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，仅在泰国就影响了60多万人。 在过去二十年中，随着越来越多的东亚移民到太平洋国家，重型地中海贫血正在成为一个重要的国内和国际健康挑战。 重型地中海贫血患者的生存依赖于每月输血。 每一次输血都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过载。 虽然每日皮下注射去铁胺的铁螯合疗法可改善大部分铁毒性，但致命的铁性心肌病仍然是常见的，通常发生在生命的第三或第四个十年。 传统的心脏监测无法及早检测到即将发生的心脏损害，从而无法进行有效的逆转治疗。 连续监测肝脏铁，虽然滴定螯合剂治疗至关重要，但尚未成功识别铁心肌病风险的患者。 心脏磁共振测量的铁敏感性弛豫时间，T2*，表现出很大的承诺，为临床前诊断心脏铁超载。 我们已经证明，肝脏T2* 测量是通过活检准确预测肝脏铁含量的指标，因此心脏T2* 测量应该类似地反映心脏铁含量。 我们进一步证明，心脏T2* 降低的患者比T2* 正常的患者静息收缩功能障碍和需要心脏药物治疗的风险显著更大。 虽然心脏T2* 代表了研究螯合疗法及其对心脏铁通量和功能的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节律和心脏铁超负荷功能的关系。 具体而言，我们假设心脏1/T2* 与心脏铁浓度呈线性相关。 由心脏T2* 反映的心肌铁负荷的大小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。 将在已建立的沙鼠铁过载模型中评估MRI定量心脏和肝脏铁的能力。 还将评估对T2* 信号的其他贡献，例如组织氧合和冠状动脉血流的变化。 验证T2*-铁在心脏中的关系是至关重要的未来分析心脏铁通量。 将在地中海贫血患者中评价心脏T2*、肝脏铁含量与心脏功能、节律和运动能力之间的关系。 将从加州和内华达州招募80名重型地中海贫血患者。 完整的心脏病学评估，包括ECG、超声心动图、霍尔特、运动负荷试验和心脏MR（将在洛杉矶儿童医院进行）。 研究目的有三个：1）确定地中海贫血患者的心律和性能的正常数据，2）确定具有高心脏铁和正常静息功能的地中海贫血患者的运动和心律异常的患病率，3）确定肝脏铁含量、铁蛋白、心脏T2* 和心脏功能之间的关系。 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.