Evaluation of aortic stiffening as an early indicator of anthracycline-induced cardiotoxicity

主动脉硬化作为蒽环类药物引起的心脏毒性早期指标的评估

• 批准号: 9809540
• 负责人: Chiara Bellini
• 金额: $ 24.32万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-10 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9809540
• 关键词: Address; Adult; Animals; Anthracyclines; Antineoplastic Agents; Aorta; Apoptosis; Behavior; Biological Assay; Biological Markers; Blood Vessels; Cancer Patient; Cancer Survivor; Cardiac; Cardiotoxicity; Cardiovascular Diseases; Cardiovascular Manifestation; Cardiovascular system; Chemotherapy-Oncologic Procedure; Childhood; Clinical; Clinical Research; Collagen; Computer Simulation; Computing Methodologies; Data; Deposition; Detection; Development; Diagnosis; Dose; Early Diagnosis; Elastic Fiber; Endothelium; Enzyme-Linked Immunosorbent Assay; Evaluation; Event; Evolution; Excision; Exposure to; Extracellular Matrix; Functional disorder; Future; Geometry; Growth; Heart Injuries; Heart failure; Histology; Human; Immunohistochemistry; In Vitro; Inflammatory Response; Injury; Lead; Left; Left Ventricular Function; Magnetic Resonance Imaging; Malignant Neoplasms; Measurement; Measures; Mechanics; Methods; Molecular; Monitor; Morbidity - disease rate; Motion; Mus; Muscle; Myocardial; Myocardial dysfunction; Outcome; Oxidative Stress; Pathway interactions; Patients; Phenotype; Physiological; Placebos; Population; Process; Production; Property; Reactive Oxygen Species; Reporting; Research; Research Activity; Research Design; Risk; Risk Factors; Smooth Muscle Myocytes; Specimen; Structure; Symptoms; Testing; Therapeutic; Thoracic aorta; Time; TimeLine; Tissues; Troponin I; Vascular remodeling; Ventricular; Western Blotting; biological adaptation to stress; cancer survival; cardiovascular disorder risk; cardiovascular health; cardiovascular risk factor; cell motility; chemotherapy; circulating biomarkers; cohort; coronary fibrosis; heart function; high risk; imaging modality; improved; in vivo; mechanical properties; mortality; mouse model; myocardial damage; oncology; preservation; pressure; response

PROJECT SUMMARY Anthracyclines are common antineoplastic agents of known cardiotoxicity. While early detection and improved therapeutic approaches have increased the odds of survival for cancer patients, adverse cardiovascular effects in cancer survivors are often discovered upon occurrence of clinical symptoms, when myocardial injury cannot be reversed. Given the increasing population of cancer survivors, there is an urgent need to identify a set of reliable metrics that can estimate the cardiovascular risk in patients treated with anthracyclines. Motivated by reports of aortic stiffening following anthracycline treatment, and recalling that aortic stiffening is an independent risk factor for cardiovascular disease, this proposal intends to evaluate the use of aortic stiffness as an early predictor of cardiovascular dysfunction following anthracycline chemotherapy. To address this question, our team brings together expertise in cardiac magnetic resonance (MR) imaging, experimental and computational vascular mechanics, and clinical cardio-oncology. Research activities will focus on a mouse model of anthracycline-induced cardiotoxicity, a first necessary step to identify temporal correlations between physiological events that can support and motivate future clinical studies on patient cohorts. In Aim 1, we will relate the onset of cardiac injury with the progression of cardiac dysfunction and the evolution of aortic stiffness. Circulating levels of cardiac troponin I will be measured as a biomarker for myocardial damage, MR imaging of the left ventricular cavity combined with invasive central pressure measurements will be used to evaluate cardiac function from pressure/volume loops, and in vitro biaxial tests will be performed on isolated aortic specimens to estimate material, structural, and active stiffness. In Aim 2, progressive changes in stiffness will be related to the microstructural reorganization of the wall. Combining diverse biological assays (histology, immunohistochemistry, western blotting), we will quantify deposition and removal of collagen, cell migration, proliferation, and apoptosis, as well as the timeline for the inflammatory response that is expected to follow the production of reactive oxygen species associated with anthracycline treatment. Experimental data will inform a computational model for the growth and remodeling of the aorta that will identify the microstructural mechanisms responsible for aortic stiffening. Computational results will set the stage for mechanicistic studies designed to uncover the molecular pathways leading to the predicted microstructural reorganization.

项目摘要 蒽环类药物是已知心脏毒性的常见抗肿瘤剂。同时提早发现并改善 治疗方法增加了癌症患者生存的几率，心血管不良影响 在发生临床症状时，经常发现癌症幸存者，当心肌损伤无法 被逆转。鉴于癌症幸存者人数增加，迫切需要确定一组 可靠的指标可以估计接受蒽环类药物治疗的患者的心血管风险。动机 关于蒽环类治疗后主动脉僵硬的报道，并回忆起主动脉僵硬是一种 心血管疾病的独立危险因素，该提案旨在评估主动脉僵硬的使用 作为蒽环类化疗后心血管功能障碍的早期预测指标。解决这个问题 问题，我们的团队汇集了心脏磁共振（MR）成像，实验和实验性的专业知识 计算血管力学和临床心脏肿瘤学。研究活动将集中于鼠标 蒽环类引起的心脏毒性的模型，这是确定时间相关性的第一步 可以支持和激发对患者队列的未来临床研究的生理事件。在AIM 1中，我们将 将心脏损伤的发作与心脏功能障碍的进展和主动脉的进化有关 刚性。循环水平的心脏肌钙蛋白I将作为心肌损伤的生物标志物测量，MR 左心室腔的成像与侵入性中央压力测量相结合 通过压力/体积回路评估心脏功能，并将在孤立的情况下进行体外双轴测试 主动脉标本以估计材料，结构和活动刚度。在AIM 2中，刚度的渐进变化 将与壁的微观结构重组有关。结合多种生物学测定（组织学， 免疫组织化学，蛋白质印迹），我们将量化胶原蛋白的沉积和去除，细胞迁移， 增殖和凋亡以及炎症反应的时间表，预计将遵循 与蒽环类药物相关的活性氧的产生。实验数据将告知 主动脉生长和重塑的计算模型，该模型将识别微观结构 导致主动脉僵硬的机制。计算结果将为力学研究奠定阶段 旨在发现导致预测微结构重组的分子途径。