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

• 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
• 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

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.

项目摘要/摘要 蒽环类抗生素是必不可少的，在约60％的小儿癌中使用的化学疗法是必不可少的 患者，但他们涉及长期剂量依赖性心脏功能障碍和心力衰竭的风险 幸存者。标准心力衰竭管理方法 - 等待左心室射血分数下降 然后开始减少后负载疗法 - 已经使用了数十年的目的地，其成功有限。 另外，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 结果。不良左心室重塑（即尺寸和形状的变化）先于前面，可能会沉淀 心力衰竭，可以用来指导这种策略。但是，迫切需要定义特定 左心室形状的不良特征，并确定重塑和两者之间的关系 蒽环类药物治疗的儿童癌症存活中可修改的危险因素和长期功能障碍。 该提案的总体目标是定义左侧与蒽环类有关的不良功能 儿童癌症生存中的心室形状，并确定重塑与两者之间的关联 可修改的危险因素，包括降低的体育锻炼和随着时间的流逝功能障碍。中心假设 该项目是蒽环类动物会导致3D左心室形状的特定不利变化。中等 剧烈的体育锻炼减轻了这种重塑过程；不利的重塑是预后的 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 青少年和年轻儿童癌症的横截面和纵向人群中的共振成像 幸存者。具体目的是1）定义与 蒽环类剂量暴露； 2）确定左心室重塑与可修改之间的关联 风险因素和3）确定左心室重塑与随后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。提前改善 检测，风险评估和临床提示；并告知未来的针对性干预措施。 Hari K. Narayan博士寻求这个职业发展奖，以实现他成为一个长期目标 独立的物理科学家致力于防止儿童癌症中与邻苯二甲酸有关的心力衰竭 幸存者。通过拟议的培训，他试图扩展超越心血管成像和 流行病学背景通过发展计算建模和机器学习分析的技能，患者 - 面向和体育锻炼研究以及学术领导。 Mentalship团队，其中包括 小儿临床试验，计算心脏图像分析，生存中的体育活动和 小儿表面肿瘤学非常适合指导他完成培训完成和过渡到 独立。 Narayan博士的目标是在开发中建立拟议的培训和研究 早期的，有针对性的干预措施，以防止儿童癌症生存中与邻苯二甲酸相关的心力衰竭。