Cardiovascular evaluation and management of iron overload cardiomyopathy in sickle cell disease
Authors: Mahazarin Ginwalla, Abdullah AlMasoud, David Tofovic, Tara Alin, Sadeer Al‐Kindi, Guilherme Oliveira, Sanjay Rajagopalan, Robert Schilz, Jane Little
Journal: American Journal of Hematology (2017)

Chronic blood transfusions in sickle cell disease (SCD) may lead to myocardial iron deposition in 2%-5% of SCD patients. This can lead to systolic and diastolic left ventricular dysfunction, heart failure, arrhythmias, and sudden cardiac death.1 Iron overload cardiomyopathy (IOC) is diagnosed using cardiac magnetic resonance imaging (MRI) using T2*. There is a clear relationship between degree of complications such as heart failure, and arrhythmias with T2* values <20 milliseconds.2 Herein we describe three different situations of IOC in SCD in whom iron chelation therapy may be considered: (1) Abnormal cardiac T2* < 20 milliseconds on MRI with reduced left ventricular ejection fraction (LVEF); (2) Abnormal cardiac T2* < 20 milliseconds with normal LVEF; (3) Borderline T2* of 20–30 milliseconds with normal LVEF and heart failure (HF) symptoms. Additionally, we describe the use of biomarkers to monitor the response to iron chelation therapy. This observational study was conducted from January 2010 to December 2017 with institutional research board approval. Out of a cohort of about 200 patients >18 years with homozygous SCD, we retrospectively identified three patients with iron deposition on cardiac MRI with a T2* of ≤20 milliseconds and four patients with a borderline T2* of 20–30 milliseconds. All the patients had elevated ferritin levels and heart failure symptoms. The medical records of the selected patients were reviewed for demographic data, transfusion and chelation history, and hematologic and biochemical parameters. All MRI examinations were performed on a Siemens 1.5 Tesla scanner (Avanto or Aera, Siemens Medical Solutions Inc. Erlangen, Germany). Multiecho gradient-echo sequences were used to collect the images for T2* analysis in the heart. An ECHO was performed at regular intervals at least annually. IOC was identified in 7 out of 200 (3.5%) adult patients with homozygous SS sickle cell disease. These patients were diagnosed by combinations of cardiac MRI, clinical features, hemodynamic measurement, and blood tests including serum ferritin. Out of seven patients four were between 20 and 30 years old, two were 40–50 years old, and one was >60 years old. Four patients were female. All patients had homozygous HgbSS sickle cell disease and severe anemia with hemoglobin levels 6–8 g/dL. Given the retrospective nature of this study, and incomplete documentation of transfusional volumes, it was not possible to accurately estimate the number of transfusions. All patients had an estimated >50 lifetime transfusions. Ferritin levels were higher than 3000 µg/L in five patients and between 1500 and 2000 µg/L in two patients at the time of diagnosis of IOC. All patients had transferrin saturation above 60%. All patients had symptoms of acute heart failure. Three patients had right ventricular dysfunction, and six patients had elevated tricuspid regurgitant velocities (TRV) >2.5 m/s. Two out of seven patients had heart failure with reduced ejection fraction (HFrEF), while five patients had preserved left ventricular ejection fraction (HFpEF, LVEF >45%). Both patients with HFrEF had partial recovery of their ejection fraction after iron chelation therapy. Deferoxamine was used in one patient who subsequently died with multiorgan failure. She had a long history of poor adherence with her medications and exchange transfusions. Her T2* was 16 milliseconds and was the lowest of the group. Six out of the seven patients were on deferasirox and one patient was on deferiprone. Four out of seven patients were prescribed hydroxyurea, with unclear adherence. All seven patients were initiated on heart failure therapy including diuretics, beta blockers, and vasodilators. Prior studies in thalassemia patients indicate that there are two main cardiac phenotypes involving the left ventricle in IOC, the restrictive phenotype, and the dilated phenotype.3 Diastolic function may be preserved on echocardiography despite restrictive physiology and it does not appear to be a reliable surrogate for echocardiographic diagnosis of IOC. Two patients with the dilated phenotype and HFrEF had only partial reversal of their LV dysfunction with institution of iron chelation therapy. This is similar to the findings by Odour et al.4 The absence of complete reversal of LV dysfunction may be attributed to established myocardial injury, persistent iron overload, or limited efficacy of iron chelators as only a portion of total body iron content is directly chelatable, with hemosiderin being the least accessible form of the three forms of stored iron.5 Thus it may be postulated that in lieu of initiating iron chelation therapy when T2* values are <20 milliseconds on MRI, it may be beneficial to initiate therapy earlier when T2* values are 20–30 milliseconds indicative of early or mild iron overload especially when patients are symptomatic, to prevent permanent myocardial damage. We evaluated serum markers in patients with IOC. All patients with IOC had ferritin levels over 1500 µg/L. Ferritin levels have not been shown to correlate directly with cardiac iron overload; however cardiac iron may be present at relatively modest elevations in ferritin.2 All patients with IOC also had elevated NT-proBNP (or BNP) levels (Figure 1A). We found that the NT-proBNP trend in four out of the six patients appeared to mirror the trend in ferritin levels and clinical course with iron chelation therapy. This is the first time that this has been demonstrated, and this may be a useful marker of myocardial iron deposition as well as reversal of cardiac iron overload with iron chelation therapy. High NT-proBNP levels in SCD > 160 pg/mL have been demonstrated to prognosticate a high risk of mortality.6 Improvement in NT-proBNP levels may indicate the improvement in neurohormonal changes that occur with iron chelation and help gain an insight into the pathophysiology of IOC reversal. Troponin levels did not appear to correlate with iron overload. Future studies are needed to help identify other markers to detect myocardial iron overload early in patients with SCD to prevent irreversible cardiac involvement. A, Ferritin and NT-proBNP levels associate in patients with IOC. Shown are serial levels of ferritin and NT-proBNP acquired in four patients with SCD and IOC followed over 15–50 months, while chelation was attempted. Suggestive associations are seen, but not at all time points. B, Evaluation and management of iron overload cardiomyopathy in sickle cell disease. Figure 1B shows the algorithm that we follow at our institution for the diagnosis and management of IOC in patients with SCD. In addition to iron chelation and exchange transfusions, the use of standard heart failure therapy including beta blockers, angiotensin converting enzyme inhibitors, and mineralocorticoid antagonists may help and should be considered if tolerated. None