Cardiac complications of cancer therapies

Abstract

The quest of defeating cancer and improving prognosis in survivors has generated remarkable strides forward in research and have advanced the development of new antineoplastic therapies. These achievements, combined with rapid screening and early detection, have considerably extended the life expectancy of patients surviving multiple types of malignancies. Consequently, chemotherapy-related toxicity in several organ systems, especially the cardiovascular system, has surfaced as one of the leading causes of morbidity and mortality among cancer survivors. Recent evidence classifies chemotherapy-induced cardiotoxicity as the second-leading cause of morbidity and mortality, closely comparing with secondary cancer malignancies. While a certain degree of cardiotoxicity has been reported to accompany most chemotherapies, including anthracyclines, anti-metabolites, and alkylating agents, even the latest targeted cancer therapies such as immune checkpoint inhibitors and tyrosine kinase inhibitors have been associated with acute and chronic cardiac sequelae. In this chapter, we focus on describing the principal mechanism(s) for each class of chemotherapeutic agents that lead to cardiotoxicity and the innovative translational research approaches that are currently being explored to prevent or treat cancer therapy-induced cardiotoxicity and related cardiac complications.

Keywords: Anthracyclines; Cancer; Cardiotoxicity; Cardiovascular imaging; Chemotherapy; Heart failure; Immune checkpoint inhibitors; Radiation therapy; Tyrosine kinase inhibitors.

Fig. 1

Mechanisms of cardiotoxicity induced by anthracycline administration. Schematic showing the principal myocardial cytotoxic effects following the administration of anthracyclines. Anthracyclines, such as doxorubicin, induce inhibition of topoisomerase IIβ, contribute to mitochondrial dysfunction, and generate reactive oxygen species (ROS). The oxidative stress generated, impairs the smooth endoplasmic reticulum (SER) with consequent intracellular altered calcium handling and lipid peroxidation. The cellular injuries accumulated post-anthracycline exposure, activate several cell death pathways with detrimental effects on the total heart physiology.

Fig. 2

T cell response to immune checkpoint inhibitors. Representation of the mechanisms used by tumor cells to evade immune systems by suppressing antitumor T cells. (1) Antigen-presenting cells activate T cells against tumor antigen presentation. Blockade of CTLA-4 co-stimulation by specific monoclonal antibodies increases the antitumor activity of T cells. (2) Tumor cells induce T cell apoptosis by exposing the programmed cell death (PD-1) and PD ligand 1 (PD-L1). The activation of the programmed cell death pathway limits T cell activation and proliferation.