Anthracycline cardiotoxicity has been a subject of research for more than 70 years, however, the exact mechanism has not yet been clarified. Early research focused on ROS-mediated cell and DNA damage. Antineoplastic agents exert their main toxic effects in tissues composed of rapidly dividing cells, however, myocardial cells have limited regenerative capability resulting in irreversible damage (29). Initial studies showed that the main cause of cardiotoxicity is oxidative stress caused by iron-anthracycline complexes that resulted in lipid peroxidation and cell membrane damage. The high sensitivity of myocardium to oxidative stress may be attributed to lower activities of ROS depleting protective mechanisms such as catalase, DOX-induced depletion of glutathione peroxidase, high myocardial metabolic activity, and high concentration of cardiolipin with positive affinity to anthracyclines (30–33).

Cardiotoxicity of anthracyclines was thought to be based on inhibition of the reduction of NAD⁺ to NADH+H⁺ during reverse electron transport in mitochondrial respiratory complex I. Furthermore, DOX caused a reduction of molecular oxygen (to O²⁻) followed by the rise of oxygen consumption by anthracycline semiquinone radicals (34). Oxidative stress leads to the activation of several apoptotic pathways such as the p53 pathway and p38 mitogen-activated protein kinase (MAPK) (35, 36). Cytochrome c is located in the inner membrane of mitochondrion and administration of DOX is causing cytochrome c release, which leads to activation of procaspase-9 and generating caspase-9 which proteolytically activates caspase-3 responsible for DNA fragmentation and apoptosis. According to many studies, DOX can trigger intrinsic, extrinsic, and endoplasmic reticulum-associated apoptotic pathways (37, 38).

Furthermore, adaptive responses to DOX were discovered. Administration of DOX increases copper-zinc superoxide dismutase (supporting the theory about DOX-induced superoxide radical production). Additionally, an increase in BCL2:BAX ratio was observed (as an adaptation to antioxidant stress). All these findings support the theory that DOX induces oxidative stress and mitochondria-mediated apoptosis which goes hand in hand with adaptive responses to protect cardiac myocytes (39). Mechanisms of anthracycline-induced cardiotoxicity with possible therapeutic targets are displayed in Figure 1.

Cardiac damage may be diagnosed or monitored by laboratory parameters or imaging methods (CMR, echocardiography). Laboratory parameters for early detection of left ventricular dysfunction include troponin and N-terminal pro B-type natriuretic peptide (NT-proBNP) (82–84).

Many parameters obtained from imaging methods were evaluated with promising results including a new parameter, the myocardial work which integrates cardiac deformation and LV pressure. In a study of 130 patients with NHL scheduled for R-CHOP, myocardial work proved to be appropriate for diagnosing subclinical cardiotoxicity and predicting left ventricle ejection fraction (LVEF) decline (85). Current standards for the identification of DOX-induced cardiotoxicity include an evaluation with LVEF and global longitudinal strain. However, other parameters are discussed including LV mass [in the study from Jordan et al. (52) evaluated from CMR] which proved to be a better predictor of heart failure symptomatology than LVEF (52, 86). The study of Jordan et al. (52) also proposed that myocellular dysfunction may not be pathophysiologically linked to impaired adaptive remodeling during anthracycline chemotherapy.

CTX is a prodrug metabolized by hepatic cytochrome C 450 into 4-hydroxycyclophosphamide and aldocyclophosphamide, which decomposes into cytotoxic phosphoramide mustard and acrolein (107). While phosphoramide is responsible for therapeutic effect (acts on seven-guanine residues of DNA leading to intrastrand and interstrand cross-links and cell death), acrolein may act as toxic mainly in the cardiovascular system interfering with the antioxidative metabolism resulting in elevated ROS production and drop of endothelial nitric oxide (NO) formation (99, 108–110). Additionally, toxic acrolein potential includes hemorrhagic cystitis and other toxicities linked to CTX such as gonadal toxicity, carcinogenesis, and bone marrow suppression (111). Some authors suggest that CTX metabolites may even cause direct damage to the endothelial cells and myocardium resulting in edema, interstitial hemorrhage and the formation of microthrombi (88). Endothelial cells are susceptible to CTX toxic effects, possibly due to their high proliferation rate and CTX -induced drop of production of endothelial NO leading to endothelial dysfunction (88).

There are studies demonstrating activation of the p38-MAPK pathway, through which acrolein may act as an upregulator of E3 ligases and MuRF1. This results in the degradation of myosin heavy chain (56, 57). Acrolein preferentially binds to nucleolar ribosomal DNA and induces oxidative stress-mediated damage and provokes ribosomal stress responses by activation of p53 (112). CTX also triggers various proinflammatory and proapoptotic mediator responses such as those mediated by nuclear factor-kappaB (NF-κB), cyclooxygenase-2, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) (113). These pathways are potential targets to antagonize CTX -induced cardiotoxicity (114, 115).

CTX therapy is associated with reduced expression of heart-type fatty acid-binding proteins (H-FABP) with a consecutive decrease of mitochondrial transport and the oxidation of long-chain fatty acid (LCFA) (116). Oxidative metabolism of free fatty acids (FFA) provides about 70% of the energy required for the normal function of the myocardium and its decline leads to energy deficiency with subsequent accumulation of FFA toxic metabolites (117). Nevertheless, daily supplementation of L-carnitine might possibly reverse these effects (117).

By these mechanisms CTX and its main metabolite acrolein cause vasospasm, myocyte dysfunction, and necrosis/apoptosis which may lead to heart failure (109). Recently Zhu et col. demonstrated that CTX induces RNA N6-methyladenosine (m6A) modification by upregulating methyltransferases METTL3 expression and suppressing junktophillin-2 (JPH2) expression. By this mechanism CTX causes calcium signaling dysregulation and cardiac dysfunction and this pathway may possibly represent target for cardioprotective therapy (118).

Nuclear factor erythroid 2-related factor 2 pathway (Nrf2) impairs both oxidative stress and inflammation response) and according to some authors it is one of the main pathways by which CTX could cause cardiotoxicity (119).

Several molecules exhibited antioxidative properties that mitigated CTX -induced cardiotoxicity in in vivo animal models. Kolaviron (mixture of flavonoids with antioxidant and membrane stabilizing effect) administered 14 days prior to CTX treatment reduced CTX -mediated alteration of cardiac structure and metabolism (108). Furthermore, the combination of curcumine (cardioprotective phytoconstituent) and piperine (bio-enhancer) exhibited significant protection against CYP-induced myocardial toxicity and pre-treatment with N-acetylcysteine provides some cardioprotective effect with no alteration of CTX metabolism and its therapeutic efficacy (120, 121).

According to the preclinical studies above, the use of antioxidants to reduce ROS generation may suppress cardiotoxic adverse events. However, further human in vivo studies are needed to show their potential therapeutic efficacy (111). Another potential cardioprotective agent seems to be nicoradil which possess potassium channel opening effect, stimulates eNOS gene expression and has anti-inflammatory and antiapoptotic properties (122). Stern et col published a study on a multicellular coculture [hepatocytes, cardiomyocytes, triple negative breast cancer (TNBC) cells] with CN06 dual activator of Nrf2 and constitutive androstane receptor for TNBC. Via selectively activation of NrF2 antioxidant signaling in cardiomyocytes but not in TNBC cells they repressed DOX induced cardiotoxicity (with reduced apoptosis and enhanced kinetics of contraction) (123).

Valvular susceptibility is higher in the left ventricle (predominantly on the aortic valve) due to higher pressure. Irradiation-induced aortic regurgitation is more common than stenosis. This is in contrast with myocardial damage and fibrosis, that are more frequently manifest in the right heart compartments, possibly due to the position of the right ventricle and anterior radiation fields (178, 180, 181).

Severe valvular disease during a median follow-up of 13 years was diagnosed in 24,5% of HL survivors with mediastinal radiotherapy vs. 3,4% without mediastinal radiotherapy. Up to 18% of monitored patients were indicated to have valvular surgery in the group which received mediastinal irradiation vs. none in the group without mediastinal radiation (182). Irradiation induces degenerative changes and the absence of valvular disease early after radiation does not indicate a low risk of late-onset valvular disease (decades after therapy discontinuation) (183).

Significant coronary artery disease developed in 18% of patients in 10 years follow-up after radiotherapy in the study by Horimoto et al. (180). Radiotherapy in patients with HL leads to the formation of macrophage-rich inflammatory atherosclerotic lesions with a tendency to intraplaque hemorrhage. This pathophysiological process directly increases the risk of atherosclerotic events (184). Radiation-associated coronary artery disease (CAD) predominantly manifests in proximal parts of the left main and right ostial coronary arteries due to higher radiation doses to the anterior surface of the heart and often affects women with low-risk factors for CAD (185, 186). Manifestation of CAD is further promoted by radiotherapy-induced chronic inflammatory state and higher prevalence of diabetes (or metabolic syndrome) (125, 187, 188). The risk of CAD manifestation was directly proportional to the mean heart dose, however, according to the study of Maazen et al., an increased level of physical activity decreased the risk of coronary artery disease in a similar manner to the general population (189).

Main adverse effects of irradiation result in microcirculatory damage and altered collagen concentration. These changes may be responsible for defective diastolic distensibility of the ventricles and marked fibrosis may cause arrhythmia such as AV block (190, 191). Defective diastolic distensibility may lead to restrictive cardiomyopathy and cause CHF which can be even more potentiated by radiation-induced coronary artery disease, pericardial or valvular disease. Moreover, case reports of takotsubo cardiomyopathy following chest radiation have been reported (192, 193).

Extensive fibrous thickening and excessive pericardial fluid were predominantly associated with older radiotherapy techniques (44). Acute pericarditis often presents in the first year after irradiation (180). Acute pericarditis results from small blood vessels proliferation through the pericardium. These vessels are usually damaged, resulting in increased ischemia and fibrosis. Furthermore, venous and lymphatic vessel damage impairs the ability to drain extracellular fluid (44). Thickening of pericardium was diagnosed in 15% of patients treated with older radiation techniques for HL with a median radiation dose of 41 Gy in a study by Lund et al. (164)

In another study by Galper et al. pericardial disease was identified in 9 patients out of 1,279 HL survivors who were treated with median dose of 40 Gy and cumulatively only 1,3% of patients needed pericardial surgery after 25 years of follow up (181, 194). Severe damage of pericardium seems to be a rare complication in standard radiation doses.

Thoracic irradiation in childhood cancer survivors is an emerging issue with a respect to the years of survival after therapy discontinuation. According to the study by Mulrooney et al. cardiac radiation exposure of 15 Gy or more during childhood increased the relative hazard of cardiac events (CHF, myocardial infarction, pericardial disease, and valvular abnormalities) by twofold to sixfold compared to non-irradiated long-term survivors (24).

In a large-scale study of 13,060 childhood cancer survivors who were followed up to the age of 50 years an individual prediction model of ischemic heart disease was proposed, and cancer survivors were categorized according to sex, chemotherapy, and heart-absorbed radiation dose to low-risk vs. high-risk groups. The cumulative incidence of ischemic heart disease at the age of 50 years among low-risk survivors was <5% compared with 20% for high-risk groups (cumulative incidence for siblings were 1%) (195). The cumulative incidence of cardiac disease in HL survivors decreases from 21% (after mediastinal radiation dose of 36 Gy) to 10%, 6%, 5%, 3% after lower mediastinal radiation doses (30 Gy, 25 Gy, 20 Gy, 0 Gy) (178).

Currently, novel radiation techniques such as mantle field techniques are employed and high doses to anterior parts of the heart are partly compensated by boost treatment from non-anterior angles potentially decreasing the risk of cardiotoxicity (196).

Prevention is mainly focused on using modern irradiation techniques with reducing heart's exposure to radiation such as prone positioning, deep inspiratory breath holding, intensity modulated techniques, intraoperative irradiation (197). Yet, there is no medicament to reduce radiation damage but in rat models N-acetyl cysteine ameliorated cardiac injury induced by RT and hence possibly could be used as radioprotector (198).

Assumingly, new cancer therapy-related cardiovascular complications will be discovered with advances in targeted therapy for malignant lymphoma (199). Ibrutinib (Bruton's tyrosine kinase (BTK) inhibitor nowadays used for refractory chronic lymphocytic leukemia or mantle cell lymphoma (200) increases the risk of atrial fibrillation potentially via inhibition of cardiac PI3K-Akt signaling (201). The second generation BTK inhibitors were introduced to reduce BTK-related cardiotoxicity. In this generation, adverse effect occur in 6.3% vs. 20.8% cases in first generation (202). Although according to Arustamyan et al. (202), the second generation BTK inhibitors have increased incidence of other adverse effects such as endocrine, gastrointestinal, neurological etc. Pirtobrutinib is highly selective BTK inhibitor and is classified as third generation. Mato et al. (203) found that less than 1% of patients suffered from atrial fibrillation and flutter and possibly unrelated to Pirtobrutinib.

Immune checkpoint inhibitors (ICI) fight tumor cells dominantly by the activation of T cells (204). Certain ICI posses significant efficacy with an overall response rate in relapse/refractory HL nevertheless in rare cases the cardiotoxic adverse effect may be lethal (205). ICI associated cardiotoxicity is mainly represented by myocarditis, pericarditis, arrhythmias and rarely by coronary spasm (206–208). The exact mechanism of ICI-related cardiotoxicity remains unclear, however proposed mechanisms include shared antigen between tumor and myocardium, T-cell receptor targeting homologous muscle antigen or certain T-cell receptors targeting dissimilar antigens (209). ICI-related cardiotoxicity in solid tumors therapy was described in 7% of patients with diabetes mellitus as an independent risk factor (204). ICI possesses not only acute cardiotoxicity but also late-onset cardiotoxicity. In the study from Dolladille (200), late-onset cardiotoxicity was defined as any cardiac adverse effect observed after more than 90 days following therapy initiation. These adverse effects were mainly represented by heart failure emphasizing the necessity of prolonged cardiac follow-up after ICI therapy (200).

Immune therapy with CAR-T cells is currently reserved for patients suffering from late stages or refractory hematological malignancies. This novel therapeutic approach yields promising results, however its alteration of immune response leads to various cytokine-related adverse events (210). The incidence of cytokine release syndrome (CRS), resulting from overactivation of immune system, occurs in 70%–90% patients receiving CAR-T cell therapy. Approximately one third of all patients with CRS experience any cardiac adverse events (211, 212). Most common are tachyarrhytmias (both supraventricular and ventricular), QT-interval prolongation, myocardial ischemia and thromboembolism (213). Further investigation of exact mechansims of CAR-T cell therapy-related cardiotoxicity is necessary to discover potential targets of cardioprotective medication.