Cardiovascular Toxicity of Immune Checkpoint Inhibitors: A Guide for Clinicians

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment and care of patients with cancer owing to unique features, including the occurrence of the so-called immune-related adverse events (irAEs). A multidisciplinary team, possibly including a cardio-oncology specialist, is warranted to achieve a favorable patient outcome. Cardiovascular toxicity, especially myocarditis, emerged as a life-threatening irAE in the real-word setting, and the European Society of Cardiology has recently published the first guideline on cardio-oncology to increase awareness and promote a standardized approach to tackle this complex multimodal issue, including diagnostic challenges, assessment, treatment, and surveillance of patients with cancer receiving ICIs. In this article, through a question & answer format made up of case vignettes, we offer a clinically oriented overview on the latest advancements of ICI-related cardiovascular toxicity, focusing on myocarditis and associated irAEs (myositis and myasthenia gravis within the so-called overlap syndrome), with the purpose of assisting clinicians and healthcare professionals in daily clinical practice.

Fig. 1

Multifaceted spectrum of cardiovascular toxicity and related events with immune checkpoint inhibitors. Albeit rare, myocarditis is the most common and serious cardiovascular presentation, with potential fulminant manifestation. Although myocarditis may occur alone, potential overlaps with other cardiovascular (e.g., heart failure, arrhythmias) or non-cardiovascular (e.g., myositis and myasthenia gravis, the so-called overlap syndrome) immune-related adverse events are possible. Please refer to the full text for details. Created with biorender.com

Fig. 2

Proposed flowchart for the diagnosis, assessment, and management of cardiovascular toxicity with immune checkpoint inhibitors. Adapted from [18, 21]. *Class of recommendations according to the 2022 ESC Cardio-Oncology guidelines [18]. AChR acetylcoline receptor antibodies, ACS acute coronary syndrome, CK creatin kinase, CV cardiovascular, CMR cardiac magnetic resonance, ECG electrocardiogram, EMB endomyocardial biopsy, HbA1c glycated hemoglobin, ICI immune checkpoint inhibitors, ICU intensive care unit, irAEs immune-related adverse events, IM immunomodulating, LV left ventricular, MCS mechanical circulatory support, NT-proBNP N-terminal pro-brain-natriuretic-peptide, TSH thyroid-stimulating hormone, TTE transthoracic echocardiography, TTS takotsubo syndrome

Fig. 3

Epidemiology and clinical features of overlap syndrome

Fig. 4

Proposed flowchart for the surveillance of cardiovascular toxicities with immune checkpoint inhibitors. The 2022 ESC guidelines defined high-risk patients as those receiving dual ICI and/or combination ICI-cardiotoxic therapy, with ICI-related non-cardiovascular events, prior cancer therapy-related cardiac dysfunction, or cardiovascular disease. Class of recommendations according to the 2022 ESC cardio-oncology guidelines [18]. AChR acetylcoline receptor antibodies, CK creatin kinase, ECG electrocardiogram, ICI immune checkpoint inhibitors, NP natriuretic peptides (B-type natriuretic peptide and NT-proBNP N-terminal pro-brain-natriuretic-peptide), TTE transthoracic echocardiography. Created with biorender.com