European Journal of Heart Failure (2020) 22, 2272–2289 POSITION PAPER doi:10.1002/ejhf.2029 Common mechanistic pathways in cancer and heart failure. A scientific roadmap on behalf of the Translational Research Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) Rudolf A. de Boer1*, Jean-Sébastien Hulot2,3, Carlo Gabriele Tocchetti4, Joseph Pierre Aboumsallem1, Pietro Ameri5,6, Stefan D. Anker7, Johann Bauersachs8, Edoardo Bertero9, Andrew J.S. Coats10, Jelena Čelutkienė11, Ovidiu Chioncel12, Pierre Dodion13, Thomas Eschenhagen14,15, Dimitrios Farmakis16,17, Antoni Bayes-Genis18,19,20, Dirk Jäger21, Ewa A. Jankowska22, Richard N. Kitsis23, Suma H. Konety24, James Larkin25, Lorenz Lehmann26,27,28, Daniel J. Lenihan29, Christoph Maack9, Javid J. Moslehi30, Oliver J. Müller31,32, Patrycja Nowak-Sliwinska33,34, Massimo Francesco Piepoli35, Piotr Ponikowski22, Radek Pudil36, Peter P. Rainer37, Frank Ruschitzka38, Douglas Sawyer39, Petar M. Seferovic40, Thomas Suter41, Thomas Thum42, Peter van der Meer1, Linda W. Van Laake43, Stephan von Haehling44,45, Stephane Heymans46,47, Alexander R. Lyon48, and Johannes Backs49,50 1 Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; 2 Université de Paris, PARCC, INSERM, Paris, France; 3 CIC1418 and DMU CARTE, AP-HP, Hôpital Européen Georges-Pompidou, Paris, France; 4 Department of Translational Medical Sciences and Interdepartmental Center of Clinical and Translational Research, Federico II University, Naples, Italy; 5 Department of Internal Medicine and Center of Excellence for Biomedical Research, University of Genova, Genoa, Italy; 6 Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy; 7 Department of Cardiology & Berlin Institute of Health Center for Regenerative Therapies (BCRT), German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Charité-Universitätsmedizin Berlin (Campus CVK), Berlin, Germany; 8 Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany; 9 Comprehensive Heart Failure Center, University Clinic Würzburg, Würzburg, Germany; 10 San Raffaele Pisana Scientific Institute, Rome, Italy; 11 Clinic of Cardiac and Vascular Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania; 12 Emergency Institute for Cardiovascular Diseases ‘Prof. C.C. Iliescu’, University of Medicine Carol Davila, Bucharest, Romania; 13 Innate Pharma, Marseille, France; 14 Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 15 Partner Site Hamburg/Kiel/Lübeck, DZHK (German Centre for Cardiovascular Research), Hamburg, Germany; 16 University of Cyprus Medical School, Nicosia, Cyprus; 17 Cardio-Oncology Clinic, Heart Failure Unit, Department of Cardiology, Athens University Hospital ‘Attikon’, National and Kapodistrian University of Athens Medical School, Athens, Greece; 18 Heart Failure Unit and Cardiology Department, Hospital Universitari Germans Trias i Pujol, CIBERCV, Badalona, Spain; 19 Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; 20 CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain; 21 Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany; 22 Department of Heart Diseases, Wroclaw Medical University, and Centre for Heart Diseases, University Hospital, Wroclaw, Poland; 23 Departments of Medicine (Cardiology) and Cell Biology, Wilf Family Cardiovascular Research Institute, Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, USA; 24 Cardiovascular Division, Cardio-Oncology Program, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA; 25 Royal Marsden NHS Foundation Trust, London, UK; 26 Cardio-Oncology Unit, Department of Cardiology, University of Heidelberg, Heidelberg, Germany; 27 DZHK (German Centre for Cardiovascular Research), partner site, Heidelberg/Mannheim, Germany; 28 DKFZ (German Cancer Research Center), Heidelberg, Germany; 29 Cardio-Oncology Center of Excellence, Cardiovascular Division, Washington University in St. Louis, St. Louis, MO, USA; 30 Division of Cardiovascular Medicine and Oncology, Cardio-Oncology Program, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; 31 Department of Internal Medicine III, University of Kiel, Kiel, Germany; 32 DZHK (German Centre for Cardiovascular Research), partner site, Hamburg/Kiel/Lübeck, Germany; 33 School of Pharmaceutical Sciences, University of Geneva, Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland; 34 Translational Research Center in Oncohaematology, Geneva, Switzerland; *Corresponding author. Department of Cardiology, University of Groningen, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands. Tel: + 31 50 361 2355, Email: r.a.de.boer@umcg.nl © 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Common mechanistic pathways in cancer and heart failure 2273 35 Heart Failure Unit, Cardiology, G. da Saliceto Hospital, Piacenza, University of Parma, Parma, Italy; 36 1st Department Medicine-Cardioangiology, University Hospital and Medical Faculty, Hradec Kralove, Czech Republic; 37 Medical University of Graz, University Heart Center – Division of Cardiology, Graz, Austria; 38 Department of Cardiology, University Hospital Zurich, University Heart Center, Zurich, Switzerland; 39 Center for Molecular Medicine, Maine Medical Center Research Institute, Maine Medical Center, Scarborough, ME, USA; 40 University of Belgrade Faculty of Medicine, Serbian Academy of Sciences and Arts, Belgrade, Serbia; 41 Swiss Cardiovascular Centre, Bern University, Bern, Switzerland; 42 Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany; 43 Division Heart and Lungs and Regenerative Medicine Centre, University Medical Centre Utrecht and Utrecht University, Utrecht, The Netherlands; 44 Department of Cardiology and Pneumology, Heart Center, University of Göttingen Medical Center, Göttingen, Germany; 45 German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany; 46 Department of Cardiology, CARIM School for Cardiovascular Diseases Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands; 47 Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium; 48 Cardio-Oncology Service, Royal Brompton Hospital, and National Heart and Lung Institute, Imperial College London, London, UK; 49 Institute of Experimental Cardiology, Heidelberg University Hospital, Heidelberg, Germany; and 50 DZHK (German Centre for Cardiovascular Research), partner site, Heidelberg/Mannheim, Germany Received 13 July 2020; revised 13 September 2020; accepted 18 October 2020 ; online publish-ahead-of-print 12 November 2020 The co-occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Furthermore, genetic predisposition and clonal haematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Additionally, altered angiogenesis is a common hallmark for failing hearts and tumours and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the two pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. To this aim, pre-clinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including patients from all ages, and men and women, with proper adjudication of both cancer and cardiovascular endpoints, are essential to accurately study these two pathologies at the same time. .......................................................................................................... Keywords Heart failure • Cancer • Cardiotoxicity • Inflammation • Clonal haematopoiesis • Angiogenesis • Metabolism • Cardio-oncology • Extracellular matrix Introduction mechanisms that partly explain their association.8 Consequently, ...................................................................... the connection between CV disease and cancer emerged as a Advances in pharmacological and device therapies of heart failure new discipline that encourages collaborations between oncolo- (HF), along with a holistic approach provided by multidisciplinary gists and cardiologists at clinical and research levels, and thereby HF teams, have improved management and reduced cardiovascular aims to optimize the management of individuals affected by these (CV) death and sudden cardiac death in particular.1–3 However, pathologies. The inclusion of both specialties in the design of future this has led to a relative shift towards a chronic state of HF pre-clinical and clinical studies should ensure precise, reproducible, with an increasing burden of comorbidities. Most attention has and meaningful readouts for both cancer and HF. been focused on atherosclerosis, renal disease, diabetes mellitus, The present document, derived by an expert panel meeting orga- and atrial fibrillation as common comorbidities in chronic HF. nized by the Translational Research Committee of the Heart Failure However, relatively little awareness has been given to cancer, which Association of the European Society of Cardiology, aims to highlight nevertheless appears to be a common disease and the leading cause the common pathways potentially underlying both HF and cancer. of non-CV mortality in chronic HF.2–5 Moreover, this manuscript summarizes available evidence and On the other hand, recent improvements in cancer manage- provides guidance to bridge past and future research approaches. ment and treatments have substantially reduced mortality associ- ated with many cancer types, while concomitantly increasing the comorbidity burden of oncological patients. CV disease is the most Coexistence of cancer and heart frequent non-cancer cause of death in patients with cancer, and an increased risk of incident HF has been reported amongst patients failure diagnosed with cancer. This is largely attributed to the cardiotoxi- A large number of epidemiological studies suggest that the inci- city of anti-cancer agents and/or radiation therapy.6,7 dence of several malignant tumours is higher in patients with HF Cancer and HF share several common risk factors. Beyond this, compared to age- and sex-matched controls. A community-based the two entities share common systemic pathogenic pathways and cohort study reported that HF patients carried a 68% higher risk © 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 2274 R.A. de Boer et al. Table 1 Common imaging, laboratory tests or drugs that may reveal or unmask cancer in heart failure patients Test/drugs Indication/reason Form of cancer that may be detected ........................................................................................................................................... Chest X-ray Dyspnoea Lung cancer Control for ICD leads Lymphoma Chest CT scan Suspicion for PE Lung cancer Pre-ablation (LA appendage, anatomy of pulmonary veins) Lymphoma Anatomy of aorta Oesophageal cancer Gastric cancer Liver cancer and metastases Cardiac MRI Cardiomyopathies Lung cancer Congenital heart disease Lymphoma Oesophageal cancer Gastric cancer Liver cancer and metastases AL amyloidosis PET scan Endocarditis (valvular, PM/ICD, PM/ICD leads) All forms of cancer Lab tests Haemoglobin, MCV, iron, TSAT Gastrointestinal cancers Genitourinary cancers Lymphoma, leukaemia Liver tests Liver cancer Hepatic metastases of other cancers BSR CRP Lymphoma, leukaemia Use of antithrombotic drugs CAD, AF, prosthetic material (valves) Gastrointestinal cancers Genitourinary cancers AF, atrial fibrillation; BSR, blood sedimentation rate; CAD, coronary artery disease; CRP, C-reactive protein; CT, computed tomography; ICD, implantable cardioverter-defibrillator; LA, left atrium; MCV, mean corpuscular volume; MRI, magnetic resonance imaging; PE, pulmonary embolism; PET, positron emission tomography; PM, pacemaker; TSAT, transferrin saturation. of incident malignancy compared to the general population,9 and which may trigger workup for suspected cancer. Consequently, ............................................................................... incident cancer in HF was associated with a 56% excess adjusted cancer will be detected at early stages due to surveillance. Second, mortality risk. In a subsequent study, the same investigators retro- a large proportion of HF patients are treated with oral anticoag- spectively evaluated 1081 first myocardial infarction (MI) survivors ulant drugs or antiplatelet therapies, which are known to cause and observed that patients who developed HF within 30 days of MI bleeding and unmask gastrointestinal and genitourinary cancers, had a 71% higher incidence of cancer compared to those without and this may prompt early detection.13 HF.10 These observations were confirmed by a Danish HF cohort Discrepancies among the outcomes of numerous cohorts are study reporting a higher risk of cancer over a 4.5-year follow-up a clear drawback, and high-quality data are urgently required. The period in patients with HF, also even after excluding all cancers apparent inconsistencies are explained by differences in cancer that occurred within a year of HF diagnosis.11 There are conflicting and HF diagnoses, guidelines, and strategies. Another reason could results however: in the Physicians’ Health Study, (self-reported) be the small sample sizes,9,10 short follow-up period,9–11 lack of HF was not associated with an increased cancer incidence nor adjustment for smoking status and HF severity,11 availability of only self-reported data, poor cancer adjudication in HF databases, cancer-specific mortality in 28 341 males enrolled.12 But overall, or limited data obtained in women.12 It should be pointed out data from a large longitudinal HF registry indicate a remarkable that most evidence originates from associations identified in ret- increase in the incidence of cancer deaths among HF patients rospective analyses. This has inherent limitations in that causality over the last decades, and2 several cancer types are consistently is not guaranteed and that retrospective analyses are hampered reported to develop in HF patients, such as lung cancer, skin by their original design, generally under powered toward specific cancer, haematological malignancies, and colorectal cancer.8 cancer outcomes. Table 1 summarizes common tests and drugs that may poten- tially uncover cancer in HF patient. HF patients are typically under closer medical observation than the non-HF populations. Repeated Common mechanisms involved radiological examinations [chest X rays and computed tomography in tumour growth and heart (CT) scans], as well as cardiac positron emission tomography (PET) scans, and magnetic resonance imaging (MRI) scans, frequently failure detect incidental tumours. HF patients also undergo frequent The association between HF and cancer is partly explained by blood tests, including markers of iron metabolism and haematinics, common risk factors.14–17 Nevertheless, even when adjusting for © 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. Common mechanistic pathways in cancer and heart failure 2275 these risk factors, the incidence of new-onset cancer in prevalent to stress. In tumours and failing hearts, glucose oxidation and ........................................................................................................................................................................ CV disease and HF is not fully explained. A growing body of glycolysis are required to ensure ATP provision and to pro- experimental and clinical evidence is unveiling several mechanisms duce metabolic intermediates that are essential for the synthesis potentially underlying both HF and cancer. Inflammation, metabolic of macromolecules, such as fatty acids and nucleotides. Specif- remodelling, clonal haematopoiesis, angiogenesis, as well as the ically, cancer cells tend to be predominantly reliant on glucose extracellular matrix (ECM) and stromal cells are of interest in this metabolism, but in contrast to differentiated cells they convert glu- ressgard.18 cose into lactate also in the presence of oxygen levels sufficient to sustain oxidative metabolism, the so-called ‘Warburg effect’.34 This overreliance on this aerobic glycolysis facilitates the incorpo- Inflammation ration of nutrients into nucleotides, amino acids, and lipids that Circulating levels of pro-inflammatory cytokines, including, inter- are required to sustain cancer cell proliferation.35 In addition to leukin (IL)-1β, IL-6 and IL-18, are elevated in chronic as well as glucose, the amino acid glutamine represents an essential carbon acute decompensated HF.19 Solid malignancies exhibit several fea- source to support the use of Krebs cycle and glucose-derived inter- tures that are typical of inflamed tissues, such as the infiltration of mediates as precursors for the biosynthesis of macromolecules in immune cells and the production of pro-inflammatory mediators, cancer cells.36 and numerous studies emphasize the key role of inflammation as The healthy myocardium predominantly uses fatty acids to sus- a mediator of malignant transformation, epithelial to mesenchymal tain ATP synthesis,37,38 but substrate preference and metabolic transition, and metastasis.20,21 Further, IL-1β and IL-6 have been flexibility of the heart are altered under pathological conditions.39 reported as important drivers of cancer.22–25 For instance, the switch from fatty acids to glucose during pres- Lending support to this hypothesis, the Canakinumab sure overload remodels metabolic fluxes to support biomass syn- Anti-Inflammatory Thrombosis Outcome Study (CANTOS) thesis, thereby contributing to the hypertrophic growth of the demonstrated a favourable impact of the IL-1β-targeting antibody heart, and protein O-GlcNAcylation, thereby contributing to cal- canakinumab on CV events and HF hospitalization. Strikingly, this cium mishandling and cardiac dysfunction.40–43 Thus, metabolic study suggests the possibility that canakinumab could significantly reprogramming in both cancer cells and cardiomyocytes is directed decrease incident lung cancer and lung cancer mortality. Neverthe- toward the synthesis of anabolic precursors that are required less, the overall rate of cancer was 1.8 per 100 patient-years and to support cell proliferation and hypertrophy, respectively. How- not significantly different among study intervention arms. Thus, ever, important differences in metabolic reprogramming exist these results should be interpreted carefully and the replication of between tumours and the heart; for instance, in contrast to can- these outcomes is required.26,27 cer cells, cardiomyocytes do not rely on glutamine for aspartate In addition to cytokines and chemokines, lipid mediators such synthesis.40,44 as prostanoids are involved in inflammatory signalling, but their In the context of cancer, several therapeutic strategies target role in cancer and CV disease has not been extensively investi- pathways that mediate energy homeostasis and macromolecule gated so far. For instance, prostaglandin E2 levels are elevated in biosynthesis. As an example, the inhibition of glucose trans- cancer, especially in gastrointestinal tumours, and this prostanoid porter 1 (GLUT1), in vitro and in vivo, diminished tumour promotes cancer initiation and suppresses the immune response growth.45 Conversely, cardiac-specific overexpression of GLUT1 directed against cancer cells.28,29 Prostaglandin E2 can also affect in transgenic mice demonstrated preventive capacities against cardiac function by activating maladaptive gene programs down- cardiac hypertrophy.46 Further, sodium–glucose co-transporter stream of the EP3 receptor on cardiomyocytes, and cardiomy- 2 (SGLT2) inhibition, which is an effective treatment for type 2 ocytes in turn secret chemokines and can induce chemoattractant diabetes, exhibits beneficial effects particularly in HF. In addition, signalling .30,31 Prostacyclin and prostaglandin analogues are used to preliminary evidence from animal studies suggests a potential treat pulmonary arterial hypertension. A pre-clinical study showed future role of SGLT2 inhibition for the treatment of particular that prostaglandin E2 promotes lung cancer migration.32 Another cancer types.47 However, more extensive research is required study in mice revealed that prostacyclin prevents lung cancer.33 before definitive conclusions can be drawn regarding this clinical However, cancer incidence has not been assessed in patients application. with pulmonary hypertension treated with prostaglandins or Other therapeutics targeting lipid metabolism have been analogues. explored. For instance, fatty acid synthase (FAS), which is a key Recent reviews have extensively discussed inflammation as a enzyme of de novo lipogenesis, is up-regulated in many malignan- potential link between cancer and HF, which encourages further cies. Pre-clinical and clinical studies revealed that FAS inhibitors research to provide deeper insights on this topic. demonstrated anti-neoplastic properties in solid cancers.48 In the context of HF, FAS was increased in 2 mouse models of HF and human hearts with end-stage cardiomyopathy.49 Conse- quently, FAS represents a potential therapeutic target for both Metabolic remodelling as a common conditions. hallmark for cancer and heart failure The common metabolic derangements between cancer and Malignant and cardiac cells undergo metabolic reprogramming HF provide opportunities to develop intersection strategies and to adapt to physiological transformations, survive, and respond therapies to combat both diseases. © 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 2276 R.A. de Boer et al. Clonal haematopoiesis of indeterminate understood, but pre-clinical studies reported that the expression ............................................................ of pro-inflammatory cytokines by TET2-deficient macrophages potential is exacerbated in atherosclerosis-prone mice, consequently Genetic risk factors are also emerging as potential common drivers accelerating plaque formation.51,56 In two murine models of HF, of cancer and CV disease (Figure 1).50 Ground-breaking studies haematopoietic TET2 or DNMT3α deficiency aggravated cardiac indicate that acquired somatic mutations in haematopoietic cells dysfunction, which was rescued by pharmacological inhibition are associated with a markedly increased risk of coronary heart of the Nod-like receptor protein 3 (NLRP3) inflammasome.57,58 disease in humans.51 The majority (>70%) of these mutations Elucidating the mechanisms linking somatic mutation-driven clonal occur in Ten-eleven translocation-2 (TET2), DNA methyltrans- haematopoiesis to CV disease holds great clinical promise in the ferase 3 alpha (DNMT3α), additional sex combs like 1 (ASXL1), context of personalized medicine, as it will provide insight into Janus kinase 2 (JAK2), and tumour protein 53 (TP53),51,52 that the predictive value of these mutations as markers of CV risk and encode for key epigenetic regulators of haematopoiesis and therapeutic responsiveness. whose mutation confers a competitive growth advantage lead- ing to the progressive clonal expansion of the mutated lineage. Clonal haematopoiesis can progress to leukaemia53 but por- Angiogenesis tends an increased risk of CV disease and stroke independent of Angiogenesis is the process of new blood vessel formation from whether it becomes clinically overt.51,54 Furthermore, somatic existing vessels and is crucially involved in the pathophysiology mutations in TET2 and DNMT3𝛼 are associated with worse of both HF and malignancies. During the early stage of chronic outcomes in patients with ischaemic HF.55 Whether and how pressure overload, cardiomyocyte hypertrophy leads to a mis- clonal haematopoiesis promotes atherosclerosis is not completely match between capillary density and increased oxygen demand. Figure 1 Graphic illustration showing somatic mutations in haematopoietic stem cells as a common path for cancer (leukaemia) and cardiovascular disease.50 In individuals with a single somatic mutation, the development of leukaemia requires additional mutations. These individuals are exposed to a higher risk of developing heart failure (HF) and atherosclerosis. This may be due to the overproduction of pro-inflammatory cytokines by cells with somatic mutations. Illustration elements are from Smart Servier Medical Art. © 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. Common mechanistic pathways in cancer and heart failure 2277 The consequent hypoxia stimulates microvascular expansion by ........................................................................................................................................................................ inducing secretion of angiogenic factors, such as vascular endothe- Non- Amyloidosis Ischemic CM No CM lial growth factor (VEGF) and angiopoietin-1 and -2.59 With Ischemic CM sustained pressure overload, however, this adaptive angiogenic response is suppressed, and the subsequent vascular rarefaction contributes to the transition to decompensated HF.60,61 The phar- macological or genetic inhibition of VEGF, as well as the blockade of other key angiogenic signalling pathways, accelerate the transition to HF.59,60,62,63 In the context of cancer, angiogenesis is crucial for tumour growth and dissemination.64 New blood vessel formation is required to nourish cancer cells when tumour growth prevents the diffusion of nutrients from the pre-existing vasculature. Fur- thermore, malignant neoplasms take advantage of the dysfunctional tumour vessels to spread throughout the body.64 Drugs inhibiting angiogenesis, such as VEGF inhibitors, have been employed in the treatment of several types of malignancies, including colorectal, kidney, brain, and lung cancer. The CV toxicities of these agents are potentially severe, and often unpredictable. Based on these findings, angiogenesis represents a favourable substrate for both diseases. Figure 2 Representative scanning electron and photomicro- Stromal cells and extracellular graphs of the three-dimensional arrangement of left ventricular extracellular matrix in the human heart. Samples are from individ- environment uals with infiltrative (amyloidosis), non-ischaemic, and ischaemic In tumours, malignant cells coexist with the ECM and other cardiomyopathy (CM) compared to an unused non-failing donor cell types that constitute the so-called tumour stroma. The heart. The top two panels show the matrix in cross-section, with paracrine interactions between neoplastic cells and stromal cells, a typical honey-comb structure that is notably less fine and orga- and among stromal cells, promote tumour growth, progression, nized, but with distinct patterns, in CM compared to non-CM myocardium. H&E stained sections from the same hearts are and invasiveness.65 Besides cardiomyocytes, the heart contains shown in the bottom row for comparison. Bars = 40 mm (top diverse cardiac stromal cell lineages that play key roles in heart row) and 2 mm (middle row). Tissue is courtesy of the Vander- repair, regeneration, and disease.66 bilt Cardiovascular Institute Biobank and images are shown with Cardiomyopathy and HF in cancer patients do not only result permission from Cristi Galindo and Sean Lenihan. from an intrinsic injury.67 Figure 2 presents the diffuse effects on the ECM in the heart either from intrinsic injury via cardiotoxicity related to chemotherapy, or extrinsic to the heart as evidenced others are unique molecular signatures that allow the identification by proteotoxicity seen with AL amyloidosis. Similarly, the ECM in of cancer and HF abnormal fibroblasts.72 Given the shared features tumours mediates cancer progression and development and plays between cancer and cardiac fibroblasts, anti-neoplastic drugs tar- a crucial role in anti-cancer treatment resistance.68,69 geting fibroblasts could be repurposed to treat HF. The intramyocardial transplantation of FAC-purified human microvascular pericytes promotes functional and structural recov- ery post-infarction via paracrine effects and cellular interactions. These therapeutic pericytes activate cardio-protective mechanisms Heart failure driving cancer that reverse ventricular remodelling, decrease cardiac fibrosis, An additional mechanistic layer, possibly accounting for the reduce chronic inflammation, and promote angiogenesis.70 In the co-occurrence of cancer and HF, is provided by experimental stud- context of cancer, blocking pericytes has failed to improve out- ies indicating that HF itself represents a pro-oncogenic condition. come in cancer patients. In fact, targeting pericytes could increase Based on evidence assembled in several reviews, HF is character- metastasis under certain circumstances.71 ized by the activation of neurohormonal systems, including the In HF, quiescent fibroblasts are replaced by proliferative fibrob- renin–angiotensin–aldosterone system and the sympathetic ner- lasts that alter the myocardial matrix and convert it to a fibrotic vous system, which are also involved in cancer development and structure, which makes the myocardium stiffer. In solid tumours, progression.73,74 Sympathetic nervous system activation induced fibroblasts act similarly and promote structural changes in the by physical stressors, such as cold or restraint, may accelerate surrounding stroma to allow tumour growth and invasion. In tumour growth and dissemination in numerous mouse models of both conditions, abnormal fibroblasts are characterized by the malignancy. The modulation of the tumour microenvironment by co-localization of extra proteins that are associated with various neurohormonal mediators, like noradrenaline and angiotensin II, biological functions. Fibroblast-specific protein 1, platelet-derived seems to play a prominent role in this process.8,14,73 The systemic growth factor receptor, fibroblast activation protein, and many sympathetic activation, as seen in HF,75 affects all the cells of © 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 2278 R.A. de Boer et al. the body. Studies to unravel the detailed mechanisms by which have been published in which these associations were sufficiently ........................................................................................................................................................................ sympathetic activation promotes carcinogenesis are urgently brought to light in the HFpEF setting. Therefore, future studies needed. should account for the comorbidities in multivariable models to assess whether there is a causative effect of HFpEF per se on car- cinogenesis beyond the cumulative effect of the comorbidities. Heart failure aetiologies and incident cancer Safety of heart failure treatments A growing body of pre-clinical research indicates that HF-secreted factors mediate or facilitate the development, progression, and dis- and medical radiology semination of tumours. In a recent study, failing hearts were shown The safety of HF treatments with regard to cancer incidence to induce tumour growth by secreting pro-oncogenic factors into is still a subject of investigation. Several studies demonstrated the circulation. The authors performed artery ligation in the hearts a higher lung cancer incidence among patients treated with of mice genetically prone to develop colorectal cancer. These mice angiotensin-converting enzyme inhibitors, especially in individuals developed eccentric hypertrophy, dilatation, and reduced ejection treated for more than 5 years,79 and a dose–response relationship fraction. between hydrochlorothiazide and both basal and squamous cell The MI group demonstrated a higher number of intestinal polyps carcinoma.80 But data from a large cohort study could not link can- and higher tumour load compared to non-MI mice. The potential cer prevalence to angiotensin receptor blocker (ARB) treatment, effects of haemodynamic load on tumour growth were excluded although in subgroup analysis a significant association between ARB by transplanting either infarcted or healthy hearts in the cervical and cancers in male genital organs was reported.81 Large random- region of mice, retaining their native heart in situ. The authors pos- ized clinical trials with irbesartan, valsartan, and losartan did not tulated that the oncogenic activity of the failing heart was mediated show any increase in the overall or site-specific cancer prevalence by secreted factors such as SerpinA3, a factor regulating tumour in patients associated with ARB use.82 In contrast to the suggestion cell survival pathways, and apoptosis.4 The mechanisms by which that HF treatments are possible factors contributing to carcino- these factors exert their function require further validation and genesis, several ongoing clinical trials are investigating the efficacy future research to uncover heart-specific tumour markers and of CV drugs to prevent cancer or improve outcomes in cancer reveal new therapeutic targets.76 A recent study indicated that patients (Table 2). MI accelerates breast cancer growth in mice. The investigators Moreover, cancer incidence associated with the exposure to reported increased circulating Ly6Chi monocyte levels and recruit- medical radiation has been previously evaluated. An observational ment to tumours in MI mice compared to sham mice. Interest- retrospective cohort detected a correlation between the cumu- ingly, the depletion of these cells abrogated MI-induced tumour lative dose of CT scan radiation and both leukaemia and brain growth.77 tumours.83 Another study reported a cancer risk attributable to Further validation has been observed in the transverse aortic radiation exposure from cardiac catheterization.84 Collectively, constriction (TAC) mouse model after implantation of cancer cells. these findings suggest that cancer incidence is relatively low, consid- The TAC-operated mice demonstrated bigger tumours, higher ering the substantial diagnostic and therapeutic value of radiation. proliferation rates, and more metastasis compared to their control. However, when considering the annual incidence of CV diseases Also, treating cancer cells, in vitro, with serum derived from necessitating examination with CT scans/cardiac catheterization, the TAC-operated mice stimulated their proliferation.78 These the overall attributable cancer risk does not lead to a negligible results validated the concept of secreted factors in the serum number of cancer cases. It should thus be re-emphasized that that promote tumour growth.4,78 The mechanisms by which these careful consideration by the treating physician should be taken factors exert their function require further validation and future before any potentially carcinogenic diagnostic/therapeutic options research to uncover heart-specific tumour markers and reveal new are considered. therapeutic targets.76 In the above-mentioned animal studies, two HF aetiologies have been investigated: the MI model is characterized by eccentric Cancer driving heart failure hypertrophy and reduced ejection fraction, and the TAC model that The cardiotoxic effects of anti-cancer treatment leading to a wide develops concentric hypertrophy with preserved ejection fraction. spectrum of CV abnormalities including HF have been well estab- The risk of cancer in human HF with reduced ejection fraction lished and extensively reviewed. In summary, several cancer ther- (HFrEF) and HF with preserved ejection fraction (HFpEF), and apies cause ventricular dysfunction and cardiomyopathy leading to whether there is a specific interaction between a specific HF HF in predisposed individuals.7 The susceptibility of patients to subtype and incident cancer, has not been investigated yet. these toxicities differs markedly, presumably reflecting genetic and In the setting of HFpEF, there are many comorbidities such epigenetic factors and pre-existing medical conditions. This applies as hypertension, chronic kidney disease, chronic obstructive pul- to chemotherapeutic and targeted agents, as exemplified by the monary disease, and diabetes. All of these individual comorbidi- anthracycline doxorubicin and trastuzumab. Doxorubicin-related ties are known to be associated with incident cancer. Thus, these cardiomyopathy involves multiple cellular perturbations including comorbidities are confounding factors that could affect the associa- DNA damage,85 mitochondrial dysfunction,86,87 activation of cyto- tion between HFpEF and cancer. No dedicated perspective studies plasmic proteases,88 impaired autophagic flux,89 and defects in © 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. Common mechanistic pathways in cancer and heart failure 2279 Table 2 A selection of ongoing clinical trials investigating the efficacy of cardiovascular drugs to prevent cancer or improve outcomes in cancer patients Title of the clinical trial Intervention(s) Outcome measures Phase Identifier ........................................................................................................................................... Clinical Research on Treatment of Propranolol Tumour size I NCT03245554 Gastrointestinal Cancer in the Preoperative by Propranolol Hydrochlorothiazide and Risk of Skin Hydrochlorothiazide Non-melanoma skin cancer N/A NCT04334824 Cancer ACEi Melanoma skin cancer Clinical Study of Propranolol Propranolol Overall response rate II NCT04005365 Combined With Neoadjuvant Chemotherapy in Gastric Cancer Colorectal Metastasis Prevention Propranolol etodolac 5-year disease-free-survival II NCT03919461 International Trial 2 Placebo Biomarkers in extracted tumour tissue samples assessing pro- and anti-metastatic processes Biomarkers in blood samples assessing pro- and anti-metastatic processes Number of patients with treatment-related adverse events Depression, anxiety, global distress Fatigue Efficacy of Chemopreventive Agents Aspirin Disease-free survival N/A NCT04245644 on Disease-free and Overall Beta-blockers Overall survival Survival in Patients With Metformin Pancreatic Ductal ACEi Adenocarcinoma: The CAOS Statins Study Propranolol Hydrochloride in Laboratory biomarker CREB phosphorylation II NCT03152786 Treating Patients With Prostate analysis BAD phosphorylation Cancer Undergoing Surgery Propranolol Hydrochloride Distress score Questionnaire administration Levels of transcripts that reflect Survey administration ADRB2/PKA activation Plasma catecholamine levels (including epinephrine) Plasma propranolol levels Self-perceived stress MELABLOCK: A Clinical Trial on the Propranolol Effect of propranolol on overall survival II/III NCT02962947 Efficacy and Safety of Propranolol Placebo for melanoma patients in stage II/IIIA 80 mg in Melanoma Patients (T2, N0 or N1, M0) Effect of propranolol on disease-free survival for melanoma patients in stage II/IIIA Effect of propranolol on specific mortality for melanoma patients in stage II/IIIA Effect of propranolol on long-term safety in melanoma patients in stage II/IIIA Beta Adrenergic Receptor Blockade Carvedilol Change in biomarkers in prostate biopsy II NCT02944201 as a Novel Therapy for Patients compared to prostatectomy tissues With Adenocarcinoma of the Change in serum PSA Prostate Anti-Cancer Effects of Carvedilol Carvedilol Survival curve of overall survival I NCT03980249 With Standard Treatment in Survival curve of progression-free Glioblastoma and Response of survival Peripheral Glioma Circulating Quantify circulating tumour cells Tumour Cells © 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 2280 R.A. de Boer et al. Table 2 (Continued) Title of the clinical trial Intervention(s) Outcome measures Phase Identifier ........................................................................................................................................... Use of Propranolol Hydrochloride in Propranolol hydrochloride Progression-free survival II NCT03108300 the Treatment of Metastatic STS Doxorubicin Overall survival Propranolol Hydrochloride in Propranolol hydrochloride Incidence of toxicity graded according to I NCT02013492 Treating Patients With Locally Common Terminology Criteria for Recurrent or Metastatic Solid Adverse Events (CTCAE) V. 4.0 Tumours That Cannot Be Change in vascular endothelial growth factor Removed By Surgery Effect of beta-adrenergic blockade on the tumour microenvironment Effect of beta-adrenergic blockade on the host immune system Progression-free survival Overall survival ACEi, angiotensin-converting enzyme inhibitor; N/A, not applicable; PSA, prostate-specific antigen. Source: ClinicalTrials.gov. contractile protein expression90 and structure.91 Although the .............................................................................................................. Table 3 Summary of therapeutic recommendations mechanisms are poorly defined, antagonism of HER2 signalling in for the management of cancer therapeutic-related cardiomyocytes by trastuzumab likely results in both cellular dys- cardiac dysfunction function and loss of cell survival pathways.92–94 Immune checkpoint inhibitors, such as ipilimumab, nivolumab, and cemiplimab were Anti-neoplastic Cardioprotective drugs/strategies developed for multiple tumours. More recently, immune check- drug point inhibitors have been associated with immune-related adverse ................................................................ events and CV complications including pericarditis, vasculitis, and Anthracyclines ACEi/ARBs arrhythmias.95–97 Daunorubicin Beta-blockers Besides drugs, chest radiotherapy, mainly for mediastinal lym- Doxorubicin Statins Epirubicin Limit cumulative dose of daunorubicin phoma, carries a risk of restrictive cardiomyopathy that typically Mitoxantrone to <800 mg/m2 develops several years after exposure and may lead to HF.98,99 Fur- Idarubicin Limit cumulative dose of doxorubicin to ther to the direct toxicity of the aforementioned therapies in the <360 mg/m2 form of cardiomyopathy, other CV complications of cancer ther- Limit cumulative dose of epirubicin to apy, such as myocardial ischaemia, arterial hypertension, pulmonary <720 mg/m2 hypertension, myocarditis or valvular heart disease, also contribute Limit cumulative dose of mitoxantrone to the development of HF.100 In addition to established approaches to <160 mg/m2 to prevent and/or to treat HF in patients receiving anti-neoplastic Limit cumulative dose of idarubicin to therapy (Table 3), there are several ongoing clinical trials investi- <150 mg/m2 gating the efficacy of CV drugs in patients undergoing potentially Dexrazoxane as an alternative cardiotoxic anti-neoplastic treatments (Table 4). Aerobic exercise Trastuzumab ACEi/ARBs Beta-blockers Heart failure induced by cancer All anti-neoplastic Examine and minimize cardiovascular metabolic byproducts drugs risk factors Treat comorbidities Metabolic alterations in HF affect not only the heart but also sev- Avoid QT prolonging drugs eral other tissues such as skeletal muscle and liver.101 Based on Manage electrolyte abnormalities pre-clinical studies, it has been postulated that systemic metabolic Minimize cardiac irradiation alterations caused by cancer cells impair cardiac function.102,103 Potential mechanisms are not limited to alterations in metabolic ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker. fuelling of the heart since it is now becoming widely accepted Adapted from the 2016 ESC guidelines.98 that metabolic intermediates can also act as signalling molecules to alter gene expression, protein function or contribute to epigenetic modifications that ultimately result in ventricular remodelling.104 Specifically, cancer-associated mutations in IDH1/2 result in a Malignancies characterized by somatic mutations in isocitrate dehy- gain-of-function enabling synthesis of 2-hydroxyglutarate (2-HG) drogenase (IDH1/2) gene provide a prominent example of how from the Krebs cycle intermediate α-ketoglutarate, and increased byproducts of cancer metabolism could alter cardiac function. circulating levels of 2-HG cause dilated cardiomyopathy by inducing © 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. Common mechanistic pathways in cancer and heart failure 2281 Table 4 A selection of ongoing clinical trials investigating the efficacy of cardiovascular drugs in patients receiving potentially cardiotoxic anti-neoplastic treatments Title of the clinical trial Intervention(s) Outcome measures Phase Identifier ........................................................................................................................................... Evaluation and Management of ACEi Echocardiographic global strain N/A NCT02818517 Cardio Toxicity in Oncologic Beta-blockers Troponin (ng/mL) Patients ACEi and beta-blocker treatment B-type natriuretic peptide (pg/mL) Cardiotoxicity Prevention in Bisoprolol Left ventricular ejection fraction III NCT02236806 Breast Cancer Patients Ramipril Treated With Anthracyclines Placebo and/or Trastuzumab S1501 Carvedilol in Preventing Carvedilol Time to the first identification of cardiac dysfunction III NCT03418961 Cardiac Toxicity in Patients Patient observation Incidence of adverse events associated with With Metastatic beta-blocker treatment HER-2-Positive Breast Cancer Rate of first interruption of trastuzumab Rate of death Time to first occurrence of cardiac event Drug adherence Carvedilol for the Prevention of Carvedilol Maximum change in left ventricular ejection fraction II NCT02177175 Anthracycline/Anti-HER2 Placebo Incidence of abnormal left ventricular ejection fraction Therapy Associated Cardiotoxicity Among Women With HER2-Positive Breast Cancer Using Myocardial Strain Imaging for Early Risk Stratification Prevention of Enalapril The occurrence of cardiac troponin elevation above the III NCT01968200 Anthracycline-induced threshold in use at the local laboratory, at any time Cardiotoxicity during the study Admissions to hospital for cardiovascular causes Cardiovascular deaths Occurrence of hypo- or hyperkinetic arrhythmias Risk-Guided Cardioprotection Carvedilol Left ventricular ejection fraction I NCT04023110 With Carvedilol in Breast Treatment adherence as measured by pill count Cancer Patients Treated With Adverse events Doxorubicin and/or Diastolic function (E/e′ ) by echocardiogram Trastuzumab Ventricular–arterial coupling measured by echocardiogram Cardiac strain measurements by echocardiogram Frequency of individuals with clinical heart failure High-sensitivity troponin level N-terminal pro B-type natriuretic peptide level STOP-CA (Statins TO Prevent Atorvastatin Left ventricular ejection fraction II NCT02943590 the Cardiotoxicity From Placebo Number of cardiac events Anthracyclines) Myocardial fibrosis Troponin T and global longitudinal strain Statins for the Primary Atorvastatin Cardiac MRI measured left ventricular ejection fraction II NCT03186404 Prevention of Heart Failure in Placebo within 4 weeks of anthracycline completion Patients Receiving Anthracycline Pilot Study Detection and Prevention of Simvastatin Change in echocardiographic global longitudinal strain II NCT02096588 Anthracycline-Related Cardiac Doxorubicin/ Number of participants with adverse events as a Toxicity With Concurrent cyclophosphamide measure of safety and tolerability Simvastatin Recurrence-free survival with concurrent simvastatin ACEi, angiotensin-converting enzyme inhibitor; MRI, magnetic resonance imaging; N/A, not applicable. Source: ClinicalTrials.gov. © 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 2282 R.A. de Boer et al. mitochondrial damage and myocardial glycogen accumulation via more hospital visits for their treatment or management, it could ........................................................................................................................................................................ the up-regulation of genes involved in glycogen biosynthesis.105 be assumed that surveillance bias could be responsible for the Whether similar mechanisms apply to other forms of cancer higher cancer incidence in this patient group. However, no study remains to be explored, but 2-HG accumulation was also observed has proven this point. On the other hand, the diagnosis of cancer or in response to cancer-induced hypoxia, although the mechanism HF might be rather delayed, partly by attribution of the symptoms behind this phenomenon remains unclear.106,107 Moreover, ele- of the former to the latter and vice versa.122 Furthermore, the CV vated 2-HG was observed in mouse hearts during ischaemic function and predictors of exercise capacity have been shown to be preconditioning.108 Further studies are necessary to investigate impaired in patients with cancer per se, i.e. even before the initiation whether strategies targeting these byproducts can be applied in of cancer therapy.123 Circulating CV hormones, such as natriuretic a clinical setting. peptides, are related to cancer progression and severity, which suggests the presence of subclinical functional and morphological heart damage. This provides hints for HF therapy in cancer patients Cachexia and cardiac wasting in cancer beyond the focus on the prevention of anti-cancer drug-induced Cachexia describes a state of involuntary weight loss that is cardiotoxicity.124 often observed in patients with cancer, particularly in pancre- Cancer and HF carry an independent risk of mortality, but atic, gastro-oesophageal, lung, head and neck and colorectal can- also interfere with the optimal treatment of one another, which cers, reaching a prevalence of 40% to 70% depending on the type increases mortality.122 To overcome these challenges, a close col- of malignancy.109,110 Weight loss affects all body compartments, laboration between cardiologists and oncologists is required and but skeletal muscle is particularly prone to be affected early in specialists should recognize the benefits of therapy for HF and can- the course of body wasting. Along with the development of car- cer, and the risks of withholding or sub-optimally treating either diac fibrosis,111,112 it has been shown in animal models that can- or both diseases. The prognostic impact of each condition should cer promotes cardiac atrophy.113 In all cases, cancer reduced the always be well defined and considered in the decision-making heart weight in animal models,114–116 and cardiac function dete- process.122 A multidisciplinary approach is encouraged and should riorated in parallel.117,118 The mechanisms behind cardiac wast- include other healthcare professionals, including cardiac rehabilita- ing started to be understood, and appear to involve activation of tion, psychology, and palliative care where necessary. the ubiquitin–proteasome system, autophagy, as well as myocyte The scientific evidence upon which clinical decisions can be apoptosis.113 Furthermore, tumour necrosis factor, as well as based is very restricted, but epidemiology suggests that the demon- IL-1β and IL-6, seem to be key mediators in this process.116,119 stration of cancer in HF patients is an increasingly common prob- One study pointed to the direct effects of secreted factors lem in an aging population. Recently, the SAFE-HEaRt trial has been from cancer cells that induce atrophy and metabolic changes in designed to test the efficacy of anti-HER2 drugs in patients with cardiomyocytes, but the exact signalling pathways in cardiomy- mildly reduced cardiac function in the setting of ongoing cardiac ocytes are still poorly understood .118 The identified secreted fac- treatment.125 Further, well-designed studies are required to clar- tors were named cachexokines. Cachexokines may be useful as ify the thresholds at which cancer treatment should not be given biomarkers for the diagnosis of cancer-induced cardiac complica- to patients with pre-existing HF, and the optimal cardioprotective tions and might lead to the identification of new therapeutic tar- and surveillance strategies for patients in whom these two worri- gets. Furthermore, espindolol, a novel non-selective beta-blocker, some conditions coexist. Modern oncology delivers personalized demonstrated striking therapeutic and preventive potentials for medicine (e.g. mutation-based) while in cardiology molecular-based cancer-related cachexia. Espindolol reversed weight loss, improved personalized medicine is virtually absent. Cardio-oncology should and maintained fat-free mass in advanced cachexia in patients with be considered as an opportunity to increase the role of per- colorectal or non-small cell lung cancer.120 Animal models suggest sonalized approaches in CV medicine too (e.g. administration of that the wasting process affecting the heart is partially attenuated cardio-protective co-treatments). by HF medications and statins.111,121 The need for appropriate pre-clinical models Translational outlook and steps Studies in animal and cell systems have been valuable components forward of translational research in many areas, including the investiga- tion of the biological mechanisms by which cancers interact with Common pathways in heart failure the CV system, and vice versa. Coupled with research in dis- and cancer: a clinical perspective ease registries, biorepositories, and clinical trials, findings in cel- As discussed above, the bidirectional relationship between the lular and animal models can help to weave together a detailed two conditions is promoted by common pathophysiological mech- and mechanistic understanding that paves the way for innova- anisms (Figure 3). Besides shared environmental and epigenetic risk tive therapeutic strategies targeting both diseases simultaneously factors, and systemic disease interaction, the heightened risk of (online supplementary Table S1). Reproducible pre-clinical models cancer in HF might partly be accounted for by a simple surveil- with both cancer and HF are required to study the interactions lance bias. Judging from the fact that HF patients need to perform and impact of new therapeutic strategies upon both diseases. © 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. Common mechanistic pathways in cancer and heart failure 2283 Anti-Neoplastic Treatment Cancer Metabolic Byproducts Cancer Development/Invasion in the CV System Cachexia/Cancer-secreted Factors Inflammation Cancer Metabolic Remodeling Heart Failure Clonal Hematopoiesis Angiogenesis Extracellular Environment HF-secreted Factors-Cardiokines (Natriuretic peptides) Figure 3 Graphical presentation that summarizes the proposed common pathways involved in the development and progression of cancer and heart failure (HF). CV, cardiovascular. Illustration elements are from Smart Servier Medical Art. Review of in vitro and pre-clinical work examining the mech- However, the connection between cancer and HF is beyond ................................................................................... anisms of anti-cancer therapy-induced cardiotoxicity over the aging. A recent registry-based cohort study investigated the associ- past 20 or more years demonstrates numerous outcomes.126–129 ation of congenital heart disease (CHD) with the risk of developing These models require further investigation, particularly with regard cancer.138 The authors found that by the age of 41 years, one out to understanding the extent to which these findings repre- of 50 patients with CHD developed cancer. They also reported sent issues faced by humans presenting cancer and heart dis- a twofold higher risk of cancer in children and young adults ease. Also, cell-based assays should be used to test and develop with CHD compared to healthy matched controls. A long-term new drugs. follow-up study evaluated cancer incidence in patients with chronic HF from the Danish registries. The cancer incidence rates were higher in all age groups. However, older HF patients (≥80 years) The need for registries and clinical had a lower incidence rate than the HF patients of the age group between 70 to 79 years.11 Also, data from a cohort of peripartum studies cardiomyopathy patients from Germany and Sweden reported a Specific studies focusing on HF–cancer interactions would be strikingly higher cancer incidence among (very young) women with needed to answer important unsolved questions such as defining peripartum cardiomyopathy compared to age-matched controls the characteristics of patients who are more susceptible to present (20–50 years).5 Harmonising national CV and cancer registries is both conditions, identifying some early and specific predictive one path to pursue as exemplified by the Virtual Cardio-Oncology biomarkers,130–137 adequately adjusting the management of those Research Initiative (VICORI) in the UK. VICORI created a national patients, and better understanding of shared mechanisms that linked data resource between the English National Cancer Regis- could lead to target common regulators of HF and cancer. To tration and Analysis Service and the six national CV audits, and answer these questions, dedicated registries and studies would will link the datasets using unique identifiers such as NHS numbers need to reach three main requirements. to track hospital admission data and mortality for patients in both The first relates to a sufficient sample size to ensure adequate cancer and CV registries. power to detect both conditions. Indeed, the incidence rates of Based on these outcomes, systematic screening for cancer both HF and cancer are strongly related to age, with a steep rise should be considered for risk stratification in young predisposed from around 55–60 and the highest incidence rates being in elderly patients, which allows early prevention and optimal management. people (80+) (online supplementary Figure S1) showing an overlay Similar studies are of pivotal clinical significance as HF and cancer of age-specific HF and cancer incidence rates. are not limited to a specific age group. © 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 2284 R.A. de Boer et al. -Establishing Preclinical models that mimic -Identification of pathogenic the human situation pathways in preclinical models -Induction of cancer and heart failure -Identification of therapeutic targets simultaneously to assess their bidirectional -Identification of biomarkers Preclinical association Research -Investigation of clinical associations -Sufficient sample size -Cardiovascular phenotyping in cancer studies -Collection of parameters to phenotype -Cancer phenotyping in cardiovascular studies -Unification of inclusion criteria -Clinical investigation of pathways -Community-based databases, national -Diagnostic & therapeutic strategies registries Clinical Validation of Outcomes Research -Collaboration between cardiologists and oncologists -Optimization of treatment of cancer and heart failure simultaneously -Defining prognostics of each condition in the decision- making Clinical Practice -Multidisciplinary approach -Definition and implementation of risk tools -Predictive biomarkers -Better quality of life -Personalized medicine -Better prognosis Figure 4 Roadmap that represents the key steps needed to guide and improve future clinical and pre-clinical research and increase the collaboration between cardiologists and oncologists. Illustration elements are from Smart Servier Medical Art. Overall, the risk of new cancers is similar or slightly higher and targets that sustain the common development of HF and .................................................................... than the risk of new HF (with an average of 5–10 per 1000 cancer. person per year for both cancer and HF).139 Consequently, the In conclusion, we now have preliminary insights into factors answers to many unsolved questions in HF–cancer interactions mediating tumour growth in HF and should not be dismissive of will come from large registries or cohorts of patients (estimated the epidemiological data. Cancer surveillance in the HF population to optimally be >100 000 general comers or >10 000 patients is essential. A holistic rather than a disease-based care plan is presenting with one or the other condition). However, cancer essential in HF patients. Future joint research efforts are needed to registries usually report CV mortality, but no cardiac morbidity identify important mediators to strengthen the connection of HF parameters.140 Community-based databases, such as health data with tumour growth (Figure 4). from the Rochester epidemiological data, have been used to describe a higher risk of new cancer in patients HF9 or after MI.10 Similarly, national health insurance registries can offer an appropriate setting to decipher HF–cancer interactions.11,141 Supplementary Information The second relates to the collection of relevant parameters to Additional supporting information may be found online in the better phenotype HF in cancer patients and reciprocally cancer in Supporting Information section at the end of the article. HF patients.142 In most clinical studies, both conditions are mutually exclusive, thus hampering specific investigations on HF–cancer interactions.143 It would also be needed to define a minimal set of Funding markers (such as cardiac biomarkers, electrocardiogram, and many R.A.d.B. is supported by the European Research Council [ERC others) that could be simply included in such studies. CoG 818 715, SECRETE-HF], and furthermore by the Netherlands The last requirement relates to the constitution of prospec- Heart Foundation (CVON DOSIS, grant [2014-40], CVON tive banking of different biological samples (including blood and SHE-PREDICTS-HF, grant [2017-21]; CVON RED-CVD, grant urine). These samples will notably help in describing pathways [2017-11]; and CVON PREDICT2, grant [2018-30]; and the © 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. Common mechanistic pathways in cancer and heart failure 2285 Innovational Research Incentives Scheme program of the Nether- supported by the European Research Council (ERC StG 680 209, ........................................................................................................................................................................ lands Organization for Scientific Research (NWO VIDI, grant OPTIM) and Swiss Innovation Agency - InnoSwiss (28747). P.D. is [917.13.350]), and by a grant from the Leducq Foundation (Cure an employee of Innate Pharma and owns shares of the company. PhosphoLambaN induced Cardiomyopathy, Cure-PLaN). S.H. gets T.T. is supported by an ERC Consolidator grant Longheart and support of the ERA-Net-CVD project MacroERA, [01KL1706], Deutsche Forschungsgemeinschaft [KFO311]. and IMI2-CARDIATEAM [N. 821 508], from the Netherlands Conflict of interest: R.A.d.B. reports grants from European Cardiovascular Research Initiative, an initiative with support of Research Council, AstraZeneca, Abbott, Bristol-Myers Squibb, the Dutch Heart Foundation, CVON2016-Early HFPEF, 2015-10, Novartis, Novo Nordisk, Roche, during the conduct of the CVON She-PREDICTS, grant [2017-21], CVON Arena-PRIME, study; personal fees from Abbott, AstraZeneca, Novartis, Roche, 2017-18, support of FWO [G091018N] (2017) and [G0B5920N] outside the submitted work. S.v.H. reports personal fees from (2019). J.B. is supported by the Collaborative Research Center Bayer, Boehringer Ingelheim, BRAHMS, Chugai, Novartis, Phar- (SFB) 1118 of the German Research Foundation (DFG), by macosmos, Roche, Vifor, outside the submitted work; and the German Centre for Cardiovascular Research (DZHK) and the owns shares in Actimed. J.B. reports personal fees from Bayer, Bundesministerium für Bildung und Forschung (BMBF) and by the outside the submitted work; has a patent EP2954322B1 (in Ministerium für Wissenschaft, Forschung und Kunst (MWK) Baden vitro method for cardiovascular risk stratification) issued. C.M. Württemberg. C.M. is funded by the German Research Foundation reports personal fees from AstraZeneca, Bristol-Myers Squibb, [DFG; Ma 2528/7-1; SFB 894; TRR 219] and the Federal Ministry of Berlin Chemie, Novartis, Amgen, Boehringer Ingelheim, Sevier, Education and Research [BMBF; BMBF; 01EO1504]. A.R.L. is sup- outside the submitted work. J.M. reports personal fees from ported by a grant from the Leducq Foundation (Cardio-Oncology Pfizer, Novartis, Takeda, Bristol-Myers Squibb, GSK, Nektar, Network). A.B.G. is supported by TerCel [RD16/0011/0006, AstraZeneca, Audentes, Myovant, Regeneron, during the conduct RD16/0011/0028], CIBER Cardiovascular - [CB16/11/00403, of the study. D.F. reports personal fees from Abbott Laboratories, the CERCA Programme/Generalitat de Catalunya, and ‘la Caixa’ Bayer, Boehringer-Ingelheim, Menarini, Novartis, Orion Pharma, Banking Foundation. C.G.T. is supported by a ‘Federico II Uni- Roche Diagnostics, outside the submitted work. A.R.L. reports versity/Ricerca di Ateneo’ grant. P.A. is supported by the Italian grants and personal fees from Servier, Pfizer, personal fees from Ministry of Health ([GR-2018-12 365 661], CHANGE Study). L.L. Novartis, Roche, Takeda, Boehringer Ingelheim, Amgen, Clinigen is supported by the German Centre for Cardiovascular Research Group, Ferring Pharmaceuticals, Eli Lily, Bristol-Myers Squibb, (DZHK). T.E. is supported by the German Centre for Cardiovascu- Eisai Ltd, Myocardial Solutions, Heartfelt Technologies, outside lar Research (DZHK) and the Bundesministerium für Bildung und the submitted work. P.A. reports personal fees from Novartis, Forschung (BMBF) and the European Horizon 2020 Programme Servier, Daiichi-Sankyo, Bayer, Pfizer, AstraZeneca, Jansenn, Merck (REANIMA), ERA-CVD Variation, and ITN TRAIN-HEART. Sharp & Dohme, GlaxoSmithKline, grants and personal fees from O.J.M. is supported by the German Research Foundation (DFG) Boehringer Ingelheim, outside the submitted work. T.E. reports a [DFG MU_1654/11–1], the German Centre for Cardiovascular speaker honorarium for Novartis, related to sacubitril/valsartan, Research (DZHK) and the Bundesministerium für Bildung und not relevant for this work. O.J.M. reports personal fees from Bayer, Forschung (BMBF) [81Z0700201] as well as the European Hori- Bristol-Myers Squibb, Daiichi-Sankyo, Pfizer, Servier, outside the zon 2020 programme [CardioReGenix]. J.S.H. is supported by submitted work. J.S.H. reports grants from Leducq Foundation, INSERM, the French National Research Agency [NADHeart Fondation pour la Recherche Médicale, Sanofi, Servier, Bioseren- ANR-17-CE17-0015-02, PACIFIC ANR-18-CE14-0032-01, ity, personal fees from Amgen, Bayer, AstraZeneca, Bristol-Myers CORRECT_LMNA ANR-19-CE17-0013-02], BPIFrance Squibb, personal fees and non-financial support from Novartis, [2018-PSPC-07], the ERA-Net-CVD [ANR-16-ECVD-0011-03] outside the submitted work. P.v.d.M. reports grants and personal (Clarify project), Fédération Française de Cardiologie, the Fon- fees from Vifor Pharma, AstraZeneca, Pfizer, grants from Ionis, dation pour la Recherche Médicale, and by a grant from the Corvidia, personal fees from Servier, outside the submitted Leducq Foundation [18CVD05]. P.v.d.M. is supported by the work. R.N.K. reports he is Co-Founder and President, ASPIDA European Research Council [ERC StG STOP-HF 715732], Dutch Therapeutics Inc. P.P.R. reports personal fees and non-financial Heart Foundation (DHF) grant eSCAPE-HF and the Human support from Novartis, non-financial support from Sanofi, Abbott, Frontier Science Program (HFSP) grant [RGY0071/2014]. R.P. Daiichi-Sankyo, Bayer, outside the submitted work. J.Č. reports is supported by Research project of Charles University Prague, personal fees from Roche Diagnostics, AstraZeneca, Servier, Progress Q40/03. R.N.K. is supported by National Institutes of Berlin-Chemie, Novartis, outside the submitted work. E.A.J. Health grants [R01HL130861 and R01HL138475]; Department reports personal fees from Boehringer Ingelheim, Vifor Pharma, of Defense grants [PR151134P1 and PR191593]; AHA grant Servier, Bayer, Berlin-Chemie, Novartis, Abbott, AstraZeneca, [18SRG34280018]; and Foundation Leducq grant [RA15CVD04]. outside the submitted work. T.T. reports personal fees from P.P.R. is supported by the ERA-NET CVD project AIR-MI and Cardior Pharmaceuticals, other from Novo Nordisk, outside the Austrian Society of Cardiology. J.B. got support from the the submitted work. J.B. reports personal fees from Abbott, Erich und Emmy Hoselmann-Stiftung. J.M. is supported by grants AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi-Sankyo, from National Institutes of Health (NIH) [R56 HL141466] and Medtronic, MSD, Novartis, Pfizer, Servier, grants and personal fees [R01 HL141466]. 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