Anthracyclines, one of the most representative and prominent examples of chemotherapies, separated from the soil microbe Streptomyces peucetius var. caesius are a class of cytostatic antibiotics that can hinder the synthesis of DNA and RNA by embedding into base pairs to form steady complexes and suppressing topoisomerase (Top) II activity, giving rise to DNA damage and inhibiting cell proliferation and metabolism ^[1][7]. Top IIβ plays a crucial role in DNA regulation by facilitating temporary single- or double-stranded breaks during vital processes such as DNA replication, transcription, recombination, and chromatin remodeling. Notably, the binding of doxorubicin to DNA and Top II isoforms leads to the formation of a ternary complex comprising Top II, doxorubicin, and DNA, ultimately resulting in the induction of double-stranded DNA breaks ^[2][8]. Interestingly, dexrazoxane is the most promising drug approved for the prevention of anthracycline-induced cardiotoxicity, and its cardioprotective effects are dependent on Top IIβ ^[3][9]. As the highly effective broad-spectrum antitumor drugs, anthracyclines are clinically widely prescribed to treat solid tumors and hematological malignancies; however, they are also well known for their cardiotoxicity ^[4][10]. The mechanisms of their cardiotoxicity tend to be highly complex, and currently, it is explicit that anthracyclines will induce damage to myocytes through the generation of free radicals ^[4][10]. For example, doxorubicin causes accumulation of free radicals in cardiomyocytes through a series of reactions, leading to lipid peroxidation of the cell membrane, damage of endoplasmic reticulum, mitochondria, and nucleic acid, and also arousing serious effluent loss of calcium in sarcoplasmic reticulum ^[5][11]. In addition, the mechanisms of cardiotoxicity may also involve the accumulation of doxorubicinol, which is a metabolite of doxorubicin in cardiomyocytes and the circulating pro-inflammatory cytokines.

Cardiotoxicity caused by anthracyclines can be broadly classified into an acute or chronic one, with chronic toxicity being the most prevalent and important manifestation. Furthermore, acute cardiotoxicity can be divided into acute or subacute toxicity, and chronic cardiotoxicity can be classified into two kinds, early-onset and late-onset. However, it is crucial to emphasize that this progression represents a continuum and not just distinct phases, which provides a more comprehensive understanding of its pathophysiology. The initial injury inflicted upon myocardial cells, although often unrecognized, has been extensively documented. This injury diminishes the cardiac reserve and sets the stage for subsequent stressors that gradually lead to cardiac decompensation and varying degrees of dysfunction. Ultimately, this progressive and cumulative cardiac impairment may contribute to the delayed onset of CTRCD.

Acute cardiotoxicity is relatively rare and typically occurs within one week after a single injection of anthracyclines or a therapy course. It may manifest as abnormal instantaneous cardiac electrical activity, myocarditis, arrhythmias, pericarditis, elevated troponin, or acute HF ^[6][7][12,13]. ECG (electrocardiogram) changes were observed in 20% to 30% of patients; as well, arrhythmias, including supraventricular, ventricular, and borderline tachycardia, covered 0.7% of patients, while more severe arrhythmias, such as atrial fibrillation or atrial flutter, were less common ^[8][14]. In a retrospective study of 64 patients with early-stage breast cancer, the results suggested that in all three groups, the incidence of ECG abnormalities peaked during the acute toxic reaction (within one week after the completion of chemotherapy), and the cardiac troponin T (cTnT) level within one week after chemotherapy was higher than that of various time points one year after chemotherapy (p < 0.05) ^[9][15].

Early-onset chronic progressive cardiotoxicity refers to cardiotoxicity that is detected within twelve months after the completion of chemotherapy and may continue to progress after the cessation of chemotherapy. The late-onset one occurs within decades after chemotherapy with an insidious onset. Once there comes initial acute myocardial injury, the ventricular function decreases significantly, which is usually irreversible and may manifest as arrhythmias, cardiomyopathy, and HF. Regarding adjuvant chemotherapy for breast carcinoma, the incidence of CHF after anthracycline treatment typically ranges from 0% to 1.6%, reaching up to 2.1% among patients treated with doxorubicin alongside sequential paclitaxel ^[10][16]. Hershman et al. ^[11][17] studied the cardiotoxicity of doxorubicin in elderly lymphoma patients (age, >65 years) and analyzed the association between doxorubicin and CHF by establishing Cox proportional hazards models. It was proven that the application of doxorubicin may increase the risk of developing CHF by 29%. Interestingly, among patients using doxorubicin therapy, 74% of survivors did not suffer from CHF, while the proportion of patients without doxorubicin was 79% over a span of eight years.

Risk factors associated with anthracyclines can be divided into two categories: patient-related risk factors and treatment-related risk factors ^[12][18]. Patient-related risk factors include almost any risk factor for heart damage, such as pre-existing cardiovascular disease, family history of cardiovascular disease, age (<5 or >65 years), female gender, and certain lifestyles (e.g., smoking, excessive alcohol consumption). Treatment-related risk factors included the cumulative dose of anthracyclines, which is considered the most important among all risk factors, combination with other treatments (e.g., trastuzumab, chest or mediastinal radiotherapy, and cyclophosphamide), and rapid administration of anthracyclines ^[13][19]. Cancer survivors who are at risk should undergo regular screening for traditional cardiovascular risk factors. The healthcare provider should determine the frequency of surveillance.

Radiation therapy can generate cardiotoxicity or the radiation-induced heart disease (RIHD) potentially caused by radiation disruption of endothelial barrier integrity, which induces a series of reactions such as oxidative stress, upregulation of inflammatory/pro-fibrotic factors, collagen deposition, proliferation of cardiomyocytes, myofibroblasts, and endothelial cells. Ultimately, it results in increased intima–media thickness, arterial wall lesions, and accelerated atherosclerosis ^[14][20]. In addition, radiation induces a decrease in microvascular density ^[15][21], which also leads to myocardial ischemia and oxidative stress, and, ultimately, cell death. Damaged and dead cardiomyocytes are swept up by macrophages as well as substituted by amyloid and fibrin, then calcification or scarring occurs. Some animal experiments show that radiation may affect mitochondrial function through the Nrf2 pathway, and the increase in mast cell number may play a protective role in RIHD ^[16][22]. These changes eventually lead to myocardial ischemia, HF, arrhythmia, abnormal movement of the heart wall, and in some cases, pericarditis and valvular disease ^[17][18][23,24].

Radiotherapy is a crucial therapy for breast cancer. Darby et al. ^[19][25] suggested that radiotherapy increased the risk of primary adverse coronary events in breast cancer patients, with nearly half of the raising occurring within 10 years after treatment and lasting up to 30 years after treatment. When the mean heart dose (MHD) was 4.9 Gy (range from 0.03 to 27.72), the risk of coronary events was proportional to the MHD, and the risk climbed by 7.4% per Gy on average. A study further validated and refined the prediction model, finding that the cumulative incidence of major coronary events increased by 16.5% (95% CI, 0.6 to 35.0) per Gy of MHD over nine years after treatment ^[20][26]. Nevertheless, this linear relationship between the incidence of heart disease and MHD does not always appear to be consistent, and it is reasonable to consider that specific cardiac substructural doses better reflect the correlation between radiation and cardiotoxicity. In addition, the increase in MHD may be the result of an increase in the mean substructural dose; for example, the right ventricular dose has close-knit links with MHD ^[21][27], the incidence of cardiac adverse diseases was higher when the mean left anterior descending vessel dose exceeded 2.8 Gy ^[22][28].

Similar to breast cancer, patients with Hodgkin’s lymphoma (HL) exhibit cardiotoxicity after radiotherapy. Van Nimwegen et al. ^[23][29] were the first to demonstrate a linear relationship between MHD and the risk of coronary events in HL survivors, with an increase of 1 Gy in MHD related to a 7.4% growth in overall risk of coronary heart disease (95% CI, 3.3% to 14.8%). A follow-up study of pediatric Hodgkin’s disease survivors who underwent mediastinal radiotherapy revealed that symptomatic/asymptomatic heart disease occurred in 50 of 1132 patients (4.42%) after treatment, with valve defects being the most common cardiotoxic manifestation (33/1132), followed by coronary artery disease (14/1132), cardiomyopathy (14/1132), conduction disorders (10/1132), and pericardial abnormalities (8/1132) ^[24][30]. The study also suggested that the utilization of lower doses of radiation therapy could decrease the incidence of heart disease.

Radiotherapy is also an important approach for patients suffering from non-small-cell lung cancer (NSCLC). Researchers have suggested that the incidence of grade ≥ 3 cardiac events in patients with locally advanced NSCLC exceeded 10% within two years after receiving radiotherapy ^[25][31]. Atkins et al. ^[26][32] conducted a retrospective study involving 748 patients with locally advanced NSCLC that indicated that the cumulative incidence of major adverse cardiovascular events (MACE) was 5.8% and the all-cause mortality was as high as 71.3% within two follow-up years, and the risk of MACE was closely related to MHD. In another retrospective analysis containing 701 individuals diagnosed with locally advanced NSCLC, MHD exceeding 7 Gy was related to an increased one-year incidence of MACE (4.8% vs. 0%) and two-year all-cause mortality (53.2% vs. 40.0%) ^[27][33]. Remarkably, the prevalence of cardiac complications in lung cancer patients was approximately 25% to 30%, hinting that a significant proportion of patients with lung cancer may be more likely to develop MACE after radiotherapy due to pre-existing cardiovascular risk factors or heart disease history when considering RIHD ^[28][34].

Large cohort studies have shown that the incidence of symptomatic RIHD is low within the initial ten years after radiation therapy, but exhibits a notable increase thereafter. One possible recommendation entails that screening for RIHD should be conducted every five years or in the presence of symptoms, irrespective of the duration of radiotherapy. Early detection of subclinical RIHD and timely initiation of therapy may improve the long-term prognosis of cancer survivors at risk for cardiac events. Therefore, screening tests may be performed more frequently (every two or three years) after ten years from radiotherapy and annually for patients at a high risk of disease progression, such as those with coronary calcification, initial valve disease, and risk of coronary artery disease ^[29][35].

Trastuzumab, a humanized anti-ERBB2 (epidermal growth factor receptor 2) monoclonal antibody (mAb), is commonly used to treat breast cancer in clinical settings by using alone or with other drugs, such as anthracycline and paclitaxel. Trastuzumab can effectively prolong the survival of patients with advanced breast cancer who are HER-2 (human epidermal growth factor receptor-2)-positive. Initially, it was believed that cardiotoxicity caused by mAbs was similar to the anthracyclines, but it was later generally classified as a Type II agent. Recent studies have suggested that, when used in combination with anthracyclines, trastuzumab contributes to and exacerbates cardiotoxicity caused by anthracyclines by affecting various cellular mechanisms related to myocardial survival and repair ^[30][36].

Currently, trastuzumab appears to have two possible mechanisms to induce cardiotoxicity. ERBB2 is vital for cardiomyocyte proliferation and function and also acts as a coenzyme of ERBB4 and NRG1, and the combination of the latter two will promote ERBB4/ERBB2 heterodimerization together with activation of ERK-MAPK and PI3K-Akt pathways, which can foster proliferation and contraction of cardiomyocytes ^[31][37]. Trastuzumab affects the growth, development, survival, and normal function of cardiomyocytes by inhibiting the assembly of key complexes involved in this process, and can also reduce the capacity of cardiomyocytes to react to stress events, leading to cardiotoxicity. Notably, anti-ERBB2 drugs are not equally cardiotoxic, such as lapatinib, which blocks epidermal growth factor receptor (EGFR), and may cause less cardiotoxic effects than trastuzumab ^[32][38]. Furthermore, trastuzumab also upregulates the ratio of pro-apoptotic proteins BCL-XS, disrupts the integrity of mitochondrial membranes, and activates apoptosis pathways ^[33][39].

The cardiotoxicity of trastuzumab can manifest as HF, cardiomyopathy, and asymptomatic decreased LVEF. Trastuzumab can even lead to severe cardiac insufficiency or death. Previous clinical trials demonstrated a significantly higher incidence of cardiotoxicity including an asymptomatic reduction in ejection fraction or significant cardiac insufficiency within three years in early-stage HER-2-positive breast cancer patients receiving chemotherapy combined with trastuzumab, compared with chemotherapy alone ^[34][40]. Furthermore, the incidence of NYHA class III or IV was nearly 4% in patients receiving chemotherapy combined with trastuzumab, whereas the proportion of NYHA class III or IV heart failure in patients receiving chemotherapy alone was close to 0%. However, subsequent studies have observed a significantly higher incidence of cardiotoxicity from trastuzumab treatment compared to previous clinical trials, possibly due to different definitions of cardiotoxic disease and the fact that clinical trials tended to involve more young women.

A study of 45,537 older patients with early breast cancer found that the incidence of HF or cardiomyopathy was 26.7% in patients receiving trastuzumab alone versus 28.2% in patients receiving a combination of anthracycline and trastuzumab, and individuals treated with anthracycline alone had the lowest incidence at 15.3% ^[35][41]. The report is noteworthy for highlighting the percentage of HF or cardiomyopathy development in otherwise healthy women. Another retrospective study, which included data from 12,500 breast cancer patients, suggested that within five years of treatment, the incidence of HF or cardiomyopathy was approximately 4.3% in patients administered anthracycline alone, 12.1% in patients receiving trastuzumab alone, and 20.1% in patients receiving anthracycline combined with trastuzumab ^[36][42]. Furthermore, cardiac toxicity was also shown to be more obvious in patients receiving trastuzumab and paclitaxel than those using paclitaxel alone ^[37][43].

Pertuzumab, another mAb targeting HER-2, also induces cardiotoxicity. Other HER2-targeted agents, such as pertuzumab, lapatinib, trastuzumab emtansine (T-DM1), and neratinib, have been shown to have lower levels of cardiotoxicity compared to trastuzumab ^[38][44]. Pertuzumab is often used with trastuzumab in neoadjuvant therapy, adjuvant therapy, and metastatic therapy. A systematic review and meta-analysis pooling data from several studies showed no significant difference in the risk of asymptomatic/mild left ventricular systolic dysfunction between the pertuzumab and placebo groups when combined with trastuzumab, chemotherapy, or T-DM1, respectively ^[39][45]. Some studies have also indicated that pertuzumab has little additional cardiac risk for trastuzumab ^[38][44]. Approximately 0.2% of lapatinib-treated patients experienced Grade III/IV systolic dysfunction as well as asymptomatic cardiac events that occurred in 1.4%. At present, there is insufficient evidence to finalize the cardiotoxicity of neratinib and T-DM1 ^[40][46]. The incidence of cardiac adverse events did not appear to change in patients who had previously received trastuzumab, regardless of the addition of these new targeted agents ^[41][47].

The most important risk factors for cardiotoxicity from HER2-targeted drugs are likely to be prior exposure to anthracyclines. Additional risk factors may include age, pre-existing cardiovascular risk factors, smoking, and obesity. Furthermore, trastuzumab cardiotoxicity appears to be independent of accumulated dose, which is distinct from anthracyclines ^[38][44]. Banke et al. ^[42][48] found that in nearly 10,000 patients with a median 5.4 follow-up years, trastuzumab was linked to a twofold higher risk of late HF in comparison to chemotherapy alone, despite the low absolute risk. The SAFE-HEaRt study’s long-term follow-up offers valuable and ongoing safety information regarding the use of HER2-targeted therapy in patients with compromised heart function, despite the rarity of late development of cardiac dysfunction ^[43][49].