New anticancer treatments have improved overall mortality (1). However, most of the anticancer drugs display a wide array of cardiovascular toxicities, leading to interruption of cancer therapies and maladaptive remodeling in hearts, affecting the short- and long-term quality of life (2–4). Oxidative stress and inflammation are inter-reliant processes involved in cardiovascular diseases and cancers (5, 6), along with apoptosis (7, 8) and necrosis (9). Tissue resident and circulating inflammatory cells (such as macrophages, mast cells, neutrophils, and monocytes) can also release both reactive oxygen species (ROS) and reactive nitrogen species (RNS) to induce an oxidative stress (6). Due to negligible detoxification capacity, the heart is particularly susceptible to ROS and RNS injury (10). Thus, high levels of ROS and RNS can debilitate cardiac cellular signaling pathways and can augment the gene expression of proinflammatory (11) and antioxidant defenses as the major cause for necrosis and apoptosis.

Classic chemotherapeutics particularly anthracyclines are the prototype of drugs causing cardiotoxicity (12). They can induce acute cardiotoxicity, including reversible hypotension, pericarditis and transient electrocardiographic abnormalities (changes in the ST-T waves, QT prolongation), and vasodilatation (13). However, after completion of cumulative dose regimens, anthracyclines promote irreversible cardiomyopathy (classified as type (1) cardiotoxicity), leading to heart failure (HF) (13, 14). Doxorubicin (DOX), the most frequently used anthracyclines can cause irreversible type 1 cardiotoxicity via accumulation of ROS and RNS (15, 16). They also target Topoisomerase IIβ (Top IIβ) in cardiomyocytes to induce DNA damage and apoptosis. Recently, the anthracycline mediated cardiotoxicity has been reviewed by Nebigil (17).

Targeted therapies also provoke some degree of cardiotoxicity. Targeting key tyrosine kinases (TKs) with TK antibodies and inhibitors has a remarkable achievement in cancer management. However, they also induce cardiotoxicity, because they block pathways that also regulate myocardial function (18). This cardiotoxicity is often reversible, and thus classified as type 2 cardiotoxicity (19, 20). It results in ultrastructural changes in cardiomyocytes, with reversible cardiac dysfunctions such as elevated blood pressure, thromboembolism, pericardial thickening, and arrhythmia (21). Type 1 and 2 forms of cardiotoxicity can overlap, when the classic and targeted therapeutics used together or subsequently. For example, in patient treated with anthracyclines earlier, trastuzumab, a monoclonal antibody anti-HER-2 can cause irreversible cardiac damage and left ventricular (LV) dysfunction (18, 22, 23). On the other hand, 27%, of patients who received both anthracycline and trastuzumab encountered cardiac dysfunction, while this rate was of 2-16% for patients treated with anthracyclines alone (24).

Recent studies have demonstrated that patients treated with immune checkpoint inhibitors (25) also develop myocarditis due to immune-related adverse events (6, 26). The therapeutic mechanisms of inhibitors mostly rely on blocking either the cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) or programmed cell death protein-1 (PD-1) pathways, while activating the host's immune system against cancer (27). CTLA-4 and PD-1 act as immune response inhibitors (6, 28). They suppress the T-cell response in order to prevent autoimmunity and maintain T-cell tolerance. Cardiac immune-related adverse events appear more frequently in patients treated with CTLA-4 antagonists compared with PD-1 inhibitors (29) and the myocarditis risk increases with combination therapy, leading to discontinuation in approximately 50% of patients (30, 31) probably due to targeting PD-1 and CTLA-4 in cardiomyocytes as well.