The Clinical Relevance of Anthracycline-Related Cardiac Remodeling in Childhood Cancer Survivors

项目总结/摘要 蒽环类抗生素是必不可少的，挽救生命的化疗药物，用于约60%的儿科癌症 患者，但他们赋予了大量的剂量依赖性的心功能障碍和心力衰竭的风险，在长期 幸存者标准的心力衰竭管理方法--等待左心室射血分数下降 然后开始后负荷减少疗法--尽管成功有限，但已经使用了几十年。 或者，由特定疾病表现指导的早期靶向治疗策略可以改善 结果。不良左心室重塑（即，在尺寸和形状上的变化）先于并可能沉淀 心力衰竭，并可用于指导这种策略。然而，迫切需要确定具体的 左心室形态的不良特征，并确定重构与两者之间的关系 接受蒽环类药物治疗的儿童癌症幸存者中可改变的危险因素和长期功能障碍 本提案的总体目标是确定左室肥厚患者与蒽环类药物相关的不良特征， 儿童癌症幸存者的心室形状，并确定重塑和两者之间的关系， 可改变的风险因素，包括随着时间的推移身体活动减少和功能障碍。的中心假设 该项目是蒽环类药物引起3D左心室形状的特定不良变化;中度至 剧烈的体力活动可以减轻这种重塑过程，而不良的重塑是预后性的。 随后的功能障碍。为了实现这些目标，我们将全面分析心脏磁共振成像。 青少年和年轻成人儿童癌症的横断面和纵向队列的共振成像 幸存者具体目的是：1）定义与以下疾病相关的左心室形状的不良特征： 蒽环类药物剂量暴露; 2）确定左心室重塑和可修饰的 危险因素; 3）确定左心室重构与随后的功能障碍之间的关系。 这项研究的预期贡献将产生新的基于成像的疾病标志物;改善早期诊断。 检测、风险评估和临床验证;并为未来的有针对性的干预提供信息。 Hari K.博士纳拉扬寻求这个职业发展奖，以实现他的长期目标，成为一个 一位独立的内科科学家专注于预防儿童癌症中蒽环类药物相关的心力衰竭 幸存者通过拟议的培训，他寻求扩大他的心血管成像， 流行病学背景，通过发展计算建模和机器学习分析技能， 导向和体育活动的研究，和学术领导。导师团队，其中包括 儿科临床试验、计算心脏图像分析、生存期体力活动方面的专业知识，以及 儿科生存肿瘤学，最适合指导他完成培训和过渡到 独立Narayan博士的目标是通过开发 早期，有针对性的干预，以防止蒽环类药物相关的心脏衰竭的儿童癌症幸存者。

PROJECT SUMMARY/ABSTRACT Anthracycline antibiotics are essential, lifesaving chemotherapies used in ~60% of pediatric cancer patients, but they confer a substantial dose-dependent risk of cardiac dysfunction and heart failure in long-term survivors. The standard heart failure management approach -- waiting for left ventricular ejection fraction decline and then starting afterload reduction therapy -- has been used for decades despite its limited success. Alternatively, an early, targeted treatment strategy guided by specific disease manifestations could improve outcomes. Adverse left ventricular remodeling (i.e., change in size and shape) precedes and may precipitate heart failure and could be used to guide such a strategy. However, there is a critical need to define the specific adverse features of left ventricular shape and to determine the relationship between remodeling and both modifiable risk factors and long-term dysfunction in childhood cancer survivors treated with anthracyclines. The overall objectives of this proposal are to define the anthracycline-related adverse features of left ventricular shape in childhood cancer survivors and to determine the associations between remodeling and both modifiable risk factors, including reduced physical activity, and dysfunction over time. The central hypothesis of this project is that anthracyclines cause specific adverse changes in 3D left ventricular shape; moderate to vigorous physical activity mitigates this remodeling process; and adverse remodeling is prognostic of subsequent dysfunction. To achieve these objectives, we will comprehensively analyze cardiac magnetic resonance imaging in cross-sectional and longitudinal cohorts of adolescent and young adult childhood cancer survivors. The Specific Aims are to 1) define the adverse features of left ventricular shape associated with anthracycline dose exposure; 2) determine the associations between left ventricular remodeling and modifiable risk factors, and 3) determine the relationship between left ventricular remodeling and subsequent dysfunction. The expected contributions of this research will yield new imaging-based disease markers; improve early detection, risk assessment, and clinical prognostication; and inform a future targeted intervention. Dr. Hari K. Narayan seeks this career development award to achieve his long-term goal of becoming an independent physician scientist focused on preventing anthracycline-related heart failure in childhood cancer survivors. Through the proposed training, he seeks to expand beyond his cardiovascular imaging and epidemiology background by developing skills in computational modeling and machine learning analysis, patient- oriented and physical activity research, and academic leadership. The mentorship team, which includes expertise in pediatric clinical trials, computational cardiac image analysis, physical activity in survivorship, and pediatric survivorship oncology, is optimally suited to guide him through training completion and his transition to independence. Dr. Narayan’s goal is to build upon the proposed training and research through the development of an early, targeted intervention to prevent anthracycline-related heart failure in childhood cancer survivors.