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Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia

Abstract

Remarkable progress has been made in the development of new therapies for cancer, dramatically changing the landscape of treatment approaches for several malignancies and continuing to increase patient survival. Accordingly, adverse effects of cancer therapies that interfere with the continuation of best-possible care, induce life-threatening risks or lead to long-term morbidity are gaining increasing importance. Cardiovascular toxic effects of cancer therapeutics and radiation therapy are the epitome of such concerns, and proper knowledge, interpretation and management are needed and have to be placed within the context of the overall care of individual patients with cancer. Furthermore, the cardiotoxicity spectrum has broadened to include myocarditis with immune checkpoint inhibitors and cardiac dysfunction in the setting of cytokine release syndrome with chimeric antigen receptor T cell therapy. An increase in the incidence of arrhythmias related to inflammation such as atrial fibrillation can also be expected, in addition to the broadening set of cancer therapeutics that can induce prolongation of the corrected QT interval. Therefore, cardiologists of today have to be familiar not only with the cardiotoxicity associated with traditional cancer therapies, such as anthracycline, trastuzumab or radiation therapy, but even more so with an ever-increasing repertoire of therapeutics. This Review provides this information, summarizing the latest developments at the juncture of cardiology, oncology and haematology.

Key points

  • Cancer therapy has evolved from the administration of chemical compounds and radiation therapy to the use of targeted agents and immunotherapies.

  • Along with these developments, the cardiovascular toxicity spectrum of cancer therapies has been changing but cardiac toxicity remains of greatest concern.

  • Inflammatory and immune mechanisms have to be taken into account when considering cardiotoxicity in patients receiving immune checkpoint inhibitor or chimeric antigen receptor T cell therapies.

  • With the newer cancer therapies, atrial fibrillation is emerging as the most relevant and practically challenging arrhythmia in patients with cancer.

  • Corrected QT interval prolongation, ventricular arrhythmias and cardiac arrest can also occur with many of the newer targeted agents.

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Fig. 1: Outline of cardiovascular toxic effects associated with cancer therapies.
Fig. 2: Timeline of cancer therapy development.
Fig. 3: Main elements in the treatment of patients with cancer and atrial fibrillation.

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Acknowledgements

The author receives support from the US National Institutes of Health (HL116952 and CA233610) and the Miami Heart Research Institute/Florida Heart Research Foundation.

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Glossary

Oncogenes

Oncogenes encode proteins that can transform cells into tumour cells. All but a few are derived from normal cellular genes (proto-oncogenes), and activation of a proto-oncogene into an oncogene generally involves a gain-of-function mutation.

Philadelphia chromosome

Named after the city in which it was discovered in 1960 as the first tumour-specific chromosomal change in the form of a shortened chromosome 22 as a result of a reciprocal translocation that leads to the oncogenic BCRABL1 gene fusion, which has a causal role in the malignant transformation of white blood cell precursors; the Philadelphia chromosome is found in 90% of patients with chronic myeloid leukaemia.

Endoplasmic reticulum stress response

Disruption of endoplasmic reticulum function leads to impairment of protein folding, accumulation of unfolded and misfolded proteins and risk of cell toxicity. The cell reacts to this endoplasmic reticulum stress by initiating the unfolded protein response to increase the capacity of the cell to handle and/or eliminate the accumulating unfolded or misfolded proteins or to initiate apoptosis.

Sentinel kinase theory

The theory that inhibition of one specific enzyme among all the enzymes that catalyse the transfer of a phosphate group from ATP onto a tyrosine, serine or threonine residue of a protein (kinome) is responsible for a specific action.

Cytokine release syndrome

(CRS). A systemic inflammatory response that can be triggered by a variety of factors such as infections, antibody-based immunotherapies and chimeric antigen receptor T cell therapy. CRS is caused by the rapid release of a large amount of cytokines into the circulation, leading to fever, nausea, headache, rash, tachycardia, hypotension and respiratory distress.

Bispecific T cell engager therapy

(BiTE therapy). BiTE antibody constructs are designed to create an immunologic synapse between an effector T cell and a tumour cell by simultaneously binding to the T cell activation molecule CD3 and a tumour-associated antigen, which is CD19 on B cells in the case of blinatumomab (approved for the treatment of B cell acute lymphoblastic leukaemia).

Cell senescence

A process defined as irreversible cell cycle arrest, driven by a variety of mechanisms, including telomere shortening, other forms of genotoxic stress, mitogens or inflammatory cytokines, that culminate in the activation of the tumour suppressor p53 and/or the cyclin-dependent kinase inhibitor p16.

Cardiovascular flow reserve

The capacity of the coronary vascular bed to increase blood flow maximally to the myocardium, often expressed as a ratio with regard to baseline blood flow.

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Herrmann, J. Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia. Nat Rev Cardiol 17, 474–502 (2020). https://doi.org/10.1038/s41569-020-0348-1

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