiaChronic anemia HbFHbF Shunt development:Shunt development:

– Bone marrow expansion – extramedullar Bone marrow expansion – extramedullar hematopoiesishematopoiesis

Hepatic injuryHepatic injury Vascular elastic tissue disorders (dilatation)Vascular elastic tissue disorders (dilatation)

Aessopos et al. Blood 2001Aessopos et al. Blood 2001

Mechanisms of heart injury in Mechanisms 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 Hb level > 9.5 g/dlHb level > 9.5 g/dl and mean Hb level between and mean Hb level between transfusions oftransfusions of 11.3gr/dL 11.3gr/dL), demonstrate ), demonstrate higher higher resting cardiac outputresting cardiac output ((Cardiac Index 4.3Cardiac Index 4.30.9/3.in TM 0.9/3.in TM cf. 3.8cf. 3.80.8 P<.01 in normal individuals) 0.8 P<.01 in normal 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. ..


1.High Cardiac Output State1.High Cardiac Output State in Thalin Thal IntermediaIntermedia


(cardiac index (l/min/m(cardiac index (l/min/m22) 5.45) 5.45o.33o.33 3.823.820.80 TI/Normals P 0.80 TI/Normals P <.001)<.001)

Vaccari et al. Vaccari et al. Chest 2002 Chest 2002 Ferrara et alFerrara et al.. H Hemoglobin 2004 emoglobin 2004 Maggio et al. [MRI study] Maggio et al. [MRI study] : : HemoglobinHemoglobin 2008 2008. .

39 year-old patient

Hb: 11gr F:(95%)

CO: 11.5 L/Min

1.High Cardiac Output State1.High Cardiac Output State

Increases cardiac load Increases cardiac load Demands increased contractility Demands increased contractility


22. Iron load. Iron load

- Transfusions administration - Transfusions administration (ΤΜ)(ΤΜ)

- Increased Iron absorption rate- Increased Iron absorption rate (ΤΙ) (ΤΙ)


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.

OVER 50,000 μg/gm dry weight

LIVER BIOPSY IRON


22. Iron load. Iron load

Direct effectDirect effect Indirect effectsIndirect effects

Direct Iron related injuryDirect Iron related injury

Iron is accumulated in cells, including Iron is accumulated in cells, including myocytes, in the form ofmyocytes, in the form of haemosiderin,haemosiderin, ferritin and free ironferritin and free iron ((labile cellular iron (LCI)labile cellular iron (LCI)

There is a significant flux between the three There is a significant flux between the three forms, with haemosiderin being the least forms, with haemosiderin being the least accessibleaccessible

TheThe LCI it is the most toxic formLCI it is the most toxic form as it as it stimulates the formation of free radicals and stimulates the formation of free radicals and is thought to be theis thought to be the most accessible tomost accessible to chelation chelation

T2* and LVEF in TMT2* and LVEF in TM

Anderson L, et al. Eur Heart J 2001; 22:2171

MRI study MRI study Total number of patients:142 Total number of patients:142

Aessopos et al. Haematologica 2007

35,21

16,915,49

32,39T2*≤ 10ms10<T2*≤ 15ms15<T2*≤ 20msT2*> 20ms

%

Heart Iron load in Heart Iron load in TMTM

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, BVoskaridou E, at al, Br J r 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;47:136A JACC 2006;47:136A

- CMR in 20 TI patient :- CMR in 20 TI patient : T2* value <20 msec in T2* value <20 msec in nonenone

Raffaella Oliga Raffaella Oliga at al,at al, Haematologica 2008 Haematologica 2008

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:

Cheung YF, Chan GC, Ha SY. Arterial stiffness and endothelial function in patients with beta-thalassemia major. Circulation. 2002 Nov Cheung YF, Chan GC, Ha SY. Arterial stiffness and endothelial function in patients with beta-thalassemia major. Circulation. 2002 Nov 12;106(20):2561-6.12;106(20):2561-6.

[1] Tsomi K, Karagiorga-Lagana M, Karabatsos F, Fragodimitri C, van Vliet-Konstantinidou C, Premetis E [1] Tsomi K, Karagiorga-Lagana M, Karabatsos F, Fragodimitri C, van Vliet-Konstantinidou C, Premetis E et alet al. Arterial elastorrhexis in beta-. Arterial elastorrhexis in beta-thalassaemia intermedia, sickle cell thalassaemia and hereditary spherocytosis.Eur J Haematol. 2001 Sep;67(3):135-41.thalassaemia intermedia, sickle cell thalassaemia and hereditary spherocytosis.Eur J Haematol. 2001 Sep;67(3):135-41.

[1] [1] Aessopos A, Farmakis D, Loukopoulos D. Aessopos A, Farmakis D, Loukopoulos D. Elastic tissue abnormalities resembling pseudoxanthoma elasticum in beta thalassemia and Elastic tissue abnormalities resembling pseudoxanthoma elasticum in beta thalassemia and the sickling syndromes.the sickling syndromes.

Kremastinos et al, Circulation 1995;91:66-71

Myocarditis in b-thalassaemia majorMyocarditis in b-thalassaemia major A cause of heart failure A cause of heart failure

MRI study MRI study total number of patients:574 total number of patients:574

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

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:

Cheung YF, Chan GC, Ha SY. Arterial stiffness and endothelial function in patients with beta-thalassemia major. Circulation. 2002 Nov 12;106(20):2561-6.Cheung YF, Chan GC, Ha SY. Arterial stiffness and endothelial function in patients with beta-thalassemia major. Circulation. 2002 Nov 12;106(20):2561-6. [1] Tsomi K, Karagiorga-Lagana M, Karabatsos F, Fragodimitri C, van Vliet-Konstantinidou C, Premetis E [1] Tsomi K, Karagiorga-Lagana M, Karabatsos F, Fragodimitri C, van Vliet-Konstantinidou C, Premetis E et alet al. Arterial elastorrhexis in beta-thalassaemia . Arterial elastorrhexis in beta-thalassaemia

intermedia, sickle cell thalassaemia and hereditary spherocytosis.Eur J Haematol. 2001 Sep;67(3):135-41.intermedia, sickle cell thalassaemia and hereditary spherocytosis.Eur J Haematol. 2001 Sep;67(3):135-41. [1] [1] Aessopos A, Farmakis D, Loukopoulos D. Aessopos A, Farmakis D, Loukopoulos D. Elastic tissue abnormalities resembling pseudoxanthoma elasticum in beta thalassemia and the sickling syndromes.Elastic tissue abnormalities resembling pseudoxanthoma elasticum in beta thalassemia and the sickling syndromes.

Indirect Iron related injuryIndirect Iron related injury Vascular InvolvementVascular Involvement

Functional changesFunctional changes

Increased Increased aarterial rterial sstiffness and tiffness and eendothelial ndothelial dysfdysfunction in unction in --tthalassemiahalassemia

CheungCheung et al, et al, Circulation 2002;106:2561-2566.Circulation 2002;106:2561-2566.

A randomized, placebo-controlled, double-blind trial A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance.major 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.

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. [e.g. diabetes M, hypothyroidism, diabetes M, hypothyroidism, hypoparathyroidism]hypoparathyroidism]

ArrhythmiasArrhythmias

2. Iron Load:2. Iron Load: direct and indirect effectsdirect and indirect effects

Decreased cardiac contractilityDecreased cardiac contractility



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 hemoglobin, free heme)heme)

- - Iron Iron (oxidative stress)(oxidative stress)

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, Aessopos A, Farmakis D, Loukopoulos D. Loukopoulos D.

Blood. 2002 Jan 1;99(1):30-5. Blood. 2002 Jan 1;99(1):30-5. Review.Review.

33.. Vascular injuryVascular injury

PXE-like elastic tissue disordersPXE-like elastic tissue disorders

Aessopos at all Am. J. Hematology 1992Aessopos at all Am. J. Hematology 1992

PXE-like elastic tissue disorders PXE-like elastic tissue disorders

Angioid streaks in thalassemia majorAngioid streaks in thalassemia majorAessopos at all Am. J. Hematology 1992Aessopos at all Am. J. Hematology 1992

““

Posterior tibial artery calcification: 55% in Posterior tibial artery calcification: 55% in patients over 30 years oldpatients over 30 years old

Aessopos et al. Angiology. 1998;49:137-143.Aessopos et al. Angiology. 1998;49:137-143.

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

PXE-like elastic tissue disorders PXE-like elastic tissue disorders Splenic artery in a Splenic artery in a 6-6-year old HS patient year old HS patient

Tsomi at al, Eur J Haematol 2001Tsomi at al, Eur J Haematol 2001

Elastic tissue abnormalities Elastic 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 old year old ΤΙΤΙ patient patient

Ca deposition (von Kossax2)

Posterior and anterior tibial Posterior and anterior tibial

artery calcification in a artery calcification in a 55year old patient with TI55year old patient with TI

- Aessopos at al. Angiology 1998

Elastic tissue abnormalities

2. 2. NO deficiency NO deficiency NO degradation NO degradation (hemolysis)(hemolysis)

Reduced Reduced ΝΟ ΝΟ synthesis due tosynthesis due to 1) Arginase release (hemolysis)1) Arginase release (hemolysis) 2) Endothelial injury 2) Endothelial injury ((oxidative stress)oxidative stress)

Vichinsky EPVichinsky EP - - Gladwin M.Gladwin M. N Engl J Med N Engl J Med 2004.2004.

33.Vascular injury.Vascular injury



4)4) Valvular injury Valvular injury ((in in 110 110 patientspatients ΤΙ) ΤΙ)

Leaflet thickening Leaflet 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 state Hyperdynamic state – – Elastic tissue disordersElastic tissue disorders))


Cardiac valvular calcifications:

a 50-year old thalassemia intermedia patient

4)4) Valvular injury Valvular injury



5)5) Hypercoagulability Hypercoagulability

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

Cardiovascular involvement in Cardiovascular involvement in Thalassemia Thalassemia

Major and IntermediaMajor and Intermedia

CLINICAL CONSEQUENCESCLINICAL CONSEQUENCES

Ophthalmological ConsequencesOphthalmological Consequences

Visual acuity impairment – Loss of Visual acuity impairment – Loss of vision due to Angioid streaksvision due to Angioid streaks

Visual loss in Thalassemia Visual loss in Thalassemia intermediaintermedia

a 50-year- old thalassemia a 50-year- old thalassemia intermedia patientintermedia patient

59-year old thalassemia intermedia patient

Cardiovascular consequencesCardiovascular consequences

Vascular complications - ArteriesVascular complications - Arteries

Leg ulcersLeg ulcers, , gastrointestinal hemorrhagegastrointestinal hemorrhage Aessopos Aessopos et al. Haematologica 2007et al. Haematologica 2007

StrokesStrokes ( (ischemic, hemorrhagicischemic, hemorrhagic)) Aessopos Aessopos et alet al. . StrokeStroke.. 1997 1997

Manfre L. AJR. 1999 Manfre 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 2002 et al. Circulation 2002 Aessopos Aessopos et et

al.al.Atherosclerosis.Atherosclerosis.20072007 Hahalis G Hahalis 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

Vascular complications - ArteriesVascular complications - Arteries

-E-Endothelial ndothelial dysfdysfunctionunction

-Elastic tissue disorders-Elastic tissue disorders

-NO deficiency-NO deficiency

-Valvular injury-Valvular injury-Arrhythmias-Arrhythmias

-Hypercoagulability-Hypercoagulability


Vascular complications - VeinsVascular complications - Veins

Thromboembolic complications:Thromboembolic complications:In In 4.3% and 5.2%4.3% and 5.2% of bothboth TM and TI respectivelyTM and TI respectivelyandand

in in 3030% % of TI pts with splenectomy of TI pts with splenectomy

Cappellini MD Cappellini MD et alet al. . Br J Haematol 2000Br J Haematol 2000

Cardiovascular consequencesCardiovascular consequences Hypercoagulability Hypercoagulability -- Thrombosis Thrombosis

Dr. Fucharoen’s Dr. Fucharoen’s collectioncollection


Right-sided Heart Right-sided Heart involvementinvolvement

1.Pulmonary hypertension1.Pulmonary hypertension( It is present in non well treated TM patients and is ( It is present in non well treated TM patients and is

the main cause of CHF in TI. the main cause of CHF in TI. Aessopos et al. Blood Aessopos et al. Blood 2001)2001)

p<.001

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Age (years)

Tric

uspi

d G

radi

ent (

mm

Hg)


PSGPSG >30 mmHg: >30 mmHg: (59.1%)(59.1%) >50 >50 mmHg: (7.3%)mmHg: (7.3%)

““


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

Pulmonary hypertension in Pulmonary hypertension in Thalassemia Thalassemia

Increased pulmonary vascular resistanceIncreased pulmonary vascular resistance

Tissue hypoxia -Chronic anemia + HbF Tissue hypoxia -Chronic anemia + HbF Chronic lung injury (infections, iron overload, bone marrow Chronic lung injury (infections, iron overload, bone marrow

expansion, high CO) expansion, high CO) Thromboembolic events Thromboembolic 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 Aessopos et al. Blood 20012001


Right-sided Heart involvementRight-sided Heart involvement

2.Iron deposition in TM2.Iron deposition in TMDecreased RV functionDecreased RV function

Aessopos et al Aessopos et al Eur J Haematol. 2008 Eur J Haematol. 2008

Feb;80(2):93-106.Feb;80(2):93-106.

Cardiovascular consequences Cardiovascular consequences

Left-sided heart dysfunctionLeft-sided heart dysfunction

High output stateHigh output state Iron depositionIron deposition Increased arterial stiffness Increased arterial stiffness (Arterio-ventricular disassociation -Coronary artery involvement)(Arterio-ventricular disassociation -Coronary artery involvement) Infections Infections Endocrine abnormalitiesEndocrine abnormalities Arrhythmias - Atrio-ventricular conduction abnormalitiesArrhythmias - Atrio-ventricular conduction abnormalities Valvular disorders Valvular disorders ((regurgitation - stenosisregurgitation - stenosis))

Dilated cardiomyopathy in Dilated cardiomyopathy in Thalassemia MajorThalassemia Major

48-year-old thalassemia 48-year-old thalassemia intermedia patientintermedia patient

AoV PSG:68mmHgAoV PSG:68mmHg 48-year-old thalassemia intermedia patient48-year-old thalassemia intermedia patient

TVPSG:38mmHgTVPSG:38mmHg48-year-old thalassemia intermedia patient48-year-old thalassemia intermedia patient

““

Coronary artery Coronary artery and mitral and mitral annularannularcalcification:calcification:

a 48-year-old a 48-year-old thalassemia thalassemia intermedia patientintermedia patient

48-year-old thalassemia intermedia 48-year-old thalassemia intermedia patientpatient

The heart in thalasemia intermedia The 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

The heart in thalassemia major The heart in thalassemia major PathophysiologyPathophysiology

under currently accepted therapyunder currently accepted therapy

Tissue hypoxia

Iron overload

LV+RV dysfunction

Pathophysiology of Pathophysiology of cardiac cardiac injury injury

chronic hypoxia

high output stateincreased PVR

PHT

poor transfusions

hypertransfusions

TI pathway TM pathway

iron overload

LV+RV dysfunction

1st Pan-Middle East Conference on Haemoglobinopathies1st Pan-Middle East Conference on Haemoglobinopathies Damascus, Syria 1st – 2nd May 2009 Damascus, Syria 1st – 2nd May 2009

Regardless of the road, difficulties will always present!

cardiovascular involvement in thalassemia major and intermedia

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bone marrow

elastic tissue

sickle cell

male tm patient

thalassaemia

vascular involvement

iron load

endothelial