Thalassemia is the most common genetic disease worldwide, affecting over 600,000 individuals in Thailand alone. With increasing East Asian immigration to the Pacific States in the last two decades, thalassemia major is becoming an important domestic as well as international health challenge. Patients with thalassemia major depend on monthly transfusions for survival. Each transfusion contributes more than a year's dietary iron intake, producing toxic iron overload in many organ systems including the heart. While daily iron chelation therapy with subcutaneous deferoxamine ameliorates much of the iron toxicity, deadly iron cardiomyopathy still remains the norm, usually in the 3 rd or 4 th decade of life. Conventional cardiac monitoring fails to detect impending cardiac compromise early enough for effective reversal therapy. Serial monitoring of liver iron, while vital to titrating chelator therapy, has not successfully identified patients at risk for iron cardiomyopathy. Cardiac MRI measurements of the ironsensitive relaxation time, T2*, demonstrate great promise for preclinical diagnosis of cardiac iron overload. We have demonstrated that liver T2* measurements are accurate predictors of liver iron content by biopsy, hence cardiac T2* measurements should similarly reflect cardiac iron content. We have further demonstrated that patients with low cardiac T2* have significantly greater risk of resting systolic dysfunction and need for cardiac medications than patients with T2* in the normal range. While cardiac T2* represents a potentially invaluable tool to study chelation therapies and their effect on cardiac iron flux and function, the relationship of cardiac T2* to heart iron and heart function needs to be clarified. Therefore, the overall objective of this proposal is to determine the etiology of myocardial T2* changes and their relationship to cardiac rhythm and function in cardiac iron overload. Specifically, we hypothesize that cardiac 1/T2* is linearly related to cardiac iron concentration. Both the magnitude of myocardial iron loading, reflected by cardiac T2*, and duration of cardiac iron exposure determine cardiac toxicity in iron loaded thalassemia patients. The ability of MRI to quantitate cardiac and liver iron will be assessed in an established gerbil iron overload model. Other contributions to the T2* signal, such as changes in tissue oxygenation and coronary blood flow, will be evaluated as well. Validation of the T2*-iron relationship in the heart is vital for future analyses of cardiac iron fluxes. The relationship between cardiac T2*, liver iron content, and cardiac function, rhythm and exercise capacity will be evaluated in thalassemia patients. Eighty thalassemia major patients will be recruited from California and Nevada. Complete cardiology evaluation, including ECG, echo, Holter, exercise stress test and cardiac MR( will be performed at Childrens Hospital Los Angeles. The study goals are three-fold l) determine normative data for cardiac rhythm and performance for thalassemia patients, 2) determine prevalence of exercise and cardiac rhythm abnormalities in thalassemia patients with high cardiac iron and normal resting function, 3) determine the relationships between liver iron content, ferritin, cardiac T2* and cardiac function. These studies will provide the necessary groundwork for longitudinal studies of cardiac iron load on cardiac performance in thalassemia patients.
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