MRI Detection of Doxorubicin Induced Cardiotoxicity

描述（由申请人提供）：多柔比星是活性最广泛的抗肿瘤药物之一;它是乳腺、软组织肉瘤和其他实体瘤现代治疗的基本要素。它被认为是治疗急性白血病，霍奇金病，非霍奇金淋巴瘤和许多儿童癌症的联合化疗的基本要素。不幸的是，2%至20%的接受阿霉素的患者发展为充血性心力衰竭（CHF），这是一种改变生命的病症，其中前向心输出量受损，导致呼吸困难、肺部积液，并且在20%的情况下死亡。到目前为止，现有的技术，除了在一个小的外科手术过程中的心脏直接活检，是无法确定许多人在发展CHF的风险。我们中心的早期结果表明，一种新开发的无创心血管磁共振（CMR）测试可以在心肌因化疗治疗而遭受灾难性损伤之前检测出心肌异常。如果在更多的受试者中发现这一点，CMR技术的这一新进展可用于监测接受阿霉素的患者。没有CMR心肌损伤证据的患者可能会从化疗方案中获得全部益处，而无需担心发生CHF。有早期损伤迹象的患者可以修改他们的化疗方案，以避免永久性心脏损伤。在对患者进行进一步测试之前，需要对我们的早期CMR研究结果有更深入的了解。在本提案中，我们将利用已建立的多柔比星诱导心脏毒性的大鼠模型，以了解CMR措施之间的关系，左心室（LV）射血分数的评估，并测量病理观察到的细胞损伤。我们假设，心脏对比增强CMR检查中观察到的信号强度升高将先于LV射血分数下降，并将指示肌细胞损伤。本研究的结果将用于提供设计人体研究所需的理解，该研究利用心血管磁共振作为接受化疗患者心肌损伤的保护性筛选程序。此外，将设计进一步的动物研究以确定多柔比星诱导的心脏毒性的治疗策略。

DESCRIPTION (provided by applicant): Doxorubicin is 1 of the most broadly active antitumor agents; it is an essential element in modern therapy of breast, soft tissue sarcomas and other solid tumors. It is thought to be an essential element of curative combination chemotherapy for acute leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, and many childhood cancers. Unfortunately, 2% to 20% of patients receiving Doxorubicin develop congestive heart failure (CHF), a life altering condition in which forward cardiac output is compromised leading to breathlessness, collection of fluid in the lungs, and in 20% of cases, death. To date, existing technologies, with the exception of a direct biopsy of the heart during a minor surgical procedure, are unable to identify many individuals at risk for developing CHF. Early results from our center indicate that a newly developed noninvasive cardiovascular magnetic resonance (CMR) test can detect abnormalities in the heart muscle before it sustains a catastrophic injury due to the chemotherapy treatment. If this is found to be true in more subjects, this new advancement in CMR technology could be used to monitor patients receiving Doxorubicin. Potentially, patients without evidence of CMR heart muscle injury could receive the full benefit of their chemotherapeutic regimen without the concern of developing CHF. Patients with early evidence of injury could undergo modification of their chemotherapy so as to avoid permanent cardiac injury. Before further testing in patients proceeds, heightened understanding of our early CMR study results is required. In this proposal, we will utilize an established rat model of Doxorubicin induced cardiotoxicity to gain understanding of the relationship between CMR measures, and assessments of left ventricular (LV) ejection fraction, and of measured cell injury observed pathologically. We hypothesize that heightened signal intensity observed on a contrast enhanced CMR examination of the heart will precede the onset of a decrement in LV ejection fraction, and will be indicative of myocellular injury. The results from this study will be used to provide the understanding necessary to design human studies utilizing cardiovascular magnetic resonance as a protective screening procedure for heart muscle injury in patients receiving chemotherapy. In addition, further animal studies will be designed to identify treatment strategies for Doxorubicin induced cardiotoxicity.