Georgiopoulos Georgios, Makris Nikolaos, Laina Ageliki, Theodorakakou Foteini, Briasoulis Alexandros, Trougakos Ioannis P, Dimopoulos Meletios-Athanasios, Kastritis Efstathios, Stamatelopoulos Kimon
Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
School of Biomedical Engineering and Imaging Sciences, King's College London, London, United Kingdom.
JACC CardioOncol. 2023 Feb 21;5(1):1-21. doi: 10.1016/j.jaccao.2022.12.005. eCollection 2023 Feb.
Proteasome inhibitors (PIs) are the backbone of combination treatments for patients with multiple myeloma and AL amyloidosis, while also indicated in Waldenström's macroglobulinemia and other malignancies. PIs act on proteasome peptidases, causing proteome instability due to accumulating aggregated, unfolded, and/or damaged polypeptides; sustained proteome instability then induces cell cycle arrest and/or apoptosis. Carfilzomib, an intravenous irreversible PI, exhibits a more severe cardiovascular toxicity profile as compared with the orally administered ixazomib or intravenous reversible PI such as bortezomib. Cardiovascular toxicity includes heart failure, hypertension, arrhythmias, and acute coronary syndromes. Because PIs are critical components of the treatment of hematological malignancies and amyloidosis, managing their cardiovascular toxicity involves identifying patients at risk, diagnosing toxicity early at the preclinical level, and offering cardioprotection if needed. Future research is required to elucidate underlying mechanisms, improve risk stratification, define the optimal management strategy, and develop new PIs with safe cardiovascular profiles.
蛋白酶体抑制剂（PIs）是多发性骨髓瘤和AL淀粉样变性患者联合治疗的支柱，同时也用于华氏巨球蛋白血症和其他恶性肿瘤的治疗。PIs作用于蛋白酶体肽酶，由于聚集、未折叠和/或受损多肽的积累导致蛋白质组不稳定；持续的蛋白质组不稳定进而诱导细胞周期停滞和/或凋亡。与口服的伊沙佐米或静脉注射的可逆性PI（如硼替佐米）相比，静脉注射的不可逆性PI卡非佐米表现出更严重的心血管毒性。心血管毒性包括心力衰竭、高血压、心律失常和急性冠状动脉综合征。由于PIs是血液系统恶性肿瘤和淀粉样变性治疗的关键组成部分，管理其心血管毒性涉及识别高危患者、在临床前水平早期诊断毒性，并在需要时提供心脏保护。未来需要开展研究以阐明潜在机制、改善风险分层、确定最佳管理策略，并开发具有安全心血管特性的新型PIs。
