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

项目摘要 蒽环类药物是已知心脏毒性的常见药物。早期发现和改进 治疗方法增加了癌症患者的生存几率， 在癌症幸存者中，通常在出现临床症状时发现，此时心肌损伤不能 被逆转。鉴于癌症幸存者人数不断增加，迫切需要确定一套 可靠的指标，可以估计心血管疾病的风险与蒽环类药物治疗的患者。出于 蒽环类抗生素治疗后主动脉硬化的报告，并回顾主动脉硬化是一种 作为心血管疾病的独立危险因素，本提案旨在评价主动脉僵硬度的使用 作为蒽环类药物化疗后心血管功能障碍的早期预测指标。为了解决这个 问题，我们的团队汇集了心脏磁共振（MR）成像，实验和 计算血管力学和临床心脏肿瘤学。研究活动将集中在一只老鼠身上 蒽环类药物诱导的心脏毒性模型，第一个必要的步骤，以确定时间之间的相关性 生理事件，可以支持和激励对患者队列的未来临床研究。在目标1中，我们 将心脏损伤的发生与心功能不全的进展和主动脉瓣的演变联系起来， 刚度将测量心肌肌钙蛋白I的循环水平，作为心肌损伤的生物标志物，MR 将使用左心室腔成像结合侵入性中心压测量， 通过压力/容积环评价心脏功能，并对分离的 主动脉标本，以估计材料、结构和主动刚度。在目标2中，刚度的渐进性变化 与墙体的微观结构重组有关。结合不同的生物测定（组织学， 免疫组织化学，蛋白质印迹），我们将定量胶原蛋白的沉积和去除，细胞迁移， 增殖和凋亡，以及预期在炎症反应之后的炎症反应的时间轴。 与蒽环类药物治疗相关的活性氧物质的产生。实验数据将告知 主动脉生长和重塑的计算模型，将识别微结构 导致主动脉硬化的机制。计算结果将为力学研究奠定基础 旨在揭示导致预测的微观结构重组的分子途径。

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.