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Successful management of cardiogenic shock in beta thalassemia major by iron chelator Righab Hamdan M.D. MSc. April, 2016 Introduction: Heart failure mediated by cardiac iron overload has accounted for considerable early mortality in β-thalassemia major [1]. Although early cardiomyopathy from iron overload is becoming less common in Thalassemia Major(TM) patients, the terminal event for older patients is often iron mediated cardiac disease. There is a lack of controlled data regarding the management of cardiomyopathy mainly comparing different chelation regimens in the management of heart failure beside the indication for heart transplantation or left ventricular assist device (LVAD) for advanced heart failure. We report the case of severe end stage heart failure in a 34 years old TM patient presenting with cardiogenic shock and successfully managed medically. Case report: We report the case of a 34 years old female patient, weighing 85 kilograms for a height of 160 cm. She is known to have thalassemia major since childhood with regular recurrent blood transfusions. She was on oral iron chelators at an appropriate dose adjusted to body weight (Deferiprone: 500mg, 4 tablets, three times daily). She was referred to our center for management of new onset heart failure. We note in her medical history, splenectomy at the age of 5, a well-treated secondary hypothyroidism as well as secondary diabetes. Cardiac ultrasound was performed regularly and the left ventricular function was normal up to 3 months prior to her admission to our center. The patient started to complain from dyspnea at mild exertion with progressive worsening, 2 months prior to her admission. A new cardiac ultrasound was performed one month later showing a slightly dilated left ventricle (LV) with moderate to severe LV dysfunction (LVEF30%). She was hospitalized and started on inotropes one week prior to her transfer to our center; she was then referred to us for further management and for failure to wean from inotropes. Upon her admission she was hypotensive (mean arterial pressure: 50 mmHg), in sinus tachycardia (120/min), with cold extremities and clinical signs of left and right heart failure: jugular vein distension, lower limbs edema, and pulmonary crackles. The chest X ray showed pulmonary edema. Blood test showed normal creatinin level, normal liver function test, very high ferritin level: 24 000µg/l, and an elevated BNP level (2560 ng/l). Cardiac ultrasound (figure 1) showed a dilated left ventricle with severely impaired function (LVEF: 20%), right ventricle (RV) was slightly dilated with moderately to severely impaired function (TAPSE: 10 mm, S: 9 cm/s). Cardiac MRI showed signs of hemochromatosis: a prolonged T2*: 6.6 ms (figure 2). Cardiac biopsy confirmed the diagnosis of secondary hemochromatosis by showing significant presence of intracellular iron granules, positive to special iron staining. Despite high dose of Dobutamine, the patient hemodynamical status deteriorated and an intra aortic balloon (IABP) was installed, and enabled better progression. She regained a good diuresis and was stable on inotropes and IABP but the weaning from these therapeutic options was difficult. Beside inotropes, intravenous diuretics, and oral iron chelators (Deferiprone), the patient was started on intravenous high dose of Deferoxamine (60 mg/Kg) since day Zero of admission. We registered the patient on the high priority transplantation list, and we discussed left ventricular assist device implantation (LVAD). On day 21 of Deferoxamine the patient started to improve with progressive weaning from the IABP at day 18 of support and then from Dobutamin. Ferritin level was decreased to 3 000 ng/l. Repeated cardiac ultrasound showed improved ejection fraction (35%). The patient was discharged home on both association Deferiprone plus Deferoxamine via a subcutaneous pump, beside regular heart failure treatment, although the doses of beta blockers and ACE inhibitors could not be titrated due to the relatively low blood pressure. On her last follow up, 6 months post discharge, the patient is doing well, with no recurrent hospitalizations for heart failure, she is in NYHA I-II. The last cardiac ultra sound at 6 months (figure 3) showed a LVEF of 50%, normal RV function, and no pulmonary hypertension. Discussion: This case is a typical illustration of reversible cardiac involvement in secondary hemochromatosis, manifested by cardiogenic shock. We disposed from the major therapeutical options available starting from optimal iron chelation, optimal heart failure medical treatment, mechanical assistance via intra aortic balloon, till candidacy to heart transplantation. Interestingly our patient progressively responded well to medical treatment despite her advanced heart failure and her critical situation. There is very few data concerning the treatment of cardiogenic shock in secondary hemochromatosis complicating thalassemia major. Heart disease remains the predominant cause of death in β-thalassemia major (TM) [1–4] During the past few decades, an impressive improvement in TM patients’ survival has been noticed. In the mid-1960s, the best survival was 16 years old. Nowadays the survival at the age of 35 years is 50% according to the UK thalassemia registry2. Cardiac complications are still the leading cause of mortality, accounting for 71% of deaths [5]. After heart failure onset, with intensified blood transfusions and regular iron chelation in addition to conventional heart failure therapy, the 5-year survival is 48%[5]. TM is a genetic condition with severe reduction or absent production of the β-globin chain constituent of hemoglobin (Hb) A, resulting in an excess of α-globin chains, and consequent ineffective erythropoiesis and profound life threatening anemia [6]. Before the introduction of regular blood transfusions, patients developed a form of high-output heart failure as a consequence of prolonged tissue hypoxia, resulting from chronic anemia. In the era of systematic transfusion therapy, myocardial iron overload is traditionally thought to be the main cause of thalassemia cardiomyopathy [5]. In terms of ventricular function, 2 different phenotypes are present [5]: (i) a dilated cardiomyopathy phenotype, characterized by left ventricular dilatation and reduced contractility, (ii) a restrictive cardiomyopathy phenotype, characterized by restrictive left ventricular filling with subsequent pulmonary hypertension, right ventricular dilatation, and heart failure. Changes in the heart in addition to ventricular systolic impairment include the following: (1) Decreased left atrial function[7], (2) Impaired right RV function, caused by the increased vulnerability of the RV to iron deposition. Tissue Doppler imaging velocity and strain imaging suggest early RV impairment in iron overload [8]. (3) Impaired endothelial function in iron overload [9]. Myocardial iron deposition can be reproducibly quantified using myocardial T2* and this is the most significant variable for predicting the need for ventricular dysfunction treatment. Myocardial iron content cannot be predicted from serum ferritin or liver iron, and conventional assessments of cardiac function can only detect those with advanced disease [10]. Cardiac iron overload is defined by T2* on cardiovascular magnetic resonance (CMR): 1) severe cardiac iron loading , T2* <10 ms and 2) mild to moderate cardiac iron loading T2*10 to 20 ms [8]. Recognition of severe cardiac siderosis by T2* CMR and intervention with suitable treatment, before the onset of symptomatic HF, is associated with improvements in ventricular function.[11] Studies suggest that a ferritin level >2500 μg/L indicates a raised risk but there is no threshold effect, and risk is increased even down to ferritin levels of 1000 μg/L [12]. The first iron chelator approved for clinical use was Deferoxamine (DFO), that needs to be given parentally, either subcutaneously, or by intravenous infusion [13]. Once severe cardiac iron loading is present, months to years of careful therapy is needed to clear the iron. Deferiprone (DFP) is an oral iron chelator that has significant compliance advantages over Deferoxamine. Deferiprone is commonly used in combination with Deferoxamine for enhanced iron clearance [13]. The combination of Deferoxamine with the Deferiprone led to the reduction of myocardial iron load as well as the improvement of both left ventricular ejection fraction and endothelial function as compared with Deferoxamine.[14] A study by Porter et al. clearly shows that DFO intensification with or without DFP is effective in improving LVEF and myocardial T2* in this severely affected patients. DFO was allowed up to 24 h/day and up to 60 mg/kg [15]. The acute mortality of New York Heart Association stage IV heart failure in thalassemia remains high, probably in excess of 50% in hospital mortality, simply because support for the heart and other failing organs, especially the kidneys and liver, often cannot be continued long enough for iron chelation to stabilize myocardial function, a process that may take many months [8]. In critical patients, like our case, immediate commencement of 24-hour-per-day continuous intravenous iron chelation treatment with Deferoxamine 50 mg.kg−1.d [16] allows higher survival. Deferiprone should be introduced as soon as possible at a dose of 75 mg.kg−1.d−1 [17]. Stabilization can occur within 14 days after commencement of continuous iron chelation treatment but can also take months. Consideration should be given to mechanical support devices to support both ventricles, bearing in mind the RV is often compromised. There is no published evidence for this approach [8]. Few reports exist concerning heart transplantation in recipients with end-stage heart failure caused by iron overload occurring with beta-thalassaemia, or haemochromatosis. A paper by Koerner et al reported seven transplanted cases for primary and secondary hemochromatosis [18]. One of these candidates had to be bridged, first with a right ventricular, then with a biventricular assist device. Five of the seven patients survived, following transplantation. These results demonstrate the feasibility of transplantation in patients with such heart failure [18]. Conclusion: We reported an interesting case of advanced heart failure presenting with cardiogenic shock in a 34 years old TM patient, responding successfully to adequate medical therapy and short duration circulatory assistance. Early detection of myocardial iron overload is crucial to avoid cardiomyopathy progression by intensifying the iron chelation regimen. References: 1. Borgna-Pignatti C, Rugolotto S, De Stefano P, Zhao H, Cappellini MD, Del Vecchio GC, Romeo MA, Forni GL, Gamberini MR, Ghilardi R, Piga A, Cnaan A. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica. 2004;89:1187–1193. 2. Modell B, Khan M, Darlison M. Survival in beta-thalassaemia major in the UK: data from the UK Thalassaemia Register. Lancet. 2000;355:2051–2052. 3. Telfer P, Coen PG, Christou S, Hadjigavriel M, Kolnakou A, Pangalou E, Pavlides N, Psiloines M, Simamonian K, Skordos G, Sitarou M, Angastiniotis M. Survival of medically treated thalassemia patients in Cyprus: trends and risk factors over the period 1980-2004. Haematologica. 2006;91:1187–1192. 4. Ladis V, Chouliaras G, Berdousi H, Kanavakis E, Kattamis C. Longitudinal study of survival and causes of death in patients with thalassemia major in Greece. Ann N Y Acad Sci. 2005;1054:445–450. 5- Kremastinos D, Farmakis D, Aessopos A, Hahalis G, Hamodraka E, Tsiapras D, Keren A. Thalassemia Cardiomyopathy History, Present Considerations, and Future Perspectives. Circ Heart Fail. 2010; 3: 451-458. 6- Engle MA, Erlandson M, Smith CH. Late cardiac complications of chronic, severe, refractory anemia with hemochromatosis. Circulation. 1964;30:698–705. 7- Trikas A, Tentolouris K, Katsimaklis G, Antoniou J, Stefanadis C, Toutouzas P. Exercise capacity in patients with beta-thalassemia major: relation to left ventricular and atrial size and function. Am Heart J. 1998;136:988–990. 8-Pennell DJ, Udelson JE, Arai AE, Bozkurt B, Cohen AR, Galanello R, Hoffman TM, Kiernan MS, Lerakis S, Piga A, Porter JB, Walker JM, Wood J. Cardiovascular function and treatment in β-thalassemia major: a consensus statement from the American Heart Association. Circulation. 2013 Jul 16;128(3):281-308. 9- Cheung YF, Chan GC, Ha SY. Arterial stiffness and endothelial function in patients with beta-thalassemia major. Circulation. 2002;106:2561–2566. 10- Anderson LJ, Holden S, Davis B, Prescott E, Charrier CC, Bunce NH, Firmin DN, Wonke B, Porter J, Walker JM, Pennell DJ. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J. 2001 Dec;22(23):2171-9. 11- Tanner MA, Galanello R, Dessi C, Smith GC, Westwood MA, Agus A, Pibiri M, Nair SV, Walker JM, Pennell DJ. Combined chelation therapy in thalassemia major for the treatment of severe myocardial siderosis with left ventricular dysfunction. J Cardiovasc Magn Reson. 2008;10:12. 12- Engle MA. Cardiac involvement in Cooley’s anemia. Ann N Y Acad Sci. 1964;119:694–702. 13- Baksi AJ, Pennell DJ. Randomized controlled trials of iron chelators for the treatment of cardiac siderosis in thalassaemia major. Front Pharmacol. 2014 Sep 23;5:217. 14-Tanner MA, Galanello R, Dessi C, Smith GC, Westwood MA, Agus A, Roughton M, Assomull R, Nair SV, Walker JM, Pennell DJ. A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Circulation.2007;115:1876 –1884. 15- Porter JB, Wood J, Olivieri N, Vichinsky EP, Taher A, Neufeld E, Giardina P, Thompson A, Moore B, Evans P, Kim HY, Macklin EA, Trachtenberg F. Treatment of heart failure in adults with thalassemia major: response in patients randomised to deferoxamine with or without deferiprone. J Cardiovasc Magn Reson. 2013 May 20;15:38. 16-Davis BA, O’Sullivan C, Jarritt PH, Porter JB. Value of sequential monitoring of left ventricular ejection fraction in the management of thalassemia major. Blood. 2004;104:263–269. 17-Tsironi M, Deftereos S, Andriopoulos P, Farmakis D, Meletis J, Aessopos A. Reversal of heart failure in thalassemia major by combined chelation therapy: a case report. Eur J Haematol. 2005;74:84–85. 18- Koerner MM1, Tenderich G, Minami K, zu Knyphausen E, Mannebach H, Kleesiek K, Meyer H, Koerfer R.Heart transplantation for end-stage heart failure caused by iron overload. Br J Haematol. 1997 May;97(2):293-6. Figures: Figure 1: The first cardiac ultra sound showed a dilated and severely impaired left ventricle (to the left), and a moderately to severely impaired RV (to the right), TAPSE: 10 (up), tissue Doppler velocity at the tricuspid annuls: 9 cm/ s (down). Figure 2: cardiac magnetic resonance confirmed the diagonosis of cardiac hemochromatosis, revealed by an extremely short T2* (6.6 ms). Figure 3: cardiac ultrasound 6 months later, showed a significant improvement of the LVEF, with residual slight impairment of the LV function at the left of the picture; on the right, we notice a normal RV, function normal TAPSE: 19 mm(up), normal tissue Doppler velocity at the tricuspid annuls: 13 cm/s (down).