Mechanisms and Management of Immune Checkpoint Inhibitor-Related Cardiac Adverse Events

Abstract

Onco-cardiology recently emerged as a novel discipline to provide effective cardioprotective care against cancer therapeutics-related cardiac adverse events (CAEs) and support the continuity of optimal cancer treatment. Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy and dramatically improved outcomes in patients with advanced or refractory cancers. However, ICIs intrinsically stimulate systemic immune responses and can potentially induce a spectrum of immune-related adverse events (irAEs), which can affect any organs of the body. The manifestation of cardiac irAEs includes myocarditis, arrhythmias and conduction abnormalities, and pericardial diseases. Takotsubo-like cardiomyopathy is also included as a manifestation of ICI-related CAEs, but the pathophysiological relevance is unclear. Although the incidence is rare, ICI-related CAEs are life-threatening and potentially fatal. Elucidating pathophysiology and establishing management measures of ICI-related CAEs are one of the most urgent challenges in the field of onco-cardiology.

Keywords: CTLA-4; PD-1; PD-L1; immune-related adverse events; myocarditis.

Figure 1.

Effects of immune checkpoint inhibitors on tumor cells and cardiomyocytes. Inhibition of suppressive factors called “immune checkpoints” accelerates activated T-cell to invade and injure tumor cells but may also allow the immune system to attack normal organs in our body, including the heart. APC, antigen-presenting cell; CTLA-4, cytotoxic T-lymphocyte antigen 4; MHC, major histocompatibility complex; PD-1, program death ligand 1; PD-L1/PD-L2, programmed cell death ligand 1 or ligand 2; TCR, T-cell receptor; TNF-α, tumor necrosis factor-α; IFN-γ, interferon-γ.

Figure 2.

Immune-related adverse events in each organ.

Figure 3.

Flow diagram for optimal cardiovascular follow-up of patients treated with ICIs. BNP, B-type natriuretic peptide; CK, creatinine kinase; CK-MB, creatine kinase myocardial band; CMR, cardiac magnetic resonance; ECG, electrocardiogram; NT-proBNP, N-terminal pro BNP; ICIs, immune checkpoint inhibitors.