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Review
. 2023;148(4):324-334.
doi: 10.1159/000529260. Epub 2023 Jan 26.

Off-Target Effects of Cancer Therapy on Development of Therapy-Induced Arrhythmia: A Review

Orly Leiva  1 , Isaac Bohart  1 , Tania Ahuja  1 , David Park  1
Affiliations
Review

Off-Target Effects of Cancer Therapy on Development of Therapy-Induced Arrhythmia: A Review

Orly Leiva et al. Cardiology. 2023.

Abstract

Background: Advances in cancer therapeutics have improved overall survival and prognosis in this patient population; however, this has come at the expense of cardiotoxicity including arrhythmia.

Summary: Cancer and its therapies are associated with cardiotoxicity via several mechanisms including inflammation, cardiomyopathy, and off-target effects. Among cancer therapies, anthracyclines and tyrosine kinase inhibitors (TKIs) are particularly known for their pro-arrhythmia effects. In addition to cardiomyopathy, anthracyclines may be pro-arrhythmogenic via reactive oxygen species (ROS) generation and altered calcium handling. TKIs may mediate their cardiotoxicity via inhibition of off-target tyrosine kinases. Ibrutinib-mediated inhibition of CSK may be responsible for the increased prevalence of atrial fibrillation. Further investigation is warranted to further elucidate the mechanisms behind arrhythmias in cancer therapies.

Key messages: Arrhythmias are a common cardiotoxicity of cancer therapies. Cancer therapies may induce arrhythmias via off-target effects. Understanding the mechanisms underlying arrhythmogenesis associated with cancer therapies may help design cancer therapies that can avoid these toxicities.

Keywords: Arrhythmia; Cardio-oncology; Cardiotoxicity.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Fig. 1.
Fig. 1.
Doxorubicin may induce arrhythmia via ROS production, activation of CaMKII, and downregulation of SERCA leading to cytosolic calcium overload. Increased ROS production activates NLPR3 inflammasome leading to increased inflammation and arrhythmia. Ibrutinib inhibits CSK, which is an inhibitor of c-SRC, leading to inflammation, fibrosis, and arrhythmia.
Fig. 2.
Fig. 2.
Ibrutinib exerts on-target antineoplastic effect by inhibition of BTK, an important step in the B-cell receptor signaling pathway leading to cellular proliferation. However, ibrutinib exerts off-target effects by inhibiting CSK leading to atrial inflammation, fibrosis, and atrial fibrillation.
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