Cardiac Function and Cardiac iron (T2*) in Thalassemia

描述（由申请人提供）：地中海贫血是世界上最常见的遗传性疾病，仅在泰国就有60多万人受到影响。在过去二十年中，随着越来越多的东亚移民到太平洋国家，地中海贫血正在成为一个重要的国内和国际卫生挑战。重度地中海贫血患者依赖每月输血维持生存。每次输血都能提供超过一年的膳食铁摄入量，在包括心脏在内的许多器官系统中产生有毒的铁超载。虽然每日用皮下去铁胺进行铁螯合治疗可以改善大部分铁毒性，但致命的铁性心肌病仍然是常态，通常发生在生命的第3或第4个十年。传统的心脏监测无法及早发现即将发生的心脏损害，从而无法进行有效的逆转治疗。肝铁的连续监测虽然对螯合剂治疗的滴定至关重要，但尚未成功识别出有铁性心肌病风险的患者。心脏MRI测量铁敏感弛豫时间T2*，为心脏铁过载的临床前诊断提供了巨大的希望。我们已经证明肝脏T2*测量是肝脏活检铁含量的准确预测指标，因此心脏T2*测量应该同样反映心脏铁含量。我们进一步证明，心脏T2*低的患者比T2*正常的患者有更大的静息期收缩功能障碍的风险和心脏药物的需求。虽然心脏T2*是研究螯合疗法及其对心脏铁通量和功能影响的潜在宝贵工具，但心脏T2*与心脏铁和心脏功能的关系需要澄清。因此，本提案的总体目标是确定心肌T2*变化的病因及其与心脏铁过载时心律和功能的关系。具体来说，我们假设心脏1/T2*与心脏铁浓度线性相关。心肌铁负荷的大小（由心脏T2*反映）和心脏铁暴露的持续时间决定了铁负荷地中海贫血患者的心脏毒性。MRI定量心脏和肝脏铁的能力将在建立沙鼠铁过载模型中进行评估。T2*信号的其他贡献，如组织氧合和冠状动脉血流的变化，也将被评估。验证心脏中T2*-铁的关系对未来分析心脏铁通量至关重要。评估地中海贫血患者心脏T2*、肝铁含量与心功能、心律和运动能力的关系。将从加利福尼亚和内华达州招募80名地中海贫血重症患者。完整的心脏病学评估，包括心电图、超声、动态心电图、运动负荷测试和心脏磁共振（将在洛杉矶儿童医院进行）。研究目标有三个方面：1)确定地中海贫血患者心律和表现的规范性数据；2)确定心脏铁含量高、静息功能正常的地中海贫血患者运动和心律异常的患病率；3)确定肝铁含量、铁蛋白、心脏T2*与心功能之间的关系。这些研究将为地中海贫血患者心脏铁负荷对心脏功能的纵向研究提供必要的基础。

DESCRIPTION (provided by applicant): 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.