Cardiovascular Toxicity of Proteasome Inhibitors: Underlying Mechanisms and Management Strategies: JACC: CardioOncology State-of-the-Art Review

Georgios Georgiopoulos; Nikolaos Makris; Ageliki Laina; Foteini Theodorakakou; Alexandros Briasoulis; Ioannis P Trougakos; Meletios-Athanasios Dimopoulos; Efstathios Kastritis; Kimon Stamatelopoulos

doi:10.1016/j.jaccao.2022.12.005

Cardiovascular Toxicity of Proteasome Inhibitors: Underlying Mechanisms and Management Strategies: JACC: CardioOncology State-of-the-Art Review

JACC CardioOncol. 2023 Feb 21;5(1):1-21. doi: 10.1016/j.jaccao.2022.12.005. eCollection 2023 Feb.

Authors

Georgios Georgiopoulos^{1

2}, Nikolaos Makris¹, Ageliki Laina¹, Foteini Theodorakakou¹, Alexandros Briasoulis¹, Ioannis P Trougakos³, Meletios-Athanasios Dimopoulos¹, Efstathios Kastritis¹, Kimon Stamatelopoulos¹

Affiliations

¹ Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
² School of Biomedical Engineering and Imaging Sciences, King's College London, London, United Kingdom.
³ Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Greece.

Abstract

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.

Keywords: ACE, angiotensin-converting enzyme; ACS, acute coronary syndrome; AE, adverse event; AF, atrial fibrillation; ARB, angiotensin receptor blocker; ASCT, autologous stem cell transplantation; BP, blood pressure; CVAE, cardiovascular adverse event; ESC, European Society of Cardiology; FMD, flow-mediated dilatation; GLS, global longitudinal strain; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; IHD, ischemic heart disease; IMiD, immunomodulatory drug; Kd, carfilzomib and dexamethasone; LA, left atrial; LV, left ventricular; LVEF, left ventricular ejection fraction; MM, multiple myeloma; NO, nitric oxide; NP, natriuretic peptide; OS, overall survival; PBMC, peripheral blood mononuclear cell; PFS, progression-free survival; PH, pulmonary hypertension; PI, proteasome inhibitor; PWV, pulse wave velocity; PrA, proteasome activity; RRMM, relapse or refractory multiple myeloma; SBP, systolic blood pressure; TMA, thrombotic microangiopathy; UPP, ubiquitin proteasome pathway; VTE, venous thromboembolism; Vd, bortezomib and dexamethasone; WM, Waldenström’s macroglobulinemia; bortezomib; cardiovascular toxicity; carfilzomib; eNOS, endothelial nitric oxide synthase; ixazomib; proteasome inhibition.

Publication types

Review