In recent decades, there have been noteworthy advancements in chemotherapy, immunotherapy and targeted treatments, resulting in improved efficacy, tolerance and subsequently improved survival rates ^[1][2][3][1,2,3]. To maintain disease remission, it may be necessary to administer multiple cycles of treatment over an extended period, whilst additional lines of treatment are available, if required.

Despite these advancements, the potential for cardiotoxic effects persists. This issue becomes more significant in the presence of shared risk factors between oncologic and cardiovascular disease (CVD), such as smoking and a lack of exercise [3]. Patients with pre-existing CVD who undergo chemotherapy may be more susceptible to cardiotoxicity, consequently increasing morbidity and mortality risk within these populations [3]. It is important to note that despite revolutionizing modern oncology, even immunotherapy is not exempt from potential cardiac adverse events [4].

2. Left Ventricular Dysfunction

Left ventricular ejection fraction (LVEF) decline and heart failure (HF) are common causes of premature interruption or discontinuation of sequential anthracycline chemotherapy ^[5][10]. Studies have reported that cardiac dysfunction can be exacerbated by the addition of trastuzumab, a human epidermal growth factor 2 (HER-2) monoclonal antibody, to existing anthracycline therapy ^[6][7][11,12]. Treatment-induced HF can be classified into two main categories: symptomatic and asymptomatic. Each category can be further classified based on the degree of symptom severity and LVEF. The LVEF values used for classification are as follows: LVEF ≤ 40% indicates HF with reduced ejection fraction (HFrEF), LVEF 41–49% indicates HF with mid-range ejection fraction (HFmrEF), and LVEF ≥ 50% indicates HF with preserved ejection fraction (HFpEF) ^[8][13]. Both the British Society of Echocardiography (BSE) and the British Society of Cardio-Oncology (BCOS) define cardiotoxicity as a decrease in LVEF by more than 10%, resulting in an LVEF value below 50% ^[9][14]. Additionally, the European Society of Medical Oncology (ESMO) interprets cardiotoxicity as a decline in LVEF exceeding 20% ^[10][15]. Moreover, probable subclinical cardiotoxicity can be characterized by an LVEF decline of more than 10%, resulting in a value above 50%, accompanied by a decrease in global longitudinal strain (GLS) exceeding 15% ^[11][16]. Possible subclinical cardiotoxicity, on the other hand, can be defined as an LVEF decline of less than 10%, leading to a value below 50%. Furthermore, an isolated reduction in GLS of more than 15% from baseline is also considered possible subclinical cardiotoxicity. In addition, brain natriuretic peptide (BNP) levels ≥ 35 pg/mL, NT-proBNP levels ≥ 125 pg/mL, or a significant increase from baseline can also serve as indicators of HF ^[12][17]. Anthracycline agents such as doxorubicin, have been widely used in chemotherapy regimens for almost five decades ^[13][18]. Doxorubicin inhibits the proliferation of cancer cells by interfering with the structure of their DNA, effectively impeding tumorigenesis and halting cancer cell division ^[14][19]. Anthracycline-induced cardiotoxicity is a well-known phenomenon that exhibits a dose-dependent relationship, culpable of irreversible HF with higher cumulative doses ^[15][16][20,21]. The estimated incidence rates are approximately 2% at a dose of 200 mg/m², 5% at 400 mg/m², 16% at 500 mg/m², and 26% at 550 mg/m^{2 [17]}[22]. HER-2, encoded by proto-oncogene ErbB2 (chromosome 17q21-22), is a transmembrane protein with a molecular weight of 185 kDa ^[18][23]. Crucially, HER-2 regulates cell growth and epithelial cell survival, although overexpression and amplification of the HER-2 oncogene is typically observed in aggressive metastatic breast cancer, as well as other malignancies, such as ovarian, bladder, lung and head and neck ^[18][23]. Trastuzumab is a humanized monoclonal antibody that targets the HER-2 tyrosine kinase receptor ^[19][24]. LVEF is reduced by approximately 7%, but it can increase to 13% when trastuzumab is administered concurrently with paclitaxel, and up to 27% with concurrent anthracyclines ^[6][11]. Trastuzumab-related cardiac dysfunction is generally classified as “type II cardiotoxicity”, which is not dose-dependent and can be reversed upon discontinuation of the drug, often without significant ultrastructural changes ^[20][25]. Neuregulin (NRG) is an important stress-mediated paracrine growth factor that signals through the ErbB2 receptors to ensure cardioprotection ^[21][26]. However, trastuzumab promotes the inhibition of the NRG-1/ErbB2 signalling pathway within the heart, leading to apoptosis, oxidative stress, and T-tubule dilation, ultimately resulting in dilated cardiomyopathy ^[22][27]. Pertuzumab is another monoclonal antibody that inhibits the dimerization of HER2 receptors, which is an essential step required for cell growth and survival in several tumour types ^[23][28]. A pooled analysis of 569 patients treated with pertuzumab across different disease subsets revealed that 5.7% of patients experienced a decrease in LVEF, and 0.7% developed symptomatic congestive heart failure (CHF) ^[23][28]. In a phase II study evaluating the safety and efficacy of combined trastuzumab-pertuzumab treatment in 66 patients previously exposed to trastuzumab, asymptomatic LVEF reduction was observed in three patients, whilst no cases of CHF were reported ^[24][29]. Lapatinib is an oral small molecule that inhibits the tyrosine kinases of HER-2 and epidermal growth factor receptor type 1 (HER-1) ^[25][30]. Clinical studies did not report significant cardiotoxicity with the use of lapatinib (reference). A review of 44 clinical studies involving 3689 patients receiving lapatinib revealed a 0.2% rate of symptomatic CHF and a 1.4% rate of asymptomatic cardiac events ^[26][31]. Cardiac toxicity is typically asymptomatic and largely reversible, suggesting cellular dysfunction rather than myocyte damage ^[26][31]. Bcr-Abl inhibitors such as imatinib act by inactivating the Bcr-Abl fusion protein, which arises from a reciprocal chromosomal translocation between chromosome 9 and 22, known as t(9,22), resulting in the formation of the Philadelphia chromosome (Ph+) ^[27][32]. This fusion protein exhibits deregulated tyrosine kinase activity, leading to uncontrolled proliferation of myeloid precursors ^[27][32]. Imatinib was the first selective Bcr-Abl tyrosine kinase inhibitor (TKI) to be approved for chronic myelogenous leukaemia (CML) ^[28][33]. To overcome mutations and resistance, several second-generation TKIs have been developed and approved for clinical use, including nilotinib and dasatinib as first- or second-line treatments, and bosutinib as a second-line option ^[29][34]. Imatinib has been reported to induce cardiomyocyte death through the endoplasmic reticulum stress response, wherein the accumulation of misfolded proteins triggers apoptosis mediated by the c-Jun N-terminal kinase (JNK) pathway ^[30][31][35,36]. Studies monitoring imatinib cardiotoxicity suggest a very low incidence of HF, ranging between 0.2% and 1.7% ^[32][37]. However, the risk of HF has been reported to be higher in those with a history of heart disease, particularly CHF, hypertension, coronary artery disease, and cardiomyopathy ^[32][37]. In randomized controlled trials of patients with diagnosed chronic phase Ph+ CML, nilotinib has demonstrated better efficacy than imatinib, supporting nilotinib as a first line treatment option at either 300 mg or 400 mg twice daily ^[33][34][38,39]. Moreover, bortezomib is a proteasome inhibitor used in the treatment of multiple myeloma and mantle cell lymphoma ^[35][40]. By preventing targeted proteolysis, multiple signalling cascades are disrupted, ultimately causing apoptosis ^[35][40]. Acute development or exacerbation of CHF and new onset of decreased LVEF have been reported during bortezomib therapy, including in patients with no pre-existing risk factors ^[36][41]. Finally, bevacizumab acts by selectively binding circulating vascular endothelial growth factor (VEGF), inhibiting its binding to cell-surface receptors ^[37][42]. This inhibition restricts microvascular growth of tumour blood vessels, leading to a limitation in blood supply to tumour tissues ^[37][42]. These effects also reduce tissue interstitial pressure, increase vascular permeability, thus potentially enhancing the delivery of chemotherapeutic agents ^[37][42]. Although hypertension is a common side effect of bevacizumab, a reduction in LVEF has also been observed during long-term use ^[37][42].

3. QT Interval Prolongation

Several factors may contribute to QT interval prolongation. This includes commonly used medications in cancer patients such as chemotherapeutic agents (particularly TKI and arsenic trioxide therapies), antiemetics and antifungals ^[38][43]. Electrolyte abnormalities and myocardial ischemia are examples of other contributory factors that may prolong the QT interval ^[38][39][43,44]. It is important to note that QT prolongation can increase the risk of potentially life-threatening arrhythmias, such as torsades de pointes (TdP) ^[39][44]. Multitargeted TKIs have been associated with varying degrees of QT prolongation. Sunitinib, for example, has been shown to cause dose-dependent QT prolongation ^[40][45]. TdP, a polymorphic ventricular tachyarrhythmia, has been observed in less than 0.1% of patients receiving sunitinib ^[41][46]. Nilotinib is also known to prolong QTc interval, and there have been five reported cases of sudden cardiac death out of 867 patients treated in initial trials, leading to a warning on the United States Food and Drug Administration (US FDA) labelling ^[40][42][45,47]. The overall proportion of QTc prolongation of any grade with nilotinib was 2.7%, with a QTc interval greater than 500 ms observed in 0.3% of cases ^[43][48]. In the case of dasatinib, QT prolongation has been reported in <1% to 3% of patients, but the occurrence of a QTc interval greater than 500 ms was <1% ^[43][48]. Vandetanib is an orally administered selective inhibitor of VEGF receptor (VEGFR), epidermal growth factor receptor (EGFR), and RET tyrosine kinases ^[43][48]. A comprehensive meta-analysis of nine trials involving 2188 patients revealed that the overall incidence of all-grade and high-grade QTc interval prolongation with vandetanib at a dose of 300 mg/day was 16.4% (95% CI, 8.1–30.4%) and 3.7% (95% CI, 1.7–7.8%), respectively, among patients with non-thyroid cancer ^[43][48]. Among patients with thyroid cancer, the incidence was 18.0% (95% CI, 10.7–28.6%) for all-grade QTc interval prolongation and 12.0% (95% CI, 4.5–28.0%) for high-grade QTc interval prolongation ^[43][48]. Enzastaurin is a protein kinase C inhibitor that exerts its effects by suppressing the PI3K/Akt pathway, resulting in anti-angiogenic effects, inhibition of tumour growth, and induction of tumour cell death ^[44][49]. In a phase I trial involving 47 patients, three individuals experienced asymptomatic grade 3 QTc prolongation ^[41][46]. Additionally, in a combination phase I trial of enzastaurin with gemcitabine, one patient exhibited grade 2 QTc interval prolongation ^[45][50]. Vorinostat is a histone deacetylase inhibitor prescribed for the management of recurrent or persistent cases of cutaneous T-cell lymphoma ^[46][51]. A retrospective review of 116 patients participating in phase I and II clinical trials, who underwent baseline and follow-up ECGs, indicated that four patients experienced Grade 2 QTc interval prolongation, while one patient had Grade 3 prolongation. Notably, no cases of TdP were reported among patients treated with vorinostat ^[47][52]. Vemurafenib, a B-raf inhibitor, is prescribed for the treatment of patients with unresectable or metastatic melanoma carrying the V600E mutation of the B-raf protein ^[48][53]. A multicentre, open-label, single-arm study involving 132 patients with B-Raf V600E mutation-positive metastatic melanoma assessed the effects of twice-daily administration of vemurafenib at a dose of 960 mg on the QTc interval ^[49][54]. Pazopanib is an oral TKI that targets VEGFR-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR), stem cell factor (SCF) and stem cell factor receptor (c-Kit) ^[50][55]. It is approved as a first-line treatment for advanced renal cell carcinoma ^[51][56]. Clinical studies investigating pazopanib have reported instances of QT interval prolongation and TdP arrhythmia, although this is considered very low risk (<1%) by a systematic review from Porta-Sanchez et al. ^[42][47].

4. Myocardial Ischemia

The fluoropyrimidines, 5-fluorouracil (5FU) and its oral prodrug capecitabine are frequently utilized in the treatment of gastrointestinal malignancies ^[52][57]. One well-documented complication associated with fluoropyrimidine therapy is coronary vasospasm, leading to myocardial ischemia (MI) and angina ^[52][53][57,58]. The reported incidence of cardiotoxicity with 5FU in the literature varies widely, ranging from 1% to 68% ^[53][58]. The toxicity appears to be influenced by both the dose and rate of administration, with higher doses (>800 mg/m²) and continuous infusion regimens being associated with elevated rates of toxicity ^[54][59]. The primary cardiotoxicity associated with taxanes is bradycardia, although ischemia has also been reported ^[55][60]. The incidence of cardiotoxicity with paclitaxel is reported to range between 0.5% and 5%, whilst with docetaxel, it is approximately 1.7% ^[41][46]. The exact mechanism underlying this cardiotoxicity is not well-defined ^[41][46]. A pooled analysis of 1745 patients enrolled in five randomized controlled trials involving colorectal, non-small cell lung cancer and metastatic breast cancer reported an incidence of angina and MI of 1.5% in the bevacizumab group ^[56][61]. In another meta-analysis investigating a total of 4617 patients from seven randomized controlled trials, the summary incidence of ischemic heart disease in patients receiving bevacizumab was 1.0% (95% CI, 0.6–1.4%) ^[57][62]. The analysis also revealed that patients treated with bevacizumab had a significantly increased risk of ischemic heart disease with a relative risk (RR) of 2.49 (95% CI, 1.37–4.52) compared to the control arm ^[57][62]. Sorafenib is a multi-targeted inhibitor that acts on tyrosine kinase receptors, including c-Kit, Flt-3, PDGFR-b, VEGFR-2 and VEGFR-3, as well as serine/threonine kinases B-Raf and Raf-1 ^[58][63]. It is approved for the treatment of advanced renal cell carcinoma, refractory differentiated thyroid carcinoma, and hepatocellular carcinoma ^[59][64]. According to an independent review from the FDA, there is a higher incidence of cardiac ischemia observed in patients treated with sorafenib compared to the placebo group (2.9% vs. 0.4%) ^[60][65]. For renal cell carcinoma specifically, MI or ischemia were more prevalent than in the control group (3% vs. <1%) ^[60][65].

5. Hypertension

Systemic anti-cancer treatment has been identified as a potential cause of secondary hypertension, and the use of bevacizumab, as mentioned previously, is often associated with an increased incidence or worsening of existing arterial hypertension ^[37][42]. The leading hypothesis for the mechanism of bevacizumab-induced hypertension is the inhibition of VEGF-mediated vasodilation, resulting in increased vascular tone ^[61][66]. Other proposed mechanisms include a reduction in capillary density, leading to elevated systemic vascular resistance and pressure in larger vessels, as well as alterations in renal function due to the role of VEGF in maintaining normal glomerular structure and filtration in kidney endothelial cells and podocytes ^[61][66]. In a comprehensive meta-analysis comprising 12,656 patients with various types of tumours across 20 studies, the incidence of all-grade hypertension in patients receiving bevacizumab was found to be 23.6%, with 7.9% classified as high-grade (grade 3 or 4) ^[62][67]. Notably, patients treated with bevacizumab were at a significantly increased risk of developing high-grade hypertension, with a RR of 5.28 compared to controls ^[62][67]. Multitargeted TKIs such as sunitinib, sorafenib, and pazopanib exert their anti-angiogenic effects by inhibiting the catalytic binding site on VEGFR2, and as a result, they are also known to induce hypertension through similar mechanisms ^[63][68]. In a comprehensive systematic review and meta-analysis encompassing 4999 patients with renal cell carcinoma and other malignancies from 13 clinical trials, the incidence of all-grade and high-grade hypertension among patients receiving sunitinib was found to be 21.6% and 6.8%, respectively ^[64][69]. Additionally, sunitinib treatment was significantly associated with a higher risk of high-grade hypertension and renal dysfunction compared to the control arm ^[64][69]. Similar findings were observed for sorafenib in another extensive systematic review and meta-analysis that included 4599 patients with renal cell carcinoma or other solid tumours ^[65][70]. Among these patients, the overall incidence of all-grade and high-grade hypertension was 23.4% (95% CI 16.0–32.9%) and 5.7% (2.5–12.6%), respectively ^[65][70]. Sorafenib treatment was significantly associated with an increased risk of all-grade hypertension in cancer patients, with a RR of 6.11 compared to controls ^[65][70]. Finally, in a small study of 35 patients, pazopanib-induced hypertension was observed in 57% of the participants ^[66][71].

6. Thromboembolic Disease

In comparison to chemotherapy alone, the combination of bevacizumab and chemotherapy has been found to carry an increased risk of arterial thromboembolism (ATE), while the risk of venous thromboembolism (VTE) remains unaffected ^[67][72]. It is believed that bevacizumab may increase the risk of arterial thrombotic events by interfering with the regeneration process of endothelial cells following incidental trauma during anti-VEGF treatment ^[68][73]. The incidence of ATE was 5.5 events per 100 person-years among those receiving combination therapy, compared to 3.1 events per 100 person-years in the chemotherapy alone group ^[67][72]. A retrospective pooled analysis of five randomized trials further confirmed the association between bevacizumab use and arterial thromboembolic events, with a higher incidence of 3.8% compared to 1.7% in patients receiving chemotherapy alone ^[67][72]. Age ≥65 and a prior history of ATE were identified as risk factors associated with the occurrence of ATE in patients treated with bevacizumab ^[69][74]. Furthermore, several VEGFR-TKIs have been found to be associated with an increased risk of thromboembolic disease ^[70][75]. A comprehensive meta-analysis, including 24,855 patients from 48 studies, revealed an overall incidence of 3.6% for all-grade VTE and 1.6% for high-grade VTE in association with VEGFR-TKIs ^[68][73]. However, the use of VEGFR-TKIs did not significantly increase the risk of developing VTE ^[68][73]. Regarding arterial thromboembolic events, the overall incidence of all-grade ATE was 2.7%, and high-grade ATE was 0.6% among patients receiving VEGFR-TKIs ^[68][73]. The use of VEGFR-TKIs was found to significantly increase the risk of developing all-grade arterial thromboembolic events, with a tendency to also increase the risk of high-grade ATE ^[68][73]. Therefore, patients with cancer who receive VEGFR-TKIs are at a higher risk of developing ATE ^[68][73]. Moreover, a systematic review and meta-analysis involving 10,255 patients from January 1966 to July 2009 reported the incidence of ATE associated with the use of sunitinib and sorafenib to be 1.4%, with the RR for ATE compared to control patients calculated as 3.03 ^[71][76]. Thalidomide and lenalidomide, immunomodulatory drugs that exhibit anti-angiogenic properties, have also demonstrated a high risk of VTE, particularly when combined with high-dose dexamethasone ^[72][77]. They are also associated with an increased risk of arterial events, leading to a concern of an elevated risk of MI and stroke ^[73][78].

7. Valvular Heart Disease

While chemotherapeutic agents do not directly impact cardiac valves, valvular heart disease (VHD) can occur in cancer patients due to various factors ^[74][79]. These include pre-existing valve lesions, radiotherapy (RT), infective endocarditis, and VHD secondary to left ventricular dysfunction (LVD) ^[74][75][79,80]. Among these, approximately 10% of patients will frequently experience RT-induced VHD, which is characterized by fibrosis and calcification, primarily affecting the aortic root, aortic valve cusps, mitral valve annulus, and the base and mid portions of the mitral valve leaflets ^[74][79]. Patients with Hodgkin lymphoma are particularly at risk, as higher radiation doses (>30 Gy) to the heart valves can significantly increase the likelihood of clinically significant VHD ^[76][81]. This represents a common cardiovascular complication following treatment.

8. Pericardial Disease

RT-induced pericarditis can manifest early, but studies have shown that the peak incidence occurs between 5 and 9 years post-RT in patients with breast cancer, with the risk and severity of pericarditis influenced by the radiation dose ^[77][78][82,83]. In a review, more than 50% of patients who received doses exceeding 30 Gy for various diseases, such as Hodgkin and non-Hodgkin lymphoma developed pericarditis ^[79][84]. In addition, studies have specifically investigated the correlation between the extent of RT to the heart and the development of RT-induced pericarditis, concluding that a larger proportion of the heart exceeding 30%, receiving a minimum dose of 50 Gy, increases the likelihood of pericarditis ^[80][85]. It is important to note that pericardial effusion can occur as a complication of pericarditis, but it can also be secondary to pericardial metastasis, which, although rare, could be the initial indication of an underlying malignancy ^[81][86]. Acutely following the administration of anthracyclines, myopericarditis can occur ^[16][82][21,87]. Furthermore, high-dose cyclophosphamides have been associated with acute cardiotoxicity, presenting as haemorrhagic myopericarditis ^[83][84][88,89]. In the context of treating acute promyelocytic leukaemia, the use of all-trans retinoic acid (ATRA) has also been reported to induce acute myopericarditis ^[85][90].

9. Cardiac Device Malfunction

A comprehensive retrospective study by Zagzoog et al. analysed data from 811 patients who underwent RT, and among them, device malfunctions were observed in 32 patients (4%) ^[86][91]. A notable association was found between higher beam energy (≥10 MV) and device malfunction (p < 0.0001) ^[86][91]. However, there was no significant difference in the dose of the RT between the group experiencing malfunctions and the group without ^[86][91].