2025 HFA／EAPC 临床共识声明：癌症患者和幸存者与癌症治疗相关的心功能障碍和心力衰竭的预防

共识心血管内科· 心力衰竭 · 2025

Prevention of cancer therapy-related cardiac dysfunction and heart failure in cancer patients and survivors. A Clinical Consensus Statement of the Heart Failure Association, the European Association of Preventive Cardiology of the ESC, and the ESC Council of Cardio-Uncology

Amina Rakisheva1, Dimitrios Farmakis2, Andrea Attanasio3,Antoni Bayes Genis4,Alain Cohen-Solal5, Geeta Gulati6,7, Martin Halle8, Loreena Hill9,Teresa Lopez Fernandez10,11, Alexander R. Lyon12, Brenda Moura13,14,Ciro Santoro15, Carlo Gabriele Tocchetti16, Sophie van Linthout17,Vassilios Vassiliou18, Yusuf Ziya Sener19, Makhabbat Bekbosynova20, Marco Metra21,Giuseppe Rosano22,23, and Massimo Piepoli3,24

1City Cardiology Center,Almaty,Kazakhstan;2HeartFailure and Cardio-Oncology Unit,Department of Cardiology,Athens University Hospital Atrikon,National and Kapodistrian University of Athens Medical School, Athens, Greece, 3 Cardiology University Department, IRCCS Policlinico San Donato, Milan, Italy; 4Heart Institute, Hospital Universitari Germans Triisai Poulobal, Badaloma, Spain; 5 Universite Paris Cite, INSEM U942, Cardiology Department, Lariboisere Hospital, AP-HP, Paris, France; 6Division of Medicine, Department of Cardiology, Oslo University Hospital, Oslo, Norway; 7.K.G.Jebsen Center for Cardiac Biomarkers, Institute of Clinical Medicine, Faculty of Medicine,University of Oslo, Oslo, Norway; 9Department of Preventive Sports Medicine and Sports Cardiology, TUM School of Medicine and Health, TUM University Hospital, Technical University of Munich, Munich, Germany; 9School of Nursing and Paramedic Science, Ulster University, Londonderry, UK; 10Cardiology Department, La Paz University Hospital,IdiPAZ Research Institute, Madrid, Spain;11Cardiology Department, Hospital Universitario Quironsalud, Madrid, Spain;12Cardio-Oncology Centre of Excellence, Royal Brompton Hospital, London; UK; 13Armed Forces Hospital, Porto, Portugal; 14Faculty of Medicine of University of Porto, Porto, Portugal; 15Department of Advanced Biomedical Science, Federico II University, Naples, Italy; 16Department of Translational Medical Sciences(DISMET), Center for Basic and Clinical Immunology Research(CISI),Interdepartmental Center of Clinical and Translational Sciences(CIRCET), Interdepartmental Hypertension Research Center(CIRIAPA), Federico Il University, Naples, Italy;17BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health (BI) at Charité- Universitatmedizin Berlin, Berlin, Germany; 18Norwich Medical School, University of East Anglia and Norfolk and Norwich University Hospital, Norwich, UK; 19Department of Cardiology, Thoraxcentrum, Erasmus MC, Rotterdam, The Netherlands; 20UMC,Astana, Kazakhstan;21ASST Spedali Civli di Brescia, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Italy;22Department of Human Sciences and Promotion of Quality of Life, Chair of Pharmacology, San Raffaele University of Rome, Rome, Italy; 23IRCCS San Raffaele, Rome, Italy; and 24Department of Biomedical Sciences for Health, University of Milan, Milan, Italy

Received 21 February 2025; revised 23 May 2025; accepted 10 June 2025

Despite advances in cancer treatments with significant improvement in patient outcomes, chemotherapy, targeted molecular therapies and radiotherapy may cause a range of cardiovascular complications, such as cancer therapy-related cardiac dysfunction(CTRCD), which represents a broad spectrum of possible presentation and aetiological link with the broad scope of various cancer therapies, including chemotherapy, targeted agents, immunotherapies,and radiation therapy,aiming at reducing the associated morbidity and mortality. However,practical guidelines on the primary prevention of CTRCD in high-risk patients, a key element in improving prognosis, are lacking in cancer patients and related evidence remains inconclusive. This Clinical Consensus Statement, authored by experts from the Heart Failure Association(HFA) and the European Association of Preventive Cardiology(EAPC) of the European Society of Cardiology(ESC), and the ESC Council of Cardio-Oncology, aims to discuss the definition and epidemiology of CTRCD, the implicated factors for risk stratification,and the appropriate early diagnostic pathways, while focusing on lifestyle modifications, and pharmacological interventions to reduce the incidence of CTRCD. In addition, a holistic cardio-oncology management approach is advised for prevention and long-term management.

Graphical Abstract

![\nPathophysiology\n\nCardiac\ndysfunction\n/heart failure\nRisk factors\nVous\nPrevious\nCVD\nCTR-CVT\n\nI\nRisk factors\nPrevious cardiotoxic therapies\nPrevious cardiotic therapies\n\nLifestyle\nliskofractors\nMedication\nLifestyle\nlifestyle therapies\n4000\nc�道or\nECG,TTE,and cardiac biomarkers abnormalities\n\nMedication/ring of risk factors\n㈩\n㈩\n㈩\n㈩\ncancer\ntreatment\nCancer\ntreatment\n㈩\n㈩\n㈩\ncancer\ntreatment\n㈩\ncancer\ntreatment\n㈩\ncancer\ntreatment\n㈩\ncancer\ntreatment\n㈩\n㈩\n㈩\n](2/aj0YEe4oUhYkBdfpda0fYP/figure470a58f9ddb74fa8b79daab971c18576_1_4.png) Prevention of cancer therapy-related cardiac dysfunction and heart failure in cancer patients and survivors. CTR-CVT, cancer therapy-related cardiovascular toxicity;CVD,cardiovascular disease;CVRF,cardiovascular risk factor;ECG,electrocardiogram;TTE,transthoracic echocardiography.

Keywords

Heart failure prevention

● Cancer therapy-related cardiac dysfunction

● Cancer patients and

Introduction

Recent advancements in antinelastic treatments have resulted in significant improvements in patient outcomes. In several cases, a durable complete response to anticancer therapy is accomplished.In contrast, in many others, prolonged remission and effective control are achieved with prolonged anticancer therapies rendering cancer a chronic disease. Unfortunately, these improvements take their toll on cardiovascular(CV) side effects of antineoplastic agents.1,2

Currently, multiple therapeutic options are available to man-age cancer therapy-related cardiac dysfunction(CTRCD) aiming at reducing the associated morbidity and mortality. However, practi-cal guidelines on primary prevention of CTRCD, a key element in improving prognosis in cancer patients, are lacking, while related evidence remains controversial and thus inconclusive.

In this Clinical Consensus Statement, experts from the Heart Failure Association(HFA), the European Association of Preventive Cardiology(EAPC), and the Council of Cardio-Oncology of the European Society of Cardiology(ESC) aim to discuss the definition and epidemiology of CTRCD and heart failure(HF), the predispos-ing conditions(CV risk factors and comorbidities), the diagnostic pathways, and the preventive interventions.

Definition

As reported in the European guidelines,1 for cardiac injury,cardiomyopathy, and HF, the descriptive term CTRCD is rec-ommended as it captures the broad spectrum of possible presentations and the aetiological link with the broad scope of various cancer therapies, including chemotherapy, targeted agents, immunotherapies, and radiation therapy. In the present consensus document, as suggested by the European guidelines,1 HF related to cardiotoxicity in patients with cancer and survivors has been defined as‘symptomatic CTRCD’. A substantial amount of effort has been devoted to identifying the mechanisms and the wide spectrum of its presentation(cardiac injury, cardiomyopathy,and HF) and the aetiological link with various cancer therapies.2 CTRCD becomes even more relevant when we consider elderly patients who may already present pre-existing chronic diseases and CV comorbidities1(Figure 1).

Epidemiology

Some cancer patients are treated with therapies(anthracycline chemotherapy, human epidermal receptor 2[HER2]-targeted ther-apies, proteasome inhibitors, breakpoint cluster region-Abelson oncogene locus[BCR-ABL] tyrosine kinase inhibitors[TKIs],RAF/MEK inhibitors, epidermal growth factor receptor[EGFR]inhibitors) that increase the risk of developing CTRCD and HF.Its incidence varies depending on the population studied and the influencing variables such as patients' clinical and demographic characteristics, cancer type, and the treatment received. Accord-ing to a recent meta-analysis, the incidence rate of CTRCD has been reported at 63.21 per 1000 person-years among cancer patients. ${}^{3}$

![Pathophysiology\nIndirect effects of anticancer therapies\nDirect effects of anticancer therapies\nPotential effects of cancer\nCardiac dysfunction / heart failure\n](2/aj0YEe4oUhYkBdfpda0fYP/figure6adcffae023b41da980e7679a49a9d28_2_10.png) Figure 1 Potential causes of cardiac dysfunction and heart fail-ure in cancer. Reproduced with permission from: Farmakis D.Pathophysiology of cardiac toxicity. In: Russo A, Maurea N, Far-makis D, Giordano A, eds. Cardio-Oncology. Cham: Humana Press;2022.p31-43.

Severe symptomatic HF accounts for only 0.5-3% of cases during treatment, but they profoundly worsen the prognosis of cancer patients.4 As most patients are asymptomatic, surveillance protocols are needed according to the baseline CV risk of toxicity as recommended by the ESC guidelines of cardio-oncology.1,5

Heart failure and cancer are closely related in terms of epidemi-ology and pathophysiology. The two conditions follow a similar inci-dence pattern according to age in both men and women and share many common risk factors, including lifestyle and metabolic factors such as smoking, obesity, and physical inactivity. Additionally, genet-ics may be a common risk factor for both HF and cancer. LEOPARD syndrome is secondary to RAS mutations and leads to both hyper-trophic cardiomyopathy and skin cancers. Clonal haematopoiesis of indeterminate potential (CHIP) may lead to myeloproliferative disorders and haematological malignancies while promoting at the same time atherosclerosis. 6 Furthermore, the coexistence of HF and cancer impairs the management and, therefore, the outcomes of both conditions, as patients may miss out on beneficial therapies that could improve their prognosis.

Many anticancer therapies can lead to myocardial dysfunction and HF,7 either by causing a direct cardiomyocyte injury or indi-rectly, through other forms of cardiotoxicity such as hyperten-sion(HTN), myocardial ischaemia, myocarditis, or arrhythmias(Figure 1). The following types of antineoplastic agents have been associated with HF: anthracycline-targeted therapies such as HER2 inhibitors, vascular endothelial growth factor(VEGF) inhibitors,multi-target TKIs, proteasome inhibitors, EGFR inhibitors and RAF/MEK inhibitors, immunotherapies including immune check-point inhibitors(ICls), cellular therapies such as chimeric antigen receptor T(CAR-T) cells and haematopoietic stem cell transplan-tation. Table 1 has been included to summarize all antineoplastic agents associated with an increased risk of HF, along with their pro-posed mechanisms and the incidence reported for each therapy8.

Approximately one-third of adult patients receiving anthracycline-based hemotherapy will experience some form of CTRCD, with the majority of cases reflecting asymptomatic cardiac dysfunction and a smaller number of HF cases with varying

# Table 1 Antitumoral drugs related to myocardial toxicity, its pathologic mechanisms, and incidence of heart failure

|Antitumoral agent|Mechanism theories|Epidemiology|References| |---|---|---|---| |Anthracycline chemotherapy (doxorubicin, epirubicin, daunorubicin, idarubicin)|Cardiomyocyte death trough oxidative stress,DNA damage and mitochondrial impairment|3-5%; with liposomal anthracyclines 2%|8| |Alkylating agents(cyclophosphamide, melphalan)|Oxidative stress and endothelial dysfunction|Up to 28%(cyclophosphamide> ifosfamide)|8| |Fluoropyrimidines (5-fluorouracil, capecitabine)|Vasospasm, myocardial inflammation|Up to 18%|8| |Taxanes(docetaxel, paclitaxel)|Fluid retention, abnormal calcium homeostasis|2.3-8%|7| |Proteasome inhibitors(carfilzomib, bortezomib, ixazomib)|Ventricular dysfunction/congressive heart failure, arterial hypertension, endothelial dysfunction, ischaemic cardiomyopathy|2-5%|7| |mTOR inhibitors(everolimus)|Dysregulation of the PI3K-AKT-m-TOR pathway|Reported odds ratio: 2.12|9| |HER2-targeted therapies(trastuzumab, pertuzumab, trastuzumab emtansine [T-DM1], lapatinib, neratinib,|Down-regulation of protective intracellular pathways(NRL-1,RAS/RAF or PI3K-AKT-mTOR) against oxidative stress, apoptosis and mitochondrial function impairment|Up to 28% if with anthracyclines (trastuzumab> lapatinib and pertuzumab)|8| |Anti-EGFR/HER1(osimertinib) Multi-targeted kinase inhibitors BCR-ABL TKIs(ponatinib, nilotinin, dasatinib, bosotinib)|Unclear, partial inhibition of HER2 pathway Off target down-regulation of cardiomyocyte growth and survival pathways|4-5% 2-5|10 7| |VEGF inhibitors TKls(sunitinib, pazopanib, sorafenib, axitibin, tvoizanab, cobazantinib, regorafenib, lenvatinib, vandetinib) and antibodies (bevacizumab, ramucirumab)|Impairment of mitochondrial function and inhibition of the AMP-kinase pathway|Up to 4%|8| |Combination RAF and MEK inhibitors|Inhibition of MEK/ERK pathway in the cardiomyocyte|29%|11| |(dabrafenib+trametinib,|cardiomyocyte||| |venurafenib+ cobimetinib, encorafenib+ binimetib)|Impairment of immunological homeostasis|3.5%|7,12| |Immune checkpoint inhibitors|Impairment of immunological homeostasis||| |Anti-PD1(nivolumab, pembrolizumab)|in the myocardium, autoimmunity against cardiomyocytes or endothelial cells||| |Anti-CTL4(ipilimumab)|cardiomyocytes or endothelial cells||| |Anti-PD-L1(avalumab, atezolizumab, durvalumab)|||| |CAR-T cells(tisagenlecleucel, axicabtagene)|Cytokine releasing syndrome and unclear off-target effects of CAR-T or lymphodepletion|Up to 30%|13| |Radiotherapy|Cardiomyocyte death through direct cardiomyocyte toxicity(oxidative stress, DNA damage) and development of coronary atherosclerosis and fibrosis in cardiac valves and pericardium|Up to 10%|14| ||||| |AMP, adenosine monophosphate; BCR-ACL, breakpoint cluster region-Abelson oncogene locus; CAR-T, chimeric antigen receptor; GHEFR, epidermal growth factor receptor; HER, human epidermal receptor; mTOR, mechanistic target of rapamycin; PD-1, programmed death ligand-1; PI3K, phosphadytidyinolositol 3-kinase; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.||||

AMP, adenosine monophosphate; BCR-ACL, breakpoint cluster region-Abelson oncogene locus; CAR-T, chimeric antigen receptor T; CTLA-4, cytotoxic T-lymphocyte antigen-4; EGFR, epidermal growth factor receptor; HER, human epidermal receptor; mTOR, mechanistic target of rapamycin; PD-1, programmed death 1-1; PI3K, phosphatidylinositol 3-kinase; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.

degrees of severity.1 Systolic dysfunction, characterized by a drop in left ventricular ejection fraction(LVEF) of at least 10% units to a value below 50%, occurs in 9% of patients after a median time of 3.5 months from the start of therapy, while severe symptomatic HF(New York Heart Association[NYHA] class III or IV) develops in

2% of patients.16 As reported in Table 1, anthracycline therapy can cause cardiac cell damage through various molecular mechanisms,potentially leading to HF. The greater the cumulative anthracycline dose, the higher the risk of cardiotoxicity and subsequent devel-opment of HF. According to the European guidelines, a cumulative

dose of≥250mg/m2 of doxorubicin or its equivalent is considered high risk. The rates of CTRCD and HF during and after ICI are still to be confirmed on a large scale, with single centre cohort studies and small registries reporting HF in the context of both ICI-related myocarditis and ICI-related non-inflammatory HF.17,18

In one registry of cancer patients treated with ICl, a 10.3/incidence of major adverse CV events has been reported over a median follow-up of 13 months, with 67% of these events concern-ing CTRCD and HF.19

Cancer, on the other hand, may also contribute to myocardial dysfunction and HF. Cancer-related cardiac conditions that may affect the heart include primary and metastatic tumours developing in the heart, carcinoid heart disease associated with neuroen-docrine tumours, and cardiac AL amyloidosis resulting from multi-ple myeloma.1 In addition, cancer promotes pro-inflammatory and other systemic effects that may further affect cardiac function20 and increase myocardial sensitivity to anthracycline chemotherapy.21

It has also been proposed that there may be a reverse relation-ship between HF and cancer, meaning that HF might predispose to cancer development or progression through different mechanisms.Preclinical data suggest that when the heart is injured during an experimental myocardial infarction(Ml), it may release substances such as serpins or small extracellular vesicles containing cytokines and regulatory microRNAs. These substances can promote the development of cancer and support the spread of tumour cells in animal models. Therefore, there is a proposed reciprocal rela-tionship between HF and cancer within the broader framework of'reverse cardio-oncology'.22

Risk factors for cancer therapy-related cardiac dysfunction

As reported in the European guidelines,1 a comprehensive CV toxicity risk stratification before starting potentially cardiotoxicity anticancer therapy is recommended for all patients with cancer(class I, level of evidence B)(Figure 2).

The following principles should be taken into account when assessing cardiotoxicity5: risk is a continuous variable; multiple CV risk factors may co-exist and have an additive or synergistic contribution to overall CV risk; and increased absolute risk is the most relevant factor for individual patient-based treatment decisions.

To date, the HFA-ICOS risk assessment should be used(class lla, level of evidence C) to stratify CV toxicity risk in patients receiving cardiotoxic anticancer therapy.1 Different risk tools are available based on the type of antineoplastic therapy scheduled for the patient.5

The above-mentioned risk tool considers five main domains:

1. Previous CV disease(CVD): HF or cardiomyopathy; severe valvular heart disease; M1 or prior coronary revascularization;stable angina; baseline LVEF.

2. Cardiac biomarkers: baseline cardiac troponin(cTn) and natri-uretic peptide(NP) levels.

3. Demographic and CV risk factors:

![Age, sex, genetics\nMedical CVD\nPrevious CVD\nCVD\nPrevious cardiotoxic\nlifestyle risk factors\nchototoxic\ntherapies\nECG, TTE, and cardiac biomarkers abnormalities\n](2/aj0YEe4oUhYkBdfpda0fYP/figure7e00ba3ab03a4e309b5ce05103f58a59_4_14.png) Figure 2 Cardiovascular toxicity risk assessment. CVD, cardio-vascular disease; CVRF, cardiovascular risk factor; ECG, electro-cardiogram; TTE, transthoracic echocardiography.

a. Age.

b. Arterial HTN defined as systolic blood pressure>140mmHg or diastolic blood pressure>90mmHg,or under treatment.

c. Diabetes mellitus defined as glycated haemoglobin>7.0%or>53 mmol/mol, or under treatment.

d. Chronic kidney disease defined as estimated glomerular filtration rate<60 ml/min/1.73m2.

4. Previous cardiotoxic cancer treatment: prior anthracycline expo-sure, radiotherapy to the left chest or mediastinum, or non-anthracycline-based chemotherapy.

5. Lifestyle risk factors: current smoking or a significant history of smoking; obesity defined as a body mass index(BMI)>30kg/m2.

6. Other factors, such as gender, genetic variants, or ethnicity,require further investigation.23.24

Oncologic treatments and their clinical complications leading to heart failure

Cardiotoxic cancer treatments can cause CTRCD and HF directly or indirectly via the development of other cardiac conditions(i.e atrial fibrillation, atherosclerosis, HTN, valvular heart disease) that then may cause HF.

Cardiovascular toxicity of chemotherapy

Left ventricular dysfunction

Anthracycline chemotherapy induces cardiomyocyte dysfunction and death via oxidative stress, DNA damage, and mitochondrial dysfunction25(Table 1). Targeted molecular cancer therapies such as HER2(HER/Erb2) and TKls may increase cardiotoxicity risks and cardiomyocyte dysfunction and death in the myocardium

previously exposed to anthracycline chemotherapy.9-11 Beyond cardiomyocytes, doxorubicin impacts endothelial cells and fibrob-lasts through reactive oxygen species production.25,26 ICls may lead to myocarditis and dilated cardiomyopathy due to immune dysregulation.27-30 CAR-T cell therapy has been associated with left ventricular dysfunction(LVD),12,13 HF, and arrhythmias, often linked to cytokine release syndrome.31-34

Arrhythmias

The use of new anticancer therapies has increased the preva-lence of cardiac arrhythmias. Factors such as patient comorbidities,inflammation, and age contribute to arrhythmic risk.23 Atrial fib-rillation and QT prolongation are particularly concerning in cancer patients, and their management requires cardiology-oncology col-laboration.36,37 Early detection and management of comorbidities are key in reducing atrial fibrillation incidence. ${}^{38}$

Arterial hypertension

Hypertension is a common side effect of oncological therapies,especially VEGF signalling pathway inhibitors(VEGFi) and pro-teasome inhibitors2,7,32(Table 2). VEGF disrupts nitric oxide production, leading to new or exacerbated HTN in 11-45% of patients, while proteasome inhibitors contribute to vasoconstric-tion.2,7 Optimal blood pressure control improves cancer treatment tolerance.2,32

Accelerated atherosclerosis and ischaemic heart disease

Several cancer therapies can lead to cardiac ischaemia or, in the worst cases, result in M1.239,40 The mechanisms by which drugs can cause vascular toxicity range from a direct vasospas-tic effect to endothelial injury or premature atherosclerosis.Gonadotropin-releasing hormone agonists, which are com-monly used in prostate cancer patients and some estrogen receptor-positive breast cancer patients, accelerate atherosclero-sis, new diabetes mellitus and increase M1 risk. Fluoropyrimidines like 5-fluorouracil and cisplatin can cause coronary artery spasms,endothelial dysfunction, and arterial thrombosis. VEGFi drugs have been linked to arterial thrombosis, further increasing CV risks.2

Cardiotoxicity of radiotherapy

Thoracic radiation poses risks for various CV complications,including coronary artery disease(CAD), pericardial disease,valvular heart disease, restrictive cardiomyopathy, and arrhyth-mias. ${}^{2,14-42}$ The severity of radiation-induced CAD correlates with the radiation dose. ${}^{43}$ Valvular heart disease and arrhythmias, such as atrial fibrillation, are also notable risks, particularly in patients receiving higher doses of radiation. ${}^{41,44,45}$

Early detection

As the majority of patients are asymptomatic, surveillance pro-tocols are needed according to the baseline CV risk of toxicity assessment. Cardiac biomarkers(NPs and cTn) and CV imaging,

Table 2 Antitumoural drugs related to common arrhythmic complications and arterial hypertension development

|Cancer therapy|Cancer drug agents| |---|---| |induced|| |Atrial fibrillation|Alkylating agents ●Cisplatin, ifosfamide, cyclophosphamide, melphalan Anthracyclines Antimetabolites| |Capecitabine,5-fluorouracil,gemcitabine Interleukin-2|Capecitabine,5-fluorouracil,gemcitabine Interleukin-2 Interferons| |Rituximab|Rituximab| |Small molecule TKIs|Small molecule TKIs| |Ponatinib, sorafenib, sunitinib, ibrutinib|Topoisomerase II inhibitors| |Amsacrine, etoposide|Amsacrine, etoposide| |Taxanes|| |Anthracyclines|Anthracyclines| |Histone deacetylase inhibitors|| |Depsipeptide, belinostat, vorinostat|| |Chemicals:arsenic trioxide|| |TKIs|| |Axitinib, bosutinib, cabozantinib, crizotinib, dabrafenib, dasatinib, lapatinib, nilotinib|| |pazopanib, ponatinib, sorafenib, sunitinib, vardetanib, vermurafenib|| |BRAF inhibitor: vemurafenib|| |CDK4/6 inhibitors: ribociblic|| |Monoclonal antibody-based TKI|| |Bevacizumab, ado-trastuzumab emtansine|| |Monoclonal antibodies|| |Alemtuzumab, ibritumomab, ofatumumab, rituximab|| |mTOR inhibitors: everolimus, temsirolimus|| |TKIs|| |Pazopanib, ponatinib, sorafenib, sunitinib, axitinib, abozantinib, ibrutinib, nilotinib,|| |ramucirumab, regorafenib, trametinib,|| |vandetanib, ziv-aflibercept|| |Proteasome inhibitors|| |Bortezomb, carfilzomib|| |Antimetabolites|| |Decitabine||

CDK4/6, cyclin-dependent kinase 4 and 6; mTOR, mechanistic target of rapamycin; TKI, tyrosine kinase inhibitor.

spanning from echocardiography to cardiac magnetic resonance(CMR), have acquired a fundamental role in the early detection of the first signs of LVD in order to prevent overt HF.

Clinical evaluation

Clinical examination is crucial, helping to assess the risk of developing HF and to detect any early signs of CTRCD. A

comprehensive clinical history that includes traditional CV risk factors or chemotherapy-related risk factors(e.g. sequential treat-ment with cardiotoxic drugs, high cumulative dosage, mediasti-nal irradiation therapy) is essential to allow the identification and control of modifiable risk factors based on the individual's risk level for developing chemotherapy-related HF.46 This information is required as part of the HFA-ICOS baseline risk assessment rec-ommended by the 2022 ESC guidelines on cardio-oncology.

Clinical findings of chemotherapy-related HF are similar to those experienced by non-oncologic patients(i.e. jugular venous disten-sion, hepatojugular reflux, orthopnoea, bendopnoea, pulmonary rales, and peripheral oedema).5 However, in the oncologic setting,signs and symptoms that are frequently observed including fatigue,weakness, or peripheral oedema, are commonly addressed as sec-ondary effects of anticancer treatment, which may mask timely diagnosis and require additional CV assessment.

Electrocardiogram

An electrocardiogram is advised in all cancer patients prior to starting a treatment which has a cardiotoxicity risk. It serves as a baseline reference if future cardiac problems develop. If abnormal at baseline, then a cardiology referral to determine the cause of the abnormality is advised unless the abnormality is previously known and investigated.

Imaging tests

General advice regarding the use of cardiac imaging techniques for detection of patients at risk for HF risk relies on expert consensus, ${}^{47}$ which supports echocardiography, particularly three-dimensional(3D) echocardiography, to first quantify heart volumes and ventricular function. A comprehensive echoc-diographic evaluation is advised including ${}^{47}$ : left ventricular size and function(LVEF by Simpson's two-dimensional[2D], or[semi]automatic 3D; 2D/3D global longitudinal strain[GLS] and global circumferential strain; 2D/3D left ventricular systolic and diastolic volumes) and right ventricular function, pulmonary artery pressure and volaemia(markers of right ventricular systolic function; velocity of tricuspid regurgitation; inferior vena cava diameter, collapse on inspiration). The 2022 ESC guidelines on cardio-oncology endorse the HFA-ICOS score for stratifying the risk of CTRDC before initiating cancer treatment.1 One of the key parameters included in this score is the baseline LVEF prior to starting cardiotoxic cancer treatment. Patients with low(<50%)or low-normal(50-54%) LVEF are at higher risk of developing HF during or after cancer treatments.1 Baseline GLS should also be measured as reduced GLS is an independent predictor of CV events in patients with low-normal LVEF, thus highlighting a subgroup of patients who require more intensive cardio-oncology monitoring.46 New data are needed on the role of right ventricular function parameters and left atrial function assessment to enhance the risk assessment of CTRCD.48

For patients with poor transthoracic echocardiography win-dow, CMR provides a precise evaluation of cardiac anatomy and biventricular ejection fraction. ${}^{47,49}$ Additionally, CMR is the gold

standard for assessing myocardial tissue abnormalities and inher-ent structural heart diseases(e.g. hypertrophic cardiomyopathy,dilated non-ischaemic cardiomyopathy, and ischaemic cardiopathy)that may increase HF risk during cancer treatment. Although not well established in clinical practice, abnormal CMR-based strain val-ues, such as fast-strain-encoded magnetic resonance imaging, can identify patients at higher risk of CTRCD.50

In asymptomatic cancer patients at high risk of CAD, non-cardiac computed tomography provides a quantification of coronary artery calcium burden to adjust CV risk, informing preventive strategies. ${}^{51}$

Biomarkers

The two licensed cardiac biomarkers, cTn and NPs, primarily pro-duced by the heart, are central in cardio-oncology clinics: their routine measurements allow to establish a reference point and detect potential haemodynamic stress and cardiomyocyte injury associated with underlying cardiac disease before beginning and during treatment.52 Isolated elevations rarely require stopping can-cer therapy. Instead, they should be used to guide discussions between oncologists and cardiologists, determining monitoring frequency, initiating cardioprotective measures, or prompting fur-ther cardiac evaluations, particularly in patients receiving ICls.52 In patients where biomarker monitoring is recommended, a baseline measurement before cancer treatment is essential. The 2022 ESC guidelines on cardio-oncology provide detailed guidance on which patients require baseline measurement and in which patients car-diac biomarker measurement during treatment is recommended.

Lipid levels, kidney function, fasting plasma glucose, glycated haemoglobin are markers of CAD risk, requiring close monitoring to prevent HF as CAD significantly contributes to the CV burden among cancer survivors. Screening might be suitable for selected survivors based on risk factors and inflammatory burden.

There are many additional biomarkers under research as myeloperoxidase, C-reactive protein, galectin-3, microRNAs,and others. In the future, polygenic risk scores and clonal haematopoiesis markers could emerge as valuable tools for predicting CAD risk.

Management of myocardial toxicity of cancer treatment

Lifestyle interventions and risk factor control combined with phar-macological therapy play a key role in mitigating HF development in cancer patients. These patients often face an increased risk of CVD due to the direct negative effects of cancer therapies, the development of therapy-associated risk factors and co-existing risk constellations such as obesity, poor diet, sedentary behaviours,increased stress and smoking.

Despite this knowledge and guideline recommendations, optimal CV risk factor control is often not given appropriate attention in clinical practice.54,55 Reasons for this may in part be explained on the one hand by the primary focus of the patient and cancer specialist to treat the cancer entity successfully, and on the other hand by the lower experience on prescribing structured lifestyle

Table 3 Lifestyle and pharmacological interventions in cardiotoxicity prevention

|Intervention|Effect|References| |---|---|---| |Lifestyle intervention||| |Obesity|Intentional weight control through a combination of dietary changes and exercise, can improve metabolic health, reduce hypertension, and decrease the risk of HF.|55-61| |Physical activity|Exercise programmes tailored to cancer patients can improve both cardiorespiratory fitness, quality of life and overall survival outcomes.|62-74| |Smoking cessation|Cigarette smoking in cancer patients is considered as an established risk factor as well as in the general population.|1,75,76| |Nutrition|Mediterranean diet, low in saturated fat and processed carbohydrates is advised.The effect of healthy nutrition is not properly established yet.|77-79| |Pharmacological intervention||| |Beta-blockers and RAASi|Despite initial benefits have been observed with combined therapy(beta-blockers and RAASi), further studies did not confirm.|80-86| |ARNi|No systematic clinical data are currently available for CRTCD primary prevention. Ongoing randomized clinical trial(PRADA II and MAINSTREAM) are evaluating ARNi in CRTCD primary prevention.|87-92| |MRAs|Small evidence may suggest a protective role for both systolic and diastolic dysfunction. However, further and more robust data are necessary to confirm its role in preventing HF.|93| |SGLT2i|Preclinical studies and retrospective data showed potential positive effect of these drugs in cardiotoxicity prevention. A recent meta-analysis observed that SGLT2i use reduced HF hospitalizations by 51%(RR 0.49, 95% CI 0.36-0.66, 12=28%, p<0.01) and new HF diagnoses by 71%(RR 0.29, 95% CI 0.10-0.87, $\hat{\imath}^{2}=71\%$ ). Multivariate analysis suggested that among breast cancer populations, studies with≥50% of patients on anthracyclines exhibited a 99% reduction in HF hospitalization risk compared with similar studies that included<50% of patients on anthracyclines. Further prospective and randomized studies are ongoing.|94-97| |Statins||| |Ivadrine|No clear benefit has been observed with hivadrine use for preventing HF in cancer patients.|98-103| |Dexrazoxane|Dexrazoxane is approved for use in adult patients with advanced or metastatic breast cancer who have received a minimum cumulative anthracycline dose of 300 mg/m2 of doxorubicin or its equivalent to reduce the risk of CRTCD. A reduction of HF(RR 0.22, 95% CI 0.11-0.43) was reported.106|1,106| |Liposomal anthracyclines|Both pegylated and non-pegylated liposomal doxorubicin formulations are approved for metastatic breast cancer, with pegylated liposomal doxorubicin doxorubicin also approved ovarian cancer, acquired immune deficiency syndrome-related Kaposi sarcoma, and multiple myeloma. Pegylated and non-peylated liposomal doxorubicin modify pharmacokinetics and tissue distribution without compromising antitumour efficacy. In a meta-analysis of 19 trials, in both the adjuvant and metastatic context, liposomal doxorubicin was reported to be less cardiotoxic than conventional events(OR 0.60, 95% CI 0.34-1.07).|1,107| |||| |ARNi, angiotensin receptor-neprilynsin inhibitor; CI, confidence interval; CRTCD, cancer-related therapy cardiac dysfunction; HF, heart failure; MRA, mineralocorticoid receptor antagonist; OR, odds ratio; RAASi, renin-angiotensin-aldosterone system inhibitor; RR, risk ratio; SGLT2i, sodium-glucose co-transporter 2 inhibitor.|||

ARNi, angiotensin receptor-neprihrysin inhibitor; CI, confidence interval; CRTCD, cancer-related therapy cardiac dysfunction; HF, heart failure; MRA, mineralocorticoid receptor antagonist; OR, odds ratio; RAASi, renin-angiotensin-aldosterone system inhibitor; RR, risk ratio; SGLT2i, sodium-glucose co-transporter 2 inhibitor.

interventions and risk factor management by for example cancer specialists in gynaecology, urology, or haematology. Therefore, a holistic treatment approach demands a network of lifestyle and specialists in addition to cancer physicians. ${}^{56,57}$

Lifestyle interventions

Appropriate lifestyle interventions include the prescription of regular exercise, a balanced diet, and minimizing alcohol intake(Table 3). Epidemiological studies have shown that rigorous phys-ical activity, higher levels of fitness, and lower BMI are associated with a lower risk of CV events. A multinational study involving over 37000 cancer survivors from the United States, the United

Kingdom, and China58 found that cancer patients who had never smoked, had minimal alcohol consumption, engaged in adequate physical activity, maintained a healthy diet, and had an optimal BMI,had a significantly lower risk of all-cause mortality. Patients may benefit from a structured cardiac rehabilitation programme, to receive advice on lifestyle changes, including nutrition as well as tailor aerobic and resistance training.

Risk factor control

Obesity and body weight control

Obesity, defined as having a BMI>30kg/m2, is a common but reversible risk factor for arterial HTN, type 2 diabetes and

subsequent HF.1,60 It is also a risk factor associated with breast cancer in postmenopausal women.61,62 In addition, obesity drives pathological inflammation and simultaneously disrupts ongo-ing antitumour immune responses.63 Cardiotoxicity induced by anthracyclines and a sequential anthracycline and trastuzumab regimen is significantly higher in obese(odds ratio[OR] 1.47,95%confidence interval[CI] 0.95-2.28) and overweight(OR 1.15,95% CI 0.83-1.58) patients.64

On the other hand, many patients may gain weight and accumu-late fat reserves during their cancer treatment, due to medications such as steroids, or the side effects of treatment, such as reduced physical activity or early menopause.

During cancer treatment, patients may also experience weight loss due to a reduction in lean muscle mass. A low muscle mass is associated with poor outcomes in cancer, and body composition studies using biochemical and imaging modalities delineate the importance of both obesity and sarcopenia in clinical outcomes.65

Intentional weight control through a combination of dietary changes and exercise, can improve metabolic health, reduce HTN,and decrease the risk of HF.66 A consensus document states that the goal for cancer patients is to maintain a BMI between 20 and 25 kg/m2 and a waist circumference of<94 cm for men and<80 cm for women.67

Whether intentional weight reduction in obese cancer patients will prevent the development of CTRCD remains to be evaluated.

Arterial hypertension

The 2024 European guidelines on arterial HTN emphasize that currently there is no clinical trial evidence specifically evaluating patients who develop HTN as a result of anticancer therapy, and recommend treating HTN in these patients in the same way as in the general population, although special attention should be given to rebound hypotension after termination of cancer ther-apy.68 The same ESC guidelines provide lifestyle recommendations which include limiting sodium intake, preferably decreasing alcohol intake, reducing sugar consumption(novel recommendation) and increasing physical activity. Cancer survivors with HTN should fol-low the guidelines for the general HTN population, and individuals with≥10% 10-year risk of CVD or with comorbidities that place them at high risk should be started on antihypertensive therapy at a blood pressure≥130/80 mmHg with a systolic blood pressure goal of 120-129 mmHg.

The 2022 ESC guidelines on cardio-oncology provide guidance on the blood pressure targets for patients receiving active cancer therapy based on their cancer prognosis,1 as for many patients with metastatic or advanced cancer and prognosis<12 months the 10-year CVD risk data are not appropriate.

Clinic blood pressure should be assessed at all consultations in cancer patients receiving cardiotoxic cancer treatments, and par-ticularly treatments associated with an increased risk of HTN.If HTN is diagnosed, then optimizing lifestyle changes and anti-hypertensive medications with careful monitoring and follow-up post-treatment.The 2022 ESC guidelines on cardio-oncology pro-vide guidance on the management of cancer therapy-related HTN.1

Sedentary habits and exercise prescription

Despite the debilitating effects of treatment, it is important for patients undergoing treatment and those who have already com-pleted treatment to remain physically active.

Regular physical activity and structured exercise training are effective in improving vascular and cardiac pathophysiology and CV risk factors.68 Effects include improvement of endothelial function, reduction of systemic inflammation, and enhancement of insulin sensitivity, all of which are key in reducing the risk of HTN, CAD, and HF.69,70 Exercise programmes tailored to cancer patients can improve both cardiorespiratory fitness, quality of life and overall survival outcomes.71-73 Breast cancer patients who maintain higher levels of cardiorespiratory fitness during and after treatment were found to have a lower all-cause mortality, including from CV causes.74 Following 11480 cancer patients for a median follow-up of 16 years from diagnosis revealed that those who exercised according to guidelines had a significant reduction in cancer mortality(hazard ratio[HR] 0.79, 95% CI 0.72-0.88) and mortality from other causes(HR 0.72, 95% CI 0.66-0.78), in comparison with patients who did not undertake exercise.75 This is supported by a 12-year follow-up study of 480 cancer survivors,whose physical activity was assessed by a 7-day accelerometer.Results from this study revealed that the quartile of survivors who undertook the highest level of light-intensity physical activity had a 63% reduction in mortality compared to participants with the lowest level of activity.75

Moreover, exercise has also been shown to reduce cancer treatment-related cardiotoxicity by improving myocardial function,reducing oxidative stress, and modulating the body's inflammatory response. The mode of exercise intervention has primarily been endurance exercise, but positive effects on upper/lower body or appendicular muscle mass(67-100%), muscle strength(61-68%),and physical function(74-100%) have been demonstrated by resis-tance exercise.65 As maintenance of muscle mass during cancer therapy and increased inactivity phases are important to allevi-ate treatment side effects as well as improving overall outcomes and quality of life,77 current American Society of Clinical Oncol-ogy(ASCO) guidelines emphasize the importance of both resis-tance and aerobic exercise during cancer treatment to mitigate side effects as well as before surgery, to reduce length of hospital stay and postoperative complications.78 Also, the ESC cardio-oncology guidelines recommend that cancer survivors engage in at least 150 min of moderate-intensity aerobic exercise per week, along with muscle-strengthening activities on two or more days.1 These recommendations are similar to exercise recommendations in HF.79,108 In patients with early signs of diastolic dysfunction or mild impairment of LVD, tailored exercise programmes should be pre-scribed according to HF guidelines and should best be referred to cardiac rehabilitation.

Early scientific evidence indicating the preventive effects of exercise on cancer therapy-induced cardiotoxicity comes from the BREXIT trial. among In early-stage breast cancer patients who adhered to exercise intervention, exercise prevented func-tional disability at 12 months and was associated with a net 3.5-ml/kg/min improvement in peak oxygen consumption, coin-ciding with greater cardiac output, stroke volume, and left and

right ventricular ejection fraction reserve(p<0.001 for all). More-over, post-chemotherapy cTn increased less in exercising patients(8-fold vs.16-fold increase;p=0.002), but NPs did not change.109 More research is necessary to confirm these results, particularly on long-term prognosis.

Smoking

The association between smoking and both CVD and cancer is well-known.110 For patients receiving cancer treatment, cigarette smoking,according to the 2022 ESC guidelines on cardio-oncology,places them at moderate risk of cardiotoxicity, or if receiving more targeted therapies such as BCR-ABL inhibitors, at high risk.1 All survivors of cancer who continue to smoke should be assessed for their readiness to quit, educated on its detrimental effects and be offered behavioural and/or pharmacological options. The role of e-cigarettes in reducing CV outcomes is, however, still unresolved. ${}^{80}$

Nutrition

Patients during cancer treatment often experience nausea and therefore opt to consume small high calorific meals. So far, no randomized controlled trials have explicitly assessed the effects of dietary intervention on the development of HF in patients receiving cancer therapy. However, in all individuals, a Mediterranean diet,low in saturated fat and processed carbohydrates is advised. Diets rich in fruits, vegetables, whole grains, and omega-3 fatty acids(including the Mediterranean diet) are associated with improved CV outcomes.81 Furthermore, specific dietary patterns, such as the DASH(Dietary Approaches to Stop Hypertension) diet, have shown efficacy in reducing blood pressure and promoting heart health.82

In the post cancer treatment phase, there is conflicting evidence on the importance of nutrition as a risk factor for CVD. A Cochrane review that included 25 randomized controlled trials where 7259 cancer survivors received a dietary intervention or usual care, found minimal or no difference in risk of mortality and secondary cancer.83 Similarly, a 16-week behavioural intervention for cancer survivors, incorporating both diet and physical activity(Fitbit), found only a tendency towards a reduction in the targeted dietary factors and an improvement in physical activity levels for those who received the intervention.

Stress management and psychosocial interventions

Cancer diagnosis and treatment are inherently stressful, and chronic stress is a known risk factor for CVD.84-86 Psychoso-cial interventions, including mindfulness-based stress reduction,cognitive behavioural therapy, and relaxation techniques, can lower stress hormones like cortisol, reduce blood pressure,and improve heart rate variability.84-86 However, specifically in cancer patients, randomized controlled trials investigating CV risk factors are scarce, and evidence on the role and poten-tial of psychological intervention for the prevention of HF is still missing.

Pharmacological intervention

Potential role of different cardiovascular medication for heart failure prevention

Cardiologists have four classes of pharmacological medication with extensive evidence of benefit in symptomatic HF with reduced ejection fraction, with sodium-glucose co-transporter 2 inhibitors(SGLT2i) also shown to benefit HF with preserved and mildly reduced ejection fraction. As for HF prevention, in patients with cancer, beta-blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and their combination have been studied with varying results. The other HF medications,such as SGLT2i, angiotensin receptor-neprilysin inhibitors(ARNi)and mineralocorticoid receptor antagonists, have not been evalu-ated in systematic and robust scientific studies. However, there are currently randomized clinical trials assessing the efficacy of ARNi and SGLT2i in HF prevention in cancer patients(Table 3).

Beta-blockers, renin-angiotensin-aldosterone system inhibitors and their combination

The OVERCOME trial demonstrated that carvedilol and enalapril may have a protective role against worsening LVEF.87 In the CECCY trial, carvediol did not prevent the decline in LVEF, though it may have reduced cTn levels, but had no effect on NP levels.88 The PRADA trial tested beta-blockers(metoprolol succinate),renin-angiotensin-aldosterone system(RAAS) inhibitors(can-desartan), or their combination and found no clear benefit in pre-venting LVEF reduction.89 The MANTICORE study evaluated the use of perindopril(RAAS inhibitor) or bisoprolol(beta-blocker)in patients undergoing trastuzumab therapy and found no signif-icant effect in preventing left ventricular remodelling, defined as differences in left ventricular end-diastolic volume.90 Additionally,no protective role of candesartan was observed in breast cancer patients previously treated with anthracyclines, neither in prevent-ing left ventricular systolic dysfunction nor in avoiding an increase in serum biomarkers.91

In the Cardiac CARE trial, patients with elevated cTn lev-els were randomized to receive either carvedilol and candesar-tan or placebo, and no significant differences in LVEF were noted.92 Recently, the PROACT trial showed no significant effect of analapril in reducing cTn levels.93 Similarly, the PREVENT-HF phase llb trial reported that low-dose carvediloliol failed to pre-vent anthracycline-induced cardiotoxicity in childhood cancer sur-vivors. ${}^{94}$

Angiotensin receptor-neprilysin inhibitors

Concerning ARNi therapy, limited clinical data are available on its use for the primary prevention of HF in patients undergoing chemotherapy. However, preclinical evidence suggests that these agents may play a significant role in preventing systolic dysfunc-tion.95 Currently, no systematic clinical data on the role of ARNi in the primary prevention of CTRCD are available. In a pilot study,Frey et al.96 demonstrated that ARNi therapy is not only well-tolerated in patients with HF and cancer but can also be

up-tritated. Martin-Garcia et al.97 observed improvements in left ventricular systolic function, NP levels, and functional class in can-cer patients diagnosed with CTRCD following ARNi therapy. Addi-tionally,Gregorietti et al.98 reported that ARNi therapy could be a promising option for cases of refractory CTRCD. Ongoing ran-domized clinical trials are currently assessing the efficacy of ARNi therapy in the primary prevention of CTRCD.99,100

Mineralcorticoid receptor antagonists

A single randomized clinical trial indicated a potential protective effect of spironolactone in preventing both systolic and diastolic dysfunction in women with breast cancer receiving anthracycline therapy,101 and therefore further research is necessary.

Sodium-glucose co-transporter 2 inhibitors

Preclinical studies suggest that SGLT2i may reduce LVD and myocardial fibrosis in animal models treated with anthracyclines,indicating potential for preventing chemotherapy-induced HF in cancer patients.102 Retrospective studies, such as those by Gongora et al.112 and Chiang et al.,103 found that SGLT2i use was not only safe for patients with diabetes receiving anthracyclines but also associated with fewer cardiac events, lower mortality rates, and reduced sepsis or febrile neutropenia. In contrast, a population-based study by Abdel-Qadir et al. ${}^{104}$ found that none of the patients in the SGLT2i group experienced hospitalization due to HF, however, when analysing the overall occurrence of HF or other CVD, no significant differences were observed.

Available data, while needing careful interpretation due to the retrospective nature of the analysis, suggest two important findings for SGLT2i: safety(no observed increase in sepsis incidence despite patient frailty due to chemotherapy) and potential promising effects against HF. To further investigate this, the EMPACT(Empagliflozin in the Prevention of Cardiotoxicity in Cancer Patients Undergoing Chemotherapy Based on Anthracyclines) trial(NCT05271162), a randomized, multicentre, placebo-controlled, double-blind clinical trial, is currently ongoing.

A recent meta-analysis ${}^{105}$ of 13 studies observed that SGLT2i use reduced HF hospitalizations by 51%(risk ratio[RR] 0.49,95% CI 0.36-0.66, $\Gamma^{2}=28\%, p<0.01$ ) and new HF diagnoses by 71%(RR 0.29, 95% CI 0.10-0.87, $\Gamma^{2}=71\%$ ). Multivariate analysis suggested that among breast cancer populations, studies with≥50% of patients on anthracyclines exhibited a 99% reduction in HF hospitalization risk compared with similar studies that included<50% of patients on anthracyclines. These findings support the need for prospective trials to further investigate the integration of SGLT2i into cancer patient management to enhance CV outcomes.

Other cardioprotective strategies

Apart from the neurohormonal therapies extensively discussed in the previous section regarding their role in HF prevention in can-cer patients, the European cardio-oncology guidelines also approve dexrazoxane and liposomal anthracyclines for patients at high or very high risk of CTRCD or for those who have already received high cumulative doses of anthracyclines.1 Currently, dexrazoxane

is approved for use in adult patients with advanced or metastatic breast cancer who have received a minimum cumulative anthra-cycline dose of 300 mg/m2 of doxorubicin or its equivalent.1,106 Both pegylated and non-pegylated liposomal doxorubicin are approved for metastatic breast cancer, with pegylated liposomal doxorubicin also approved for advanced ovarian cancer, acquired immune deficiency syndrome-related Kaposi sarcoma, and multi-ple myeloma.1,107 In addition to these established therapies, several other agents have been investigated for HF prevention in cancer patients, although in smaller studies.

Statins

Although preclinical studies suggest a potential role for statins in preventing post-chemotherapy cardiotoxicity,113-115 recent clini-cal trials have shown conflicting results. Neilan et al.116 found that 40mg of atorvastatin reduced the risk of cardiac dysfunction in lymphoma patients treated with anthracyclines over 12 months but without a significant difference in HF incidence. In breast cancer or lymphoma patients treated with doxorubicin, Hundley et al.117 observed no considerable difference in LVEF reduction. Thavendi-ranathan et al.118 also noted no significant effect of atorvastatin on LVEF, tissue characterization(oedema and/or myocardial fibrosis)on CMR, or biomarkers in high-risk patients.

Ivadrine

Considering the evidence that cancer patients with a high resting heart rate(over 75 bpm) have a poorer prognosis,119 the efficacy of ivadrabine has also been investigated in a small prospective,randomized, open-label study which found no difference in the primary endpoint, defined as a reduction of more than 15% in GLS.120 Therefore, based on current evidence, no data recommend ivabradine therapy.

Anti-inflammatory drugs

In special scenarios like immune-related myocarditis, immuno-suppressive therapies may be necessary to halt immune-related adverse events and major adverse CV events.121 In the case of cytokine release syndrome after CAR-T cell infusion, the early inhibition of inflammatory cascade can mitigate the severity of CV complications. ${}^{34,122}$

Holistic cardio-oncology service

Each point of contact, no matter the purpose of the consultation,should be perceived as an opportunity for patient education,lifestyle education and management of risk factors, fundamental to optimal patient care.123 Due to the complex needs of many of these patients, their lives can become a roller-coaster of healthcare appointments. This can result in a disjointed service with slow decision-making.

In recent years, the development of multidisciplinary cardio-oncology programmes has enhanced patient well-being and improved clinical outcomes. These optimally include experts

![Strategies to prevent heart failure\nCancer diagnosis\nCancer treatment\nPost cancer treatment\nOncology consultation\nCardiovascular assessment\nExercise / nutrition / smoking assessment, exercise training / diet / smoking cessation\nMedication / risk factor control\n](2/aj0YEe4oUhYkBdfpda0fYP/figure45ebb59b5f0e4c49b74fcece0d8bd5ed_11_2.png) Figure 3 A comprehensive model of care and follow-up of patients with cancer to prevent heart failure.

from oncology, haematology, cardiology, sports medicine, sports science, physiotherapy, nutrition medicine and psychology, who will develop an individual lifestyle intervention programme, if needed to be combined with pharmacological treatment to mini-mize unnecessary interruptions in cancer treatment and prevent cardiotoxicity124(Figure 3). This approach is dependent on the patient's symptoms, obesity/weight control versus cachexia man-agement, CV risk factor control, assessment of exercise capacity and planning of prevention programme, all dependent on cancer treatment and stage of the disease.125,126 This comprehensive model of care requires further development to provide an out-reach service into the community, to prevent or mitigate CV events.57

Future needs and gaps in knowledge

Further research is required to improve the prevention of CTRCDR and HF. First, more clinical trials are needed to better identify specific CRTCD risk factors and validate existing risk assessment tools, such as the HFA-ICOS algorithm, and to evaluate the effectiveness of CV risk scores(e.g. EuroSCORE II, SCORE2) in

predicting those at risk of CTRCD and HF. Integrating clinical,biochemical, and imaging data could improve early detection,with artificial intelligence and advanced analytics offering new possibilities for recognizing early signs of cardiac damage. Research into genetic factors may enable personalized risk stratification and targeted prevention strategies for high-risk patients.

Despite progress, critical knowledge gaps persist. While some CV drugs have been studied, randomized trials evaluating compre-hensive cardioprotective strategies, including drugs like ARNi and SGLT2i, are still lacking.The combined use of clinical, imaging, and biochemical markers for early CRTCD detection remains under-developed. A more integrated, multidisciplinary approach could significantly improve early diagnosis and prevention, but further studies are required to fully assess its potential.

Funding

A.R.L. is supported by the Fondation Leducq Network of Excel-lence in Cardio-Oncology and the Royal Brompton Cardio-Oncology Centre of Excellence is supported by The Big Heart Foundation.C.G.T. is supported by two grants from the Italian Ministry of Health(PNRR-MAD-2022-12376632 and PNRR-MCNT2-2023-12376981).

Conflict of interest: A.R. reports speaker honoraria from AstraZeneca,Novartis, Roche.D.F reports speaker honoraria, consultation fees or travel grants from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Roche.G.G. has received speaker honoraria as Astellas, Novariaa, TstraZeneca,and Bristol Myers Squibb. M.H. reports honoraria for lectures from Abbott, Ambott, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb,Daiichi-Sankyo,Lilly,Medi,Novartis,Pfizer and Roche,Consulting fees from Medical Park, and being the past-president of the European Association of Preventive Cardiology(presidancy 2020-2022), outside the submitted work.T.L.F. reports speaker, advisory board, or consultancy fees from Philips,Janssen,Daiichi Sankyo,Myocardial Solutions,AstraZeneca,Phizer,Begen,Gene,Bayer,Roche and BMS,not related with this work.A.R.L. reports speaker, advisory board or consultancy and consultee fees and/or research grants from Pfizer,Novartis, Servier, AstraZeneca, Bristol Myers Squibb, GSK,Amgen,Takeda,Roche,Janssen-Cilag,Ld,Clinings Group,Eli,Yisal,Lf, Ferring Pharmaceuticals, Boehringer Ingelheim, Akcea Therapeutics, Myocardial Solutions, IOOWNA Health, Heartelft Technologies Ltd., ARMA Biosciences and Epilic Life Ltd.C.S. reports speaker, advisory board, or consultancy fees from GE Healthcare,Amgen,unrelated to this work,C.G.T.R. reports homo-raria or consultation fees from VivaLyfe, Univers Formazione, Solaris, Sum-meet,AstraZeneca, Myocardial Solutions, Medtronic, funding from Amgen and MSD, outside of the submitted work. V.V. reports grants unrelated to this work from NIHR,BHF, Wellcome and B Braun.M.M. reports consul-tancy, speaker fees from Abbott Structural, AstraZeneca, Boehringer inegel,heim,Cytokinetics,Edwards Lifesciences,Novo Nordisk,Roche Diagnos-tics.M.P reports consultancy, speaker fees from AstraZeneca, Boehringer Ingelheim, Novo Nordisk. Payment for writing or reviewing the manuscript from Menarini, Servier. All other authors have nothing to disclose.

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表 1
Antitumoral agent	Mechanism theories	Epidemiology	References
Anthracycline chemotherapy (doxorubicin, epirubicin, daunorubicin, idarubicin)	Cardiomyocyte death trough oxidative stress,DNA damage and mitochondrial impairment	3-5%; with liposomal anthracyclines 2%	8
Alkylating agents(cyclophosphamide, melphalan)	Oxidative stress and endothelial dysfunction	Up to 28%(cyclophosphamide> ifosfamide)	8
Fluoropyrimidines (5-fluorouracil, capecitabine)	Vasospasm, myocardial inflammation	Up to 18%	8
Taxanes(docetaxel, paclitaxel)	Fluid retention, abnormal calcium homeostasis	2.3-8%	7
Proteasome inhibitors(carfilzomib, bortezomib, ixazomib)	Ventricular dysfunction/congressive heart failure, arterial hypertension, endothelial dysfunction, ischaemic cardiomyopathy	2-5%	7
mTOR inhibitors(everolimus)	Dysregulation of the PI3K-AKT-m-TOR pathway	Reported odds ratio: 2.12	9
HER2-targeted therapies(trastuzumab, pertuzumab, trastuzumab emtansine [T-DM1], lapatinib, neratinib,	Down-regulation of protective intracellular pathways(NRL-1,RAS/RAF or PI3K-AKT-mTOR) against oxidative stress, apoptosis and mitochondrial function impairment	Up to 28% if with anthracyclines (trastuzumab> lapatinib and pertuzumab)	8
Anti-EGFR/HER1(osimertinib) Multi-targeted kinase inhibitors BCR-ABL TKIs(ponatinib, nilotinin, dasatinib, bosotinib)	Unclear, partial inhibition of HER2 pathway Off target down-regulation of cardiomyocyte growth and survival pathways	4-5% 2-5	10 7
VEGF inhibitors TKls(sunitinib, pazopanib, sorafenib, axitibin, tvoizanab, cobazantinib, regorafenib, lenvatinib, vandetinib) and antibodies (bevacizumab, ramucirumab)	Impairment of mitochondrial function and inhibition of the AMP-kinase pathway	Up to 4%	8
Combination RAF and MEK inhibitors	Inhibition of MEK/ERK pathway in the cardiomyocyte	29%	11
(dabrafenib+trametinib,	cardiomyocyte
venurafenib+ cobimetinib, encorafenib+ binimetib)	Impairment of immunological homeostasis	3.5%	7,12
Immune checkpoint inhibitors	Impairment of immunological homeostasis
Anti-PD1(nivolumab, pembrolizumab)	in the myocardium, autoimmunity against cardiomyocytes or endothelial cells
Anti-CTL4(ipilimumab)	cardiomyocytes or endothelial cells
Anti-PD-L1(avalumab, atezolizumab, durvalumab)
CAR-T cells(tisagenlecleucel, axicabtagene)	Cytokine releasing syndrome and unclear off-target effects of CAR-T or lymphodepletion	Up to 30%	13
Radiotherapy	Cardiomyocyte death through direct cardiomyocyte toxicity(oxidative stress, DNA damage) and development of coronary atherosclerosis and fibrosis in cardiac valves and pericardium	Up to 10%	14

AMP, adenosine monophosphate; BCR-ACL, breakpoint cluster region-Abelson oncogene locus; CAR-T, chimeric antigen receptor; GHEFR, epidermal growth factor receptor; HER, human epidermal receptor; mTOR, mechanistic target of rapamycin; PD-1, programmed death ligand-1; PI3K, phosphadytidyinolositol 3-kinase; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.

表 2
Cancer therapy	Cancer drug agents
induced
Atrial fibrillation	Alkylating agents ●Cisplatin, ifosfamide, cyclophosphamide, melphalan Anthracyclines Antimetabolites
Capecitabine,5-fluorouracil,gemcitabine Interleukin-2	Capecitabine,5-fluorouracil,gemcitabine Interleukin-2 Interferons
Rituximab	Rituximab
Small molecule TKIs	Small molecule TKIs
Ponatinib, sorafenib, sunitinib, ibrutinib	Topoisomerase II inhibitors
Amsacrine, etoposide	Amsacrine, etoposide
Taxanes
Anthracyclines	Anthracyclines
Histone deacetylase inhibitors
Depsipeptide, belinostat, vorinostat
Chemicals:arsenic trioxide
TKIs
Axitinib, bosutinib, cabozantinib, crizotinib, dabrafenib, dasatinib, lapatinib, nilotinib
pazopanib, ponatinib, sorafenib, sunitinib, vardetanib, vermurafenib
BRAF inhibitor: vemurafenib
CDK4/6 inhibitors: ribociblic
Monoclonal antibody-based TKI
Bevacizumab, ado-trastuzumab emtansine
Monoclonal antibodies
Alemtuzumab, ibritumomab, ofatumumab, rituximab
mTOR inhibitors: everolimus, temsirolimus
TKIs
Pazopanib, ponatinib, sorafenib, sunitinib, axitinib, abozantinib, ibrutinib, nilotinib,
ramucirumab, regorafenib, trametinib,
vandetanib, ziv-aflibercept
Proteasome inhibitors
Bortezomb, carfilzomib
Antimetabolites
Decitabine

表 3
Intervention	Effect	References
Lifestyle intervention
Obesity	Intentional weight control through a combination of dietary changes and exercise, can improve metabolic health, reduce hypertension, and decrease the risk of HF.	55-61
Physical activity	Exercise programmes tailored to cancer patients can improve both cardiorespiratory fitness, quality of life and overall survival outcomes.	62-74
Smoking cessation	Cigarette smoking in cancer patients is considered as an established risk factor as well as in the general population.	1,75,76
Nutrition	Mediterranean diet, low in saturated fat and processed carbohydrates is advised.The effect of healthy nutrition is not properly established yet.	77-79
Pharmacological intervention
Beta-blockers and RAASi	Despite initial benefits have been observed with combined therapy(beta-blockers and RAASi), further studies did not confirm.	80-86
ARNi	No systematic clinical data are currently available for CRTCD primary prevention. Ongoing randomized clinical trial(PRADA II and MAINSTREAM) are evaluating ARNi in CRTCD primary prevention.	87-92
MRAs	Small evidence may suggest a protective role for both systolic and diastolic dysfunction. However, further and more robust data are necessary to confirm its role in preventing HF.	93
SGLT2i	Preclinical studies and retrospective data showed potential positive effect of these drugs in cardiotoxicity prevention. A recent meta-analysis observed that SGLT2i use reduced HF hospitalizations by 51%(RR 0.49, 95% CI 0.36-0.66, 12=28%, p<0.01) and new HF diagnoses by 71%(RR 0.29, 95% CI 0.10-0.87, $\hat{\imath}^{2}=71\%$ ). Multivariate analysis suggested that among breast cancer populations, studies with≥50% of patients on anthracyclines exhibited a 99% reduction in HF hospitalization risk compared with similar studies that included<50% of patients on anthracyclines. Further prospective and randomized studies are ongoing.	94-97
Statins
Ivadrine	No clear benefit has been observed with hivadrine use for preventing HF in cancer patients.	98-103
Dexrazoxane	Dexrazoxane is approved for use in adult patients with advanced or metastatic breast cancer who have received a minimum cumulative anthracycline dose of 300 mg/m2 of doxorubicin or its equivalent to reduce the risk of CRTCD. A reduction of HF(RR 0.22, 95% CI 0.11-0.43) was reported.106	1,106
Liposomal anthracyclines	Both pegylated and non-pegylated liposomal doxorubicin formulations are approved for metastatic breast cancer, with pegylated liposomal doxorubicin doxorubicin also approved ovarian cancer, acquired immune deficiency syndrome-related Kaposi sarcoma, and multiple myeloma. Pegylated and non-peylated liposomal doxorubicin modify pharmacokinetics and tissue distribution without compromising antitumour efficacy. In a meta-analysis of 19 trials, in both the adjuvant and metastatic context, liposomal doxorubicin was reported to be less cardiotoxic than conventional events(OR 0.60, 95% CI 0.34-1.07).	1,107

ARNi, angiotensin receptor-neprilynsin inhibitor; CI, confidence interval; CRTCD, cancer-related therapy cardiac dysfunction; HF, heart failure; MRA, mineralocorticoid receptor antagonist; OR, odds ratio; RAASi, renin-angiotensin-aldosterone system inhibitor; RR, risk ratio; SGLT2i, sodium-glucose co-transporter 2 inhibitor.

图示：Pathophysiology Cardiac dysfunction /heart failure Risk factors Vous Previous CVD CTR-CVT I Risk factors Previous cardiotoxic therapies Previous cardiotic therapies Lifestyle liskofractors Medication Lifestyle lifestyle therapies 4000 c�道or ECG,TTE,and cardiac biomarkers abnormalities Medication/ring of risk factors ㈩㈩㈩㈩ cancer treatment Cancer treatment ㈩㈩㈩ cancer treatment ㈩ cancer treatment ㈩ cancer treatment ㈩ cancer treatment ㈩㈩㈩

图示：Pathophysiology Indirect effects of anticancer therapies Direct effects of anticancer therapies Potential effects of cancer Cardiac dysfunction / heart failure

图示：Age, sex, genetics Medical CVD Previous CVD CVD Previous cardiotoxic lifestyle risk factors chototoxic therapies ECG, TTE, and cardiac biomarkers abnormalities

图示：Strategies to prevent heart failure Cancer diagnosis Cancer treatment Post cancer treatment Oncology consultation Cardiovascular assessment Exercise / nutrition / smoking assessment, exercise training / diet / smoking cessation Medication / risk factor control

引用 / 出处

2025 HFA／EAPC 临床共识声明：癌症患者和幸存者与癌症治疗相关的心功能障碍和心力衰竭的预防. 2025.

2025 HFA／EAPC 临床共识声明：癌症患者和幸 存者与癌症治疗相关的心功能障碍和心力衰竭的预防

Prevention of cancer therapy-related cardiac dysfunction and heart failure in cancer patients and survivors. A Clinical Consensus Statement of the Heart Failure Association, the European Association of Preventive Cardiology of the ESC, and the ESC Council of Cardio-Uncology

Graphical Abstract

Introduction

Definition

Epidemiology

Risk factors for cancer therapy-related cardiac dysfunction

Oncologic treatments and their clinical complications leading to heart failure

Cardiovascular toxicity of chemotherapy

Left ventricular dysfunction

Arrhythmias

Arterial hypertension

Accelerated atherosclerosis and ischaemic heart disease

Cardiotoxicity of radiotherapy

Early detection

Clinical evaluation

Electrocardiogram

Imaging tests

Biomarkers

Management of myocardial toxicity of cancer treatment

Lifestyle interventions

Risk factor control

Obesity and body weight control

Arterial hypertension

Sedentary habits and exercise prescription

Smoking

Nutrition

Stress management and psychosocial interventions

Pharmacological intervention

Potential role of different cardiovascular medication for heart failure prevention

Beta-blockers, renin-angiotensin-aldosterone system inhibitors and their combination

Angiotensin receptor-neprilysin inhibitors

Mineralcorticoid receptor antagonists

Sodium-glucose co-transporter 2 inhibitors

Other cardioprotective strategies

Statins

Ivadrine

Anti-inflammatory drugs

Holistic cardio-oncology service

Future needs and gaps in knowledge

Funding

References

相关指南

引用 / 出处

2025 HFA／EAPC 临床共识声明：癌症患者和幸存者与癌症治疗相关的心功能障碍和心力衰竭的预防