Immune Checkpoint Inhibitor Associated Myocarditis and Cardiomyopathy: A Translational Review

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized oncology and transformed the treatment of various malignancies. By unleashing the natural immunological brake of the immune system, ICIs were initially considered an effective, gentle therapy with few side effects. However, accumulated clinical knowledge reveals that ICIs are associated with inflammation and tissue damage in multiple organs, leading to immune-related adverse effects (irAEs). Most irAEs involve the skin and gastrointestinal tract; however, cardiovascular involvement is associated with very high mortality rates, and its underlying pathomechanisms are poorly understood. Ranging from acute myocarditis to chronic cardiomyopathies, ICI-induced cardiotoxicity can present in various forms and entities. Revealing the inciting factors, understanding the pathogenesis, and identifying effective treatment strategies are needed to improve the care of tumor patients and our understanding of the immune and cardiovascular systems.

Keywords: adverse effects; cardio-oncology; cardiomyopathy; heart failure; immune checkpoint inhibitor; myocarditis.

Figure 1

Interaction of immune checkpoints from antigen-presenting cells and tumor-cells with T-cells. Activation and proliferation of T-cells depend on the net results of active stimulatory and inhibitory signals. APC = antigen-presenting cell; CD = cluster of differentiation; CTLA-4 = cytotoxic T-lymphocyte antigen 4; MHC = major histocompatibility complex; PD-1 = programmed cell death 1; PD-L1 = programmed cell death ligand 1; TCR = T-cell receptor; LAG-3 = lymphocyte activation gene-3.

Figure 2

ICI-induced cardiomyopathies and possible underlying pathomechanisms. Besides myocarditis, non-inflammatory cardiomyopathies, such as dilated cardiomyopathy, Tako-Tsubo-cardiomyopathy, myocardial infarction, and ischemic cardiomyopathy, have been observed under ICI therapy.

Figure 3

Clinical diagnosis and management of ICI-induced myocarditis (based on the ESC guidelines on cardio-oncology 2022). ACS, acute coronary syndrome; CMR, cardiac MRI; LV, left ventricular; ICU, intensive care unit.