Χριστίνα Χρυσοχόου Α Καρδιολογική Κλινική Πανεπιστηίου Αθηνών
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1 Ιωάννης Ανδρέου Χριστίνα Χρυσοχόου Α Καρδιολογική Κλινική Πανεπιστηίου Αθηνών Ιπποκράτειο Γ.Ν.Α
2 Splenectomy at the age of 7yrs Episodes of persistent atrial fibrillation Hypothyroidism Osteoporosis Noncompliant with longterm deferoxamine chelation 44yearold man suffering from βthalassemiamajor diagnosed at the age of 1yr Despite optimal medical treatment with enalapril, carvedilol, furosemideand spironolactone, the patient experienced progressive severe dyspnea, with symptoms caused by minimal activities (NYHA Class III IV) Last year multiple admissions for acute decompensations
3 Physical examination jaundice poor musculature hepatomegaly leg ulcers skeletal changes resulting from expansion of the bone marrow The jugular veins were palpable and dilated dilated abdomen with diffuse tenderness, ascitesand liver enlargement The arterial pressure was 90/60 mmhg The chest roentgenogram revealed increased cardiothoracic ratio and right lung pleural effusion Electrocardiogram sinus rhythm, RBBB
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7 Echocardiography
8 Echocardiography
9 Apical 4 chamber view
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12 Magnetic resonance imaging of the heart showed a very low T2* value, consistent with a relevant myocardial iron overload
13 Assessment of Iron Overload with T2* Magnetic Resonance Imaging Method of choice for tissue iron assessment T2* is a magnetic relaxation property of any tissue and is inversely related to intracellular iron stores
14 2005
15 Epidemiology Genetics βthalassemiais caused by the reduced or absent synthesis of the beta globinchainsof the hemoglobin tetramer 3 clinical and hematological conditions of increasing severity are recognized thalassemiaminor betathalassemiacarrier state (results from heterozygosity for betathalassemia) thalassemiaintermedia (heterogeneous group of thalassemialike disorders) thalassemia major (severe transfusiondependent anemia)
16 5000 pts with βthalassemia in Greece
17 The life of patients with thalassemia has improved both in duration and in quality in industrialized countries Complications are still common and include heart disease (heart failure and arrhythmias) chronic liver hepatitis, which can evolve in cirrhosis and, rarely, in hepatocellular carcinoma endocrine problems (hypogonadism, hypothyroidism, diabetes, hypoparathyr oidism) stunted growth osteoporosis thrombophilia Higgs DR et al. Lancet 2012;379:373*83
18 βthalassemiamajor major mid1960s : only 37% survival at the age of 16 years 2004 : a 83% survival rate beyond 40 years oral iron chelators deferipronein 2000 deferasirox in 2007 Kremastinos DT et al. Circ Heart Fail 2010;3:451458
19 βthalassemia Cardiomyopathy Cardiac complications are the cause of the deaths in 7080% of the patients with β thalassemia major Cardiac failure and serious arrhythmias are the major causes of lifethreatening morbidity and mortality in ironoverload patients βthalassemiapatients are susceptible to benign pericarditis, possibly caused by viral and mycoplasmal organisms, bacterial or fungal infections Ginzburg Y, Rivella S Blood 2011;118:432130
20 βthalassemia Cardiomyopathy (i) a dilated cardiomyopathy phenotype characterized by left ventricular dilatation and reduced contractility, leading to congestive heart failure; (ii) a restrictive cardiomyopathy phenotype characterized by restrictive left ventricular filling with subsequent pulmonary hypertension, right ventricular dilatation, and heart failure. (iii) mixed type HF Myocardial iron depositionin some patients with thalassemiamajor may not directly affect left ventricular contractility, but it may rather cause left ventricular myocardial restriction Kremastinos DT et al. Circ Heart Fail 2010;3:451*458
21 Pathophysiology Before the introduction of regular blood transfusions, patients developed a form of highoutput heart failure In the era of systematic transfusion therapy, myocardial iron overload is traditionally thought to be the main cause of thalassemia cardiomyopathy its main cause is the repetitive blood transfusions ineffective erythropoiesis peripheral hemolysis increased intestinal iron absorption Iron toxicity has been attributed to the production of free oxygen radicals Higgs DR et al. Lancet 2012;379:37383
22 Pathophysiology Myocarditisalso seems to play a role in the pathogenesis of cardiomyopathyin patients with thalassemia The role of viral infections seems to be of particular relevance in patients with thalassemiabecause of their repetitive exposure to a significant, transfusion associated viral burden The role of immunogeneticmechanisms in the pathogenesis of thalassemiacardiomyopathyhas been stressed by the reported differences in human leukocyte antigen profile between patients with thalassemiawith and without heart failure Kremastinos DT et al. Circ Heart Fail 2010;3:451458
23 Management Thalassemia patients respond poorly to the usual pharmacological treatment with ACEinhibitors, beta blockers and diuretics. The recent introduction of dual ironchelation therapy, by combining the traditional parenteral chelator deferoxamine with the newer oral one deferiprone seems to enhance the efficacy of treatment. Patients with overt heart failure (moderate to severe) and marked myocardial iron overload tend to be less responsive to intensive chelation Ginzburg Y, Rivella S Blood 2011;118:432130
24 Management 1. Regular longlife red blood cell transfusions 2. Iron chelation therapy to remove iron introduced in excess with transfusions The only definitive cure is bone marrow transplantation Therapies under investigation are the induction of fetal hemoglobin with pharmacologic compounds and stem cell gene therapy. Ginzburg Y, Rivella S Blood 2011;118:432130
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26 Myocardial iron is hard to measure Serum ferritinconcentration, useful but rather rough estimate of total body iron load (Ferritin levels less than 2,500 ng/ml are associated with improved survival. However, ferritin levels are unreliable when liver disease is present) Olivieri NF et al. N Engl J Med 1994;331:574-8 Cardiovascular MRI allows an accurate assessment of iron (T2* imaging) provides a precise quantification of myocardial and hepatic iron load and has become a useful tool for the evaluation of patients and for the therapeutic guidance and follow-up of iron chelation therapy Kirk P et al. Circulation 2009;120:1961-8
27 Cardiac function is monitored annually beginning at Cardiac function is monitored annually beginning at 7 or 8 years of age by electrocardiogram, echocardiogram, 24hour Holter monitor, and recently by cardiac T2* MRI, which can detect preclinical cardiac iron accumulation
28 Prognosis In the developed world, life expectancy is years, depending on compliance with medical treatment. Untreated individuals with βthalassemiamajor live an average of 17 years and usually die by 30 years of age. Patients transfused with blood screened for viruses and treated with iron chelating agents survive well into the 5th decade The 5year survival of heart failure in patients with thalassemiamajor was similar to that of the regular heart failure populationafter the addition to the regular heart failure treatment of intensified blood transfusions to maintain a sufficiently high hemoglobin level and iron chelation Higgs DR et al. Lancet 2012;379:37383
29 Conclusion Heart disease is the primary determinant of prognosis and survival in βthalassemia. Myocardial iron deposition seems to be the trigger for the development of heart failure in thalassemia major. Iron overload in combination with other factors Iron overload in combination with other factors (inflammatory and immunogenetic) can cause left ventricular systolic dysfunction, dilatation, and failure, whereas iron alone may result in left ventricular diastolic dysfunction with myocardial restriction and subsequent pulmonary hypertension and right ventricular dilatation.
30 Conclusion Assessment of myocardial siderosisand monitoring ofcardiac function combined with red cell transfusion and intensification of ironchelationhave converted a once universally fatal diseaseto a chronic illness Excellent longterm prognosisis expected for children who have been chelatedsince avery young age
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