Cardiac Iron Overload Causes Clinically Evident Heart Failure and Arrhythmia in Sickle Cell Anemia Patients: Evidence From Three Cases
Authors: Mehta Bhakti P. , Berdoukas Vasilios , Puliyel Mammen , Bush Adam , Hofstra Thomas , Claster Susan , Nord Anne , Carson Susan , Hernandez Tatiana , Dongelyan Ani , Wood John C , Coates Thomas D. 
Published: October 2019

Abstract
Abstract 4846
Transfusional iron overload is associated with poor outcomes in sickle cell disease (SCD). Unlike in thalassemia major (TM), there is no evidence that the iron overload per se causes morbidity in SCD. We present two patients with clear evidence of heart failure and arrhythmia secondary to transfusion induced cardiac iron overload, whose symptoms and signs completely resolved after a short period of intensive iron chelation. We studied 134 patients with SCD with magnetic resonance imaging (MRI). Over 50% of patients with TM and 70% of patients with transfusion dependent Diamond Blackfan Anemia demonstrate cardiac iron overload. We reviewed 472 MRIs in 134 patients with SCD. The median liver iron concentration (LIC) was 10.2 mg/g dry weight (dw). Ten percent of the patients had liver iron > 35mg/g dw. Three (2.2%) demonstrated cardiac iron overload.
Patient 1 is now 27 years old and began transfusions at the age of 15 years because of pulmonary hypertension. The first MRI performed at the age of 22 years showed LIC >50 mg/g dw and a cardiac R2* of 128 sec−1 (T2* 7.8 ms) that indicates severe cardiac iron load. At this time she was changed from deferasirox to continuous infusion of desferrioxamine. After 6 months the LIC was 47 mg/g dw and her cardiac R2* was 123sec−1 (T2* 8.1ms). She had dyspnea on mild exertion, ankle edema, and orthopnea. Her left ventricular ejection fraction (LVEF) by MRI at that time was 45%. She started intensive chelation therapy with deferiprone (on compassionate basis) 100mg/kg/day and deferasirox 40mg/kg/day. Her symptoms and signs of clinical heart failure resolved within two months. She remains asymptomatic. After 7 months cardiac R2* is 88 sec−1 (T2*11.3ms) with an LVEF of 55% and LIC of 36 mg/g dw.
Patient 2 is now 32 years of age. She started regular blood transfusions at the age of 9 years. Her first MRI at the age of 27 years showed a LIC of >60 mg/g dw and no evidence of cardiac iron overload with a cardiac R2* of 29 sec−1(T2* 34.9ms) with an LVEF of 61%. After 2.5 years her cardiac R2* was 68 sec−1 (T2* 14.7 ms) with an LVEF of 65.7% and 18 months later it was 123 sec−1(T2* 8.1 ms) with an LVEF of 72%. She developed significant arrhythmias coincident with her rapid cardiac iron loading. She was started on compassionate use deferiprone and deferoxamine, with which she is poorly compliant. Repeat cardiac MRI showed a worsening of cardiac iron with R2* of 204 sec−1 (T2* 4.9ms) after 8 months with an improved LVEF of 72%. She currently continues of her regular transfusions and deferiprone and is awaiting repeat MRI. Her LVEF improved while on the chelation therapy despite the deterioration in her cardiac iron content. This is consistent with our observation that LVEF tends to improve even with intermittent chelation although the cardiac iron may not decrease.
Patient 3 died of numerous complications of SCD at the age of 19 years. She had started transfusions at the age of 10 years, because of a cerebrovascular accident. At the age of 14 years her first abdominal MRI demonstrated a LIC of 12.8 mg/g dw. She had her first cardiac MRI at the age of 16 years which showed no evidence of cardiac iron with a R2* of 30 sec−1 (T2* 32.7ms), which worsened to 57 (T2* 17.4ms) at the age of 17, reflecting a small but rapid increase in cardiac iron.
Patient 1 and 2 demonstrate that transfusional iron overload can directly cause life threatening complications in patients with SCD. Patient 1 in particular, was in overt clinical heart failure that responded dramatically to intensification of chelation therapy. These data underscore the importance of direct measurement of tissue iron concentrations and points out that though uncommon, cardiac iron overload can occur in patients with sickle cell anemia with serious consequences.

Disclosures:
Berdoukas: ApoPharma Inc.: Consultancy. Carson:ApoPharma Inc.: Honoraria; Novartis Inc: Speakers Bureau. Wood:Cooleys Anemia Foundation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ferrokin Biosciences: Consultancy; Novartis: Research Funding. Coates:Novartis Inc: Speakers Bureau.