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

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 (AF). 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.

Cancer Therapy-Associated Pulmonary Hypertension and Right Ventricular Dysfunction: Etiologies and Prognostic Implications

“…The development of tyrosine kinase inhibitors (TKIs) has revolutionized therapy paradigms for a broad range of hematologic and solid tumor malignancies, including but not limited to CML, chronic lymphocytic leukemia (CLL), non-small cell lung cancer (NSCLC), gastrointestinal stromal tumors (GIST), melanoma, and colorectal cancer [ 51 ]. Despite their relatively specific mechanism of action against tumor progression, TKIs may cause cardiotoxicity mainly through inhibition of tyrosine kinases not involved in oncogenesis [ 3 ]. The development of PH has been a well-documented toxicity of certain TKIs [ 52 ].…”

“…Cancer is a leading cause of mortality worldwide but advances in cancer therapies have led to improved survival [ 1 ]. Cardiovascular toxicities associated with cancer therapies are increasingly recognized sources of morbidity and mortality among patients with cancer [ 2 , 3 , 4 , 5 ]. Cardiomyopathy and myocardial injury are most associated with cancer therapies.…”