MRI Detection of Doxorubicin Induced Cardiotoxicity

描述（由申请人提供）：阿霉素是最广泛活性的抗肿瘤药物之一；它是现代乳腺、软组织肉瘤和其他实体瘤治疗中必不可少的元素。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% - 20%接受阿霉素治疗的患者发生充血性心力衰竭（CHF），这是一种改变生命的疾病，前心输出量减少，导致呼吸困难，肺部积液，20%的患者死亡。迄今为止，除了在小手术过程中直接进行心脏活检外，现有技术无法识别许多有发生CHF风险的个体。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而遭受灾难性损伤之前检测出异常。如果在更多的受试者中发现这是正确的，CMR技术的这一新进展可用于监测接受阿霉素治疗的患者。潜在地，没有CMR心肌损伤证据的患者可以获得化疗方案的全部益处，而不必担心发生CHF。早期有损伤迹象的患者可调整化疗方案，以避免永久性心脏损伤。在进行进一步的患者试验之前，需要加深对我们早期CMR研究结果的理解。在本提案中，我们将利用建立的大鼠阿霉素诱导心脏毒性模型来了解CMR测量与左心室射血分数评估以及病理观察到的测量细胞损伤之间的关系。我们假设在增强CMR心脏造影检查中观察到的高信号强度将先于左室射血分数下降，并将指示心肌细胞损伤。这项研究的结果将为设计人体研究提供必要的理解，利用心血管磁共振作为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，以确定阿霉素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.