Cardiac Toxicities Associated with Immune Checkpoints Inhibitors: Mechanisms, Manifestations and Management

Abstract

Immune checkpoint inhibitor (ICI) associated cardiovascular adverse events (CVAE) have become more frequent with the growing use of cancer immunotherapy. CVAEs include a wide spectrum of diseases such as myocarditis, pericarditis, heart failure, arrhythmias, coronary artery disease, and hypertension. The induction of cardiovascular side effects by ICI use is hypothesized to occur due to inflammation and immune dysregulation of normal tissue in response to immunotherapy. Management of ICI-associated CVAEs mitigates an overactive immune response by utilizing steroids, immunomodulatory drugs and hemodynamic stabilization. However, few controlled studies on the cardiovascular safety of ICIs exist and treatment of their side effects are mostly from limited case series. Our review seeks to provide the most recent understanding of ICI-associated CVAEs and their management.

Keywords: CTLA-4; Immune checkpoint inhibitor; Myocarditis; PD-1; PD-L1.

Figure 1. (A) Mechanism used by the tumor cells to evade the immune system. (B) Mechanism immune checkpoint inhibitors use to inhibit the tumor cells from evading the immune system.

ACP = antigen presenting cells; CTLA-4 = cytotoxic T-lymphocyte-associated antigen 4; MHC = major histocompatibility complex; PD-1 = programmed cell death receptor-1; PD-L1 = programmed cell death ligand-1; TCR = T-cell receptor. ^*Created with BioRender.com.

Figure 2. Treatment algorithm of ICI-associated cardiotoxicity by symptom type.

ACC = American College of Cardiology; AHA = American Heart Association; ICI = immune checkpoint inhibitor. ^*Insufficient evidence to support safety of rechallenging ICI therapy. ^†Secondary treatments include: infliximab (not to be used in moderate to severe heart failure), anti-thymocyte globulin, mycophenolate mofetil, tacrolimus, intravenous immunoglobulin, plasmapheresis.

Figure 3. Surveillance and Evaluation of ICI cardiotoxicity.

ECG = electrocardiography; FDG = fluorodeoxyglucose; ICI = immune checkpoint inhibitor; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; NT pro-BNP = N-terminal pro B-type natriuretic peptide; PET/CT = positron emission tomography/computed tomography; TnI = troponin I. ^*Patients with diabetes mellitus, obstructive sleep apnea, elevated body mass index, abnormal LVEF on baseline echocardiography, previous cardiovascular disease or combination therapy (including chemotherapy with cardiovascular side effect).