Genetic factors in the pathogenesis of cardio-oncology

Abstract

In recent years, with advancements in medicine, the survival period of patients with tumours has significantly increased. The adverse effects of tumour treatment on patients, especially cardiac toxicity, have become increasingly prominent. In elderly patients with breast cancer, treatment-related cardiovascular toxicity has surpassed cancer itself as the leading cause of death. Moreover, in recent years, an increasing number of novel antitumour drugs, such as multitargeted agents, antibody‒drug conjugates (ADCs), and immunotherapies, have been applied in clinical practice. The cardiotoxicity induced by these drugs has become more pronounced, leading to a complex and diverse mechanism of cardiac damage. The risks of unintended cardiovascular toxicity are increased by high-dose anthracyclines, immunotherapies, and concurrent radiation, in addition to traditional cardiovascular risk factors such as smoking, hypertension, diabetes, hyperlipidaemia, and obesity. However, these factors do not fully explain why only a subset of individuals experience treatment-related cardiac toxicity, whereas others with similar clinical features do not. Recent studies indicate that genetics play a significant role in susceptibility to the development of cardiovascular toxicity from cancer therapies. These genes are involved in drug metabolism, oxidative damage, cardiac dysfunction, and other processes. Moreover, emerging evidence suggests that epigenetics also plays a role in drug-induced cardiovascular toxicity. We conducted a review focusing on breast cancer as an example to help oncologists and cardiologists better understand the mechanisms and effects of genetic factors on cardiac toxicity. In this review, we specifically address the relationship between genetic alterations and cardiac toxicity, including chemotherapy-related genetic changes, targeted therapy-related genetic changes, and immune therapy-related genetic changes. We also discuss the role of epigenetic factors in cardiac toxicity. We hope that this review will improve the risk stratification of patients and enable therapeutic interventions that mitigate these unintended adverse consequences of life-saving cancer treatments.

Introduction

In recent years, with advancements in tumour diagnosis and treatment, especially precision medicine guided by multiomics approaches and molecular targeted therapy, immunotherapy, and other treatments, the survival period of cancer patients has continuously increased. Many types of tumours gradually develop into chronic disease-like patterns after treatment [1]. With the increase in cancer patient survival, an array of adverse effects associated with anticancer treatments are becoming more pronounced. Among these factors, cardiac toxicity is a significant concern and is emerging as a leading cause of mortality in cancer patients. For example, in breast cancer patients older than 66 years, cardiovascular disease (CVD) (15.9%) has surpassed breast cancer-related events (15.1%) as the primary cause of death [2]. A meticulous evaluation of cardiovascular risk factors is imperative prior to the initiation of anticancer treatments for the prevention and early detection of cancer therapy-related cardiovascular toxicity (CTR-CVT). A comprehensive assessment, followed by the appropriate initiation of risk-reduction strategies, can significantly reduce the risk of developing cardiovascular complications. Various risk factors have been identified, including previous cardiotoxic therapy, previous cardiovascular disease, lifestyle risk factors, hypertension, and diabetes [3,4,5,6,7] (Fig. 1). The use of these risk factors allows for the stratification of patients, identifying those at high risk of CTR-CVT [6, 7]. However, currently, these parameters still have many limitations. Why some high-risk populations do not experience cardiac toxicity after receiving treatment with cardiotoxic drugs, whereas some low-risk populations still experience cardiac toxicity remain unclear. This difference may be due to the differential susceptibility of patients to cardiac injury, which may depend on the patient’s genotype. Moreover, this screening method has low specificity. The mechanisms of cardiac injury caused by chemotherapy, targeted therapy, and immunotherapy are different; hence, these parameters do not effectively identify populations at high risk of CTR-CVT. Therefore, more specific indicators are needed to stratify patients.

Genetic studies provide a novel approach to identify individuals susceptible to CTR-CVT. Genetic variations can impact cardiac susceptibility to drugs through various mechanisms. Some genetic alterations affect the transport of antitumour drugs in the body [8, 9], and others influence drug metabolism [10,11,12]. Certain genetic variations can induce cardiac injury through the generation of reactive oxygen species (ROS) [13], and others can affect the immune system, leading to immune-related cardiac damage [14]. Genetic screening based on patient genotypes provides a more specific method for identifying potential cardiac injury patients. Recently, some studies have identified genetic changes associated with cardiac toxicity induced by anthracycline-based chemotherapy drugs. Recently, studies have also explored gene variations related to cardiac toxicity induced by targeted therapy and immunotherapy. We conducted this review to summarize the advancements in this field and to assist oncologists and cardiologists in gaining a comprehensive understanding of this field, thereby enabling the implementation of preventive and intervention measures to prevent and treat CTR-CVT. In this study, we review the relationships between genetic variations and CTR-CVT, elucidating the associations between genetic variations and chemotherapy-related cardiac injury. We also review the relationships between genetic variations and targeted therapy-related cardiac injury, between genetic variations and immune-related cardiac injury, and between other types of genetic alterations and cardiac injury. We hope to provide several valuable insights for the prediction, early diagnosis, and management of CTR-CVT.

Fig. 1

Baseline cardiovascular toxicity risk assessment checklist. (a) Gene variants are discussed in this manuscript. (b) Cardiomyopathy, Cancer therapy-related cardiac dysfunction, Percutaneous coronary intervention or coronary artery bypass graft, Stable angina, Abnormal ankle-brachial pressure index, Pulmonary hypertension, Arterial thrombosis with TKI, Venous thrombosis, QTc ≥ 480 ms, Prior proteasome inhibitors CV toxicity, Prior ICI-related CV toxicity. ECG: Electrocardiogram; TTE: Transthoracic echocardiography; cTn: Cardiac troponin; BNP: B-type natriuretic peptide; NT-proBNP: N-terminal pro-BNP; TKI: Tyrosine kinase inhibitors; CV: Cardiovascular; ICI: Immune checkpoint inhibitor

Gene variants associated with cardiotoxicity

Gene variants associated with cardiac injury induced by chemotherapy

Gene variants related to drug transport

Variations in drug transport genes are among the factors contributing to treatment-related cardiac toxicity. Adenosine triphosphate-binding cassette (ABC) transporter proteins play active roles in transporting multiple drugs, including anthracyclines, across cellular membranes [15, 16]. In humans, multiple ABC genes encode transmembrane proteins involved in the transport of a wide range of drug substrates. Within the myocardium, ABC transporters facilitate the export of various chemotherapeutic agents from cardiac cells. Notably, at least 8 different variants in 5 different ABC genes, including ABCC1, ABCC2, ABCC5, ABCB1 and ABCB4, have been identified in association with anthracycline-induced cardiomyopathy (AIC) [17,18,19,20]. In many instances, variants in these ABC genes can lead to defects in drug export, resulting in the accumulation of anthracycline within cardiomyocytes and increasing the risk of cardiac dysfunction and AIC. Conversely, a genetic variant in ABCB1 (rs1045642) appears to confer cardioprotective effects [21]. Given that this gene encodes an efflux transporter, a plausible explanation for its protective effect is that the single nucleotide polymorphisms (SNP) increases drug clearance within cardiomyocytes.

Genetic variations within the soluble carrier (SLC) transporter gene family also exert a protective effect on AIC. The SLC superfamily genes encode transporter proteins that play crucial roles in facilitating the absorption and transportation of various molecules such as amino acids, ions, metals, and fatty acids across cellular membranes. Anthracycline drugs are well-known substrates of SLC transporters, which facilitate their excretion and renal clearance. The identified genetic variants, including rs4982753 in the SLC22A17 gene, rs4149178 in the SLC22A7 gene, rs487784 in the SLC28A3 gene, rs7853758 in the SLC28A3 gene and rs9514091 in the SLC10A2 gene, are associated with potential protective effects on AIC [18, 22,23,24].

Gene variants related to drug metabolism

GSTM1

Tumour patients often present with metabolic disorders such as disrupted fatty acid metabolism and glycolysis, and most antitumour drugs can induce or exacerbate metabolic disturbances. In a rat model of anthracycline-induced heart failure, the occurrence of heart failure was mainly associated with metabolic disturbances, including disturbances in fatty acid metabolism, glycolysis, the tricarboxylic acid cycle, glycerophospholipid metabolism, and glutathione metabolism [25]. These metabolic disturbances affect myocardial energy metabolism, oxidative stress, and myocardial contraction.

The metabolic pathways of taurine in the heart and skeletal muscles are affected by myocardial toxicity induced by tyrosine kinase inhibitors, leading to a significant decrease in taurine abundance. Taurine has shown to regulate oxidative stress, protein stability, and stress responses [26].

These studies indicate that metabolic disturbances play a crucial role in the occurrence of drug-induced cardiac injury, with metabolism-related genes serving as major regulatory factors. Several metabolism-related genes have been confirmed to be associated with cardiac injury.

UDP-glucuronosyltransferases (UGTs) catalyse the glucuronidation of endogenous and exogenous compounds, increasing their water solubility to facilitate elimination [22]. UGT1A6 encodes the UGT family 1 member A6, which converts lipophilic anthracene derivatives into water-soluble and excretable metabolites [22, 27]. Therefore, the UGT1A6 protein plays a crucial role in the clearance of anthracene derivatives. The UGT1A6 rs17863783 variant is associated with AIC [22, 28]. Glutathione S-transferases (GSTs) are a crucial group of phase II metabolic enzymes involved in biotransformation in the human body. GSTs are expressed in nearly all cells and tissues, and their main function is to catalyse the reaction between various electrophilic carcinogens and glutathione, increasing their water solubility for excretion and thereby exerting detoxification effects [29]. GSTM1 encodes glutathione S-transferase M1, which catalyses the detoxification of many carcinogens and drugs, including anthracene derivatives [29]. The GSTM1 protein also scavenges free radicals, reducing the oxidative damage caused by toxic compounds such as anthracene derivatives. Therefore, any genetic variation affecting GSTM1 enzyme expression levels and/or function increases the risk of anthracene-induced cardiotoxicity.

The association between GSTM1 gene deletion (GSTM1 null genotype) and anthracycline-related cardiomyopathy was explored in cancer patients. A gene analysis was conducted for 75 patients with clinically confirmed cardiomyopathy and 92 matched control individuals without cardiomyopathy [12]. These results suggested a significant association between a GSTM1 gene deletion and cardiomyopathy occurrence. After adjusting for factors such as sex, age at cancer diagnosis, chest radiation therapy, and anthracycline dosage, the conditional logistic regression analysis still revealed a significant relationship between a GSTM1 gene deletion and the cardiomyopathy risk.

Researchers further examined peripheral blood GSTM1 gene expression in 20 cardiomyopathy patients and 20 control individuals [12]. Concurrently, the expression of the GSTM1 gene was assessed in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients (3 with cardiomyopathy and 3 without cardiomyopathy). The results indicated that GSTM1 expression in the peripheral blood was significantly lower in cardiomyopathy patients than in control individuals (mean relative expression 0.67 ± 0.57 vs. 1.33 ± 1.33, p = 0.049). Additionally, GSTM1 expression levels were significantly reduced in hiPSC-CMs derived from cardiomyopathy patients (p = 0.007). This study confirmed the close association between GSTM1 gene deletions and anthracycline-related cardiomyopathy.

CRB3

The CRB3 gene regulates another drug-metabolizing enzyme, carbonyl reductase 3, which catalyses the reduction of anthracyclines to cardiotoxic alcohol metabolites [30]. Polymorphisms of the CBR3 gene can influence the synthesis of this metabolite, exerting a regulatory effect on AIC. The V244M polymorphism in the CBR3 gene generates two protein isoforms, CBR3 V244 (G allele) and CBR3 M244 (A allele), with distinct catalytic rates. The V244 variant promotes doxorubicinol formation at a rate 2.6 times faster than the M244 variant [31]. Blanco et al. conducted a comparative analysis of data from 170 tumour patients with concomitant cardiomyopathy and 317 tumour patients without cardiomyopathy [32]. The results revealed that when patients were exposed to low to moderate doses (1-250 mg/m²) of anthracyclines, patients with the CBR3:GG genotype presented a significantly increased risk of AIC compared with patients with the CBR3:GA/AA genotype (Odds Ratio (OR) = 3.30, p = 0.006).

Another study involving 1191 breast cancer patients and an analysis of 618,863 SNPs revealed an association between a SNP (Val244Met; rs1056892) in CBR3 and a decreased left ventricular ejection fraction induced by anthracyclines [33].

These studies suggest that CBR3 plays a significant role in the AIC. This information is important for a deeper understanding of the mechanisms underlying AIC and provides new directions for future treatments of cardiac toxicity.

Gene variants related to antioxidation

Hyaluronic acid (HA) is a long-chain polysaccharide synthesized by hyaluronic acid synthase (HAS). It is an important component of the extracellular matrix (ECM). HA is widely distributed in the human body and has various physiological functions. One of the important functions of HA is its antioxidant activity. It can specifically interact with CD44 receptors on myocardial cells, stimulating cell proliferation, maintaining the integrity of myocardial cells during ROS damage, and preventing the activation of death receptors, thereby preserving cardiomyocyte survival and function [34,35,36,37].

Wang et al. [38]. employed a matched case‒control design to analyse SNPs in 2100 genes related to cardiovascular diseases. They identified a common SNP (rs2232228) in HAS3 that was closely associated with anthracycline dose-dependent cardiac injury. When exposed to low doses (< 250 mg/m2) of anthracyclines, patients with the rs2232228 GG/AA/GA genotype had lower rates of cardiomyopathy. However, when individuals were exposed to high doses (> 250 mg/m2) of anthracyclines, a significant change in the incidence of cardiomyopathy was not observed in individuals with the rs2232228 GG genotype, but this risk increased significantly in patients with the AA and GA genotypes. The risk of cardiomyopathy was highest in patients with the AA genotype, as this risk was 8.9-fold higher in these patients than in patients with the GG genotype. A genotype‒phenotype analysis revealed reduced HAS3 mRNA expression in cardiac samples from patients with the HAS3 rs2232228 AA genotype. Anthracycline inflict myocardial damage by prompting apoptosis in cardiomyocytes. Following myocardial injury, ECM serves as a structural framework for the alignment of myocytes, fibroblasts, endothelial cells, and blood vessels. HA, a constituent of the ECM, has been observed to accumulate in the damaged myocardium of rats following myocardial infarction.

Taken together, these data suggest that HA plays a significant role in AIC, and simultaneously indicate that lower cardiac HAS3 mRNA expression (AA genotype) may lead to a decreased synthesis of the antioxidant HA, thereby increasing the risk of cardiomyopathy for individuals with the AA genotype.

Top2b-mediated DNA damage

Top2b encodes topoisomerase-IIβ, which is expressed in quiescent cells, including adult cardiomyocytes. Specific knockout of the Top2b gene in cardiomyocytes reduces defective mitochondrial biogenesis and the generation of ROS [39]. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from progressive heart failure induced by doxorubicin [39]. These findings indicate that Top2b plays a significant role in drug-related cardiac toxicity. Top2b is also involved in regulating of cardiac injury via another mechanism. The RARG gene encodes a retinoic acid (RA) receptor belonging to the nuclear hormone receptor family. This RA receptor is a ligand-dependent transcriptional regulatory factor that binds to retinoic acid response elements in the promoter regions of target genes to regulate their expression. The RARG gene is highly expressed in the heart, and Top2b is one of its target genes [40].

In a genome-wide association study involving paediatric cancer patients receiving anthracycline therapy, Aminkeng et al. [41] identified a nonsynonymous variant (rs2229774) in the coding region of RARG. This variant induces the expression of Top2b, resulting in a 4.7-fold increased risk of AIC. Further investigations revealed that individuals carrying RARG rs2229774 are highly susceptible to AIC, and their hiPSC-CMs exhibit increased sensitivity to the cardiotoxic effects of anthracycline drugs [42, 43].

Gene variants associated with sarcomere dysfunction

Genetic variations impacting the architecture of sarcomeres, the fundamental contractile units of cardiomyocytes, may also play a role in the onset of cardiotoxicity following cancer treatments. The CELF protein family comprises a set of splicing regulatory factors that govern developmental processes and tissue-specific splicing events, thereby modulating alternative gene splicing and influencing the cardiac structure [44]. TNNT2 is a classic target of the CELF family, and this gene encodes cardiac troponin T (cTnT). CELF activity can promote the generation of distinct cTnT variants, and the concurrent presence of multiple cTnT variants leads to the dysregulated contraction of myocardial sarcomeres, thereby diminishing myocardial contractility and precipitating cardiac injury. An analysis of the CELF4 sequence indicated that the G allele of rs1786814 possesses a potential splice donor site and that the A allele lacks this splice site [45]. The GG genotype of rs1786814 is correlated with the coexistence of more than one TNNT2 alternatively spliced isoforms, suggesting that AIC may occur through CELF protein-mediated aberrant TNNT2 splicing [46]. A genome-wide association study targeting paediatric tumour patients confirmed that the SNP rs1786814 located in the CELF4 gene is associated with AIC. Patients with the AA genotype have a low incidence of cardiomyopathy [46]. However, when the dose of anthracyclines exceeds 300 mg/m², patients with the rs1786814 GG genotype have a 10.2-fold increased risk of cardiomyopathy compared with patients with the GA/AA genotypes.

Another gene implicated in anticancer treatment-related cardiac injury due to its impact on myocardial structure is gene TTN. Truncating variants in TTN (TTNtvs) are one of the most important causes of AIC in both paediatric and adult cancer patients [47]. The TTN gene encodes titin, the primary sarcomeric scaffold protein regulating cardiac contraction [48]. Its integrity is vital for the sarcomere’s proper function. TTNtvs can lead to the production of incomplete titin proteins. These mutations are found in about 15 to 20% of patients with dilated cardiomyopathy (DCM), compared to a mere 1% in the general population [49,50,51,52]. Consequently, TTNtvs have emerged as the most prevalent known cause of DCM. Moreover, recent studies have uncovered a high prevalence of TTNtvs in cardiomyopathy resulting from diverse triggers such as alcohol [53] and pregnancy [54], suggesting that individuals with TTNtvs are particularly vulnerable to developing cardiomyopathy in response to a variety of insults.

Gene variants associated with cardiac injury induced by targeted therapy

Cardiac injury caused by anticancer chemotherapy drugs typically presents as type I toxicity, often resulting from a myocardial cell microstructural disruption leading to irreversible damage through apoptosis [55]. In contrast, type II cardiac toxicity, characterized by reversible damage, often occurs without a concurrent myocardial cell microstructural disruption [55]. This form of injury is commonly associated with targeted anticancer therapies, with anti-HER-2 treatment being a notable example. Therefore, genetic alterations related to cardiac toxicity induced by anti-HER2 drugs may differ from those associated with chemotherapy agents.

In addition to its expression in breast tumour cells, HER2 is also expressed in cardiac myocytes [56]. The HER-2 pathway stabilizes the tissue fibre structure through a series of signalling cascades, thereby inhibiting the apoptosis of cardiac myocytes. This pathway can promote cell survival by reducing ROS levels. However, HER-2-targeted therapies disrupt the HER-2 pathway by binding to HER-2, leading to the accumulation of excessive ROS and damage to cardiac myocytes [57, 58]. Under normal circumstances, coronary artery microvascular endothelial cells and the endocardium release neuregulin-1, which induces the signalling pathway mediated by the HER-2/HER-4 heterodimer. This pathway protects the heart through various mechanisms, including maintaining the myocardial fibre structure; promoting cardiac myocyte survival, growth, and proliferation; balancing β-adrenergic effects; maintaining calcium homeostasis; improving angiogenesis; and stimulating stem cell differentiation into cardiomyocytes [59]. Therefore, the disruption of this signalling pathway by anti-HER-2 therapy may impair myocardial function and lead to heart failure. Trastuzumab can also induce cardiomyocyte damage by downregulating the antiapoptotic protein Bcl-xl and upregulating the proapoptotic protein Bcl-xs, leading to a loss of mitochondrial membrane integrity, disruption of electron transport, free radical generation, reduced adenosine triphosphate (ATP) production, and subsequent damage to cardiomyocytes [60]. Additionally, trastuzumab can affect downstream signalling pathways of HER-2, including the phosphatidylinositol 3-kinase (PI3k)-protein kinase B and extracellular signal-regulated kinase-mitogen-activated protein kinase (MAPK) pathways, thereby influencing mitochondrial function and causing damage to or even the death of cardiac myocytes [61].

Somatic and germline mutations in the HER2 gene that affect the transmembrane domain of the HER-2 protein have been identified, including germline mutations in codon 654 [62]. The Ile654Val SNP is closely associated with the incidence of breast cancer and the response to trastuzumab [63, 64]. A study involving 61 patients with HER-2-positive advanced breast cancer treated with trastuzumab included 36 patients with Ile/Ile (59%), 21 patients with Ile/Val (34.4%), and 4 patients with Val/Val (6.6%). After treatment, 5 patients (8.2%) experienced a decrease in the left ventricular ejection fraction of ≥ 20%, all of whom had the Ile/Val genotype [65]. These findings suggest that the Val655Ile genotype is associated with cardiotoxicity.

The 1170 Pro/Ala SNP in HER2 is associated with cardiac toxicity. Two studies [66, 67] that included a total of 346 patients reported a significant association between the HER2 1170 Pro/Ala SNP and anticancer treatment-related myocardial injury. These studies revealed that the presence of this SNP is a protective factor against anticancer treatment-related cardiac damage. Stanton et al. demonstrated that the CC genotype (Pro/Pro) was independently associated with anticancer treatment-related cardiac injury (OR = 2.60, p = 0.046) compared with SNP carriers of the C/G (Pro/Ala) and G/G (Ala/Ala) variants. Similarly, Boekhout et al. reported that the homozygous genotype variant G/G (Ala/Ala) was associated with a lower likelihood of cardiac events (OR = 0.09, p = 0.003).

A genome-wide association study (GWAS) conducted in a Japanese population compared 11 patients with cardiac toxicity to 257 patients without cardiac toxicity [68]. The researchers identified the top 100 SNPs with the smallest p values. Subsequently, they performed validation using a verification cohort consisting of 14 patients with cardiac toxicity and 199 control individuals. This study identified five loci on chromosomes (rs9316695 on chromosome 13q14.3, rs28415722 on chromosome 15q26.3, rs7406710 on chromosome 17q25.3, rs11932853 on chromosome 4q25, and rs8032978 on chromosome 15q26.3) that may be associated with trastuzumab-induced cardiac toxicity. The researchers developed a risk prediction model based on these five SNPs to predict the risk of trastuzumab-induced cardiac toxicity. The results showed that patients with a risk score ≥ 5 had a significantly greater incidence of trastuzumab-induced cardiac toxicity than did those with a risk score ≤ 4 (42.5% vs. 1.8%, p = 7.82 × 10¹⁵, relative risk = 40.0).

In another retrospective study, CTR-CVT was observed in 19 (7.8%) of 243 patients treated with trastuzumab [69]. They identified a total of 239,360 genetic variants in 9 of the 19 patients with CTR-CVT. The strongest association with CTR-CVT was found for a locus on chromosome 6q12 (rs139944387).

ADCs targeting HER-2 constitute another class of anti-HER-2 drugs [70, 71].No studies have explored the relationship between genetic alterations and cardiac toxicity induced by ADCs. Therefore, research is needed to identify specific gene alterations that are associated with cardiotoxicity caused by ADCs.

Gene variants associated with cardiac injury induced by immunotherapy

In recent years, immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, significantly improving the prognosis of cancer patients [72]. PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors are commonly used immune checkpoint inhibitors in clinical practice. However, while they offer clinical benefits, they also lead to immune-related adverse events. Among these adverse events, immune-related myocarditis is particularly notable, although its incidence is only 0.06–3.8% [2, 73,74,75,76,77] However, the mortality rate can reach 39.7–66.0% [2, 78], with a higher risk of death in patients receiving combination therapy with ICIs (44% vs. 66%) [2].

The clinical findings of ICI-mediated cardiovascular disease (ICI-CVD) suggest a potential mechanistic role of immune checkpoint signalling in the development of cardiac pathologies. ICIs are associated with adverse cardiovascular effects, indicating a possible role for immune checkpoint signalling in the onset of cardiac pathologies. The function of immune checkpoints has been extensively studied in certain cardiovascular diseases [79]. For example, several immune checkpoints are involved in the development of atherosclerosis [80,81,82]. Additionally, blocking coinhibitory checkpoints has been found to exacerbate atherosclerosis in cancer patients. Building on these insights from mechanisms and clinical observations, modulating immune checkpoints has emerged as a potential therapeutic strategy for the treatment of atherosclerotic cardiovascular disease [83]. The precise mechanisms underlying ICI-related cardiotoxicity remain incompletely understood, but several potential pathways have been suggested. Notably, the current evidence on immune checkpoints in heart failure primarily stems from preclinical research or from observational studies on human samples. Consequently, the available data lay the groundwork for future experimental and clinical studies.

One of the reasons is that ICI therapy disrupts immune tolerance within the body. By engaging with CTLA-4, CTLA-4 inhibitors competitively bind to CD80/CD86, and PD-1 inhibitors and PD-L1 inhibitors disturb peripheral immune tolerance by blocking the interaction between PD-1 and its ligand PD-L1. In preclinical studies, CTLA-4, PD-1, and PD-L1 were shown to help protect the heart muscle from immune-related damage. Conversely, animal models lacking immune checkpoint function exhibit increased levels of cardiac myosin-specific autoimmune CD4 + and CD8 + T cells [84,85,86]. Furthermore, myocardial biopsy samples from patients with immune-related myocarditis revealed the presence of cardiac myosin-specific CD8 + cytotoxic T cells [87]. These findings indicate that ICI therapy disrupts immune tolerance, facilitating T-cell activation, which can lead to cardiac damage.

Furthermore, autopsies of patients with ICI-related myocarditis have revealed abundant T-cell infiltration in the myocardium, skeletal muscle, and tumour tissue [73]. High levels of clonal expansion were observed in infiltrating lymphocytes through T-cell receptor sequencing [73]. Additionally, muscle-specific antigens were detected in tumour tissue, suggesting that shared antigens between the myocardium and tumour tissue may contribute to ICI-related cardiotoxicity mechanisms [73]. Dysregulated lipid metabolism [88] and macrophage conversion to a proinflammatory phenotype [89] have also been proposed as mechanisms underlying the development of immune-related myocarditis.

Various risk indicators, including genetic markers, are being explored to facilitate the early identification and diagnosis of ICI-CVD, thereby reducing the mortality associated with such adverse events. A prominent genetic susceptibility factor linked to the occurrence of ICI-CVD involves variations in either coinhibitory or costimulatory immune checkpoints.

Preclinical studies shown that genetic deletion of the gene encoding PD1 (Pdcd1) results in acute myocarditis in mice, accompanied by the detection of autoantibodies against cardiac troponin I in peripheral blood, suggesting an autoimmune response against the myocardium [86, 90]. Research using single-cell RNA sequencing has also demonstrated that the expression of Pdcd1 is upregulated in regulatory T cells within the hearts of mice experiencing heart failure due to pressure overload [91]. Blocking PD1 in these mice led to a decline in heart function and an increase in cardiac inflammation. Furthermore, genetic deletion of Pdcd1 in mice has been linked to the development of dilated cardiomyopathy [90].

CTLA4 has been suggested as a susceptibility gene for DCM, given that patients with DCM are more likely to have a genetic variant in CTLA4 than are healthy individuals [92]. Similarly, genetic deletion of Ctla4 induced fatal immune myocarditis in mice [93]. In mice treated with TAC, both Ctla4 and Pdcd1 expression levels in immune cells in the heart are increased [91]. Furthermore, in Pdcd1-deficient mice, Ctla4 knockout leads to immune myocarditis in approximately half of the mice. This finding is consistent with the increased cardiotoxicity observed when CTLA-4 inhibitors are combined with PD-1 inhibitors [73]. In addition to PD1, PDL1, and CTLA4, costimulatory factors for T cell activation, such as CD28 and B7, also play crucial roles in ICI-CVD. CD28 or B7 knockout significantly attenuated aortic constriction-induced congestive heart failure development [94]. Furthermore, CD28/B7 blockade by CTLA4Ig treatment also attenuated cardiac hypertrophy and dysfunction. 4-1BB is another costimulatory protein expressed on the surface of various immune cells that becomes activated upon binding to its ligand, 4-1BBL.The genetic deletion of gene encoding 4-1BBL has been shown to mitigate the injury associated with ischaemia and reperfusion in mice [95].

Both Ctla4 and Pdcd1expression levels in immune cells in the heart are increased in mice with pressure-overload-induced heart failure after transverse aortic constriction (TAC) surgery [91]. Furthermore, mice with a CD28 or B7 deficiency have lower cardiac inflammation, hypertrophy, fibrosis and dysfunction after TAC surgery than wild-type mice [94]. Similarly, CD28 or B7 blockade with CTLA4 immunoglobulin treatment attenuated TAC-induced cardiac hypertrophy and dysfunction [94]. CTLA4 immunoglobulin treatment also prevents the development of heart failure in mice with pressure-overload induced cardiac hypertrophy [96].

PDL1 has also been linked to the development of ICI-CVD. In a study using human heart tissue samples, the expression of PDL1 was more prominent and frequent in patients with a history of myocardial infarction than in healthy controls [97]. Moreover, a significant negative correlation was observed between the PDL1 expression level and the left ventricular ejection fraction. A preclinical study revealed that PDL1 is expressed in heart failure models and that serum levels of PDL1 are associated with disease severity [98].

In addition to Pdcd1, PDCD1LG1, and CTLA4/Ctla4, other genetic alterations associated with the development of immune-related myocarditis have also been identified. Luo et al. [99] conducted an integrated analysis of single-cell RNA sequencing and bulk sequencing data and reported that the S100A protein family, which includes S100A8, S100A9, S100A11, and S100A12, was significantly upregulated in patients with ICI-related myocarditis. The S100 proteins, encoded by the S100A genes on chromosome 21, belong to a family of calcium-binding proteins. Studies have shown a significant increase in the expression of the S100 protein family in tumour tissues, suggesting potential roles in the immune response and pathogenesis of certain diseases, including ICI-related myocarditis [100,101,102,103].In summary, research on the associations between genetic variants and the risk of immune-related myocarditis is still in the exploratory stage. However, some preliminary findings have identified genetic variants that may be associated with immune-related cardiac toxicity, indicating a promising direction for further investigation.

Epigenetics associated with cardiotoxicity

In addition to gene variants, epigenetics can influence the expression of genes, thereby affecting cell differentiation, development, and disease risk. In recent years, several studies have suggested that circulating free DNA (cfDNA) methylation can serve as a predictive biomarker for tissue injury, including drug-induced cardiotoxicity. After damaged, the heart can release DNA into the peripheral blood in the form of cfDNA, theoretically allowing the diagnosis of cardiac injury through cfDNA methylation detection [104]. Recently, Israeli researchers published a human cell methylation atlas of the characteristic methylation markers of different tissues, including the heart [105]. The atlas provides an essential resource for studying disease-associated genetic variants and potential tissue-specific biomarkers for use in liquid biopsies, enabling the possibility of diagnosing cardiac injury through cfDNA methylation.

Several studies have revealed a notable increase in the levels of cfDNA methylation markers originating from the heart in patients with myocardial infarction. Ren et al. compared cfDNA methylation levels in plasma between myocardial infarction patients and healthy individuals and identified six heart-specific hypermethylation patterns. These authors also reported that the methylation concentration was correlated with disease severity [106]. Additionally, another study reported a significant elevation in the concentration of heart-derived cfDNA in patients with acute myocardial infarction. Furthermore, in patients with sepsis, markedly increased levels of heart-derived cfDNA were detected, which was correlated with a significantly increased risk of cardiac death in these individuals [104].

In preclinical research [107], the use of a congestive heart failure model facilitated the analysis of N6-methyladenosine (6 mA) methylation patterns in mitochondrial DNA (mtDNA) of cardiomyocytes. An increase in mtDNA 6 mA levels was observed in cardiomyocytes from hearts with heart failure. Upon upregulating the expression of the methyltransferase METTL4, an elevation in mtDNA 6 mA levels ensued, leading to spontaneous mitochondrial dysfunction and the onset of heart failure. Conversely, by knocking out the cardiomyocyte-specific mettl4 gene to reduce mtDNA 6 mA levels, heart failure was alleviated. These findings suggest a close association between mtDNA 6 mA and cardiac dysfunction.In terms of chemotherapy-induced cardiac injury, a study compared the methylation profiles of peripheral blood mononuclear cells (PBMCs) between 9 patients with an abnormal left ventricular ejection fraction (LVEF) and 10 patients with a normal LVEF [108]. They identified 14,883 differentially methylated CpGs at baseline and after the first cycle of chemotherapy (doxorubicin), that were significantly associated with the LVEF status. In patients with an abnormal LVEF, regions with significant differential methylation were found in the promoters and gene bodies of SLFN12, IRF6, and RNF39. The results of this study suggest that the DNA methylation profile of PBMCs may be able to predict the risk of chemotherapy-induced cardiac toxicity.

These results indicate that epigenetic changes are linked to cardiac dysfunction triggered by a range of factors, cancer treatment among them. Nevertheless, the study of epigenetic modifications in the context of cardio-oncology is a relatively unexplored area that requires more in-depth research. Future studies should delve into the potential connections between other epigenetic modifications and CTR-CVT. Additionally, it will be important to investigate the utility of epigenetic modifications in the filed of cardio-oncology, such as utilizing methylation patterns as diagnostic markers or prognostic indicators for cardiac injury.

Conclusion and future directions

Cardiovascular disease and cancer are the two major causes of morbidity and mortality worldwide, accounting for at least 70% of the medical reasons for mortality worldwide. Cancer patients often have multiple comorbidities that can profoundly influence their cancer care and clinical outcomes. As cancer patient survival rates increase due to the development of effective cancer therapies, cancer therapy-induced cardiovascular toxicity has increasingly become a significant threat to cancer patients. The risk factors associated with cardiotoxicity related to tumour treatment have not been fully identified, and effective evaluations and predictive models for the cardiovascular risk are lacking. Genetic studies of both human populations and animal models have elucidated the mechanisms of cancer therapy-induced cardiotoxicity, providing opportunities to optimize patient care during cancer treatment. The European Society of Cardiology (ESC) guidelines classify genetic variants as risk factors for CTR-CVT, specifically identifying seven genetic abnormalities that are known to drive CTR-CVT. However, these variants are limited and are associated primarily with AIC. This review summarizes the epidemiological data and pathogenic mechanisms of anticancer drug-related cardiac injury, particularly the relationships between genetic alterations and CTR-CVT from four perspectives: chemotherapy-related cardiac injury (Table 1), targeted therapy-related cardiac injury (Table 2), immunotherapy-related cardiac injury (Table 3) and the relationship between epigenetics and cardiotoxicity (Fig. 2). This study provides a more comprehensive summary of genetic variants associated with CTR-CVT, which could serve as a supplement to the ESC guidelines. This approach enable oncologists and cardiologists to gain a more thorough understanding of the genetic alterations related to CTR-CVT, facilitating the assessment of the risk of cardiovascular toxicity that could be caused by treatment prior to its initiation. This finding also suggests that by stratifying patients according to genetic features, early identification of individuals susceptible to cardiac injury can be achieved. The detection of both common and rare monogenic variants that impact the risk of CTR-CVT in patients following cardiotoxic cancer therapies can significantly refine the cardiovascular risk stratification for these individuals. A burgeoning focus on constructing risk prediction models that utilize clinical data and genetic information has been noted, with the goal of facilitating personalized treatment approaches for cancer patients [109,110,111]. The identification of further genetic risk factors in addition to clinical risk factors will facilitate the establishment of a better prediction score model and improve its predictability for CTR-CVT. This approach enables personalized cancer treatment based on known genetic factors and thus reduces the incidence of drug-induced cardiac injury. Genetic susceptibility not only elevates the risk of cardiotoxicity but also detrimentally affects clinical outcomes [112]. Personalizing cancer treatment plans and cardiovascular monitoring strategies based on individual genetic profiles before, during, and after cancer therapy may improve clinical outcomes, a strategy that requires additional research to validate its efficacy.

Table 1 Common genetic variants that are associated with risk of anthracycline-induced cardiotoxicity

Table 2 Common genetic variants that are associated with risk of trastuzumab-induced cardiotoxicity

Table 3 The role of genetic susceptibility to immune checkpoint inhibitor-related cardiac dysfunction

In summary, genetic predisposition plays an essential role in both the development and clinical outcomes of cardiovascular toxicity following cancer therapies. Nevertheless, numerous challenges remain to be addressed and significant additional work is required to refine the understanding and management of this area. RCT evidence in this field is limited. Therefore, an increased number of well-designed RCTs that can yield more credible evidence is a pressing need. Furthermore, long-term follow-up of patients is necessary to gain a comprehensive understanding of their cardiotoxicity, given that cardiovascular toxicity is typically a chronic process. Current research has been limited in terms of the populations involved, with many trials not adequately representing diverse groups such as women and elderly patients, and accumulating data suggest that the interaction of anticancer therapeutics may differ between groups [113]. Currently, studies have focused primarily on the cardiovascular toxicity of traditional chemotherapy drugs such as anthracycline, whereas investigations into newer treatment modalities, such as ICI-related-cardiotoxicity, are relatively limited. Additional studies are needed to explore this emerging area of concern further. Cardio-oncology is an integrative discipline, and cardio-oncology providers with knowledge of the broad scopes of cardiology, oncology, and haematology are limited. Courses and programs focused on cardio-oncology care networks and cardio-oncology services are needed to meet the increased clinical demand. Finally, although some researches have established risk factor-based stratification for cardiotoxicity associated with anticancer treatment, the existing tools are not entirely satisfactory. In the future, leveraging multiomics, big data, and artificial intelligence tools may be necessary to develop and validate more sensitive and specific stratification tools.

Fig. 2

Genetic factors in the pathogenesis of Cardio-Oncology. (A) Gene variants associated with cardiac injury induced by chemotherapy includes gene variants related to drug metabolism (such as GSTM1, UTG1A6, CRB3), sarcomere dysfunction (such as CELF4 and TTN), drug transport (such as ABC and SCL), DNA damage (such as Trop2b) and antioxidation (such as HAS3). (B) Gene variants associated with cardiac injury induced by molecular targeted therapy includes HER-2, and loci on chromosomes 13q14.3, 17q25.3, 4q25, and 15q26.3. (C) Gene variants associated with cardiac injury induced by immunotherapy includes Pdcd1, PDL1, CTLA4/Ctla4. (D) Epigenetic associated with cardiotoxicity (such as cfDNA methylation and m6A methylation in mitochondrial DNA)