Cardio-oncology: Why Is this Recently Surfaced Field Necessary?

Cardio-oncology is a rapidly developing field that tackles the escalating prevalence of cardiovascular diseases (CVDs) among cancer patients during and after cancer treatment. The combination of enhanced cancer survival rates, targeted molecular therapies, and the continued utilisation of chemo and radiation therapies have resulted in a notable upsurge in cancer patients experiencing CVDs. Naturally, this trend is particularly pronounced in individuals who have received or are undergoing cancer treatments with known cardiovascular (CV) toxicity. The advancements in cancer therapy have also brought to light both short and long-term CV complications, leading to premature morbidity and mortality among cancer survivors. Shockingly, over 40% of cancer patient deaths can be attributed to CVDs rather than cancer itself. Advancements in precision medicine, encompassing deep phenotyping strategies and omics technologies, offer tremendous potential in this field. By integrating clinical data, genetic information, biomolecular analysis, and demographic profiling, precision medicine can unveil sensitive CV biomarkers, facilitate risk stratification, and guide personalised therapeutic interventions. Consequently, it is crucial to comprehend and implement the principles of precision medicine within the realm of cardio-oncology to effectively prevent, diagnose, and treat CV complications associated with cancer therapy.

Figure 1. The current frontiers in cardio-oncology. (Hajjar et al., 2020)

What is Cardiotoxicity?

The European Society of Cardiology (ESC) defines CV toxicity as any harm to the heart, whether it affects its function or structure, caused by cancer treatment. That includes not only chemotherapy and radiotherapy but also the cancer itself. CV toxicity can manifest shortly after treatment, gradually over time, or even years later. It impacts various components of the heart and can result in heart failure, coronary artery disease, valvular heart disease, arrhythmias (including disturbances in the heart's electrical conduction), and pericardial disease. The most prevalent type of cardiotoxicity arising from cancer therapies is the impairment or dysfunction of the left ventricle, which can lead to heart failure. Anthracyclines and certain targeted chemotherapies elevate the risk of these diseases. Early detection of left ventricular dysfunction or heart failure is increasingly crucial to commence treatment promptly and prevent further deterioration. Often, biomarkers are utilised to assess cardiotoxicity before any observable changes in left ventricular ejection fraction (LVEF) or clinical signs and symptoms of heart failure occur. Nevertheless, it is essential to emphasise that biomarkers should be considered alongside other factors. These include imaging findings, risk factors, clinical symptoms, and the specific circumstances of cancer (e.g., localised or metastatic disease and cancer prognosis). Integrating the identification of cardiac biomarkers with regular imaging can yield a highly effective approach to quickly identify toxicity and guide interventions aimed at safeguarding the heart (Ananthan & Lyon, 2020).

Manifestations of Cardiotoxicity

Cancer treatment cardiotoxicity encompasses various mechanisms, and several theories have been proposed to explain its occurrence. While current treatment methods effectively target different cancer types, they can interfere with DNA replication, inhibit DNA repair, induce endothelial dysfunction, generate reactive oxygen species (ROS), or trigger non-specific immune responses. Anthracycline cardiotoxicity affects approximately 9% of patients receiving chemotherapy. Two schools of thought exist pertaining to its multifactorial mechanism. The primary hypothesis revolves around oxidative stress, where ROS are generated in the presence of iron, causing lipid peroxidation of the cell membrane and subsequent damage to cardiomyocytes. Another hypothesis involves the inhibition of topoisomerase II, an enzyme active in nonproliferating cardiomyocytes, which can activate cell death pathways and hinder mitochondrial biogenesis. Dysregulation of cardiomyocyte autophagy has also been suggested as a potential mechanism. The occurrence of anthracycline toxicity is dose-dependent, with higher cumulative doses correlating with increased cardiotoxicity rates. Other cancer treatments, such as trastuzumab, 5-fluorouracil, cisplatin, cyclophosphamide, and tyrosine kinase inhibitors, can also induce cardiotoxicity through various mechanisms involving mitochondrial dysfunction, oxidative stress, apoptosis, and immune-related inflammation (Elad et al., 2022).

Radiation-induced CVDs pose a complex and challenging situation in clinical practice. Research by Galper et al. showcased that patients who received chest radiation therapy had a 2% higher absolute risk of experiencing cardiac morbidity after five years and a 23% higher absolute risk of cardiac death after 20 years compared to those who did not undergo radiation treatment (Galper et al., 2011). Unlike the toxicity associated with chemotherapy, which is influenced by factors such as metabolic rates and genetic variations, the adverse effects of radiation therapy are directly correlated with the dose administered to the heart or nearby organs. In the context of precision medicine advancements, radiation oncologists have proposed therapeutic approaches like gene-expression assays to identify specific genetic markers that can potentially predict adverse reactions to radiation therapy. This concept, known as genomic-adjusted radiation dose, aims to tailor radiation dosing guidelines based on individual genetic profiles. Moreover, radiation-induced CV damage is believed to involve the activation of monocytes, inflammation, and the formation of atherosclerotic plaque and intimal fatty streaks, which can result in vessel blockage, impaired perfusion, myocardial necrosis, and fibrosis. To address these concerns, radiation therapy patients can benefit from surveillance and risk assessment using radionuclide imaging techniques. These advanced imaging methods provide valuable insights into the development and progression of CV complications caused by radiation therapy (Dreyfuss et al., 2019).

Cardiotoxicity resulting from cancer therapies exhibits diverse clinical manifestations. Recent ESC guidelines classify CV complications associated with cancer treatment into nine broad categories, including myocardial dysfunction, coronary artery disease, valvular heart disease, arrhythmias, and pericardial diseases. The wide range of CV issues can be attributed, in part, to the increasing variety of cancer treatments used in clinical practice, each with its unique way of causing damage. These treatments encompass traditional chemotherapeutics like anthracyclines, targeted therapies such as trastuzumab or antiangiogenic tyrosine kinase inhibitors, and immunotherapies. Recognising the significance of early detection, prompt diagnosis, and treatment of cardiotoxicity has been shown to improve recovery of LVEF and reduce cardiac events in patients with cancer therapy-induced cardiomyopathy. Recommendations for managing potential cardiac dysfunction in patients receiving cardiotoxic therapies involve regular monitoring of LVEF through serial echocardiograms, stratifying the population based on the treatments received and pre-existing CV risk factors like age and hypertension, and utilising serum cardiac biomarkers such as troponin for surveillance. A staging system ranging from stages A to D exists for heart failure, with each stage representing varying levels of exposure to cardiotoxic substances and observed cardiac dysfunction. While these guidelines represent progress, they often need more specificity, and evidence-based data for clinical decision-making is limited. The limitations of current approaches emphasise the potential for precision medicine in the field of cardio-oncology. Current risk stratification models rely primarily on basic clinical characteristics and fail to incorporate the information that could be obtained through in-depth phenotyping. Even with the emergence of more refined risk stratification models, clinical management primarily focuses on adjusting surveillance frequency and medication dosages. Adopting a multidisciplinary commitment to precision medicine approaches is crucial, with molecular imaging and omics sciences leading the way towards promising new paradigms (Dreyfuss et al., 2019).

Figure 2. Cardiotoxicity consequences. (Gabani et al., 2021)

The Impact and Importance of Measuring Cardiotoxicity

A thorough understanding of cardiotoxicity mechanisms is essential for appropriately selecting biomarkers to diagnose and monitor the condition. Initially, anthracyclines and radiation therapy were identified as the first treatments associated with CV toxicity. Anthracyclines primarily cause dysfunction in the left ventricle, while radiation toxicity leads to valvular dysfunction and coronary artery disease. Specific targeted cancer therapies, including HER2 inhibitors (trastuzumab), RAF-MEK inhibitors, and EGFR inhibitor osimertinib, can also lead to left ventricular dysfunction and heart failure. Vascular endothelial growth factor (VEGF) signalling inhibitors and multi-targeted tyrosine kinase inhibitors have a broader range of CV side effects, encompassing left ventricular dysfunction, vascular toxicity, QT prolongation, increased arrhythmia risk, and in some cases, pulmonary hypertension. Cardiotoxicity resulting from anthracycline chemotherapy is attributed to oxidative stress and mitochondrial dysfunction induced by generating ROS. VEGF inhibitors and BCR-ABL tyrosine kinase inhibitors can, directly and indirectly, contribute to left ventricular dysfunction through the development of coronary artery disease and hypertension. Thrombotic events and myocardial infarction are associated with higher mortality rates among patients receiving VEGF inhibitors. Immune checkpoint inhibitors (ICIs) can trigger immune-mediated CV toxicities, including autoimmune myocarditis, complete heart block, acute coronary syndromes, pericarditis, and non-inflammatory left ventricular dysfunction. Further research is necessary to understand the range of CV toxicities associated with ICIs entirely and to investigate the role of biomarkers in diagnosing, monitoring, and assessing treatment responses (Ananthan & Lyon, 2020).

One characteristic of cardiotoxicity, defined by the American Society of Echocardiography and the European Association of Cardiovascular Imaging, refers to a reduction in LVEF greater than 10%, resulting in a value below 53% (normal limit if 2-Dimensional echocardiography is used). The ESC 2016 highlighted echocardiography as the preferred method for detecting cardiotoxicity and left ventricular dysfunction throughout all stages of chemotherapy. The frequency of assessments needed to identify cardiotoxicity depends on various factors, including the specific cancer being treated, the type and duration of cardiotoxic cancer therapy, the total dose administered, and the patient's baseline CV risk. It is now widely acknowledged that relying solely on symptoms or waiting for a symptomatic decline in ejection fraction is insufficient, as irreversible damage to heart muscle cells may have already occurred. Furthermore, this approach fails to detect structural manifestations of cardiotoxicity, such as myocarditis (Ananthan & Lyon, 2020).

A prospective study by Cardinale et al. involving a substantial number of patients demonstrated that regular echocardiography enabled the identification of cardiotoxicity in 98% of patients within the first year of treatment. With ACE inhibitors and beta-blockers, 82% of patients could recover and achieve a normal ejection fraction during follow-up. However, in 71% of patients, the ejection fraction achieved with medical treatment remained below their pre-chemotherapy value. Hence, the importance of early detection of cardiotoxicity before a decline in ejection fraction occurs underscores the significance of biomarkers as a valuable tool for early detection in current cardio-oncology practice (Cardinale et al., 2015).

Figure 3. The factors which contribute to baseline CV risk in cancer patients and a checklist of clinical history. (Lyon et al., 2020)

Assessing the baseline CV risk in cancer patients before initiating therapies that may have CV toxicity is a critical step that follows fundamental principles. These regulations include acknowledging that risk is a continuous variable, ranging from low to high risk. They also include understanding that multiple CV risk factors can coexist and have an additive or synergistic effect and that the parameters must be supported by evidence or expert opinion. Treatment decisions should be made in collaboration between oncologists, haematologists, and cardiologists, considering both treatment efficacy and CV risk. The patient has to be fully informed and involved in the decision-making process. Emphasised and prompt assessment without causing delays in cancer treatment initiation is essential. Comprehensive and systematic baseline CV risk assessment is vital in tailoring cancer therapies and optimising patient outcomes while minimising potential CV complications (Lyon et al., 2020).

Pareek et al. launched a five-year consecutive 'real-world experience of the first purpose-designed cardio-oncology service', highlighting the importance of a personalised approach in evaluating and optimising high-risk patients or those with myocardial toxicity. They found preliminary evidence suggesting that CV optimisation and continued cancer treatment may be associated with improved survival, particularly in the highest-risk patients with left ventricular systolic dysfunction. One of the main objectives of a cardio-oncology service is to enhance LVEF and functional capacity, enabling patients to better tolerate and benefit from continuous cancer treatments. It is especially crucial since interruptions in cancer treatment were linked to an increased risk of cancer recurrence. Despite the limited data on cardio-oncology service outcomes, Pareek et al. demonstrated that with CV optimisation, most referred patients were deemed fit to continue cancer treatment without significant delays or lower treatment rates. Additionally, they developed an assessment tool to identify high-risk patients and followed ESC guidelines tailored to the individual patient's needs (Pareek et al., 2018).

Figure 4. Study population cancer types and reasons for referral to the cardio-oncology service. (Pareek et al., 2018)

Panomics as a Helpful Tool in Cardio-oncology

Panomics, which involves the comprehensive integration of omics measurements collected systematically from various samples, holds great potential for conducting in-depth systems biology analyses to uncover biological processes' origins, relationships, and impacts. Typically employed in longitudinal studies, panomics offers wide-ranging applicability and finds extensive utility in pharmaceutical research (Vakili et al., 2021).

In recent years, significant advancements in omics technologies have profoundly improved the clinical relevance of phenotyping in scale and breadth. Through the computational analysis of extensive data networks, omics sciences aim to uncover patterns and understand the underlying causes of diseases. This approach holds tremendous potential in cardio-oncology, particularly in therapy-induced cardiotoxicity, where it can reveal new disease metrics that inform personalised medicine. However, it is crucial to acknowledge the inherent limitation of a systems-based analysis that is not heart-specific when predicting cardiac effects. While omic technologies used in broad discovery studies may identify measurable changes in specific candidate markers, it is vital to consider their lack of specificity for cardiac tissue. Variations in these markers could be influenced by processes unrelated to the CV system, emphasising the need to recognise potential confounding variables when interpreting phenomics results for biomarker identification (Dreyfuss et al., 2019).

Figure 5. Deep phenotyping in cardio-oncology patients. (Dreyfuss et al., 2019)

Genome-wide association studies involving childhood survivors provided insights into the genetics of anthracycline-induced cardiotoxicity. These studies have identified specific genetic variations, known as single-nucleotide polymorphisms, in carbonyl reductase and hyaluronan synthase 3, independently modifying the risk of anthracycline-related cardiomyopathy. Carbonyl reductases are involved in converting anthracyclines into cardiotoxic alcohol metabolites. At the same time, the hyaluronan synthase 3 gene contributes to the synthesis of hyaluronan, a component of the extracellular matrix that affects tissue response to injury. Moreover, investigations in childhood cancer survivors have revealed genetic variations in genes that regulate the intracellular transport of anthracyclines as independent predictors of cardiomyopathy risk. Similar studies in adult patients undergoing hematopoietic cell transplantation and treated with anthracyclines have identified an association between a genetic variation in the doxorubicin efflux transporter and cardiotoxicity (Dreyfuss et al., 2019).

Circulating micro-RNAs, which reflect genomic profiles, show significant potential for identifying early cardiac damage in patients undergoing specific therapies. These noncoding small RNA molecules circulate in the bloodstream, enter distant recipient cells, and regulate gene expression. They have already demonstrated their value as biomarkers for CVDs. Studies have found associations between specific micro-RNAs and decreased LVEF in children receiving anthracycline chemotherapy. Another study comparing children receiving anthracycline and non-cardiotoxic chemotherapy revealed greater micro-RNA dysregulation in patients receiving anthracyclines. Proteomic studies, which focus on analysing proteins, have also been employed for biomarker identification. By examining heart tissue samples from control rats and rats exposed to cardiotoxic drugs, these studies have identified proteins involved in energy production that are differentially expressed, with some proteins associated with lower mortality rates (Dreyfuss et al., 2019).

Metabolite profiles provide unique insights into various molecular influences, connecting changes in DNA sequences, cellular physiology, and environmental factors. Although studies investigating metabolic changes related to cancer therapy-related CVD are limited, metabolomics has emerged as a potential tool for cardio-oncologists to analyse chemical intermediates in various biosamples. Abnormal cardiac metabolism has been increasingly linked to CVD, and metabolomics studies in general CVD have provided valuable insights into the pathophysiological changes occurring in specific disease states, such as heart failure and myocardial ischemia. Furthermore, metabolomics shows promise in predicting CVD risk by discovering novel biomarkers. Sequentially integrating progressively macroscopic-omics approaches, from genomics to clinical phenotyping, holds potential in modelling and monitoring the progression of a disease. This approach challenges the current paradigm, where changes in clinical phenotypes drive investigations into progressively microscopic pathophysiology, typically from clinical chemistry and imaging to genomics (Dreyfuss et al., 2019).

Figure 6. Summary of the mentioned omics data types. (Vakili et al., 2021)

Regarding risk prediction, the ability to perform real-time monitoring of blood or urine metabolites could enable clinicians to identify novel molecular biomarkers associated with distinct clinical trajectories. Additionally, changes in metabolite profiles over time, such as after drug administration, could be utilised to determine an individual's response to therapy and guide subsequent management decisions (Dreyfuss et al., 2019).

Treatment Options and Prevention

Drugs like Dexrazoxane have a notable protective effect; however, their usage is restricted due to their high cost and concerns regarding potential drawbacks such as decreased anti-cancer efficacy and an increased risk of secondary tumours. Apart from Dexrazoxane, the current research focus in this field has been on employing medications that target maladaptive neurohormonal activation to prevent further deterioration of cardiac function. Traditional drugs for heart failure have shown limited effectiveness in mitigating chemotherapy-induced cardiac damage. According to the 2016 ESC guidelines, the benefits of preventive treatment with ACE inhibitors, ARBs, or beta-blockers remain uncertain, and no specific recommendations are currently available (Elad et al., 2022). Research conducted by Arinno et al. on rats indicated that Metformin possesses both anti-cancer and cardio-protective properties, although additional research is required to substantiate these findings (Arinno et al., 2021).

Figure 7. Common mechanisms mediating cardiotoxicity and positively affected by exercise

(DM = Diabetes Mellitus). (Elad et al., 2022)

Rehabilitation for cancer patients aims to restore physical activity, prevent frailty, and enhance aerobic capacity. Aerobic exercise training is widely recognised as an effective therapy for improving cardiorespiratory fitness by enhancing oxygen transport and utilisation, resulting in favourable increases in VO2peak. In 2019, the American Heart Association emphasised the need for a comprehensive model within cardio-oncology rehabilitation programs to identify high-risk cancer patients with CVDs or cardiotoxicity from cancer treatments and to implement a multimodal approach to prevent or mitigate CV events. However, there are limitations to cancer patient participation in rehabilitation programs, including treatment side effects, fever, neutropenia, and the risk of complications in hospital or clinic settings. Also, fluctuating haemoglobin levels and anaemia render establishing and adjusting exercise intensity based on pulse range indicators challenging.

Regular exercise at a moderate-to-vigorous intensity reduces the risks of all-cause mortality, CVD, hypertension, stroke, metabolic syndrome, diabetes, and cancer. Those with high exercise levels tend to live longer and have lower mortality rates for CVD and cancer. Exercise alters gene expression, rapidly improving CV parameters and overall fitness. It may prevent cellular ageing, affect oxidative stress and vascular function, and enhance DNA repair mechanisms. Regarding exercise-induced oxidative stress, moderate ROS levels promote positive adaptations in skeletal muscles, while excessive ROS production damages cellular structures. Endurance exercise maintains vascular regularity and prevents endothelial dysfunction. Trained individuals show improved endothelial function, higher antioxidant levels and reduced oxidative stress (Elad et al., 2022).

Conclusions

Addressing the CV complications associated with cardiotoxic cancer therapies requires a personalised and deep phenotyping approach to clinical management. Molecular imaging holds promise in enabling precise diagnostics and surveillance based on the underlying pathophysiology. The shift toward individualised medicine will be pivotal in evidence-based, risk-specific precision medicine in cardio-oncology. By implementing baseline CV risk assessments and utilising markers such as troponins, healthcare professionals can identify cancer patients at increased risk of CV complications and implement appropriate measures to mitigate their risk. The ultimate goal is to allow cancer patients to undergo evidence-based cancer treatments safely, free from CV toxicity and complications, improving overall survival and enhancing their quality of life. Continued investment in research and resources will be crucial in reducing CV morbidity and mortality in the growing population of cancer patients and survivors.

Bibliographical References

Ananthan, K., & Lyon, A. R. (2020). The Role of Biomarkers in Cardio-Oncology. Journal of Cardiovascular Translational Research, 13(3), 431–450. https://doi.org/10.1007/s12265-020-10042-3

Arinno, A., Maneechote, C., Khuanjing, T., Ongnok, B., Prathumsap, N., Chunchai, T., Arunsak, B., Kerdphoo, S., Shinlapawittayatorn, K., Chattipakorn, S. C., & Chattipakorn, N. (2021). Cardioprotective effects of melatonin and metformin against doxorubicin-induced cardiotoxicity in rats are through preserving mitochondrial function and dynamics. Biochemical Pharmacology, 192(May), 114743. https://doi.org/10.1016/j.bcp.2021.114743

Cardinale, D., Colombo, A., Bacchiani, G., Tedeschi, I., Meroni, C. A., Veglia, F., Civelli, M., Lamantia, G., Colombo, N., Curigliano, G., Fiorentini, C., & Cipolla, C. M. (2015). Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation, 131(22), 1981–1988. https://doi.org/10.1161/CIRCULATIONAHA.114.013777

Dreyfuss, A. D., Bravo, P. E., Koumenis, C., & Ky, B. (2019). Precision cardio-oncology. Journal of Nuclear Medicine, 60(4), 443–450. https://doi.org/10.2967/jnumed.118.220137

Elad, B., Habib, M., & Caspi, O. (2022). Cardio-Oncology Rehabilitation — Present and Future Perspectives. 1–13.

Galper, S. L., Yu, J. B., Mauch, P. M., Strasser, J. F., Silver, B., LaCasce, A., Marcus, K. J., Stevenson, M. A., Chen, M. H., & Ng, A. K. (2011). Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation. Blood, 117(2), 412–418. https://doi.org/10.1182/blood-2010-06-291328

Lyon, A. R., Dent, S., & Stanway, S. (2020). Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society. European Journal of Heart Failure, 176(3), 139–148. https://doi.org/10.1053/j.gastro.2016.08.014.CagY

Pareek, N., Cevallos, J., Moliner, P., Shah, M., Tan, L. L., Chambers, V., Baksi, A. J., Khattar, R. S., Sharma, R., Rosen, S. D., & Lyon, A. R. (2018). Activity and outcomes of a cardio-oncology service in the United Kingdom—a five-year experience. European Journal of Heart Failure, 20(12), 1721–1731. https://doi.org/10.1002/ejhf.1292

Vakili, D., Radenkovic, D., Chawla, S., & Bhatt, D. L. (2021). Panomics: New Databases for Advancing Cardiology. Frontiers in Cardiovascular Medicine, 8(May 2021). https://doi.org/10.3389/fcvm.2021.587768

Visual References

Cover Image Oren, O. (2020). [Image displaying a heart and cancer cells, Illustration]. American College of Cardiology. https://www.acc.org/Membership/Sections-and-Councils/Fellows-in-Training-Section/Section-Updates/2020/04/08/12/42/When-Its-Not-Only-the-Cancer-or-Only-the-Heart-The-Intricate-and-Essential-Interaction-Between-Cardiology-and-Oncology

Figure 1. The current frontiers in cardio-oncology. Hajjar,L.A., Costa,I.B.S.S. , Lopes,M.A.C.Q., Hoff,P.M.G., Diz,M.D.P.E., Fonseca,S.M.R., Bittar,C.S., Rehder,M.H.H.S., Rizk,S.I., Almeida,D.R., Fernandes,G.S., Beck-da-Silva,L., Campos,C.A.H.M., Montera,M.W., Alves,S.M.M., Fukushima,J.T., Santos,M.V.C. , Negrão,C.E., Silva,T.L.F. , Ferreira,S.M.A., Malachias,M.V.B., Moreira,M.C.V., Valente Neto,M.M.R., Fonseca,V.C.Q., Soeiro,M.C.F.A., Alves,J.B.S., Silva,C.M.P.D.C., Sbano,J., Pavanello,R., Pinto,I.M.F., Simão,A.F., Dracoulakis,M.D.A., Hoff,A.O., Assunção,B.M.B.L., Novis,Y., Testa,L., Alencar Filho,A.C. , Cruz,C.B.B.V., Pereira,J., Garcia,D.R., Nomura,C.H., Rochitte,C.E., Macedo,A.V.S., Marcatti,P.T.F., Mathias Junior,W., Wiermann,E.G., Val,R. , Freitas,H., Coutinho,A., Mathias,C.M.C., Vieira,F.M.A.C., Sasse,A.D., Rocha,V., Ramires,J.A.F., & Kalil Filho,R. (2020). [Illustration]. Brazilian Cardio-oncology Guideline – 2020. Arq. Bras. Cardiol.,115(5), 1006-1043.

Figure 2. Cardiotoxicity consequences. Gabani M, Castañeda D, Nguyen Q, et al. (September 22, 2021) [Illustration]. Association of Cardiotoxicity With Doxorubicin and Trastuzumab: A Double-Edged Sword in Chemotherapy. Cureus 13(9): e18194. doi:10.7759/cureus.18194

Figure 3. The factors which contribute to baseline CV risk in cancer patients and a checklist of clinical history. Lyon, A. R., Dent, S., & Stanway, S. (2020). [Illustration]. Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society. European Journal of Heart Failure, 176(3), 139–148. https://doi.org/10.1053/j.gastro.2016.08.014.CagY

Figure 4. Study population cancer types and reasons for referral to the cardio-oncology service. Pareek, N., Cevallos, J., Moliner, P., Shah, M., Tan, L. L., Chambers, V., Baksi, A. J., Khattar, R. S., Sharma, R., Rosen, S. D., & Lyon, A. R. (2018). [Illustration]. Activity and outcomes of a cardio-oncology service in the United Kingdom—a five-year experience. European Journal of Heart Failure, 20(12), 1721–1731. https://doi.org/10.1002/ejhf.1292

Figure 5. Deep phenotyping in cardio-oncology patients. Dreyfuss, A. D., Bravo, P. E., Koumenis, C., & Ky, B. (2019). [Illustration]. Precision cardio-oncology. Journal of Nuclear Medicine, 60(4), 443–450. https://doi.org/10.2967/jnumed.118.220137

Figure 6. Summary of the mentioned omics data types. Vakili, D., Radenkovic, D., Chawla, S., & Bhatt, D. L. (2021). [Illustration]. Panomics: New Databases for Advancing Cardiology. Frontiers in Cardiovascular Medicine, 8(May 2021). https://doi.org/10.3389/fcvm.2021.587768

Figure 7. Common mechanisms mediating cardiotoxicity and positively affected by exercise. Elad, B., Habib, M., & Caspi, O. (2022). [Illustration]. Cardio-Oncology Rehabilitation — Present and Future Perspectives. 1–13.