Update on preclinical models of cancer therapy-related cardiac dysfunction: Challenges and perspectives. A scientific statement of the Heart Failure Association (HFA) of the ESC, the ESC Council of Cardio-Oncology, and the ESC Working Group on Cellular Biology of the Heart.

Introduction and scope

Cancer therapy‐related cardiovascular toxicity is an important clinical problem. Medications with established cardiotoxicity, but also high efficacy, like anthracycline chemotherapy and human epidermal growth factor receptor 2 (HER2)‐targeted therapies, are widely used in clinical practice. In addition, many new anticancer therapies with potential cardiac side effects are continuously introduced into clinical practice. Cancer therapy‐related cardiovascular toxicity can manifest as a wide range of potentially life‐threatening complications, including cancer therapy‐related cardiac dysfunction (CTRCD), arrhythmias, and myocarditis. 1 Preclinical models, including two‐ (2D) and three‐dimensional (3D) cellular systems as well as small and large animals, have proven to be indispensable tools for elucidating the mechanistic pathways responsible for the cardiac side effects of traditional anticancer therapies. 2 This scientific statement summarizes studies from the past 5 years (2019–2024) that have utilized these models to advance the mechanistic understanding of the cardiotoxicity of new generation oncological treatments, and of the complex interaction between cancer and heart failure (HF). It also discusses the current gaps between preclinical modelling and clinical observations in patients ( Figure 1 ), how these gaps affect regulatory pathways and the overall feasibility of the drug development process, and provides recommendations for closing these gaps. While anticancer therapies can have various adverse effects on the cardiovascular system, such as arrhythmias, hypertension, and thrombosis, and others, this review will specifically concentrate on the mechanisms leading to cardiac dysfunction and HF, aiming to provide a detailed analysis while maintaining a clear and targeted scope.

Mechanisms and clinical manifestation of cardiac dysfunction of conventional and emerging cancer therapies

Conventional therapies

Conventional cancer treatments with known cardiotoxic effects include anthracyclines, anti‐HER2 therapies, tyrosine kinase inhibitors and radiotherapy. Anthracycline‐induced cardiotoxicity (AIC), which irreversibly progresses from asymptomatic left ventricular dysfunction to HF, 1 , 3 , 4 is the most extensively studied form of cardiotoxicity due to the availability of established preclinical models across various species. Studies using zebrafish, rodents, pigs and human cells have identified increased reactive oxygen species, activation of the DNA damage response, impaired autophagy, and mitochondrial dysfunction as key drivers of toxicity in cardiomyocytes 5 and other cardiac cell types. 6 , 7

Another example is trastuzumab, a humanized monoclonal antibody targeting the ERBB2/HER2 receptor tyrosine kinase. Unlike anthracycline regimens, trastuzumab‐induced cardiotoxicity is highly reversible, but can amplify and exacerbate AIC when co‐administered. 1 Initial insights into the cardiotoxicity of anti‐HER2 therapies came from conditional ErbB2 mouse mutants that develop severe dilated cardiomyopathy 8 and from mice with cardiac‐specific ErbB2 overexpression that are protected against doxorubicin‐induced oxidative stress. 9 Human‐induced pluripotent stem cells (iPSCs) subsequently extended our mechanistic understanding of trastuzumab cardiotoxicity beyond inhibition of the pro‐survival NRG1/ErbB pathway in cardiomyocytes 10 and revealed alterations in metabolic pathways 11 and in the interaction between cardiomyocytes and vascular endothelial cells. 12

Tyrosine kinase inhibitors (TKIs) also cause cardiac side effects. 1 Although some are specific, the majority of clinically licensed TKIs inhibit multiple kinases. Targeting BCR‐ABL with ponatinib causes cardiomyopathy, HF, and vascular occlusion, 13 with mitochondrial toxicity, 14 integrated stress response activation 14 and S100A8/A9‐NLRP3‐interleukin (IL)‐1β‐mediated inflammation 15 identified as key mechanisms in human iPSC and murine models. 14 , 15 Sunitinib, a multi‐targeted TKI in the class of vascular endothelial growth factor (VEGF) TKIs that causes hypertension and left ventricular dysfunction, 1 similarly induces mitochondrial dysfunction in engineered cardiac microtissues. 16 Bruton's tyrosine kinase inhibitors (BTKi) have revolutionized the treatment of B‐cell malignancies including chronic lymphocytic leukaemia and mantle cell lymphoma. Patients treated with BTKi have an increased risk of arterial hypertension, atrial fibrillation and CTRCD. Insights from studies in mice lacking an active Bruton's tyrosine kinase suggest that part of the arrhythmia risk associated with the BTKi ibrutinib is related to an off‐target blockade of C‐terminal Src kinase. 17 However, more specific second‐generation BTKi also have an increased risk of atrial fibrillation and hypertension, 18 suggesting that direct Bruton's tyrosine kinase inhibition may be relevant in the pathogenesis of atrial fibrillation and hypertension in humans.

Radiation‐induced heart disease, which typically manifests several years to decades after therapy, includes coronary artery disease, valvular heart disease, pericardial disease, conduction abnormalities, and HF. 1 , 19 Studies in myocytes and mice exposed to radiation that mimics the dose, fractionation, and beam delivery of clinical radiotherapy protocols have identified cardiac fibrosis 20 and cardiomyocyte Ca 2+ mishandling 21 as key pathogenic events in radiation‐induced heart disease.

Two decades of preclinical research have revealed the molecular underpinnings of the cardiotoxicity of most conventional oncological treatments, as extensively reviewed in Morelli et al . 22 However, the potential interactions between cancer therapies in multimodal regimens, as well as the effects of cardiotoxic treatments against the backdrop of pre‐existing cardiovascular risk factors or disease, have been insufficiently addressed in preclinical modelling and should be the focus of future studies.

Immune checkpoint inhibitors

The therapeutic landscape in cancer has been profoundly transformed by the advent of immune checkpoint inhibitors (ICIs), a class of monoclonal antibodies that boost the anticancer immune response by targeting immune‐cell surface receptors. 23 ICIs target various co‐stimulatory signalling molecules on T lymphocytes and antigen‐presenting cells, such as cytotoxic T‐lymphocyte antigen 4 (CTLA‐4), programmed cell death protein 1 (PD‐1), and its ligand (PD‐L1), thereby breaking the immune tolerance of T cells against cancer cells. 24

Despite their proven efficacy, 25 , 26 the use of ICIs has led to the occurrence of several immune‐related adverse events (irAEs) caused by the hyperactivation of the immune system against non‐cancerous tissues. 27 Although irAEs depend on the type of cancer, the ICI used, the duration of exposure and the dose administered, ICI immunotherapy is associated with an increased risk of cardiac events, including myocarditis, arrhythmias, HF, and cardiovascular death. 28 , 29 , 30 , 31

Animal models have been instrumental in deciphering the exact pathophysiological mechanisms underlying the cardiovascular toxicities of ICIs (extensively reviewed in Tocchetti et al . 31 and Gergely et al . 32 ). Studies in mice with genetic deletion of immune checkpoints like Pdcd1 and Ctla4 , which are the murine equivalents of the genes encoding human PD‐1 and CTLA‐4, have shown that ICI cardiovascular toxicity is associated with increased inflammation. This is secondary to infiltration of macrophages 33 and cytotoxic CD8 + T cells specific for α‐myosin 34 into the heart. In mice with monoallelic loss of Ctla4 combined with a complete genetic absence of Pdcd1 , myocardial infiltration was associated with severe electrocardiographic abnormalities and left ventricular dysfunction observed in some ICI‐treated patients. 35 Interestingly, in this murine model, which closely recapitulates the clinical and pathological features of ICI‐associated myocarditis, intervention with CTLA4‐Ig (abatacept) ameliorated disease progression. 35 This was supported by a case series of patients receiving abatacept, which successfully attenuated the fulminant course of ICI myocarditis, although the optimal dosing for this indication and pharmacokinetics in humans are complex and have not been definitively established. 35

Preclinical models will be essential to validate new strategies, like fasting mimicking diet cycles, 36 to protect the heart from the adverse effects of immunotherapy. At the same time, these models should be used to address current knowledge gaps. The observation that only 1–1.5% of all patients receiving ICI develop severe cardiovascular toxicity, 27 , 31 along with the variable progression of ICI‐mediated myocarditis among individuals, suggests that additional genetic and environmental factors must contribute to the manifestation of this condition. Indeed, traditional cardiovascular risk factors such as diabetes, hypertension, and dyslipidaemia do not predict which patients are at risk. In contrast, patients undergoing combination ICI therapy, those with pre‐existing autoimmune diseases, and those with specific cancers, such as thymic cancers, are at increased risk. 31 , 37 This indicates that the immune phenotype plays a critical role, presenting a challenge for translational models due to significant species‐related differences in immunobiology. Therefore, preclinical models which recapitulate the human immune response are critical to decipher the patient‐specific response towards ICI.

CAR ‐T and TCR ‐T cells

Chimeric antigen receptor T cell (CAR‐T) therapy is a form of immunotherapy in which patient's own T cells are genetically engineered to recognize and eliminate cancer cells. CAR‐T cells are generated by inducing the expression of an artificial protein, the chimeric antigen receptor, consisting of a T cell signalling domain and an antigen recognition domain that selectively targets a cancer‐specific antigen. CAR‐T therapy has drastically improved the prognosis of previously incurable haematologic malignancies, particularly those derived from B cells. 38 The potential of CAR‐T cells to treat a range of conditions beyond cancer, including autoimmune diseases, chronic infections, cardiac fibrosis, senescence‐associated diseases and other conditions, is also being explored in preclinical models. 39

The therapeutic efficacy of CAR‐T therapy is compromised by serious clinical complications, the most common being cytokine release syndrome (CRS), a systemic inflammatory syndrome characterized by immune cell activation and high levels of circulating cytokines. 40 CRS develops on average 5–7 days after CAR‐T infusion and its manifestation varies in severity from fever, with or without constitutional symptoms, to a potentially life‐threatening condition. 41 Evidence from preclinical mouse models 42 has demonstrated the importance of IL‐1β 43 and IL‐6 44 in the pathophysiology of CRS, and the benefit of IL‐1 receptor and IL‐6 blockade in ameliorating CRS. To date, several clinical trials are underway testing the efficacy of CAR‐Ts combined with IL‐1 receptor antagonism, 45 while IL‐6 receptor blockade with tocilizumab has shown benefit in patients with moderate or severe CRS. 46

Cardiovascular toxicity is a frequently reported complication of CAR‐T therapy. CAR‐T‐related cardiovascular toxicity often occurs in the context of CRS, 47 , 48 and the risk of cardiovascular events correlates with CRS severity. 49 The most common manifestations are new‐onset HF and supraventricular tachyarrhythmias, but CAR‐T‐related severe CRS and cardiac dysfunction can also lead to refractory cardiogenic shock and death ( Table 1 ). 47 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 However, it is important to emphasize that these clinical data are derived from retrospective analyses, which are inherently susceptible to bias and may not fully reflect real‐world clinical scenarios. The pathophysiology of CAR‐T‐related cardiovascular toxicity has not been investigated so far in animal models of CRS, 57 but myocardial depressing effects of cytokines like IL‐6 have been described in mice. 58

Cardiac safety concerns have also arisen with T cell receptor (TCR) T cell (TCR‐T) therapies, immunotherapies which use engineered TCR‐Ts expressing cancer antigen‐specific TCRs to redirect T cells against tumour cells. 59 Unlike CAR‐T, which target cell surface antigens, TCR‐T recognize epitopes presented by the major histocompatibility complex (MHC). Although TCR‐T is less likely to induce CRS compared with CAR‐T therapy, 59 two cases of fatal myocarditis due to TCR‐T targeting MHC class I‐restricted epitopes derived from the melanoma‐associated antigen‐3 (MAGE‐A3) have been reported. 60 , 61 Mechanistically, these effects were linked to cross‐reactivity against titin, as demonstrated in iPSC‐derived cardiomyocytes (iPSC‐CMs) exposed to MAGE‐A3‐transduced T cells. 60 , 61

In conclusion, CAR‐T and TCR‐T therapies are associated with cardiac events stemming from cardiotoxic effects of interleukins in the context of CRS, and off‐target cytotoxic effects of engineered T cells, respectively. A deeper understanding of these pathomechanisms requires further investigation in appropriate preclinical models. 57

Preclinical models to study cancer therapy‐related cardiac dysfunction

In vitro models

Induced pluripotent stem cell‐derived cardiomyocyte and non‐cardiomyocyte cells in 2D and 3D tissue models

For a long time, there was a lack of human cardiomyocyte culture models that could be used to understand the molecular and cellular physiology of CTRCD; as a result, preclinical cardio‐oncology research relied primarily on rodent cardiomyocytes as an in vitro model. More recently, the development of 2D and 3D culture systems has enabled the use of iPSC‐CMs as a screening platform for cardiotoxic effects of cancer therapies, to predict cardiotoxicity risk, 62 , 63 or to analyse the underlying pathophysiology. 10 , 11 By generating human iPSC‐CM and non‐cardiomyocyte cell types, it is possible to establish patient‐specific disease models to define cardiotoxicities at the individual and population levels. In addition, patient‐specific iPSC models can be used to identify and validate single nucleotide polymorphisms associated with CTRCD, ultimately guiding the design of clinical trials. 64

Healthy control iPSC‐CMs have initially been used to demonstrate general cardiotoxic effects of anthracyclines, such as apoptosis, reactive oxygen species production, mitochondrial dysfunction, and electrophysiological and Ca 2+ changes, 65 , 66 and led to the identification of telomerase overexpression as a therapeutic option in CTRCD. 67 On the other hand, patient‐specific iPSC models have been shown to recapitulate the predisposition of individual breast cancer patients to low doxorubicin‐induced cardiotoxicity 62 or trastuzumab‐induced cardiac dysfunction. 11 Another patient‐specific stem cell model of CTRCD demonstrated that patients with aggressive B‐cell lymphoma are persistently more susceptible to detrimental effects of high doxorubicin treatment with hyperactivation of Ca 2+ /calmodulin‐dependent protein kinase II δ (CaMKIIδ), resulting in arrhythmogenic triggers and cellular dysfunction. 68 Furthermore, iPSC‐CMs generated from paediatric oncology patients with acute anthracycline cardiotoxicity identified cardioprotective micro 69 and circular 70 RNAs. Finally, a stem cell model of paediatric CTRCD patients allowed the identification of genomic variants of drug transporters associated with doxorubicin‐induced cardiotoxicity, thereby confirming the evidence for a genetic predisposition to CTRCD, 71 including several somatic and systemic mutations that trigger the development of CTRCD. 68 , 72

Although iPSC‐CMs hold great promise as an in vitro research tool for understanding the cardiotoxicity of oncological drugs, they also differ significantly from adult cardiomyocytes in that they are structurally and functionally immature, resembling foetal cardiomyocytes. 73 This immaturity can be partially corrected by embedding the iPSC‐CMs in a 3D environment, such as the so‐called dynamic engineered heart tissue model 74 or engineered heart myocardium. 75 In addition to promoting maturation, as shown by a faster conduction velocity, better alignment, and increased contractile power, this also provided a method to analyse iPSC‐CM behaviour in a more physiological environment and the possibility to include other cell types, including endothelial cells and cardiac fibroblasts. Exposing dynamic engineered heart tissues or engineered heart myocardium to anthracyclines resulted in tissue dilatation and reduced contractile force, both key features of the clinical phenotype of AIC. 68 , 76 Furthermore, these 3D dynamic‐engineered cardiac tissues could recapitulate the induction of senescence observed in the hearts of patients with severe doxorubicin‐induced cardiotoxicity. However, pharmacological inhibition of senescence did not show any functional improvement in these models, calling into question the use of senolytic drugs as a potential cardioprotective therapy. 76 Other maturation strategies for iPSC‐CMs currently being explored include long‐term culture, mechanical and/or electrical stimulation, 3D cardiac organoids of different cell types, the addition of anti‐inflammatory macrophages 77 and combinatorial approaches. 78 , 79 While the majority of the studies with CTRCD stem cell models have focused specifically on autonomic iPSC‐CM processes, the interaction with other relevant (cardiovascular) cell types, including immune cells, and their integration into 3D engineered tissue systems, should also be considered. The inclusion of multicellular models into preclinical studies of CTRCD is expected to uncover previously unexplored aspects of the disease. Beyond immaturity and limited ability to reproduce multicellular communications, iPSC‐CMs face additional challenges, including subtype specification, scarce interlaboratory reproducibility, labour‐intensive protocols, and high costs. 80 Moreover, the reprogramming, culture, and differentiation of human iPSCs demand significant time and resources, limiting the feasibility of large‐scale research for non‐established iPSC laboratories. While substantial progress has been made, 81 , 82 further efforts are needed to optimize cardiomyocyte differentiation protocols, prioritizing simplicity, reproducibility, and cost‐effectiveness, to enable broader application.

Cardiac slices

Although iPSC models have revolutionized our understanding of CTRCD, they still do not fully emulate the complex cellular composition of human heart tissue. Myocardial slices – thin, living sections of heart tissue – offer a unique advantage for studying cardiac function and drug effects in a context that closely resembles the native tissue environment. Using a biomimetic culture system, pig and human heart slices can remain completely viable and functionally and structurally intact for 6 days in culture, also enabling the assessment of contraction and relaxation kinetics on isolated single myofibrils after culture. 83 , 84 To date, canine, porcine, and human myocardial slices have been used to study the cardiotoxicity of doxorubicin, trastuzumab, and sunitinib. Heart slices effectively recapitulate the expected toxicity of doxorubicin 85 , 86 and trastuzumab, 86 similar to human iPSC‐CMs, but are superior in detecting sunitinib cardiovascular toxicity at clinically relevant concentrations. 86 Therefore, these systems should be considered for validating translational findings from other preclinical models in future studies.

In vivo models

Zebrafish

The zebrafish is an in vivo whole organism model that has been used for decades to study the mechanisms of cardiovascular disease (CVD), as well as cancer growth and metastasis. In cardio‐oncology, zebrafish have been used to identify new small molecule therapies that protect against doxorubicin‐induced cardiomyopathy without compromising anti‐tumour activity. 87 Zebrafish models have also been developed to study cardiovascular toxicities associated with cyclophosphamide 88 and VEGF inhibitors. 89 , 90 Zebrafish have the following strengths when compared to in vitro , rodent, or large animal models: (1) small size and optical transparency in the embryonic stage, facilitating high throughput screening with direct cardiac imaging; (2) high degree of genetic conservation between zebrafish and humans, particularly for metabolic and cell death‐related pathways; (3) advances in genome editing technology, allowing rapid and efficient generation of CRISPR/Cas9 mutants; (4) studies at scale with large numbers and significantly lower cost compared to rodent models. One disadvantage is the early developmental stage required for most high‐throughput applications. As a result, validation of new molecular mechanisms discovered in zebrafish embryos typically requires the use of complementary adult model systems.

Rodents

Rodents are the most widely used preclinical model in cardio‐oncology research. CTRCD can be easily recapitulated by treating rats and mice with the anticancer drug according to protocols that closely mimic human therapeutic regimens in terms of route of administration, dosage and pharmacokinetic profile. 2 Over the past decades, these models have been instrumental in identifying the mechanisms behind the cardiotoxicity of conventional chemotherapies, primarily anthracyclines, and in discovering potential cardioprotective strategies. 91 However, direct treatment of rodents with anticancer therapies does not always effectively reproduce the associated cardiotoxicity, as seen with trastuzumab and other anti‐HER2 antibodies, because these drugs are unable to recognize the murine counterpart of the HER2 receptor. 92 Homozygous human HER2 transgenic mice do not represent a valuable alternative as they are embryonic lethal. 93 Consequently, most of the knowledge on the cardiotoxicity of anti‐HER2 therapies has been obtained from mice with cardiomyocyte‐specific ErbB2 deletion or overexpression. 8 , 9 These studies, along with later investigations involving the genetic deletion of immune checkpoints, exemplify the strengths of mouse genetics in advancing our understanding of the mechanistic basis of cardiotoxicity. Furthermore, this highlights the added value of murine models, particularly compared to large animals, where genetic manipulation is more challenging.

Another significant advantage of rodent models over human in vitro systems is the ability to assess the impact of novel cardioprotective candidates on the anti‐tumour activity of cancer therapies. For example, xenotransplantation of cells derived from cutaneous melanoma, a prototypical cancer type treated with immunotherapy, originally led to the identification of tumour necrosis factor (TNF)‐α blockade, but not CD8 + T cell depletion, as a means of preventing ICI‐mediated myocarditis without compromising the anticancer efficacy of the anti‐PD1 therapy. 94 Nevertheless, despite this positive preclinical evidence, caution is advised against the use of TNF‐α antibodies for ICI myocarditis and HF, 1 as clinical studies in HF patients have shown neutral or even negative outcomes. 95 In addition to xenotransplantation of solid tumours into syngeneic mice, the use of patient‐derived xenografts (PDX) can further strengthen the translational value of the study. PDX generated using tissue from a woman with triple‐negative breast cancer, and implanted in severe combined immunodeficiency mice, demonstrated that a small molecule allosteric inhibitor of the pro‐apoptotic molecule BAX can provide cardioprotection, without compromising the efficacy of doxorubicin in reducing the burden of breast cancer in vivo . 96 However, a major disadvantage of xenografts in immunodeficient mice is the inability to model interactions of the immune system with the tumour and the cardiovascular system. In this respect, genetic models with spontaneous tumour growth represent a valuable alternative. For example, using ErbB2/Neu transgenic mice, it has been shown that inhibition of PI3Kγ effectively protects against AIC, while inducing anti‐tumour immune responses, leading to reduced mammary cancer growth. 97

In summary, although novel human in vitro models of CTRCD are emerging, rodents remain invaluable for studying complex cell–cell and organ–organ interactions, including tumour–heart interactions as well as the involvement of the immune system.

Large animals

Despite their scientific value, murine models differ significantly from human anatomy and physiology, limiting the straightforward translation to the clinic. Because the hearts of large mammals have increased similarity to humans, diagnostic and therapeutic strategies that prove beneficial in large animal studies are more likely to succeed in clinical trials than those tested only in small animals. 98 Several large animal models of CTRCD (e.g. pigs, primates, sheep, cows, dogs) have been reported, 99 , 100 , 101 , 102 , 103 , 104 , 105 most of which test for cardiac side effects of anthracyclines. Large animal models offer the opportunity to test diagnostic protocols that can be replicated in humans using exactly the same equipment. One example is the discovery of T2 relaxation time prolongation on magnetic resonance imaging as a very early marker of anthracycline cardiotoxicity in pigs and monkeys, 102 , 104 which was later validated in clinical studies. 106 , 107

Large animal models are also useful when testing potential cardioprotective therapies prior to clinical trials. Through the use of these models, there are examples of some therapies that have been withdrawn from the translational portfolio because they did not show any benefit in a large animal model. 100 A successful example of this strategy is the testing of remote ischaemic conditioning as an intervention to prevent AIC. This non‐invasive intervention was tested in a porcine model of AIC and showed that its use prior to each doxorubicin injection resulted in a significant improvement in left ventricular ejection fraction through a mechanism involving mitochondrial protection. 108 These results in the pig model have served as basis for the execution of the ongoing RESILIENCE trial ( NCT05223413 ), which is investigating the benefits of weekly remote ischaemic conditioning in a population of cancer patients at high risk of AIC.

Despite their undeniable advantages, large animal models present significant challenges, including high costs, specialized infrastructure and handling requirements, and longer lifespans and gestation periods. Additionally, genetic manipulation in these animals is complex and may raise ethical concerns. 98 Consequently, small animals, like murine models, remain the preferred choice in preclinical research, including in the field of cardio‐oncology.

Mechanisms and preclinical models of reverse cardio‐oncology

Recent studies suggest that the relationship between CVD and cancer extends well beyond CTRCD. Community‐based cohort studies have shown that individuals with HF are at increased risk of cancer incidence and mortality compared with the general population, a phenomenon referred to as ‘reverse cardio‐oncology’. 109 , 110 , 111 Murine models, particularly tumour xenografts, have been instrumental in demonstrating that the relationship between cancer and HF is not merely a clinical association, but rather a causal one. Landmark studies first demonstrated that HF, induced by permanent ligation of the left anterior descending coronary artery or by pressure overload‐induced left ventricular remodelling via transverse aortic constriction, leads to increased tumour burden in a mouse model of spontaneous intestinal adenomatosis, 112 , 113 independent of haemodynamic changes. 113 Subsequent studies have confirmed these findings, showing that cardiac remodelling from left anterior descending coronary artery ligation, transverse aortic constriction, ATF3 overexpression, or prolonged low‐dose phenylephrine infusion promotes proliferation, and in some cases metastatic dissemination, of MMTV‐PyMT or 4T1 mammary cancer and Lewis lung carcinoma cells ( Table 2 ). 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121

Preclinical models have further provided evidence for the role of secreted factors 113 and the immune system 118 as mediators between HF and cancer. Remodelling factors that have been suggested as mediators of the tumour‐supporting effect of HF include serpinA3, periostin, nerve growth factor, connective tissue growth factor, fibronectin, and inflammatory cytokines. 112 , 113 , 114 , 115 , 117 , 120 , 121 Myocardial infarction (MI)‐induced epigenetic reprogramming of Ly6C hi monocytes in the bone marrow reservoir to an immunosuppressive phenotype and their recruitment to tumours has also been shown to underlie MI‐induced tumour growth. 118 However, HF induced by transverse aortic constriction surgery also promoted tumorigenesis in immunodeficient mice, indicating that immune dysregulation may not be essential. 114 In addition, microbial dysbiosis, which often is observed in HF, is present in a mouse model of MI‐induced HF and transplantation of the ‘HF‐related microbiome’ into recipient mice accelerated colon tumour growth. 116

In summary, preclinical models suggest that HF may promote cancer growth through secreted factors and inflammatory mediators, indicating the potential of available preclinical models to evaluate the anticancer effect of HF medication. 122

Novel insights from drugs with both cardioprotective and anti‐tumour activity

In addition to the intriguing concept that HF may be tumorigenic, the fact that patients with CVD also have a higher risk of cancer than that in the general population suggests potential common mechanisms and therapeutic targets. 123 , 124 , 125 This notion has been supported by some recently developed anti‐tumour therapies, particularly those that target the NLRP3 inflammasome, such as NLRP3 and IL‐1 inhibitors, which have also been shown to protect the cardiovascular system.

Consistent with preclinical results obtained on the role of IL‐1 in tumour progression, IL‐1 receptor antagonists and anti‐IL‐1 monoclonal antibodies can inhibit primary tumour growth and metastasis in animal studies. 126 Furthermore, genetic associations in cancer patients indicate that combining anti‐IL‐1 strategies with checkpoint blockade immunotherapy may benefit patients with haematological, pancreatic or breast cancer, and clinical trials are ongoing. 126 As IL‐1 can stimulate CRS‐related toxicity of CAR‐T therapy, this combination might not only be effective against cancer but may also help to reduce the cardiovascular toxicity associated with cell therapies. 57 The Canakinumab Anti‐Inflammatory Thrombosis Outcome Study (CANTOS), a large, randomized, double‐blind, placebo‐controlled phase 3 trial of canakinumab in patients with a history of MI with atherosclerosis, 127 showed that canakinumab was associated with a dramatic (>60%) reduction in lung cancer incidence and mortality, 128 specifically in molecular subtypes of lung cancer. 129 Based on these results, single‐agent canakinumab has been prospectively investigated in a randomized, double‐blind, placebo‐controlled phase 3 trial in patients with surgically resected stage II–III non‐small cell lung cancer ( NCT03447769 ). However, this trial (CANOPY‐A) did not show a benefit in disease‐free survival, 130 and further results from other trials will follow.

NLRP3 inhibition is another therapy with potential combined anti‐tumour and cardioprotective properties. The NLRP3 inflammasome is a source of IL‐1β and IL‐18, and regulates pyroptosis, autophagy, and oxidative stress, 131 as evidenced by the known anti‐inflammatory and cardiovascular protective properties of colchicine, 132 , 133 the oldest non‐specific inflammasome inhibitor. Colchicine is an effective treatment for pericarditis and may also reduce the risk of ischaemic cardiovascular events in patients with a recent MI, although at the expense of increased non‐CVD mortality. 134 Beside preclinical evidence of its potential cardioprotective properties, and the clinical evidence of IL‐1 and IL‐6 inhibition against cardiovascular risk, 135 direct clinical evidence of NLRP3 inhibition in protecting against HF or CVD is still lacking. Various clinical trials studying colchicine or IL‐1 inhibition in stable or acutely decompensated HF with reduced ejection fraction (reviewed in Olsen et al . 136 ) have also failed to convincingly demonstrate a strong protective potential. On the other hand, targeting the NLRP3 inflammasome to further improve immunotherapy may be a promising therapeutic approach for prostate, breast, colorectal and lung cancer, as well as melanoma. 137 However, NLRP3 may act as a double‐edged sword in carcinogenesis, exerting both positive and negative effects. 138 More preclinical and clinical research is therefore needed to identify the best subgroup of cancer patients who will benefit from NLRP3 inhibition with common cardiovascular and cancer risk. This also applies to the danger associated with molecular pattern and activator of the NLRP3 inflammasome, S100A9, 139 , 140 which has an ambivalent role in cancer 141 and CVD. 142

In conclusion, specific inflammatory molecular pathways, particularly those related to the NLRP3 inflammasome, may serve as common therapeutic targets for both cancer and HF. However, further mechanistic validation in preclinical models is essential, especially given the unclear role of the NLRP3 inflammasome (and its drivers) in both tumorigenesis and CVD.

Limitations of current models

Gaps between preclinical modelling and clinical observations in human patients

The interpretation of data from preclinical modelling is crucial for avoiding translational failures. 143 The aim is not only to avoid loss of time and the misallocation of funds and resources, but more importantly to avoid patients entering clinical phases that are doomed to fail or, conversely, to reduce the risk of promising new therapies being overlooked. Information obtained in the preclinical phase of a new chemical entity, or a new method, provides valuable insights during the clinical development phases. Ignoring or misinterpreting such signs has proven to be costly and even dangerous when candidate therapies enter clinical evaluation, leading to time and resources lost, and patients enrolled in fruitless trials. This underscores the importance of effective translational preclinical models and the need for precise preclinical model requirements to guide translational scientists.

Despite efforts to replicate the key features of human CTRCD, current preclinical models have significant limitations that need to be addressed in future research ( Table 3 , Figure 1 ). To accurately model CTRCD, it is essential to recognize that many anticancer treatments cause late‐onset cardiotoxicity, requiring the development of in vivo and in vitro models that reflect the progressive dysfunction observed in patients. 76 , 144 , 145 This can be accomplished by mimicking clinical regimens with repeated exposures to low to medium doses of anticancer drugs or radiotherapy. Yet, a significant number of preclinical studies still utilize in vivo or in vitro systems exposed to a single high dose of anticancer treatment, which raises concerns about the translational relevance of the study conclusions. Another important aspect to consider in preclinical modelling of CTRCD is species selection. For instance, the use of inappropriate animal species, such as rodents, has led to confusion in studies investigating the cardiotoxicity of the humanized monoclonal antibody trastuzumab, which does not bind to the equivalent of the HER2 receptor (Neu) in rats or mice. 92 Therefore, future research on the cardiac side effects of the emerging class of drugs known as antibody‐drug conjugates 156 should involve careful species selection or the use of humanized models, 157 particularly for those based on trastuzumab.

Efforts should also focus on modelling inter‐organ interactions, which are increasingly recognized as crucial in the pathogenesis of CTRCD. In this respect, despite increasing political pressure to reduce animal research in the European Union, animal models remain indispensable in basic cardio‐oncology studies. They play a crucial role in the translational pathway, providing the only means of gaining essential pathophysiological insights into disease mechanisms at both (inter)‐organ and systemic level. 98 Specifically, interactions between the myocardium and the primary target of anticancer therapies, the tumour, are essential to understand. While most basic cardio‐oncology research is conducted using tumour‐free models, growing evidence suggests that CTRCD can arise not only from the direct toxic effects of anticancer drugs on cardiac cells, but also from effects mediated through the tumour. Consequently, the effects of cancer therapy can vary depending on whether it is administered to tumour‐free or tumour‐bearing animals. For example, ICI therapy has been shown to induce left ventricular dysfunction in mice transplanted with syngeneic PD1‐sensitive melanomas but not in tumour‐free animals. 94 Therefore, employing tumour‐bearing models is advised to more accurately replicate all factors involved in CTRCD pathogenesis ( Table 3 ). In large animals, this approach is rarely feasible due to the lack of syngeneic tumour cell lines and immunocompromised strains. This limitation requires the use of immunosuppressive therapy, which can lead to severe and difficult‐to‐manage complications, 158 while also altering the effects of drugs or interventions. This limitation is effectively addressed by murine xenograft models, which utilize either syngeneic tumour cell implantation or human tumour cell inoculation in immunocompromised mice, as well as genetically engineered mice with spontaneous tumour growth ( Table 2 ). Additionally, in vitro heart‐tumour chips offer a promising alternative for studying these tumour–heart–drug interactions.

The immune system also plays a critical role in interacting with the myocardium and contributing to the development of CTRCD. However, immune cells are still rarely incorporated into in vitro models of CTRCD, highlighting the need for a more comprehensive use of cardiac slices and 2D and 3D co‐culture systems including inflammatory cells. 77

Finally, as previously pointed out, recognizing early warning signs in the translational phase is essential for drug development in cardiovascular medicine. Ignoring these signs could become costly and dangerous when candidate therapies move into clinical evaluation. 143

In conclusion, growing evidence suggests that genetic, 159 gender, 151 and ethnic 155 factors influence predisposition to CTRCD. While groundbreaking research using genomic editing of human iPSC have started validating significant variants identified in candidate‐gene and genome‐wide association studies, 160 , 161 , 162 gender and ethnic considerations have been largely overlooked in preclinical modelling of CTRCD. Therefore, future research should address these neglected aspects by increasing the inclusion of both male and female animals as well as utilizing in vitro model systems with cells from patients of diverse ethnic backgrounds.

Impact of limitations on regulatory paths and full development process

Pathways for drug approval are becoming increasingly complex, with both the European Medicines Agency and US Food and Drug Administration (FDA) focusing on accelerated approval pathways. Regulatory agencies face the challenge of balancing the demand for rapid access to new and effective drugs with the need for comprehensive safety and efficacy data prior to patient use. Unfortunately, drug development regulations in different therapeutic areas are far from harmonized, and this affects the number of new chemical entities reaching the market. 163 As an example, under the FDA's new ‘breakthrough therapy’, designation of the approvals granted from 1987 to 2017, approximately 50% were for oncology, 20% for infectious diseases, and none for CVDs. 164 There is no doubt that many CVDs, including the acute or chronic consequences of cancer treatment, should be considered severely‐debilitating or life‐threatening diseases, and it stands to reason that the approval of severely‐debilitating or life‐threatening disease therapeutics should parallel that of advanced oncology drugs. However, although the FDA provides regulatory guidelines for advanced cancer therapies, 165 there is minimal FDA guidance for the early development of drugs for severely‐debilitating or life‐threatening diseases for which there are few available therapeutic options. Consequently, from an industry business perspective, drug development projects in CVDs could become less attractive, which may contribute to the diversion of funds to other areas deemed more lucrative. A negative trend can be already seen in the percentages of new CVD treatment over the total approval by FDA in the latest decades: between 2000 and 2017, in fact, the approved CVD therapies over the total of the new approvals by FDA declined from 9.09% to 5.29%. 166 Industry‐funded development research will just focus elsewhere if the trend continues.

From an academic perspective, several factors can hinder or slow down the development process, including limited awareness and infrastructure for patenting, spin‐offs, and industry partnerships. Researchers often prioritize publishing over commercial applications, missing opportunities to translate innovations into practical solutions, particularly in fields like life sciences where intellectual property protection is crucial. Many lack knowledge of the patenting process, including optimal timing and procedures. While universities have technology transfer offices, their effectiveness varies, and structured pathways for spin‐offs are often lacking. Early industry collaborations, which provide funding and expertise, are underutilized due to limited connections and concerns over research independence. Strengthening academia–industry networks, improving intellectual property training, and fostering entrepreneurial support would help streamline the development process. 167 , 168

For these reasons, we cannot emphasize enough the need for continuous and open discussions between translational researchers, trialists, pharmaceutical industry representatives and regulatory authorities to ensure that cardio‐oncology is properly positioned in the regulatory compass and, overall, in the world health‐economic compass.

Conclusions and future directions

Over the past decade, cancer therapy has experienced a paradigm shift from non‐specific cytotoxic chemotherapies, such as anthracyclines, to more targeted treatments including monoclonal antibodies, TKIs, ICIs, and cell therapies. While these advancements have led to better clinical outcomes for patients with both solid and haematological malignancies, they also come with a broad spectrum of side effects, including cardiac toxicity. Consequently, the development of new anticancer drugs presents the challenge of uncovering the mechanisms underlying the relative CTRCD, which necessitates the creation of effective preclinical disease models. Although a combination of preclinical in vitro and in vivo models across various species has provided a comprehensive understanding of the cardiotoxicity associated with conventional anticancer therapies, the cardiac effects of some newer treatments are only beginning to be explored, while others remain largely unexplored and warrant future research. For instance, further investigation is required into the cardiac impact of cyclin‐dependent kinase 4/6 inhibitors 169 or the antibody‐drug conjugates – an innovative and evolving class of antineoplastic agents that combine monoclonal antibodies with biologically active drugs. 156 Furthermore, the potential interactions among cancer therapies in multimodal regimens have been insufficiently addressed in preclinical modelling, and thus warrant the attention of future studies.

The development of new immunotherapies, coupled with the growing recognition of the pivotal role of the immune system in CTRCD, and as a common denominator in cancer and HF, 170 underscores the importance of using immunocompetent animals and multicellular 2D and 3D model systems, encompassing, in addition to cardiomyocytes, fibroblasts (which possess inflammatory properties) 171 and immune cells. The mutual interaction between the tumour and the heart further supports the use of tumour‐bearing animals 94 and of heart‐tumour‐on‐a‐chip platforms. 147 Genetic predisposition to 154 and sex‐based differences in CTRCD 151 also highlight the importance of genomic editing of human iPSC for validation of significant genetic variants associated with CTRCD and the testing of anticancer therapies in both male and female cells/model systems. 152 Racial/ethnic disparity in CTRCD emphasizes the need for in vitro model systems with cells from patients with different ethnical background. 155 Finally, in view of personalized medicine, patient‐derived model systems may serve as predictive models of CTRCD. 172 Beyond the recognized use of patient‐specific iPSC‐CM and multicellular model systems, the use of cardiac slices derived from endomyocardial biopsies holds promise.

In conclusion, the emergence of novel anticancer drugs, the recognition of the role of the immune system in CTRCD, our increased understanding of the reciprocal relationship between the heart and cancer, and the growing appreciation for sex‐based and ethnic disparities of CTRCD are driving the development of novel, improved preclinical model systems and approaches to close the gap between preclinical models and clinical observations in patients.

Acknowledgement

Open access publishing facilitated by Università degli Studi di Torino, as part of the Wiley ‐ CRUI‐CARE agreement.

Funding

A.G. was supported by grants from the Italian Ministry of Health (GR‐2021‐12371950) and the Italian Ministry of Education, Universities and Research (PRIN 2022 20223YPL49; PRIN PNRR 2022 P2022ZB72T). P.A. was supported by PNRR‐MAD‐2022‐12376632 (CUP C63C22001360006) funded by the European Union ‐ Next Generation EU ‐ NRRP M6C2 ‐ Investment 2.1 Enhancement and strengthening of biomedical research in the NHS. A.A. is supported by NIH R01HL163172, R01HL166541, and R01HL157530; a sponsored research agreement with Genentech; and a HESI Thrive Award. R.A.d.B. is supported by the Netherlands Heart Foundation (grants 2020B005 and 01–003–2022‐0358) and by the European Research Council (ERC CoG 818715). A.Go. was supported by the Spanish Ministry of Science, Innovation and Universities (Instituto de Salud Carlos III: CB16/11/00483 and PI21/00946 co‐financed with ERDF funds and CIBERCV InCare project). B.I. is supported by grants from the European Commission (ERC‐CoG 819775 and H2020‐HEALTH 945118), the Spanish Ministry of Science and Innovation (PID2022‐140176OB‐I00), La Caixa Foundation (HR22‐00533), and the Red Madrileña de Nanomedicina en Imagen Molecular ‐Comunidad de Madrid (P2022/BMD‐7403 RENIM‐CM). A.R.L. is supported by the Fondation Leducq Network of Excellence in Cardio‐Oncology, the Royal Brompton Cardio‐Oncology Centre of Excellence and The Big Heart Foundation. K.S. is supported by grants from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (MODVASC, grant agreement No 759248), the German Research Foundation DFG (CRC1366 C07, project number 394046768), the Health+Life Science Alliance Heidelberg Mannheim GmbH and the Biotechnology and Biological Sciences Research Council (BBSRC) of the UK Research and Innovation (UKRI). K.S.B. is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, Project 471241922, CRC1213‐B07 and the research training group RTG2824). C.G.T. is supported by the Italian Ministry of Health (PNRR‐MAD‐2022‐12376632 and RF‐2016‐02362988). T.T. was supported by the ERC Advanced Grant REVERSE and the Deutsche Forschungsgemeinschaft (CRC1470). P.v.d.M. is supported by a grant from the European Research Council (ERC CoG 101045236, DISSECT‐HF). S.V.L. is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, CRC‐1470‐A07 and Project 536819681) and the Deutsche Krebshilfe (Project 70115119).

Conflict of interest : A.G. is co‐founder and shareholder of Kither Biotech, a pharmaceutical company focused on the development of PI3K inhibitors for airway diseases not in conflict with the content of this manuscript. P.A. received speaker and/or advisory fees from Boehringer Ingelheim, AstraZeneca, Bayer, Daiichi‐Sankyo, MSD, Janssen, and Gossamer Bio, outside the scope of this work. A.A. serves as the PI for a sponsored research agreement with Genentech, receives royalties from patent #US20210163495A1 (Mass General Brigham), and sits on the Board of Directors for Corventum, Inc. The institution of R.A.d.B. has received research grants and/or fees from Alnylam, AstraZeneca, Abbott, Bristol‐Myers Squibb, Cardior Pharmaceuticals GmbH, Novo Nordisk, and Roche; R.A.d.B. has had speaker engagements with and/or received fees from and/or served on an advisory board for Abbott, AstraZeneca, Bristol Myers Squibb, Cardior Pharmaceuticals GmbH, Novo Nordisk, and Roche; travel support from Abbott, Cardior Pharmaceuticals GmbH, and Novo Nordisk. D.F. reports speaker honoraria or consultation fees from Abbott Laboratories, AstraZeneca, Bayer, Boehringer Ingelheim, Leo, Roche Diagnostics and Viatris, outside the submitted work. S.H. receives personal fees for independent scientific advice on early development in the field of heart failure for AstraZeneca, Ribocure, and CSL Behring, and research support from AstraZeneca and CSL Behring. T.L.F. has received speaker, advisory board or consultancy fees from AstraZeneca, Bristol Myers Squibb, Roche, Janssens‐Cilag Ltd, Eisai Ltd, Myocardial Solutions, Philips, Bayer, Daiichi‐Sankyo and Beigene. A.R.L. has received speaker, advisory board or consultancy fees and/or research grants from Pfizer, Novartis, Servier, AstraZeneca, Bristol Myers Squibb, GSK, Astellas, Amgen, Takeda, Roche, Janssens‐Cilag Ltd, Clinigen Group, Eli Lily, Eisai Ltd, Ferring Pharmaceuticals, Boehringer Ingelheim, Akcea Therapeutics, Myocardial Solutions, iOWNA Health and Heartfelt Technologies Ltd. K.S.B. received research support from Novartis, BionTECH, and speaker honoraria from Novartis. C.G.T. has received honoraria or consultation fees from VivaLyfe, Univers Formazione, Solaris, Summeet, AstraZeneca, Medtronic, and Myocardial Solutions, and funding from Amgen and MSD, outside the submitted work, and is listed as an inventor of two patents related to heart failure. T.T. is founder and CSO/CMO of Cardior Pharmaceuticals GmbH, a wholly‐owned subsidiary of Novo Nordisk Europe A/S. The UMCG, which employs P.v.d.M., received consultancy fees and/or grants from Novartis, Pharmacosmos, Vifor Pharma, AstraZeneca, Pfizer, Pharma Nord, BridgeBio, Novo Nordisk, Daiichi Sankyo, Boehringer Ingelheim and Ionis. M.M. has received consulting honoraria from Abbott Structural Heart, AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences, Novo Nordisk, Pharmacosmos, Roche Diagnostics in the last 3 years. All other authors have nothing to disclose.

References

1 Lyon AR , Lopez‐Fernandez T , Couch LS , Asteggiano R , Aznar MC , Bergler‐Klein J , et al . 2022 ESC Guidelines on cardio‐oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio‐Oncology Society (IC‐OS) . Eur Heart J Cardiovasc Imaging 2022 ; 23 : e333 ‐ e465 . 10.1093/ehjci/jeac106 36017575

2 Asnani A , Moslehi JJ , Adhikari BB , Baik AH , Beyer AM , de Boer RA , et al .; American Heart Association Council on Basic Cardiovascular Sciences; Cardio‐Oncology Science Subcommittee of Council on Genomic and Precision Medicine and Council on Clinical Cardiology; Council on Peripheral Vascular Disease; and Council on Arteriosclerosis, Thrombosis and Vascular Biology . Preclinical models of cancer therapy‐associated cardiovascular toxicity: A scientific statement from the American Heart Association . Circ Res 2021 ; 129 : e21 – e34 . 10.1161/RES.0000000000000473 33934611 PMC8423100

3 Larsen CM , Garcia Arango M , Dasari H , Arciniegas Calle M , Adjei E , Rico Mesa J , et al . Association of anthracycline with heart failure in patients treated for breast cancer or lymphoma, 1985‐2010 . JAMA Netw Open 2023 ; 6 : e2254669 . 10.1001/jamanetworkopen.2022.54669 36735254 PMC9898820

4 Herrmann J , Lenihan D , Armenian S , Barac A , Blaes A , Cardinale D , et al . Defining cardiovascular toxicities of cancer therapies: An International Cardio‐Oncology Society (IC‐OS) consensus statement . Eur Heart J 2021 ; 43 : 280 – 299 . 10.1093/eurheartj/ehab674 PMC8803367 34904661

5 Salloum FN , Tocchetti CG , Ameri P , Ardehali H , Asnani A , de Boer RA , et al .; International Cardio‐Oncology Society . Priorities in cardio‐oncology basic and translational science: GCOS 2023 Symposium Proceedings: JACC: CardioOncology state‐of‐the‐art review . JACC CardioOncol 2023 ; 5 : 715 – 731 . 10.1016/j.jaccao.2023.08.003 38205010 PMC10774781

6 Farhad , H , Staziaki , PV , Addison D , Coelho‐Filho OR, Shah RV, Mitchell RN, et al Characterization of the changes in cardiac structure and function in mice treated with anthracyclines using serial cardiac magnetic resonance imaging . Circ Cardiovasc Imaging 2016 ; 9 : e003584 . 10.1161/CIRCIMAGING.115.003584 27923796 PMC5147427

7 Tocchetti CG , Ameri P , de Boer RA , D'Alessandra Y , Russo M , Sorriento D , et al . Cardiac dysfunction in cancer patients: Beyond direct cardiomyocyte damage of anticancer drugs: Novel cardio‐oncology insights from the joint 2019 meeting of the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart . Cardiovasc Res 2020 ; 116 : 1820 – 1834 . 10.1093/cvr/cvaa222 32683451

8 Ozcelik C , Erdmann B , Pilz B , Wettschureck N , Britsch S , Hübner N , et al . Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy . Proc Natl Acad Sci U S A 2002 ; 99 : 8880 – 8885 . 10.1073/pnas.122249299 12072561 PMC124392

9 Belmonte F , Das S , Sysa‐Shah P , Sivakumaran V , Stanley B , Guo X , et al . ErbB2 overexpression upregulates antioxidant enzymes, reduces basal levels of reactive oxygen species, and protects against doxorubicin cardiotoxicity . Am J Physiol Heart Circ Physiol 2015 ; 309 : H1271 ‐ 1280 . 10.1152/ajpheart.00517.2014 26254336 PMC4666964

10 Lyra‐Leite DM , Burridge PW . Pluripotent stem cell modeling of anticancer therapy‐induced cardiotoxicity . Curr Cardiol Rep 2020 ; 22 : 56 . 10.1007/s11886-020-01325-x 32562096 PMC11260186

11 Kitani T , Ong SG , Lam CK , Rhee JW , Zhang JZ , Oikonomopoulos A , et al . Human‐induced pluripotent stem cell model of trastuzumab‐induced cardiac dysfunction in patients with breast cancer . Circulation 2019 ; 139 : 2451 – 2465 . 10.1161/CIRCULATIONAHA.118.037357 30866650 PMC6528817

12 Xu Z , Gao Z , Fu H , Zeng Y , Jin Y , Xu B , et al . PTX3 from vascular endothelial cells contributes to trastuzumab‐induced cardiac complications . Cardiovasc Res 2023 ; 119 : 1250 – 1264 . 10.1093/cvr/cvad012 36651911 PMC10202646

13 Medeiros BC , Possick J , Fradley M . Cardiovascular, pulmonary, and metabolic toxicities complicating tyrosine kinase inhibitor therapy in chronic myeloid leukemia: Strategies for monitoring, detecting, and managing . Blood Rev 2018 ; 32 : 289 – 299 . 10.1016/j.blre.2018.01.004 29454474

14 Yan G , Han Z , Kwon Y , Jousma J , Nukala SB , Prosser BL , et al . Integrated stress response potentiates ponatinib‐induced cardiotoxicity . Circ Res 2024 ; 134 : 482 – 501 . 10.1161/CIRCRESAHA.123.323683 38323474 PMC10940206

15 Tousif S , Singh AP , Umbarkar P , Galindo C , Wheeler N , Toro Cora A , et al . Ponatinib drives cardiotoxicity by S100A8/A9‐NLRP3‐IL‐1β mediated inflammation . Circ Res 2023 ; 132 : 267 – 289 . 10.1161/CIRCRESAHA.122.321504 36625265 PMC9898181

16 Truitt R , Mu A , Corbin EA , Vite A , Brandimarto J , Ky B , et al . Increased afterload augments sunitinib‐induced cardiotoxicity in an engineered cardiac microtissue model . JACC Basic Transl Sci 2018 ; 3 : 265 – 276 . 10.1016/j.jacbts.2017.12.007 30062212 PMC6059907

17 Xiao L , Salem JE , Clauss S , Hanley A , Bapat A , Hulsmans M , et al . Ibrutinib‐mediated atrial fibrillation attributable to inhibition of C‐terminal Src kinase . Circulation 2020 ; 142 : 2443 – 2455 . 10.1161/CIRCULATIONAHA.120.049210 33092403 PMC9661397

18 Quartermaine C , Ghazi SM , Yasin A , Awan FT , Fradley M , Wiczer T , et al . Cardiovascular toxicities of BTK inhibitors in chronic lymphocytic leukemia: JACC: CardioOncology state‐of‐the‐art review . JACC CardioOncol 2023 ; 5 : 570 – 590 . 10.1016/j.jaccao.2023.09.002 37969643 PMC10635896

19 Mitchell JD , Cehic DA , Morgia M , Bergom C , Toohey J , Guerrero PA , et al . Cardiovascular manifestations from therapeutic radiation: A multidisciplinary expert consensus statement from the International Cardio‐Oncology Society . JACC CardioOncol 2021 ; 3 : 360 – 380 . 10.1016/j.jaccao.2021.06.003 34604797 PMC8463721

20 Lee CL , Lee JW , Daniel AR , Holbrook M , Hasapis S , Wright AO , et al . Characterization of cardiovascular injury in mice following partial‐heart irradiation with clinically relevant dose and fractionation . Radiother Oncol 2021 ; 157 : 155 – 162 . 10.1016/j.radonc.2021.01.023 33545252 PMC8480511

21 Sag CM , Wolff HA , Neumann K , Opiela MK , Zhang J , Steuer F , et al . Ionizing radiation regulates cardiac Ca handling via increased ROS and activated CaMKII . Basic Res Cardiol 2013 ; 108 : 385 . 10.1007/s00395-013-0385-6 24068185 PMC3898380

22 Morelli MB , Bongiovanni C , Da Pra S , Miano C , Sacchi F , Lauriola M , et al . Cardiotoxicity of anticancer drugs: Molecular mechanisms and strategies for cardioprotection . Front Cardiovasc Med 2022 ; 9 : 847012 . 10.3389/fcvm.2022.847012 35497981 PMC9051244

23 Thuny F , Naidoo J , Neilan TG . Cardiovascular complications of immune checkpoint inhibitors for cancer . Eur Heart J 2022 ; 43 : 4458 – 4468 . 10.1093/eurheartj/ehac456 36040835 PMC10263267

24 Ball S , Ghosh RK , Wongsaengsak S , Bandyopadhyay D , Ghosh GC , Aronow WS , et al . Cardiovascular toxicities of immune checkpoint inhibitors . J Am Coll Cardiol 2019 ; 74 : 1714 – 1727 . 10.1016/j.jacc.2019.07.079 31558256

25 Robert C , Schachter J , Long GV , Arance A , Grob JJ , Mortier L , et al .; KEYNOTE‐006 Investigators. Pembrolizumab versus ipilimumab in advanced melanoma . N Engl J Med 2015 ; 372 : 2521 – 2532 . 10.1056/NEJMoa1503093 25891173

26 Wolchok JD , Chiarion‐Sileni V , Gonzalez R , Rutkowski P , Grob J‐J , Cowey CL , et al . Overall survival with combined nivolumab and ipilimumab in advanced melanoma . N Engl J Med 2017 ; 377 : 1345 – 1356 . 10.1056/NEJMoa1709684 28889792 PMC5706778

27 Martins F , Sofiya L , Sykiotis GP , Lamine F , Maillard M , Fraga M , et al . Adverse effects of immune‐checkpoint inhibitors: Epidemiology, management and surveillance . Nat Rev Clin Oncol 2019 ; 16 : 563 – 580 . 10.1038/s41571-019-0218-0 31092901

28 D'Souza M , Nielsen D , Svane IM , D'Souza M , Iversen K , Rasmussen PV , et al . The risk of cardiac events in patients receiving immune checkpoint inhibitors: A nationwide Danish study . Eur Heart J 2020 ; 42 : 1621 – 1631 . 10.1093/eurheartj/ehaa884 33291147

29 Moslehi JJ , Salem JE , Sosman JA , Lebrun‐Vignes B , Johnson DB . Increased reporting of fatal immune checkpoint inhibitor‐associated myocarditis . Lancet 2018 ; 391 : 933 . 10.1016/S0140-6736(18)30533-6 PMC6668330 29536852

30 Rubio‐Infante N , Ramirez‐Flores YA , Castillo EC , Lozano O , García‐Rivas G , Torre‐Amione G . Cardiotoxicity associated with immune checkpoint inhibitor therapy: A meta‐analysis . Eur J Heart Fail 2021 ; 23 : 1739 – 1747 . 10.1002/ejhf.2289 34196077

31 Tocchetti CG , Farmakis D , Koop Y , Andres MS , Couch LS , Formisano L , et al . Cardiovascular toxicities of immune therapies for cancer – a scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Council of Cardio‐Oncology . Eur J Heart Fail 2024 ; 26 : 2055 – 2076 . 10.1002/ejhf.3340 39087551

32 Gergely TG , Drobni ZD , Kallikourdis M , Zhu H , Meijers WC , Neilan TG , et al . Immune checkpoints in cardiac physiology and pathology: Therapeutic targets for heart failure . Nat Rev Cardiol 2024 ; 21 : 443 – 462 . 10.1038/s41569-023-00986-9 38279046

33 Grabie N , Lichtman AH , Padera R . T cell checkpoint regulators in the heart . Cardiovasc Res 2019 ; 115 : 869 – 877 . 10.1093/cvr/cvz025 30721928 PMC6452292

34 Axelrod ML , Meijers WC , Screever EM , Qin J , Carroll MG , Sun X , et al . T cells specific for α‐myosin drive immunotherapy‐related myocarditis . Nature 2022 ; 611 : 818 – 826 . 10.1038/s41586-022-05432-3 36385524 PMC9930174

35 Wei SC , Meijers WC , Axelrod ML , Anang NAS , Screever EM , Wescott EC , et al . A genetic mouse model recapitulates immune checkpoint inhibitor‐associated myocarditis and supports a mechanism‐based therapeutic intervention . Cancer Discov 2021 ; 11 : 614 – 625 . 10.1158/2159-8290.CD-20-0856 33257470 PMC8041233

36 Cortellino S , Quagliariello V , Delfanti G , Blaževitš O , Chiodoni C , Maurea N , et al . Fasting mimicking diet in mice delays cancer growth and reduces immunotherapy‐associated cardiovascular and systemic side effects . Nat Commun 2023 ; 14 : 5529 . 10.1038/s41467-023-41066-3 37684243 PMC10491752

37 Fenioux C , Abbar B , Boussouar S , Bretagne M , Power JR , Moslehi JJ , et al . Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis . Nat Med 2023 ; 29 : 3100 – 3110 . 10.1038/s41591-023-02591-2 37884625

38 Irvine DJ , Maus MV , Mooney DJ , Wong WW . The future of engineered immune cell therapies . Science 2022 ; 378 : 853 – 858 . 10.1126/science.abq6990 36423279 PMC9919886

39 Baker DJ , Arany Z , Baur JA , Epstein JA , June CH . CAR T therapy beyond cancer: The evolution of a living drug . Nature 2023 ; 619 : 707 – 715 . 10.1038/s41586-023-06243-w 37495877 PMC12522170

40 Fajgenbaum DC , June CH . Cytokine storm . N Engl J Med 2020 ; 383 : 2255 – 2273 . 10.1056/NEJMra2026131 33264547 PMC7727315

41 Lee DW , Santomasso BD , Locke FL , Ghobadi A , Turtle CJ , Brudno JN , et al . ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells . Biol Blood Marrow Transplant 2019 ; 25 : 625 – 638 . 10.1016/j.bbmt.2018.12.758 30592986 PMC12180426

42 Jamali A , Ho N , Braun A , Adabi E , Thalheimer FB , Buchholz CJ . Early induction of cytokine release syndrome by rapidly generated CAR T cells in preclinical models . EMBO Mol Med 2024 ; 16 : 784 – 804 . 10.1038/s44321-024-00055-9 38514793 PMC11018744

43 Giavridis T , van der Stegen SJC , Eyquem J , Hamieh M , Piersigilli A , Sadelain M . CAR T cell‐induced cytokine release syndrome is mediated by macrophages and abated by IL‐1 blockade . Nat Med 2018 ; 24 : 731 – 738 . 10.1038/s41591-018-0041-7 29808005 PMC6410714

44 Li X , Gong N , Tian F , Zhang S , Zhang Y , Wang Y , et al . Suppression of cytokine release syndrome during CAR‐T‐cell therapy via a subcutaneously injected interleukin‐6‐adsorbing hydrogel . Nat Biomed Eng 2023 ; 7 : 1129 – 1141 . 10.1038/s41551-023-01084-4 37696984

45 Gelfo V , Romaniello D , Mazzeschi M , Sgarzi M , Grilli G , Morselli A , et al . Roles of IL‐1 in cancer: From tumor progression to resistance to targeted therapies . Int J Mol Sci 2020 ; 21 : 6009 . 10.3390/ijms21176009 32825489 PMC7503335

46 Lee DW , Gardner R , Porter DL , Louis CU , Ahmed N , Jensen M , et al . Current concepts in the diagnosis and management of cytokine release syndrome . Blood 2014 ; 124 : 188 – 195 . 10.1182/blood-2014-05-552729 24876563 PMC4093680

47 Alvi RM , Frigault MJ , Fradley MG , Jain MD , Mahmood SS , Awadalla M , et al . Cardiovascular events among adults treated with chimeric antigen receptor T‐cells (CAR‐T) . J Am Coll Cardiol 2019 ; 74 : 3099 – 3108 . 10.1016/j.jacc.2019.10.038 31856966 PMC6938409

48 Salem JE , Ederhy S , Lebrun‐Vignes B , Moslehi JJ . Cardiac events associated with chimeric antigen receptor T‐cells (CAR‐T): A VigiBase perspective . J Am Coll Cardiol 2020 ; 75 : 2521 – 2523 . 10.1016/j.jacc.2020.02.070 32408984

49 Lefebvre B , Kang Y , Smith AM , Frey NV , Carver JR , Scherrer‐Crosbie M . Cardiovascular effects of CAR T cell therapy . JACC CardioOncol 2020 ; 2 : 193 – 203 . 10.1016/j.jaccao.2020.04.012 32776016 PMC7413146

50 Ganatra S , Redd R , Hayek SS , Parikh R , Azam T , Yanik GA , et al . Chimeric antigen receptor T‐cell therapy‐associated cardiomyopathy in patients with refractory or relapsed non‐Hodgkin lymphoma . Circulation 2020 ; 142 : 1687 – 1690 . 10.1161/CIRCULATIONAHA.120.048100 33104402

51 Goldman A , Maor E , Bomze D , Liu JE , Herrmann J , Fein J , et al . Adverse cardiovascular and pulmonary events associated with chimeric antigen receptor T‐cell therapy . J Am Coll Cardiol 2021 ; 78 : 1800 – 1813 . 10.1016/j.jacc.2021.08.044 34711339 PMC8562317

52 Qi K , Yan Z , Cheng H , Chen W , Wang Y , Wang X , et al . An analysis of cardiac disorders associated with chimeric antigen receptor T cell therapy in 126 patients: A single‐centre retrospective study . Front Oncol 2021 ; 11 : 691064 . 10.3389/fonc.2021.691064 34195092 PMC8237759

53 Lee DH , Kumar A , Mohammed T , Peres LC , Alsina M , Bachmeier C , et al . Cardiac events after standard of care idecabtagene vicleucel for relapsed and refractory multiple myeloma . Blood Adv 2023 ; 7 : 4247 – 4257 . 10.1182/bloodadvances.2023009766 37307173 PMC10424134

54 Lefebvre B , Kang Y , Vakilpour A , Onoue T , Frey NV , Brahmbhatt P , et al . Incidence of MACE in patients treated with CAR‐T cell therapy: A prospective study . JACC CardioOncol 2023 ; 5 : 747 – 754 . 10.1016/j.jaccao.2023.07.009 38204993 PMC10774789

55 Mahmood SS , Riedell PA , Feldman S , George G , Sansoterra SA , Althaus T , et al . Biomarkers and cardiovascular outcomes in chimeric antigen receptor T‐cell therapy recipients . Eur Heart J 2023 ; 44 : 2029 – 2042 . 10.1093/eurheartj/ehad117 36939851 PMC10256191

56 Korell F , Entenmann L , Romann S , Giannitsis E , Schmitt A , Müller‐Tidow C , et al . Evaluation of all‐cause mortality and cardiovascular safety in patients receiving chimeric antigen receptor T cell therapy: A prospective cohort study . EClinicalMedicine 2024 ; 69 : 102504 . 10.1016/j.eclinm.2024.102504 38544797 PMC10965403

57 Norelli M , Camisa B , Barbiera G , Falcone L , Purevdorj A , Genua M , et al . Monocyte‐derived IL‐1 and IL‐6 are differentially required for cytokine‐release syndrome and neurotoxicity due to CAR T cells . Nat Med 2018 ; 24 : 739 – 748 . 10.1038/s41591-018-0036-4 29808007

58 Pathan N , Hemingway CA , Alizadeh AA , Stephens AC , Boldrick JC , Oragui EE , et al . Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock . Lancet 2004 ; 363 : 203 – 209 . 10.1016/S0140-6736(03)15326-3 14738793

59 Shafer P , Kelly LM , Hoyos V . Cancer therapy with TCR‐engineered T cells: Current strategies, challenges, and prospects . Front Immunol 2022 ; 13 : 835762 . 10.3389/fimmu.2022.835762 35309357 PMC8928448

60 Cameron BJ , Gerry AB , Dukes J , Harper JV , Kannan V , Bianchi FC , et al . Identification of a titin‐derived HLA‐A1‐presented peptide as a cross‐reactive target for engineered MAGE A3‐directed T cells . Sci Transl Med 2013 ; 5 : 197ra103 . 10.1126/scitranslmed.3006034 PMC6002776 23926201

61 Linette GP , Stadtmauer EA , Maus MV , Rapoport AP , Levine BL , Emery L , et al . Cardiovascular toxicity and titin cross‐reactivity of affinity‐enhanced T cells in myeloma and melanoma . Blood 2013 ; 122 : 863 – 871 . 10.1182/blood-2013-03-490565 23770775 PMC3743463

62 Burridge PW , Li YF , Matsa E , Wu H , Ong SG , Sharma A , et al . Human induced pluripotent stem cell‐derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin‐induced cardiotoxicity . Nature Med 2016 ; 22 : 547 – 556 . 10.1038/nm.4087 27089514 PMC5086256

63 Sang L , Zhou Z , Luo S , Zhang Y , Qian H , Zhou Y , et al . An in silico platform to predict cardiotoxicity risk of anti‐tumor drug combination with hiPSC‐CMs based in vitro study . Pharm Res 2024 ; 41 : 247 – 262 . 10.1007/s11095-023-03644-4 38148384 PMC10879352

64 Pinheiro EA , Fetterman KA , Burridge PW . hiPSCs in cardio‐oncology: Deciphering the genomics . Cardiovasc Res 2019 ; 115 : 935 – 948 . 10.1093/cvr/cvz018 30689737 PMC6452310

65 Karhu ST , Kinnunen SM , Tolli M , Valimaki MJ , Szabo Z , Talman V , et al . GATA4‐targeted compound exhibits cardioprotective actions against doxorubicin‐induced toxicity in vitro and in vivo: Establishment of a chronic cardiotoxicity model using human iPSC‐derived cardiomyocytes . Arch Toxicol 2020 ; 94 : 2113 – 2130 . 10.1007/s00204-020-02711-8 32185414 PMC7303099

66 Maillet A , Tan K , Chai X , Sadananda SN , Mehta A , Ooi J , et al . Modeling doxorubicin‐induced cardiotoxicity in human pluripotent stem cell derived‐cardiomyocytes . Sci Rep 2016 ; 6 : 25333 . 10.1038/srep25333 27142468 PMC4855185

67 Chatterjee S , Hofer T , Costa A , Lu D , Batkai S , Gupta SK , et al . Telomerase therapy attenuates cardiotoxic effects of doxorubicin . Mol Ther 2021 ; 29 : 1395 – 1410 . 10.1016/j.ymthe.2020.12.035 33388418 PMC8058493

68 Haupt LP , Rebs S , Maurer W , Hübscher D , Tiburcy M , Pabel S , et al . Doxorubicin induces cardiotoxicity in a pluripotent stem cell model of aggressive B cell lymphoma cancer patients . Basic Res Cardiol 2022 ; 117 : 13 . 10.1007/s00395-022-00918-7 35260914 PMC8904375

69 Reinal I , Ontoria‐Oviedo I , Selva M , Casini M , Peiró‐Molina E , Fambuena‐Santos C , et al . Modeling cardiotoxicity in pediatric oncology patients using patient‐specific iPSC‐derived cardiomyocytes reveals downregulation of cardioprotective microRNAs . Antioxidants (Basel) 2023 ; 12 : 1378 . 10.3390/antiox12071378 37507917 PMC10376252

70 Lu D , Chatterjee S , Xiao K , Riedel I , Huang CK , Costa A , et al . A circular RNA derived from the insulin receptor locus protects against doxorubicin‐induced cardiotoxicity . Eur Heart J 2022 ; 43 : 4496 – 4511 . 10.1093/eurheartj/ehac337 35758064 PMC9637424

71 Rassaf T , Totzeck M , Backs J , Bokemeyer C , Hallek M , Hilfiker‐Kleiner D , et al . Onco‐cardiology: Consensus paper of the German Cardiac Society, the German Society for Pediatric Cardiology and Congenital Heart Defects and the German Society for Hematology and Medical Oncology . Clin Res Cardiol 2020 ; 109 : 1197 – 1222 . 10.1007/s00392-020-01636-7 32405737 PMC7515958

72 Wojnowski L , Kulle B , Schirmer M , Schlüter G , Schmidt A , Rosenberger A , et al . NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin‐induced cardiotoxicity . Circulation 2005 ; 112 : 3754 – 3762 . 10.1161/CIRCULATIONAHA.105.576850 16330681

73 Kane C , Couch L , Terracciano CM . Excitation‐contraction coupling of human induced pluripotent stem cell‐derived cardiomyocytes . Front Cell Dev Biol 2015 ; 3 : 59 . 10.3389/fcell.2015.00059 26484342 PMC4586503

74 Bliley , JM , Vermeer , M , Duffy , RM , Batalov I , Kramer D , Tashman JW , et al Dynamic loading of human engineered heart tissue enhances contractile function and drives a desmosome‐linked disease phenotype . Sci Transl Med 2021 ; 13 : 1 – 15 . 10.1126/scitranslmed.abd1817 34290054

75 Tiburcy M , Hudson JE , Balfanz P , Schlick S , Meyer T , Chang Liao ML , et al . Defined engineered human myocardium with advanced maturation for applications in heart failure modeling and repair . Circulation 2017 ; 135 : 1832 – 1847 . 10.1161/CIRCULATIONAHA.116.024145 28167635 PMC5501412

76 Linders AN , Dias IB , Ovchinnikova ES , Vermeer MCSC , Hoes MF , Markousis Mavrogenis G , et al . Evaluation of senescence and its prevention in doxorubicin‐induced cardiotoxicity using dynamic engineered heart tissues . JACC CardioOncol 2023 ; 5 : 298 – 315 . 10.1016/j.jaccao.2023.03.012 37397084 PMC10308053

77 Long C , Guo R , Han R , Li K , Wan Y , Xu J , et al . Effects of macrophages on the proliferation and cardiac differentiation of human induced pluripotent stem cells . Cell Commun Signal 2022 ; 20 : 108 . 10.1186/s12964-022-00916-1 35850719 PMC9290307

78 Emanuelli G , Zoccarato A , Reumiller CM , Papadopoulos A , Chong M , Rebs S , et al . A roadmap for the characterization of energy metabolism in human cardiomyocytes derived from induced pluripotent stem cells . J Mol Cell Cardiol 2022 ; 164 : 136 – 147 . 10.1016/j.yjmcc.2021.12.001 34923199

79 Ronaldson‐Bouchard K , Ma SP , Yeager K , Chen T , Song LJ , Sirabella D , et al . Advanced maturation of human cardiac tissue grown from pluripotent stem cells . Nature 2018 ; 556 : 239 – 243 . 10.1038/s41586-018-0016-3 29618819 PMC5895513

80 Gintant G , Burridge P , Gepstein L , Harding S , Herron T , Hong C , et al . Use of human induced pluripotent stem cell‐derived cardiomyocytes in preclinical cancer drug cardiotoxicity testing: A scientific statement from the American Heart Association . Circ Res 2019 ; 125 : e75 – e92 . 10.1161/RES.0000000000000291 31533542 PMC7398423

81 Lyra‐Leite DM , Copley RR , Freeman PP , Pongpamorn P , Shah D , McKenna DE , et al . Nutritional requirements of human induced pluripotent stem cells . Stem Cell Reports 2023 ; 18 : 1371 – 1387 . 10.1016/j.stemcr.2023.05.004 37315525 PMC10277817

82 Lyra‐Leite DM , Fonoudi H , Gharib M , Burridge PW . An updated protocol for the cost‐effective and weekend‐free culture of human induced pluripotent stem cells . STAR Protoc 2021 ; 2 : 100213 . 10.1016/j.xpro.2020.100213 33786455 PMC7988236

83 Ou Q , Jacobson Z , Abouleisa RRE , Tang XL , Hindi SM , Kumar A , et al . Physiological biomimetic culture system for pig and human heart slices . Circ Res 2019 ; 125 : 628 – 642 . 10.1161/CIRCRESAHA.119.314996 31310161 PMC6715512

84 Shi R , Reichardt M , Fiegle DJ , Küpfer LK , Czajka T , Sun Z , et al . Contractility measurements for cardiotoxicity screening with ventricular myocardial slices of pigs . Cardiovasc Res 2023 ; 119 : 2469 – 2481 . 10.1093/cvr/cvad141 37934066 PMC10651213

85 Boukhalfa A , Robinson SR , Meola DM , Robinson NA , Ling LA , LaMastro JN , et al . Using cultured canine cardiac slices to model the autophagic flux with doxorubicin . PLoS One 2023 ; 18 : e0282859 . 10.1371/journal.pone.0282859 36928870 PMC10019679

86 Miller JM , Meki MH , Ou Q , George SA , Gams A , Abouleisa RRE , et al . Heart slice culture system reliably demonstrates clinical drug‐related cardiotoxicity . Toxicol Appl Pharmacol 2020 ; 406 : 115213 . 10.1016/j.taap.2020.115213 32877659 PMC7554180

87 Liu Y , Asnani A , Zou L , Bentley VL , Yu M , Wang Y , et al . Visnagin protects against doxorubicin‐induced cardiomyopathy through modulation of mitochondrial malate dehydrogenase . Sci Transl Med 2014 ; 6 : 266ra170 . 10.1126/scitranslmed.3010189 PMC4360984 25504881

88 Zhu JJ , Xu YQ , He JH , Yu HP , Huang CJ , Gao JM , et al . Human cardiotoxic drugs delivered by soaking and microinjection induce cardiovascular toxicity in zebrafish . J Appl Toxicol 2014 ; 34 : 139 – 148 . 10.1002/jat.2843 23307606

89 Cheng H , Kari G , Dicker AP , Rodeck U , Koch WJ , Force T . A novel preclinical strategy for identifying cardiotoxic kinase inhibitors and mechanisms of cardiotoxicity . Circ Res 2011 ; 109 : 1401 – 1409 . 10.1161/CIRCRESAHA.111.255695 21998323 PMC3908774

90 Singh AP , Glennon MS , Umbarkar P , Gupte M , Galindo CL , Zhang Q , et al . Ponatinib‐induced cardiotoxicity: Delineating the signalling mechanisms and potential rescue strategies . Cardiovasc Res 2019 ; 115 : 966 – 977 . 10.1093/cvr/cvz006 30629146 PMC6452321

91 Sawicki KT , Sala V , Prever L , Hirsch E , Ardehali H , Ghigo A . Preventing and treating anthracycline cardiotoxicity: New insights . Annu Rev Pharmacol Toxicol 2021 ; 61 : 309 – 332 . 10.1146/annurev-pharmtox-030620-104842 33022184

92 Lewis Phillips G , Guo J , Kiefer JR , Proctor W , Bumbaca Yadav D , Dybdal N , et al . Trastuzumab does not bind rat or mouse ErbB2/neu: Implications for selection of non‐clinical safety models for trastuzumab‐based therapeutics . Breast Cancer Res Treat 2022 ; 191 : 303 – 317 . 10.1007/s10549-021-06427-w 34708303 PMC8763818

93 Yong CS , Sharkey J , Duscio B , Yong CSM , Venville B , Wei WZ , et al . Embryonic lethality in homozygous human Her‐2 transgenic mice due to disruption of the Pds5b gene . PLoS One 2015 ; 10 : e0136817 . 10.1371/journal.pone.0136817 26334628 PMC4559457

94 Michel L , Helfrich I , Hendgen‐Cotta UB , Mincu RI , Korste S , Mrotzek SM , et al . Targeting early stages of cardiotoxicity from anti‐PD1 immune checkpoint inhibitor therapy . Eur Heart J 2021 ; 43 : 316 – 329 . 10.1093/eurheartj/ehab430 34389849

95 Liu X , Wu W , Fang L , Liu Y , Chen W . TNF‐alpha inhibitors and other biologic agents for the treatment of immune checkpoint inhibitor‐induced myocarditis . Front Immunol 2022 ; 13 : 922782 . 10.3389/fimmu.2022.922782 35844550 PMC9283712

96 Amgalan D , Garner TP , Pekson R , Jia XF , Yanamandala M , Paulino V , et al . A small‐molecule allosteric inhibitor of BAX protects against doxorubicin‐induced cardiomyopathy . Nat Cancer 2020 ; 1 : 315 – 328 . 10.1038/s43018-020-0039-1 32776015 PMC7413180

97 Li M , Sala V , De Santis MC , Cimino J , Cappello P , Pianca N , et al . Phosphoinositide 3‐kinase gamma inhibition protects from anthracycline cardiotoxicity and reduces tumor growth . Circulation 2018 ; 138 : 696 – 711 . 10.1161/CIRCULATIONAHA.117.030352 29348263

98 van der Velden J , Asselbergs FW , Bakkers J , Batkai S , Bertrand L , Bezzina CR , et al . Animal models and animal‐free innovations for cardiovascular research: Current status and routes to be explored. Consensus document of the ESC Working Group on Myocardial Function and the ESC Working Group on Cellular Biology of the Heart . Cardiovasc Res 2022 ; 118 : 3016 – 3051 . 10.1093/cvr/cvab370 34999816 PMC9732557

99 Bartoli CR , Brittian KR , Giridharan GA , Koenig SC , Hamid T , Prabhu SD . Bovine model of doxorubicin‐induced cardiomyopathy . J Biomed Biotechnol 2011 ; 2011 : 758736 . 10.1155/2011/758736 21253525 PMC3018676

100 Carbone A , Psaltis PJ , Nelson AJ , Metcalf R , Richardson JD , Weightman M , et al . Dietary omega‐3 supplementation exacerbates left ventricular dysfunction in an ovine model of anthracycline‐induced cardiotoxicity . J Card Fail 2012 ; 18 : 502 – 511 . 10.1016/j.cardfail.2012.03.005 22633309

101 Engwall MJ , Everds N , Turk JR , Vargas HM . The effects of repeat‐dose doxorubicin on cardiovascular functional endpoints and biomarkers in the telemetry‐equipped Cynomolgus monkey . Front Cardiovasc Med 2021 ; 8 : 587149 . 10.3389/fcvm.2021.587149 33708802 PMC7941602

102 Galan‐Arriola C , Lobo M , Vilchez‐Tschischke JP , López GJ, de Molina‐Iracheta A, Pérez‐Martínez C, et al . Serial magnetic resonance imaging to identify early stages of anthracycline‐induced cardiotoxicity . J Am Coll Cardiol 2019 ; 73 : 779 – 791 . 10.1016/j.jacc.2018.11.046 30784671

103 Galan‐Arriola C , Vilchez‐Tschischke JP , Lobo M , López GJ, de Molina‐Iracheta A, Pérez‐Martínez C, et al . Coronary microcirculation damage in anthracycline cardiotoxicity . Cardiovasc Res 2022 ; 118 : 531 – 541 . 10.1093/cvr/cvab053 33605403 PMC8803079

104 Melendez GC , Vasu S , Lesnefsky EJ , Kaplan JR , Appt S , D'Agostino RB Jr , et al . Myocardial extracellular and cardiomyocyte volume expand after doxorubicin treatment similar to adjuvant breast cancer therapy . JACC Cardiovasc Imaging 2020 ; 13 : 1084 – 1085 . 10.1016/j.jcmg.2019.10.020 31864989 PMC7887569

105 Muehlberg F , Funk S , Zange L , von Knobelsdorff‐Brenkenhoff F , Blaszczyk E , Schulz A , et al . Native myocardial T1 time can predict development of subsequent anthracycline‐induced cardiomyopathy . ESC Heart Fail 2018 ; 5 : 620 – 629 . 10.1002/ehf2.12277 29673122 PMC6073029

106 Giusca S , Korosoglou G , Montenbruck M , Geršak B , Schwarz AK , Esch S , et al . Multiparametric early detection and prediction of cardiotoxicity using myocardial strain, T1 and T2 mapping, and biochemical markers: A longitudinal cardiac resonance imaging study during 2 years of follow‐up . Circ Cardiovasc Imaging 2021 ; 14 : e012459 . 10.1161/CIRCIMAGING.121.012459 34126756 PMC8208092

107 Martin‐Garcia A , Diaz‐Pelaez E , Lopez‐Corral L , Sanchez‐Pablo C , Macias de Plasencia G , Galan‐Arriola C , et al . T2 mapping identifies early anthracycline‐induced cardiotoxicity in elderly patients with cancer . JACC Cardiovasc Imaging 2020 ; 13 : 1630 – 1632 . 10.1016/j.jcmg.2020.01.017 32199840

108 Galan‐Arriola C , Villena‐Gutierrez R , Higuero‐Verdejo MI , Díaz‐Rengifo IA, Pizarro G, López GJ, et al . Remote ischaemic preconditioning ameliorates anthracycline‐induced cardiotoxicity and preserves mitochondrial integrity . Cardiovasc Res 2021 ; 117 : 1132 – 1143 . 10.1093/cvr/cvaa181 32597960 PMC7983009

109 Aboumsallem JP , Moslehi J , de Boer RA . Reverse cardio‐oncology: Cancer development in patients with cardiovascular disease . J Am Heart Assoc 2020 ; 9 : e013754 . 10.1161/JAHA.119.013754 31960736 PMC7033852

110 Bertero E , Robusto F , Rulli E , D'Ettorre A , Bisceglia L , Staszewsky L , et al . Cancer incidence and mortality according to pre‐existing heart failure in a community‐based cohort . JACC CardioOncol 2022 ; 4 : 98 – 109 . 10.1016/j.jaccao.2021.11.007 35492831 PMC9040106

111 Jaiswal V , Ang SP , Agrawal V , Hameed M , Saleeb MRA , Jaiswal A , et al . Association between heart failure and the incidence of cancer: A systematic review and meta‐analysis . Eur Heart J Open 2023 ; 3 : oead073 . 10.1093/ehjopen/oead073 37818223 PMC10561890

112 de Wit S , Aboumsallem JP , Shi C , Schouten EM , Bracun V , Meijers WC , et al . Pressure overload‐induced cardiac hypertrophy stimulates tumor growth in tumor‐prone Apc Min mice . Circ Heart Fail 2023 ; 16 : e010740 . 10.1161/CIRCHEARTFAILURE.123.010740 37609881

113 Meijers WC , Maglione M , Bakker SJL , Oberhuber R , Kieneker LM , de Jong S , et al . Heart failure stimulates tumor growth by circulating factors . Circulation 2018 ; 138 : 678 – 691 . 10.1161/CIRCULATIONAHA.117.030816 29459363

114 Avraham S , Abu‐Sharki S , Shofti R , Haas T , Korin B , Kalfon R , et al . Early cardiac remodeling promotes tumor growth and metastasis . Circulation 2020 ; 142 : 670 – 683 . 10.1161/CIRCULATIONAHA.120.046471 32475164

115 Langier Goncalves I , Awwad L , Aviram S , Izraeli T , Achlaug L , Aronheim A . Heart failure promotes cancer progression in an integrin β1‐dependent manner . Int J Mol Sci 2023 ; 24 : 17367 . 10.3390/ijms242417367 38139195 PMC10744241

116 de Wit W , Geerlings L , Shi C , Dronkers J , Schouten EM , Blancke G , et al . Heart failure‐induced microbial dysbiosis contributes to colonic tumour formation in mice . Cardiovasc Res 2024 ; 120 : 612 – 622 . 10.1093/cvr/cvae038 38400709 PMC11074794

117 Tani T , Oikawa M , Misaka T , Ishida T , Takeishi Y . Heart failure post‐myocardial infarction promotes mammary tumor growth through the NGF‐TRKA pathway . JACC CardioOncol 2024 ; 6 : 55 – 66 . 10.1016/j.jaccao.2023.10.002 38510296 PMC10950436

118 Koelwyn GJ , Newman AAC , van Afonso MS , Solingen C , Corr EM , Brown EJ , et al . Myocardial infarction accelerates breast cancer via innate immune reprogramming . Nat Med 2020 ; 26 : 1452 – 1458 . 10.1038/s41591-020-0964-7 32661390 PMC7789095

119 Shi C , Aboumsallem JP , de Wit S , Schouten EM , Bracun V , Meijers WC , et al . Evaluation of renal cancer progression in a mouse model of heart failure . Cancer Commun (Lond) 2021 ; 41 : 796 – 799 . 10.1002/cac2.12185 34240830 PMC8360637

120 Awwad L , Aronheim A . Cardiac dysfunction promotes cancer progression via multiple secreted factors . Cancer Res 2022 ; 82 : 1753 – 1761 . 10.1158/0008-5472.CAN-21-2463 35260887 PMC9359722

121 Awwad L , Goldenberg T , Langier‐Goncalves I , Aronheim A . Cardiac remodeling in the absence of cardiac contractile dysfunction is sufficient to promote cancer progression . Cells 2022 ; 11 : 1108 . 10.3390/cells11071108 35406672 PMC8997578

122 Koelwyn GJ , Aboumsallem JP , Moore KJ , de Boer RA . Reverse cardio‐oncology: Exploring the effects of cardiovascular disease on cancer pathogenesis . J Mol Cell Cardiol 2022 ; 163 : 1 – 8 . 10.1016/j.yjmcc.2021.09.008 34582824 PMC8816816

123 Bertero E , Carmisciano L , Jonasson C , Butler J , Maack C , Ameri P . Association of inflammatory markers with incident heart failure or cancer in the HUNT3 and Health ABC population studies . Eur J Prev Cardiol 2024 ; 31 : 1400 – 1407 . 10.1093/eurjpc/zwae089 38429011

124 Jovani M , Liu EE , Paniagua SM , Lau ES , Li SX , Takvorian KS , et al . Cardiovascular disease related circulating biomarkers and cancer incidence and mortality: Is there an association? Cardiovasc Res 2022 ; 118 : 2317 – 2328 . 10.1093/cvr/cvab282 34469519 PMC9328284

125 Meijers WC , de Boer RA . Common risk factors for heart failure and cancer . Cardiovasc Res 2019 ; 115 : 844 – 853 . 10.1093/cvr/cvz035 30715247 PMC6452432

126 Garlanda C , Mantovani A . Interleukin‐1 in tumor progression, therapy, and prevention . Cancer Cell 2021 ; 39 : 1023 – 1027 . 10.1016/j.ccell.2021.04.011 33989512

127 Ridker PM , Everett BM , Thuren T , MacFadyen JG , Chang WH , Ballantyne C , et al .; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease . N Engl J Med 2017 ; 377 : 1119 – 1131 . 10.1056/NEJMoa1707914 28845751

128 Ridker PM MacFadyen JG Thuren T B. M. Everett P. Libby R. J. Glynn , et al .; CANTOS Trial Group. Effect of interleukin‐1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: Exploratory results from a randomised, double‐blind, placebo‐controlled trial Lancet 2017 390 1833 1842 10.1016/S0140-6736(17)32247-X 10105 28855077

129 Wong CC , Baum J , Silvestro A , Beste MT , Bharani‐Dharan B , Xu S , et al . Inhibition of IL1β by canakinumab may be effective against diverse molecular subtypes of lung cancer: An exploratory analysis of the CANTOS trial . Cancer Res 2020 ; 80 : 5597 – 5605 . 10.1158/0008-5472.CAN-19-3176 33023946

130 Garon EB , Lu S , Goto Y , De Marchi P , Paz‐Ares L , Spigel DR , et al . Canakinumab as adjuvant therapy in patients with completely resected non‐small‐cell lung cancer: Results from the CANOPY‐A double‐blind, randomized clinical trial . J Clin Oncol 2024 ; 42 : 180 – 191 . 10.1200/JCO.23.00910 37788412

131 Paik S , Kim JK , Silwal P , Sasakawa C , Jo EK . An update on the regulatory mechanisms of NLRP3 inflammasome activation . Cell Mol Immunol 2021 ; 18 : 1141 – 1160 . 10.1038/s41423-021-00670-3 33850310 PMC8093260

132 Nidorf SM , Fiolet ATL , Mosterd A , Eikelboom JW , Schut A , Opstal TSJ , et al .; LoDoCo2 Trial Investigators. Colchicine in patients with chronic coronary disease . N Engl J Med 2020 ; 383 : 1838 – 1847 . 10.1056/NEJMoa2021372 32865380

133 Pappritz K , Lin J , El‐Shafeey M , Fechner H , Kühl U , Alogna A , et al . Colchicine prevents disease progression in viral myocarditis via modulating the NLRP3 inflammasome in the cardiosplenic axis . ESC Heart Fail 2022 ; 9 : 925 – 941 . 10.1002/ehf2.13845 35178861 PMC8934990

134 Tardif JC , Kouz S , Waters DD , Bertrand OF , Diaz R , Maggioni AP , et al . Efficacy and safety of low‐dose colchicine after myocardial infarction . N Engl J Med 2019 ; 381 : 2497 – 2505 . 10.1056/NEJMoa1912388 31733140

135 He F , Xie T , Ni D , Tang T , Cheng X . Efficacy and safety of inhibiting the NLRP3/IL‐1beta/IL‐6 pathway in patients with ST‐elevation myocardial infarction: A meta‐analysis . Eur J Clin Invest 2023 ; 53 : e14062 . 10.1111/eci.14062 37427709

136 Olsen MB , Gregersen I , Sandanger O , Yang K , Sokolova M , Halvorsen BE , et al . Targeting the inflammasome in cardiovascular disease . JACC Basic Transl Sci 2022 ; 7 : 84 – 98 . 10.1016/j.jacbts.2021.08.006 35128212 PMC8807732

137 Shadab A , Mahjoor M , Abbasi‐Kolli M , Afkhami H , Moeinian P , Safdarian AR . Divergent functions of NLRP3 inflammasomes in cancer: A review . Cell Commun Signal 2023 ; 21 : 232 . 10.1186/s12964-023-01235-9 37715239 PMC10503066

138 Van Linthout S , Volk HD . Immuno‐cardio‐oncology: Killing two birds with one stone? Front Immunol 2022 ; 13 : 1018772 . 10.3389/fimmu.2022.1018772 36466820 PMC9714344

139 Muller I , Vogl T , Kuhl U , Krannich A , Banks A , Trippel T , et al . Serum alarmin S100A8/S100A9 levels and its potential role as biomarker in myocarditis . ESC Heart Fail 2020 ; 7 : 1442 – 1451 . 10.1002/ehf2.12760 32462801 PMC7373886

140 Muller I , Vogl T , Pappritz K , Miteva K , Savvatis K , Rohde D , et al . Pathogenic role of the damage‐associated molecular patterns S100A8 and S100A9 in Coxsackievirus B3‐induced myocarditis . Circ Heart Fail 2017 ; 10 . 10.1161/CIRCHEARTFAILURE.117.004125 , 10 29158436

141 Low D , Subramaniam R , Lin L , Aomatsu T , Mizoguchi A , Ng A , et al . Chitinase 3‐like 1 induces survival and proliferation of intestinal epithelial cells during chronic inflammation and colitis‐associated cancer by regulating S100A9 . Oncotarget 2015 ; 6 : 36535 – 36550 . 10.18632/oncotarget.5440 26431492 PMC4742194

142 Marinkovic G , Koenis DS , de Camp L , Jablonowski R , Graber N , de Waard V , et al . S100A9 links inflammation and repair in myocardial infarction . Circ Res 2020 ; 127 : 664 – 676 . 10.1161/CIRCRESAHA.120.315865 32434457

143 Papp Z , Pollesello P , Borbely A . Recognizing early signs in the translational phase is essential for drug development in cardiovascular medicine . ESC Heart Fail 2023 ; 10 : 2147 – 2149 . 10.1002/ehf2.14402 37165705 PMC10375176

144 Li DL , Wang ZV , Ding G , Tan W , Luo X , Criollo A , et al . Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification . Circulation 2016 ; 133 : 1668 – 1687 . 10.1161/CIRCULATIONAHA.115.017443 26984939 PMC4856587

145 Robinson EL , Ameri P , Delrue L , Vanderheyden M , Bartunek J , Altieri P , et al . Differential expression of epigenetic modifiers in early and late cardiotoxic heart failure reveals DNA methylation as a key regulator of cardiotoxicity . Front Cardiovasc Med 2023 ; 10 : 884174 . 10.3389/fcvm.2023.884174 36970338 PMC10034031

146 Zhou X , Liu Y , Shen Y , Chen L , Hu W , Yan Y , et al . Rescue of cardiac dysfunction during chemotherapy in acute myeloid leukaemia by blocking IL‐1α . Eur Heart J 2024 ; 45 : 2235 – 2250 . 10.1093/eurheartj/ehae188 38607560

147 Lee J , Mehrotra S , Zare‐Eelanjegh E , Rodrigues RO , Akbarinejad A , Ge D , et al . A heart‐breast cancer‐on‐a‐chip platform for disease modeling and monitoring of cardiotoxicity induced by cancer chemotherapy . Small 2021 ; 17 : e2004258 . 10.1002/smll.202004258 33094918 PMC8049959

148 Nickel AG , von Hardenberg A , Hohl M , Nickel A G , Löffler J R , Kohlhaas M , et al . Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure . Cell Metab 2015 ; 22 : 472 – 484 . 10.1016/j.cmet.2015.07.008 26256392

149 Zeiss CJ , Gatti DM , Toro‐Salazar O , Davis C , Lutz CM , Spinale F , et al . Doxorubicin‐induced cardiotoxicity in collaborative cross (CC) mice recapitulates individual cardiotoxicity in humans . G3 (Bethesda) 2019 ; 9 : 2637 – 2646 . 10.1534/g3.119.400232 31263061 PMC6686936

150 Kilkenny C , Browne WJ , Cuthill IC , Emerson M , Altman DG . Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research . PLoS Biol 2010 ; 8 : e1000412 . 10.1371/journal.pbio.1000412 20613859 PMC2893951

151 Wilcox NS , Rotz SJ , Mullen M , Song EJ , Ky Hamilton B , Moslehi J , et al . Sex‐specific cardiovascular risks of cancer and its therapies . Circ Res 2022 ; 130 : 632 – 651 . 10.1161/CIRCRESAHA.121.319901 35175846 PMC8915444

152 Rosano GMC , Stolfo D , Anderson L , Abdelhamid M , Adamo M , Bauersachs J , et al . Differences in presentation, diagnosis and management of heart failure in women. A scientific statement of the Heart Failure Association of the ESC . Eur J Heart Fail 2024 ; 26 : 1669 – 1686 . 10.1002/ejhf.3284 38783694

153 Waldhorn I , Turetsky T , Steiner D , Gil Y , Benyamini H , Gropp M , et al . Modeling sex differences in humans using isogenic induced pluripotent stem cells . Stem Cell Reports 2022 ; 17 : 2732 – 2744 . 10.1016/j.stemcr.2022.10.017 36427492 PMC9768579

154 Pinheiro EA , Magdy T , Burridge PW . Human in vitro models for assessing the genomic basis of chemotherapy‐induced cardiovascular toxicity . J Cardiovasc Transl Res 2020 ; 13 : 377 – 389 . 10.1007/s12265-020-09962-x 32078739 PMC7365753

155 Balaji S , Antony AK , Tonchev H , Scichilone G , Morsy M , Deen H , et al . Racial disparity in anthracycline‐induced cardiotoxicity in breast cancer patients . Biomedicine 2023 ; 11 : 2286 . 10.3390/biomedicines11082286 PMC10452913 37626782

156 D'Arienzo A , Verrazzo A , Pagliuca M , D'Arienzo A , Napolitano F , Parola S , et al . Toxicity profile of antibody‐drug conjugates in breast cancer: Practical considerations . EClinicalMedicine 2023 ; 62 : 102113 . 10.1016/j.eclinm.2023.102113 37554126 PMC10404866

157 Ursini‐Siegel J , Schade B , Cardiff RD , Muller WJ . Insights from transgenic mouse models of ERBB2‐induced breast cancer . Nat Rev Cancer 2007 ; 7 : 389 – 397 . 10.1038/nrc2127 17446858

158 Hoopes PJ , Tavakkoli AD , Moodie KA , Maurer KJ , Meehan KR , Wallin DJ , et al . Porcine‐human glioma xenograft model. Immunosuppression and model reproducibility . Cancer Treat Res Commun 2024 ; 38 : 100789 . 10.1016/j.ctarc.2024.100789 38262125 PMC11026118

159 Farmakis D , Papingiotis G , Filippatos G . Genetic predisposition to cardiovascular disease in patients with cancer: A clinical perspective . JACC CardioOncol 2023 ; 5 : 402 – 405 . 10.1016/j.jaccao.2022.12.008 37397087 PMC10308038

160 Fonoudi H , Jouni M , Cejas RB , Magdy T , Blancard M , Ge N , et al . Functional validation of doxorubicin‐induced cardiotoxicity‐related genes . JACC CardioOncol 2024 ; 6 : 38 – 50 . 10.1016/j.jaccao.2023.11.008 38510289 PMC10950437

161 Magdy T , Jiang Z , Jouni M , Fonoudi H , Lyra‐Leite D , Jung G , et al . RARG variant predictive of doxorubicin‐induced cardiotoxicity identifies a cardioprotective therapy . Cell Stem Cell 2021 ; 28 : 2076 – 2089 . 10.1016/j.stem.2021.08.006 34525346 PMC8642268

162 Magdy T , Jouni M , Kuo HH , Weddle CJ , Lyra‐Leite D , Fonoudi H , et al . Identification of drug transporter genomic variants and inhibitors that protect against doxorubicin‐induced cardiotoxicity . Circulation 2022 ; 145 : 279 – 294 . 10.1161/CIRCULATIONAHA.121.055801 34874743 PMC8792344

163 Van Norman GA . Overcoming the declining trends in innovation and investment in cardiovascular therapeutics: Beyond EROOM's law . JACC Basic Transl Sci 2017 ; 2 : 613 – 625 . 10.1016/j.jacbts.2017.09.002 30062175 PMC6058942

164 Ringel MS , Shah NA , Baedeker M , Lim CT , Lamichhane A , Schulze U . Occlusion in the flow of new drugs for cardiovascular disease . Clin Pharmacol Ther 2017 ; 102 : 246 – 253 . 10.1002/cpt.691 28378877

165 Prescott JS , Andrews PA , Baker RW , Bogdanffy MS , Fields FO , Keller DA , et al . Evaluation of therapeutics for advanced‐stage heart failure and other severely‐debilitating or life‐threatening diseases . Clin Pharmacol Ther 2017 ; 102 : 219 – 227 . 10.1002/cpt.730 28474798

166 Walker , N. . Drug Approval Trends: Significant Acceleration in Recent Years . July 1, 2020. https://www.pharmasalmanac.com/articles/drug‐approval‐trends‐significant‐acceleration‐in‐recent‐years . Accessed October 28, 2024.

167 Romero‐Sanchez A , Perdomo‐Charry G , Burbano‐Vallejo EL . Exploring the entrepreneurial landscape of university‐industry collaboration on public university spin‐off creation: A systematic literature review . Heliyon 2024 ; 10 : e27258 . 10.1016/j.heliyon.2024.e27258 39430447 PMC11489156

168 Sanberg PR , Gharib M , Harker PT , Kaler EW , Marchase RB , Sands TD , et al . Changing the academic culture: Valuing patents and commercialization toward tenure and career advancement . Proc Natl Acad Sci U S A 2014 ; 111 : 6542 – 6547 . 10.1073/pnas.1404094111 24778248 PMC4020064

169 Fradley MG , Nguyen NHK , Madnick D , Chen Y , DeMichele A , Makhlin I , et al . Adverse cardiovascular events associated with cyclin‐dependent kinase 4/6 inhibitors in patients with metastatic breast cancer . J Am Heart Assoc 2023 ; 12 : e029361 . 10.1161/JAHA.123.029361 37301767 PMC10356048

170 Ferrara AL , Loffredo S , Tocchetti CG . Inflammation in cardio‐oncology: Beyond immunotherapies . Eur Heart J 2024 ; 45 : 2251 – 2253 . 10.1093/eurheartj/ehae333 38865293

171 Matz I , Pappritz K , Springer J , Van Linthout S . Left ventricle‐ and skeletal muscle‐derived fibroblasts exhibit a differential inflammatory and metabolic responsiveness to interleukin‐6 . Front Immunol 2022 ; 13 : 947267 . 10.3389/fimmu.2022.947267 35967380 PMC9366145

172 Sayed N , Ameen M , Wu JC . Personalized medicine in cardio‐oncology: The role of induced pluripotent stem cell . Cardiovasc Res 2019 ; 115 : 949 – 959 . 10.1093/cvr/cvz024 30768178 PMC6933506