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Cardiotoxicity of immune checkpoint inhibitors
  1. Gilda Varricchi1,2,3,
  2. Maria Rosaria Galdiero1,2,3,
  3. Giancarlo Marone4,5,
  4. Gjada Criscuolo1,
  5. Maria Triassi4,
  6. Domenico Bonaduce1,2,3,
  7. Gianni Marone1,2,3,6,
  8. Carlo Gabriele Tocchetti1,2,3
  1. 1Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
  2. 2Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
  3. 3WAO Center of Excellence, University of Naples Federico II, Naples, Italy
  4. 4Department of Public Health, Section of Hygiene, University of Naples Federico II, Naples, Italy
  5. 5Monaldi Hospital Pharmacy, Naples, Italy
  6. 6Institute of Experimental Endocrinology and Oncology ‘Gaetano Salvatore’, National Research Council (CNR), Naples, Italy
  1. Correspondence to Dr Gilda Varricchi; gildanet{at}


Cardiac toxicity after conventional antineoplastic drugs (eg, anthracyclines) has historically been a relevant issue. In addition, targeted therapies and biological molecules can also induce cardiotoxicity. Immune checkpoint inhibitors are a novel class of anticancer drugs, distinct from targeted or tumour type-specific therapies. Cancer immunotherapy with immune checkpoint blockers (ie, monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1) and its ligand (PD-L1)) has revolutionised the management of a wide variety of malignancies endowed with poor prognosis. These inhibitors unleash antitumour immunity, mediate cancer regression and improve the survival in a percentage of patients with different types of malignancies, but can also produce a wide spectrum of immune-related adverse events. Interestingly, PD-1 and PD-L1 are expressed in rodent and human cardiomyocytes, and early animal studies have demonstrated that CTLA-4 and PD-1 deletion can cause autoimmune myocarditis. Cardiac toxicity has largely been underestimated in recent reviews of toxicity of checkpoint inhibitors, but during the last years several cases of myocarditis and fatal heart failure have been reported in patients treated with checkpoint inhibitors alone and in combination. Here we describe the mechanisms of the most prominent checkpoint inhibitors, specifically ipilimumab (anti-CTLA-4, the godfather of checkpoint inhibitors) patient and monoclonal antibodies targeting PD-1 (eg, nivolumab, pembrolizumab) and PD-L1 (eg, atezolizumab). We also discuss what is known and what needs to be done about cardiotoxicity of checkpoint inhibitors in patients with cancer. Severe cardiovascular effects associated with checkpoint blockade introduce important issues for oncologists, cardiologists and immunologists.

  • cancer
  • cardiotoxicity
  • immune checkpoints
  • CTLA-4
  • melanoma
  • myocarditis
  • PD-1
  • PD-L1

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  • Contributors Gilda Varricchi, Gianni Marone and Carlo Gabriele Tocchetti drafted the first version of the manuscript. All authors revised the manuscript and approved the final version of the manuscript. Gilda Varricchi and Carlo Gabriele Tocchetti are responsible for the overall content as guarantors.

  • Funding This work was supported in part by grants from Regione Campania CISI-Lab, CRÈME Project and TIMING Project, and Ricerca di Ateneo.

  • Competing interests CGT received travel support from Alere.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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