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

儿童癌症幸存者中蒽环类药物相关心脏重塑的临床意义

基本信息

批准号：
10740728
负责人：
Hari Kope Narayan
金额：
$ 19.66万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10740728
关键词：
3-Dimensional Accelerometer Adolescent and Young Adult Anthracycline Antibiotics Antineoplastic Agents Atrophic Cancer Patient Cardiac Cardiac Myocytes Cell Death Childhood Clinical Clinical Trials Computer Models Data Development Diameter Disease Disease Marker Dose Early Diagnosis Functional disorder Future Goals Heart failure Hypertension Hypertrophy Image Image Analysis Intervention K-Series Research Career Programs Leadership Left Left Ventricular Ejection Fraction Left Ventricular Remodeling Life Long-Term Survivors Longitudinal cohort Machine Learning Magnetic Resonance Imaging Malignant Childhood Neoplasm Mentorship Myocardial Myocardial dysfunction Obesity Oncology Patient Selection Pattern Physical activity Physical assessment Physicians Physiological Population Process Public Health Research Research Activity Risk Risk Assessment Risk Factors Scientist Shapes Survivors Thinness Time Training Variant Ventricular Work cardiac magnetic resonance imaging cardiovascular disorder epidemiology cardiovascular imaging chemotherapy childhood cancer survivor clinically relevant cohort design effective intervention exercise intervention follow-up functional decline heart imaging imaging biomarker improved improved outcome moderate-to-vigorous physical activity modifiable risk patient oriented patient oriented research prevent prognostic prognostication recruit risk stratification skills success survivorship targeted treatment treatment strategy

项目摘要

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.

项目概要/摘要蒽环类抗生素是必不可少的救生化疗药物，用于约 60% 的儿科癌症患者，但长期来看，它们会带来显着的剂量依赖性心功能不全和心力衰竭风险标准心力衰竭治疗方法——等待左心室射血分数下降。然后开始后负荷减轻疗法——尽管取得的成功有限，但已经使用了几十年。或者，以特定疾病表现为指导的早期、有针对性的治疗策略可以改善不良的左心室重塑（即大小和形状的变化）先于并可能引发。心力衰竭并可用于指导此类策略然而，迫切需要定义具体的策略。左心室形状的不良特征并确定重构与两者之间的关系使用蒽环类药物治疗的儿童癌症幸存者的可改变的危险因素和长期功能障碍。该提案的总体目标是确定左翼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，并确定重塑与两者之间的关联可改变的危险因素，包括体力活动减少和随着时间的推移而出现功能障碍。该项目是蒽环类药物会导致 3D 左心室形状发生中度至特定的不良变化；剧烈的体力活动会减轻这种重塑过程；而不良重塑则具有预后意义。为了实现这些目标，我们将全面分析心脏磁。青少年和青年儿童癌症横断面和纵向队列的共振成像幸存者的具体目标是 1) 定义与左心室形状相关的不良特征。蒽环类药物剂量暴露；2) 确定左心室重构与可改变之间的关联危险因素，3) 确定左心室重构和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记物，从而早期改善；检测、风险评估和临床预后；并为未来的有针对性的干预提供信息。 Hari K. Narayan 博士寻求获得这一职业发展奖，以实现他成为一名独立医师科学家专注于预防儿童癌症中与蒽环类药物相关的心力衰竭通过拟议的培训，他寻求超越心血管成像和通过培养计算建模和机器学习分析技能、患者的流行病学背景导向和体育活动研究以及学术领导团队，其中包括。儿科临床试验、计算心脏图像分析、生存体力活动等方面的专业知识儿科生存肿瘤学，最适合指导他完成培训并过渡到纳拉扬博士的目标是通过开发来建立拟议的培训和研究。早期、有针对性的干预措施，以预防儿童癌症幸存者与蒽环类药物相关的心力衰竭。