Department of Medicine, Division of Cardiovascular Medicine, UCSD Cardiovascular Institute, University of California, San Diego, CA, U.S.A.
Department of Pediatrics, Division of Cardiology, University of California, San Diego, CA, U.S.A.
Clin Sci (Lond). 2021 May 28;135(10):1311-1332. doi: 10.1042/CS20200301.
Anthracyclines are effective chemotherapeutic agents, commonly used in the treatment of a variety of hematologic malignancies and solid tumors. However, their use is associated with a significant risk of cardiovascular toxicities and may result in cardiomyopathy and heart failure. Cardiomyocyte toxicity occurs via multiple molecular mechanisms, including topoisomerase II-mediated DNA double-strand breaks and reactive oxygen species (ROS) formation via effects on the mitochondrial electron transport chain, NADPH oxidases (NOXs), and nitric oxide synthases (NOSs). Excess ROS may cause mitochondrial dysfunction, endoplasmic reticulum stress, calcium release, and DNA damage, which may result in cardiomyocyte dysfunction or cell death. These pathophysiologic mechanisms cause tissue-level manifestations, including characteristic histopathologic changes (myocyte vacuolization, myofibrillar loss, and cell death), atrophy and fibrosis, and organ-level manifestations including cardiac contractile dysfunction and vascular dysfunction. In addition, these mechanisms are relevant to current and emerging strategies to diagnose, prevent, and treat anthracycline-induced cardiomyopathy. This review details the established and emerging data regarding the molecular mechanisms of anthracycline-induced cardiovascular toxicity.
蒽环类药物是有效的化疗药物，常用于治疗多种血液系统恶性肿瘤和实体瘤。然而，其使用与心血管毒性的显著风险相关，并可能导致心肌病和心力衰竭。心肌细胞毒性通过多种分子机制发生，包括拓扑异构酶 II 介导的 DNA 双链断裂和通过对线粒体电子传递链、NADPH 氧化酶 (NOX) 和一氧化氮合酶 (NOS) 的影响形成活性氧 (ROS)。过量的 ROS 可能导致线粒体功能障碍、内质网应激、钙释放和 DNA 损伤，从而导致心肌细胞功能障碍或细胞死亡。这些病理生理机制导致组织水平的表现，包括特征性的组织病理学变化（肌细胞空泡化、肌原纤维丢失和细胞死亡）、萎缩和纤维化，以及器官水平的表现，包括心脏收缩功能障碍和血管功能障碍。此外，这些机制与目前和新兴的诊断、预防和治疗蒽环类药物诱导性心肌病的策略相关。本综述详细介绍了蒽环类药物诱导心血管毒性的分子机制的现有和新兴数据。
