Anticancer drugs and cardiotoxicity: the role of cardiomyocyte and non-cardiomyocyte cells

Abstract

Cardiotoxicity can be defined as "chemically induced heart disease", which can occur with many different drug classes treating a range of diseases. It is the primary cause of drug attrition during pre-clinical development and withdrawal from the market. Drug induced cardiovascular toxicity can result from both functional effects with alteration of the contractile and electrical regulation in the heart and structural changes with morphological changes to cardiomyocytes and other cardiac cells. These adverse effects result in conditions such as arrhythmia or a more serious reduction in left ventricular ejection fraction (LVEF), which can lead to heart failure and death. Anticancer drugs can adversely affect cardiomyocyte function as well as cardiac fibroblasts and cardiac endothelial cells, interfering in autocrine and paracrine signalling between these cell types and ultimately altering cardiac cellular homeostasis. This review aims to highlight potential toxicity mechanisms involving cardiomyocytes and non-cardiomyocyte cells by first introducing the physiological roles of these cells within the myocardium and secondly, identifying the physiological pathways perturbed by anticancer drugs in these cells.

Keywords: cardio-oncology; cardiomyocytes; cardiotoxicity; endothelial; fibroblast.

Figure 1

Origin and lineage relationship of cardiac cell types. (A) Contribution of three embryonic heart progenitor populations—cardiogenic mesoderm (red), cardiac neural crest (purple), and proepicardial organ (yellow)—to various heart compartments during cardiac morphogenesis. Cardiogenic mesoderm progenitors first appear beneath the head folds (HFs) at embryonic day 7.5 (E7.5) in the mouse embryo, then migrate ventrally to the midline (ML), forming the linear heart tube, which subsequently develops into the four heart chambers. Following heart tube looping (E8.5), cardiac neural crest progenitors migrate from the dorsal neural tube to the aortic arch arteries, differentiating into vascular smooth muscle cells of the outflow tract (OFT) by E10.5. Concurrently, proepicardial organ precursors contact the heart's surface, forming the epicardial mantle and later contributing to the coronary vasculature. By foetal stage E14, the heart chambers undergo septation and establish connections to the pulmonary trunk (PT) and aorta (Ao). (B) Cardiac cell types arising from the lineage diversification of the three embryonic precursor pools in the mouse heart. AA, aortic arch; IVS, interventricular septum; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. Adapted with permission from (10).

Figure 2

Distinction between functional and structural toxicity. Drug-induced cardiovascular toxicity can potentially affect all components and functions of the cardiovascular system. Functional toxicity can occur in the heart causing effects on cardiomyocyte electrophysiology and rate and force of contraction. Functional toxicity can also occur in the blood and vascular system with adverse effects on blood pressure, oedema and thrombosis. Structural toxicity can cause morphological changes in the heart with effects on cardiomyocytes, valvular endothelial cells, cardiac fibroblasts resulting in a range of pathologies such as necrosis, fibrosis, cardiomyopathy, myocarditis, hypertrophy and valvulopathy. Structural toxicity can also occur in the blood and vascular system with adverse effects on endothelial cells and smooth muscle cells resulting in vasculopathies, vasculitis and vascular remodelling. Structural and functional toxicity within the cardiac and vascular system ultimately clinically manifests in the development of arrhythmia, LV systolic dysfunction, cardiomyopathy, myocardial infarction and heart failure.

Figure 3

Drug-induced cardiovascular toxicity can affect multiple cells within the myocardium. Diagram showing the adverse effects of anti-cancer drugs on cardiac endothelial cells, vascular pericytes, cardiac fibroblasts and cardiomyocytes resulting in a range of morphological changes in these cells, ultimately contributing to the clinical manifestation of cardiac toxicity. These adverse effects are discussed in detail in the text.