1. Pathophysiology of cardiovascular disease in haemoglobinopathies and rare anaemias 3rd Pan European Conference on haemoglobinopathies and rare anaemias 24-26 October 1912 Limassos Cyprus A. Aessopos, M.D. First Dept. of Internal Medicine, University of Athens, Medical School

2. Pathophysiology of cardiovascular disease in rare anaemias Rare anemias: They have a global prevalence of less than 5 per 10,000 individuals and encompass almost 90 different conditions

3. Pathophysiology of cardiovascular disease in rare anaemias Rare anemias: Due to their extremely low prevalence, their complications are not extensively explored. In some of those anemias such as hemoglobinopathies, their local prevalence is significantly high and those diseases are exposed to a better observation. Regarding the cardiovascular system, most of the rare anemias share some basic features that can affect the system. Thus, the accumulated knowledge from hemoglobinopathies can be useful for the rest of the rare anemias.

4. Pathophysiology of cardiovascular disease in rare anaemias Common features exist in most of the rare anemias Different degree of severity of pathogenetic mechanisms for cardiovascular injury Cardiovascular CLINICAL CONSEQUENCES

5. Pathophysiology of cardiovascular disease in rare anaemias Common features exist in most of the rare anemias Anemia Bone marrow expansion, extra-medullar hematopoiesis, hepato- splenomegaly Transfusion needs Increased intestinal iron absorption Red blood cell defects –hemolysis Impaired immune competence

6. Pathophysiology of cardiovascular disease in rare anaemias Mechanisms of cardiovascular injury in RA 1) High output state -Chronic anemia -Shunt development: Bone marrow expansion – extramedullar hematopoiesis Hepatic injury -Vascular elastic tissue disorders (dilatation) Aessopos et al. Blood 2001

7. Pathophysiology of cardiovascular disease in rare anaemias 2. Iron load - Transfusions - Increased iron absorption Direct effect: free radicals formation Indirect effects: Endocrine abnormalities Arrhythmias Infections Vascular Iinjury (Afterload ) Mechanisms of cardiovascular injury in RA

8. Pathophysiology of cardiovascular disease in rare anaemias 3.Elastic tissue damage (PXE-like syndrome) (Skin, ocular and arterial finding) -Hemolysis (release of membrane particles, hemoglobin, free heme) -Iron load Aessopos A, Farmakis D, Loukopoulos D. Blood 2002 Mechanisms of cardiovascular injury in RA oxidative stress - thalassemia major, thalassemia intermedia, - sickle cell anemia, sickle thalassemia, - inherited spherocytosis, congenital dyserythropoietic anemia type III

9. PXE-like elastic tissue disorders Aessopos at all Am. J. Hematology 1992

10. 61 year-old TI patient Arterial calcifications in 51 years old man

11. Elastic tissue abnormalities Tsomi at all. Eur. J. Haematol 2001 Splenic artery in a 9-year old ΤΙ patient Ca deposition (von Kossax2)

12. Elastic tissue abnormalities Tsomi at all. Eur. J. Haematol 2001 Splenic hilar artery from a 12 years old with TM

13. PXE-like elastic tissue disorders Splenic artery in a 6-year old HS patient Tsomi at al, Eur J Haematol 2001

14. Pathophysiology of cardiovascular disease in rare anaemias Mechanisms of cardiovascular injury in RA 4. NO deficiency (hemolysis-oxidative stress) NO degradation (hemolysis) Reduced ΝΟ synthesis due to 1) Arginase release (hemolysis) 2) Endothelial injury (oxidative stress) Vichinsky EP, Gladwin M. N Engl J Med 2004.

15. Pathophysiology of cardiovascular disease in rare anaemias 5. Hypercoagulability -RBC membrane injury -NO reduction -Endothelial dysfunction (hemolysis-iron load) -Thrombocytosis due to splenectomy -Platelet activation Cappellini et al. Br J Haematol 2000 Eldor & Rachmilewitz. Blood 2002 Mechanisms of cardiovascular injury in RA

16. Pathophysiology of cardiovascular disease in rare anaemias 6.Susceptibility to infections Anemia Iron load Chelation therapy Immune competence is impaired. Infections: Viral(pericarditis and myocarditis) – Bacterial infections (siderophore bacteria, such as yersinia and klebsiella ) Mechanisms of cardiovascular injury in RA Farmakis D. et al. Med Sci Monit 2003

17. Pathophysiology of cardiovascular disease in rare anaemias High output state Iron load Elastic tissue damage NO redaction Hypercoagulability Susceptibility to infections Mechanisms of cardiovascular injury in RA

18. Cardiovascular CLINICAL CONSEQUENCES 1. Vascular complications - Arteries Increased arterial stiffness – endothelial dysfunction Oxidative stress- Elastic tissue damage Cheung YF et al. Circulation 2002 Aessopos et al.Atherosclerosis.2007 Hahalis G Atherosclerosis.2008 Strokes (ischemic, hemorrhagic) Hypercoagulability Elastic tissue damage -Valvular disorders Arrhythmias - LV dysfunction Aessopos et al. Stroke. 1997 Manfre L. AJR. 1999 Karimi M…Rachmilewitz EA., AJ H. 2008 Leg ulcers, gastrointestinal hemorrhage Anemia- Elastic tissue damage Aessopos et al. Haematologica 2007

19. 65 year-old patient with SSD PXE-like syndrome and GI angiodysplasias (pill camera)

20. Cardiovascular CLINICAL CONSEQUENCES 1.Vascular complications - Veins Thrombosis and Thromboembolic complications: In 4.3% and 5.2% TM and TI respectively In 4.3% and 5.2% of TM and TI respectively and in 30% of TI pts with splenectomy Cappellini et al. Br J Haematol 2000 DVT: 8.1% in TI, 0% in TM DVT: 8.1% in TI, 0% in well treated TM Aessopos et al, Chest 2005 Aessopos et al, Chest 2005 - thalassemia major, thalassemia intermedia, - sickle cell anemia, sickle thalassemia, - inherited spherocytosis, NPH

21. Cardiovascular consequences Hypercoagulability - Thrombosis Dr. Fucharoen’s collection

22. TM Thrombous formation in LV apex

23. 2.Right-sided Heart dysfunction High output state : (increased contractility) Pulmonary hypertension: (increased afterload) Iron deposition : (Decreased contractility ) Cardiovascular CLINICAL CONSEQUENCES

24. 2.Right-sided Heart involvement a. Pulmonary hypertension It is present : a)In non-well treated TM patients and is the main cause of CHF in TI. Aessopos et al. Blood 2001 b)In SCD Vichinsky EP - Gladwin M. N Engl J Med 2004 c) In NPH Hill A et al, Br J Haematol 2012 d) In hereditary spherocytosis Crary SE et al, Am J Hematol 2011

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26. Cardiovascular CLINICAL CONSEQUENCES Pulmonary hypertension cardiac output x pulmonary vascular resistance => pulmonary hypertension => CHF

27. 39 year-old patient Hb: 11gr F:(95%) CO: 11.5 L/Min

28. Pulmonary hypertension in Thalassemia Increased pulmonary vascular resistance Tissue hypoxia -Chronic anemia Chronic lung injury (infections, iron overload, bone marrow expansion, high CO) Thromboembolic events Endothelial dysfunction (  NO) (Hemolysis – iron overload) Elastic tissue disorders (PXE-like) LV dysfunction Aessopos et al. Blood 2001

29. RIGHT HEART INVOLVEMENT Iron deposition 319 patients iron loaded patients (TM) T2* >20 ms, normal RVEF in 98% of cases T2*<20 ms, progressive decline of RVEF, as with LVEF Alpendurada et al, Eur Heart J 2010

30. Cardiovascular CLINICAL CONSEQUENCES 3.Left-sided heart dysfunction High output state Increased arterial stiffness Iron deposition(systolic and diastolic dysfunction) Endocrine abnormalities Arrhythmias - Atrio-ventricular conduction abnormalities Valvular disorders (regurgitation - stenosis) Infections (Myocarditis)

32. Cardiac valvular calcifications: a 50-year old thalassemia intermedia patient Valvular injury Aessopos et al. Blood 2001

33. Kremastinos et al, Circulation 1995;91:66-71 Myocarditis in b-thalassaemia major A cause of heart failure

34. Cardiovascular CLINICAL CONSEQUENCES Viral infections Iron load 4.Pericardial involvement Pericarditis in TM 50% Engle a tall : Circulation 1964 in well treated TM 5% Aessopos a tall: Eur.J. Haematol 2004

35. 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 major constrictive pericarditis

36. Cardiovascular CLINICAL CONSEQUENCES 1 -Vascular complications ( –Veins) 1 -Vascular complications (Arteries –Veins) 2 -Right-sided Heart involvement 1.Pulmonary hypertension 2.Iron deposition (Decreased RV function ) 3 -Left-sided heart dysfunction 4 -Pericardium involvement

37. Pathophysiology of cardiovascular disease in rare anaemias Conclusions Common features exist in most of the rare anemias Their degree of the severity may affect in different way the cardiovascular system and one or the other may dominate the clinical picture Any cardiovascular finding has to be considered related to the main disease before is thought to be as a coincidence Particular features of each disease may represent additional mechanisms of cardiovascular injury

38. Thank you!

39. Pathophysiology of cardiovascular disease in rare anaemias Rare anemias: According to the definition of the European Commission(EC), Rare anemias have a global prevalence of less than 5 per 10,000 individuals. Encompass a large and markedly heterogeneous group of nearly 90 different conditions, mostly congenital or genetically determined