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

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.

Graphical abstract

Central Illustration

Cardiovascular Adverse Events of Proteasome Inhibitors, Mechanisms, and Risk Stratification Proteasome inhibitors and especially carfilzomib may exhibit a variety of cardiovascular adverse events. Understanding the underlying pathophysiological mechanisms of proteasome inhibitor–related cardiovascular toxicity, is crucial to develop effective strategies for early identification and management of high-risk patients, ensuring continuation of life-saving cancer therapy. BP = blood pressure; ER = endoplasmic reticulum; LV = left ventricular; NFkB = nuclear factor kappa B; NO = nitric oxide; ROS = reactive oxygen species.

Figure 1

Effects of Proteasome Inhibitors on Cardiac and Vascular Cells The extent of damage at the cellular level is similar among different mitotic (eg, endothelial) or post-mitotic (eg, cardiomyocytes) cell types, as it relates to increasing proteome instability (eg, polypeptides oxidation, aggregation, etc.), endoplasmic reticulum (ER) stress, mitochondrial/energetics dysfunction, reactive oxygen species (ROS) accumulation, genomic instability, and stress-induced premature senescence; nonetheless, at a higher tissue/organ (ie, heart, vasculature) organization level, induced damage is likely tissue-specific. The relative enrichment of cardiac ventricles (vs atria) in cardiomyocytes, along with the noted ventricle/atria-specific differences in electrophysiological, contractile, and secretory processes of resident cardiomyocytes may explain the predisposition of the ventricle to proteasome inhibition–mediated adverse events (AEs). Arrows indicate sequence of events. LV = left ventricular; MM = multiple myeloma; PI = proteasome inhibitor.

Figure 2

Proposed Management of PI-Related CV Toxicity at Our Cardio-Oncology Center The proposed algorithm for the management of proteasome inhibitor (PI)-related cardiovascular (CV) toxicity consists of PI-specific recommendations from guidelines, guidelines’ recommendations for cardiotoxic anticancer medications, and recommendations from consensus and position papers. Guideline recommendations for monitoring by echocardiographic and circulating biomarkers are not supported by a strong level of evidence. Arrows indicate recommendations. The striped box indicates lower strength of recommendation and decisions are made by consensus based on combined assessment of multiple biomarkers, clinical evidence, and shared decision-making with the patient. ACEi = angiotensin-converting enzyme inhibitor; ACS = acute coronary syndrome; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor-neprilysin inhibitor; BB = beta-blocker; BP = blood pressure; CV = cardiovascular; CVAE = cardiovascular adverse event; DBP = diastolic blood pressure; ECG = electrocardiogram; GLS = global longitudinal strain; Gr = grade; HBPM = home blood pressure monitoring; HF = heart failure; HTN = hypertension; IV = intravenous; LVEF = left ventricular ejection fraction; MDT = multidisciplinary; MRA = mineralocorticoid receptor antagonist; NP = natriuretic peptide; SBP = systolic blood pressure; SGLT2i = sodium/glucose cotransporter-2 inhibitor; TTE = transthoracic echocardiogram; VTE = venous thromboembolism.