History and current impact of cardiac magnetic resonance imaging on the management of iron overload.

Briefly, they report that a cardiac T2* value 10 ms had a sensitivity of 98% and a specificity of 86% for prediction of symptomatic heart failure in 1 year. Risk was graded with respect to T2*, with 47% of patients having T2* 6 ms developing cardiac failure in the same interval. Similar, but less striking, risk stratification was also observed for prospective arrhythmia risk. Metrics of total body iron stores, liver iron concentration, and serum ferritin performed little better than chance in predicting heart failure. To place these observations in context, it is important to review iron overload and its past and present management. Iron overload is a surprisingly common clinical problem, occurring through increased iron absorption (primary hemochromatosis) or through frequent blood transfusion therapy (secondary hemochromatosis).2 Primary hemochromatosis disorders, such as hfe mutations, are relatively common in white populations. However, variable hfe gene penetrance, increased genetic surveillance, and severity of noncardiac symptoms result in fewer hereditary hemochromatosis patients presenting with ironmediated cardiac disease. By contrast, iron cardiomyopathy remains a major cause of death in secondary hemochromatosis disorders such as the thalassemia, Blackfan-Diamond anemia, and myelodysplastic syndromes because the iron-loading rates are many-fold greater than for primary hemochromatosis.3 The hemoglobinopathies are the most common genetic disorders in the world, particularly in regions where malaria is or was previously endemic, such as the Mediterranean, northern Africa, the Middle East, and Southeast Asia. Increasing economic and ethnic globalization has increased the importance of these disorders in the United States, and their impact is increasing. Iron overload is also becoming an increasingly critical problem in myelodysplasia syndromes because novel therapeutics have markedly increased life expectancy in lowand intermediate-risk patients. Before the availability of deferoxamine iron chelation therapy, patients receiving long-term transfusions succumbed to arrhythmias and congestive heart failure once their transfusional burden exceeded approximately 200 U, usually in the second decade of life.4 Cardiac signs and symptoms were a late finding, usually heralding death within 6 months. Birth cohorts born after routine implementation of iron chelation demonstrate steadily improved survival.5 Classically, screening for iron cardiomyopathy consisted of serum ferritin or liver iron measurements combined with assessments of cardiac systolic function. This regimen was successful in reducing cardiac deaths in the second and third decade of life.6,7 Nonetheless, iron cardiomyopathy continues to be the leading cause of death in thalassemia patients, appearing even in patients with apparently good control of their somatic iron stores.8 Some postulated that such patients were succumbing to myocarditis, not iron cardiomyopathy, but autopsies almost inevitably confirmed severe, previously silent, cardiac iron accumulation. Cardiac biopsy was performed in some patients having decreased ventricular function or arrhythmias, but its invasiveness and variability precluded use in routine screening. In 2001, the Royal Brompton group published its first report of the use of cardiac T2* to detect preclinical cardiac iron in 103 patients with thalassemia major. Figure 1 demonstrates left ventricular ejection fraction as a function of cardiac T2*.9 The MRI relaxation time, T2*, is typically 37 5 ms in normal subjects but shortens in the presence of iron. A lower cutoff of 20 ms has generally been used to eliminate false-positive diagnosis from motion and magnetic susceptibility artifacts as well as possible contributions from fluctuations in deoxygenated hemoglobin concentration. The authors made 6 key observations in their seminal article: (1) All patients lacking detectable cardiac iron had normal cardiac function. Thus, a T2* 20 ms yields a high negative predictive value. (2) Thalassemia patients lacking cardiac iron appeared to have higher ejection fractions than population norms. This was confirmed in a subsequent study and likely reflects lower cardiac afterload and greater cardiac preload associated with chronic anemia.10 (3) There was a graded negative relationship between cardiac T2* and cardiac ejection fraction as T2* decreased below 20 ms, indicating an association between increased cardiac iron and cardiac dysfunction. (4) Many patients with detectable cardiac iron exhibited normal cardiac function, which suggested that T2* was identifying preclinical iron deposition. (5) Iron appeared to clear more quickly from the liver than from the heart. In a subsequent study, the effective half-life of cardiac iron clearance in response to continuous deferoxamine therapy was found to be 13.5 months compared with 1.4 months for liver iron reduction.11 (6) Lastly, no statistical association was observed between cardiac and liver iron concentration or serum ferritin. This final observation was particularly challenging to the thalassemia community, and the authors faced severe criticism when they used T2* methods to compare chelator efficacy (see letters to the editor that follow their 2002 case–control study.12 The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Departments of Pediatrics and Radiology, Children’s Hospital of Los Angeles, Los Angeles, Calif. Correspondence to John C. Wood, MD, PhD, Division of Cardiology, Mailstop 34, Children’s Hospital of Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027. E-mail [email protected] (Circulation. 2009;120:1937-1939.) © 2009 American Heart Association, Inc.