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Background: Cardiovascular disease (CVD) and cancer are the two leading causes of death worldwide. Given their high prevalence, it is important to understand the disease burden of cancer mortality in CVD patients., Objective: We aimed to evaluate whether patients with incident CVD have a higher risk of malignancy-related mortality, compared to the general population without CVD., Methods: We performed a national population-based cohort study selecting patients with incident CVD in the Netherlands between 01 April 2000 and 31 December 2005. A reference cohort was selected from the Dutch population using age, sex and ethnicity. Mortality follow-up data were evaluated after data linkage of national registries from Statistics Netherlands until 31 December 2020., Results: A total of 2,240,879 individuals were selected with a mean follow-up of 12 years (range 0.4-21.0), of which 738,666 patients with incident CVD with a mean age of 71 ± 15 years. Malignancy mortality per 1000 person years was 84 for the reference group and 118 for patients with CVD, with the highest rate of 258 in patients with heart failure. Patients with CVD had a higher malignancy mortality risk, compared to the reference group: HR 1.35 (95%CI 1.33-1.36). Highest risks were observed in patients with venous diseases (HR 2.27, 95%CI 2.17-2.36) and peripheral artery disease (HR 1.87, 95%CI 1.84-2.01)., Conclusion: Results show that CVD predisposes to a higher cancer mortality rate. Of all CVD subtypes, HF patients have the highest cancer mortality rate and the hazards were highest in patients with venous diseases and peripheral artery disease., (© 2024 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Galectin-3 and Suppression of tumorigenicity-2 (ST2) are known markers of cardiac fibrosis. We investigated the prognostic value of fibrotic markers for the development of diastolic dysfunction and long-term outcome in patients suffering an ST-elevated myocardial infarction (STEMI). We analyzed 236 patients from the GIPS-III cohort with available echocardiographic studies and plasma measurements at hospitalization and after 4 months follow-up. Adjusted logistic mixed effects modelling revealed no association between the occurrence of diastolic dysfunction over time with abnormal plasma levels of galectin-3 and ST2. We observed no differences regarding survival outcome at follow-up of 5 years between patients with normal versus abnormal values in both galectin-3 (P = 0.75), and ST2 (P = 0.85). In conclusion, galectin-3 and sST2 were not associated with the development of diastolic dysfunction in non-diabetic patients that presented with a STEMI., (© 2024. The Author(s).)

Background: Within cardio-oncology, emerging epidemiologic studies have demonstrated a bi-directional relationship between heart failure (HF) and cancer. In the current study, we aimed to further explore this relationship and investigate the underlying pathophysiological pathways that connect these two disease entities., Methods: We conducted a post-hoc analysis in which we identified 24 Gene Ontology (GO) processes associated with the hallmarks of cancer based on 92 biomarkers in 1960 patients with HF. We performed Spearman's correlations and Cox-regression analyses to evaluate associations with HF biomarkers, severity and all-cause mortality., Results: Out of a total of 24 GO processes, 9 biological processes were significantly associated with adverse clinical outcome. Positive regulation of mononuclear cell proliferation demonstrated the highest hazard for reaching the clinical endpoint, even after adjusting for confounders: all-cause mortality HR 2.00 (95% CI 1.17-3.42), p = 0.012. In contrast, negative regulation of apoptotic process was consistently associated with a lower hazard of reaching the clinical outcome, even after adjusting for confounders: all-cause mortality HR 0.74 (95% CI 0.59-0.95), p = 0.016. All processes significantly correlated with HF biomarkers, renal function and HF severity., Conclusions: In patients with HF, GO processes associated with hallmarks of cancer are associated with HF biomarkers, severity and all-cause mortality., (© 2024. The Author(s).)

Immune checkpoint molecules are physiological regulators of the adaptive immune response. Immune checkpoint inhibitors (ICIs), such as monoclonal antibodies targeting programmed cell death protein 1 or cytotoxic T lymphocyte-associated protein 4, have revolutionized cancer treatment and their clinical use is increasing. However, ICIs can cause various immune-related adverse events, including acute and chronic cardiotoxicity. Of these cardiovascular complications, ICI-induced acute fulminant myocarditis is the most studied, although emerging clinical and preclinical data are uncovering the importance of other ICI-related chronic cardiovascular complications, such as accelerated atherosclerosis and non-myocarditis-related heart failure. These complications could be more difficult to diagnose, given that they might only be present alongside other comorbidities. The occurrence of these complications suggests a potential role of immune checkpoint molecules in maintaining cardiovascular homeostasis, and disruption of physiological immune checkpoint signalling might thus lead to cardiac pathologies, including heart failure. Although inflammation is a long-known contributor to the development of heart failure, the therapeutic targeting of pro-inflammatory pathways has not been successful thus far. The increasingly recognized role of immune checkpoint molecules in the failing heart highlights their potential use as immunotherapeutic targets for heart failure. In this Review, we summarize the available data on ICI-induced cardiac dysfunction and heart failure, and discuss how immune checkpoint signalling is altered in the failing heart. Furthermore, we describe how pharmacological targeting of immune checkpoints could be used to treat heart failure., (© 2024. Springer Nature Limited.)

Aims: Heart failure (HF) and cancer are the leading causes of death worldwide. Epidemiological studies revealed that HF patients are prone to develop cancer. Preclinical studies provided some insights into this connection, but the exact mechanisms remain elusive. In colorectal cancer (CRC), gut microbial dysbiosis is linked to cancer progression and recent studies have shown that HF patients display microbial dysbiosis. This current study focussed on the effects of HF-induced microbial dysbiosis on colonic tumour formation., Methods and Results: C57BL/6J mice were subjected to myocardial infarction (MI), with sham surgery as control. After six weeks faeces were collected, processed for 16 s rRNA sequencing, and pooled for faecal microbiota transplantation. CRC tumour growth was provoked in germ-free mice by treating them with Azoxymethane/Dextran sodium sulphate. The CRC mice were transplanted with faeces from MI or sham mice. MI-induced HF resulted in microbial dysbiosis, characterized by a decreased α-diversity and microbial alterations on the genus level, several of which have been associated with CRC. We then performed faecal microbiota transplantation with faeces from HF mice in CRC mice, which resulted in a higher endoscopic disease score and an increase in the number of tumours in CRC mice., Conclusion: We demonstrated that MI-induced HF contributes to colonic tumour formation by altering the gut microbiota composition, providing a mechanistic explanation for the observed association between HF and increased risk for cancer. Targeting the microbiome may present as a tool to mitigate HF-associated co-morbidities, especially cancer., Competing Interests: Conflict of interest: The UMCG which employs several of the authors has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Inc., Novo Nordisk, and Roche. R.A.d.B. has had speaker engagements with and/or received fees from and/or served on an advisory board for Abbott, AstraZeneca, Bristol Myers Squibb, Cardior Pharmaceuticals GmbH, NovoNordisk, and Roche, and received travel support from Abbott, Cardior Cardior Pharmaceuticals GmbH, and NovoNordisk., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies. To this end, in this review, (i) proposed effects and mechanisms of action of guideline-directed HF drugs on cancer derived from pre-clinical data will be described, (ii) the evidence from both observational studies and randomized controlled trials on the effects of guideline-directed medical therapy on cancer incidence and cancer-related outcomes, as synthetized by meta-analyses will be reviewed, and (iii) considerations for future pre-clinical and clinical investigations will be provided., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Despite improvements in cancer survival, cancer therapy-related cardiovascular toxicity has risen to become a prominent clinical challenge. This has led to the growth of the burgeoning field of cardio-oncology, which aims to advance the cardiovascular health of cancer patients and survivors, through actionable and translatable science. In these Global Cardio-Oncology Symposium 2023 scientific symposium proceedings, we present a focused review on the mechanisms that contribute to common cardiovascular toxicities discussed at this meeting, the ongoing international collaborative efforts to improve patient outcomes, and the bidirectional challenges of translating basic research to clinical care. We acknowledge that there are many additional therapies that are of significance but were not topics of discussion at this symposium. We hope that through this symposium-based review we can highlight the knowledge gaps and clinical priorities to inform the design of future studies that aim to prevent and mitigate cardiovascular disease in cancer patients and survivors., Competing Interests: Dr Salloum is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Numbers R35HL155651 and R44HL164314, and the American Heart Association Strategically Focused Research Network Award Number 23SFRNPCS1063855. Dr Tocchetti is supported by grants from the Italian Ministry of Health (PNRR-MAD-2022-12376632 and RF-2016-02362988). Dr Ameri is supported by the European Union - Next Generation EU - NRRP M6C2 - Investment 2.1 “Enhancement and strengthening of biomedical research in the NHS” (Italian Ministry of Health PNRR-MAD-2022-12376632). Dr Ardehali is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Numbers HL127646, HL140973, HL138982, and HL140927. Dr Asnani is supported by R01HL163172, R01HL166541, R01HL157530, and K08HL145019 from the National Institutes of Health/National Heart, Lung, and Blood Institute and by a sponsored research agreement with Genentech. Dr de Boer is supported by the Netherlands Heart Foundation (grants 2017-21, 2017-11, 2018-30, and 2020B005), the Leducq Foundation (Cure-PLaN), and the European Research Council (ERC CoG 818715). Dr Fernández-Velasco is supported by the Carlos III Health Institute (ISCIII) (PI20-01482 and PMP22/00098). Dr Fradley is funded by Medtronic and AstraZeneca. Dr Fuster is supported by grant RYC-2016-20026 from the Spanish Ministerio de Ciencia e Innovación (MICIN/AEI/10.13039/501100011033 and “ESF Investing in your future”) and the European Research Area Network on Cardiovascular Diseases CHEMICAL (grant AC19/00133, funded by ISCIII and co-funded by the European Union, ERDF, “A way to make Europe”). Drs Galán-Arriola, García-Lunar, Ibáñez, and Martin and the Centro Nacional de Investigaciones Cardiovasculares (CNIC) are supported by the ISCIII, the Ministry of Science and Innovation, and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033). Dr Ibáñez is supported by a European Research Council grant (ERC-CoG 819775). The RESILIENCE project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 945118. Dr Kitsis is supported by the national Heart, Lung, and Blood Institute of the National Institutes of Health under Award Numbers R01HL159062, R01HL157319, R01HL164772, and DOD PR191593. Dr Martin is supported by MCIN-ISCIII-Fondo de Investigación Sanitaria (PI22/01759; PMPTA22/00090-BIOCARDIOTOX) and the Comunidad de Madrid (P2022/BMD-7209-INTEGRAMUNE-CM). Dr Mauro is supported by T32HL149645. Dr Mazo Vega is supported by European Union’s H2020 Program under grant agreement No 874827 (BRAV∃) and the Ministerio de Ciencia e Innovación CARDIOPRINT (PLEC2021-008127). Dr Neilan is supported by a gift from A. Curt Greer and Pamela Kohlberg and from Christina and Paul Kazilionis, the Michael and Kathryn Park Endowed Chair in Cardiology, and a Hassenfeld Scholar Award, and is supported by additional grant funding from the National Institutes of Health/National Heart, Lung, and Blood Institute under Award Numbers R01HL137562 and K24HL150238. Dr Rassaf is supported by the German Research Foundation Lower Saxony (DFG RA969/12-1), Ministry of Science and Culture REBIRTH I/II (ZN3440), and Stiftung Gerdes. Dr Ricke-Hoch is supported by the Lower Saxony Ministry of Science and Culture REBIRTH I/II (ZN3440) and Stiftung Gerdes. Dr van der Meer is supported by a grant from the European Research Council (ERC CoG 101045236, DISSECT-HF). Dr Thavendiranathan is supported by a Tier II Canada Research Chair in Cardiooncology (950-232646). Dr Ky is supported by National Institutes of Health grants R01 HL148272, R01 HL152707, R34 HL146927, R21 HL152148, R21HL157886, and K24 HL167127 and American Heart Association Strategically Focused Research Network Awards 849569 and 869105. Dr Sepulveda is supported by ISCIII (PMPTA2022/00011). Drs Ghigo, Lyon, Ibáñez, Hirsch, Ricke-Hoch, and Rassaf are supported by the Leducq Foundation Transatlantic Networks of Excellence (19CVD02). Dr Salloum has received consulting fees from Ring Therapeutics and funding from Novartis Pharmaceuticals, not related to this work; and served on the advisory board for NovoMedix, LLC, in cardio-oncology but not directly related to this work. Dr Tocchetti has received honoraria or consultation fees from VivaLyfe, Univers Formazione, Solaris, Summeet, AstraZeneca, and Myocardial Solutions; has received funding from Amgen and MSD, outside the submitted work; and is listed as an inventor of 2 patents related to heart failure. Dr Ameri has received speaker and/or advisor fees from AstraZeneca, Boehringer Ingelheim, Bayer, Novartis, Daiichi Sankyo, Janssen, and MSD, all outside the submitted work. Dr Asnani has served as a consultant or advisory board member for Sanofi, AstraZeneca, Cytokinetics, and OncLive; served as the principal investigator of a sponsored research agreement with Genentech; and received honoraria from UpToDate. Dr de Boer has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Novo Nordisk, and Roche; and served as a speaker for Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and Roche. Dr Fradley has served as a consultant for AbbVie, AstraZeneca, Johnson and Johnson, Pfizer/Myovant, and Zoll. Drs Ghigo and Hirsch are co-founders and shareholders of Kither Biotech, a pharmaceutical company focused on the development of PI3K inhibitors for airway diseases not in conflict with the content of this paper. Dr Kitsis is a founder of ASPIDA Therapeutics Inc. Dr Lyon has received speaker, advisory board, or consulting fees and/or research grants from Pfizer, Novartis, Servier, AstraZeneca, Bristol Myers Squibb, GSK, Amgen, Takeda, Roche, Janssen-Cilag Ltd, Astellas Pharma, Clinigen Group, Eli Lilly, Eisai Ltd, Ferring Pharmaceuticals, Boehringer Ingelheim, Akcea Therapeutics, Myocardial Solutions, iOWNA Health, and Heartfelt Technologies Ltd. Dr Neilan has served as a consultant for and received fees from Bristol Myers Squibb, Genentech, CRC Oncology, Roche, Sanofi, and Parexel Imaging Pharmaceuticals; and received grant funding from AstraZeneca and Bristol Myers Squibb related to immune therapies. Dr Rassaf has received honoraria, lecture fees, and grant support from Edwards Lifesciences, AstraZeneca, Bayer, Novartis, Berlin Chemie, Daiichi Sankyo, Boehringer Ingelheim, Novo Nordisk, Cardiac Dimensions, and Pfizer, all unrelated to this work. Dr Thavendiranathan’s institution has received speaker honoraria or consultation fees from Amgen, Novartis, Boehringer Ingelheim, and Takeda. Dr van der Meer has received consulting fees and/or grants from Novartis, Pharmacosmos, Vifor Pharma, AstraZeneca, Pfizer, Pharma Nord, BridgeBio, Novo Nordisk, Boehringer Ingelheim, and Ionis. Dr Ky has received honoraria or grants from Pfizer; and honoraria from Roche, Bristol Myers Squibb, and AstraZeneca. Dr López-Fernández has received speaker fees from Philips, Janssen, Daichi Sankyo, Myocardial Solutions, AstraZeneca, Beigene, and Bayer, not related to the current work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Competing Interests: Disclosures The University Medical Center Groningen, which employs several of the authors, has received research grants and fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals Inc, Novo Nordisk, and Roche. Dr de Boer has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and Roche. Dr Meijers received speaker fees from Daiichi Sankyo and Novartis. The other authors report no conflicts.

Background: Giant cell arteritis (GCA) causes severe inflammation of the aorta and its branches and is characterized by intense effector T-cell infiltration. The roles that immune checkpoints play in the pathogenesis of GCA are still unclear. Our aim was to study the immune checkpoint interplay in GCA., Methods: First, we used VigiBase, the World Health Organization international pharmacovigilance database, to evaluate the relationship between GCA occurrence and immune checkpoint inhibitors treatments. We then further dissected the role of immune checkpoint inhibitors in the pathogenesis of GCA, using immunohistochemistry, immunofluorescence, transcriptomics, and flow cytometry on peripheral blood mononuclear cells and aortic tissues of GCA patients and appropriated controls., Results: Using VigiBase, we identified GCA as a significant immune-related adverse event associated with anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) but not anti-PD-1 (anti-programmed death-1) nor anti-PD-L1 (anti-programmed death-ligand 1) treatment. We further dissected a critical role for the CTLA-4 pathway in GCA by identification of the dysregulation of CTLA-4-derived gene pathways and proteins in CD4 + (cluster of differentiation 4) T cells (and specifically regulatory T cells) present in blood and aorta of GCA patients versus controls. While regulatory T cells were less abundant and activated/suppressive in blood and aorta of GCA versus controls, they still specifically upregulated CTLA-4. Activated and proliferating CTLA-4 + Ki-67 + regulatory T cells from GCA were more sensitive to anti-CTLA-4 (ipilimumab)-mediated in vitro depletion versus controls., Conclusions: We highlighted the instrumental role of CTLA-4 immune checkpoint in GCA, which provides a strong rationale for targeting this pathway., Competing Interests: Disclosures None.

Aims: There are limited data examining the role of immune checkpoint (IC) ligands in the pathophysiology of heart failure (HF). Therefore, we explore this in three HF animal models and in three different human cohorts (healthy, stable, and worsening HF)., Methods and Results: Transcriptomic analyses of cardiac tissue of three different HF mouse models revealed differentially expressed IC receptors and their ligands compared with control mice. Based on this observation, serum levels of three well-known IC ligands (i.e. sPD-L1, sPD-L2 and galectin-9) were measured in stable HF patients from the Vitamin D Chronic Heart Failure (VitD-CHF) study (n = 101), as well as healthy individuals from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study (n = 58). sPD-L1, sPD-L2, and galectin-9 were all associated with New York Heart Association classification. In multivariate linear regression analyses, all three IC ligands were associated with galectin-3 (β = 0.230, β = 0.283, and β = 0.304, respectively). sPD-L1 and galectin-9 were also associated with hs-troponin-T (β = 0.386 and β = 0.314). Regarding prognosis, higher serum levels of sPD-L1 and galectin-9 were significantly associated with increased risk for HF hospitalization and all-cause mortality [hazard ratio 1.69 (1.09-2.59) and hazard ratio 1.50 (1.06-2.12)]. Furthermore, the importance of IC ligands was tested in another stage of HF, namely worsening HF patients. In the worsening HF cohort (The BIOlogy Study to Tailored Treatment in Chronic Heart Failure) (n = 2032), sPD-L2 and galectin-9 were associated with New York Heart Association classification and significantly predicted outcome with an increased relative risk of 15% and 20%, after multivariable adjustment, respectively., Conclusions: IC ligands are expressed in cardiac disease models, and serum levels of IC ligands are elevated in HF patients, are associated with disease severity, and significantly predict prognosis. These data indicate a potential role for IC ligands in HF pathogenesis., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Cancer and heart failure (HF) are the leading causes of death in the Western world. Shared mechanisms such as fibrosis may underlie either disease entity, furthermore it is unknown whether this relationship is sex-specific., Objectives: We sought to investigate how fibrosis-related biomarker galectin-3 (gal-3) aids in identifying individuals at risk for new-onset cancer and HF, and how this differs between sexes., Methods: Gal-3 was measured at baseline and at 4-year follow-up in 5,786 patients of the PREVEND (Prevention of Renal and Vascular Endstage Disease) study. The total follow-up period was 11.5 years. An increase of ≥50% in gal-3 levels between measurements was considered relevant. We performed sex-stratified log-rank tests and Cox regression analyses overall and by sex to evaluate the association of gal-3 over time with both new-onset cancer and new-onset HF., Results: Of the 5,786 healthy participants (50% males), 399 (59% males) developed new-onset cancer, and 192 (65% males) developed new-onset HF. In males, an increase in gal-3 was significantly associated with new-onset cancer (both combined and certain cancer-specific subtypes), after adjusting for age, body mass index, hypertension, smoking status, estimated glomerular filtration rate, diabetes mellitus, triglycerides, coronary artery disease, and C-reactive protein (HR: 1.89; 95% CI: 1.32-2.71; P  < 0.001). Similar analyses demonstrated an association with new-onset HF in males (HR: 1.77; 95% CI: 1.07-2.95; P  = 0.028). In females, changes in gal-3 over time were neither associated with new-onset cancer nor new-onset HF., Conclusions: Gal-3, a marker of fibrosis, is associated with new-onset cancer and new-onset HF in males, but not in females., Competing Interests: Financial support was also provided by the European Research Council (ERC CoG 818715, SECRETE-HF). Dr Meijers is supported by the Mandema-Stipendium of the Junior Scientific Masterclass 2020-10 of the University Medical Center Groningen (UMCG; P.F. van den Berg, C. Shi, S. de Wit, L. Geerlings, S. Bakker, B. van der Vegt, H. Silljé, R. de Boer and W. Meijers) and by the Dutch Heart Foundation (Dekker grant 03-005-2021-T005). Dr de Boer has received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche. The UMCG, which employs/employed several of the authors, has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc., Novo Nordisk, and Roche. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

The transforming growth factor-β (TGF-β) superfamily member, myostatin, is a negative regulator of muscle growth and may contribute to adverse cardiac remodeling. Whether suppressing myostatin could benefit pressure-overloaded heart remains unclear. We investigated the effects of pharmacological inhibition of myostatin on cardiac fibrosis and hypertrophy in a mouse model of pressure overload induced by transverse aortic constriction (TAC). Two weeks after the surgery, TAC and sham mice were randomly divided into groups receiving mRK35, a monoclonal anti-myostatin antibody, or vehicle (PBS) for 8 wk. Significant progressive cardiac hypertrophy was observed in TAC mice, as reflected by the increased wall thickness, ventricular weight, and cross-sectional area of cardiomyocytes. In the groups treated with mRK35, compared with sham mice, cardiac fibrosis was increased in TAC mice, accompanied with elevated mRNA expression of fibrotic genes. However, among the TAC mice, mRK35 did not reduce cardiac hypertrophy or fibrosis. Body weight, lean mass, and wet weights of tibialis anterior and gastrocnemius muscle bundle were increased by mRK35. When compared with the TAC-PBS group, the TAC mice treated with mRK35 demonstrated greater forelimb grip strength and a larger mean size of gastrocnemius fibers. Our data suggest that mRK35 does not attenuate cardiac hypertrophy and fibrosis in a TAC mouse model but has positive effects on muscle mass and muscle strength. Anti-myostatin treatment may have therapeutic value against muscle wasting in cardiac vascular disease. NEW & NOTEWORTHY Recent research has highlighted the importance of inhibiting TGF-β signaling in mitigating cardiac dysfunction and remodeling. As myostatin belongs to the TGF-β family, we evaluated the impact of myostatin inhibition using mRK35 in TAC-operated mice. Our data demonstrate that mRK35 significantly increased body weight, muscle mass, and muscle strength but did not attenuate cardiac hypertrophy or fibrosis. Pharmacological inhibition of myostatin may provide therapeutic benefits for the management of muscle wasting in cardiovascular diseases.

Purpose of Review: Immune checkpoint inhibitors (ICIs) have improved the field of cancer, especially in patients with advanced malignancies. Nevertheless, cardiovascular immune-related adverse events (irAEs) with high mortality and morbidity have been observed, including myocarditis, pericarditis, and vasculitis. To date, only a few clinical risk factors have been described and are currently being investigated., Recent Findings: In this review, we address the four most prevailing risk factors for cardiovascular irAEs. ICI combination therapy is a predominant risk factor for developing ICI-mediated myocarditis. Additionally, ICI combined with other anti-cancer treatments (e.g., tyrosine kinase inhibitors, radiation, chemotherapy) seems to increase the risk of developing cardiovascular irAEs. Other risk factors include female sex, pre-existing cardiovascular disease, and specific tumors, on which we will further elaborate in this review. An a priori risk strategy to determine who is at risk to develop these cardiovascular irAEs is needed. Insights into the impact of risk factors are therefore warranted to help clinicians improve care and disease management in these patients., (© 2023. The Author(s).)

In the Netherlands, concerns have been raised regarding the high unemployment rates and the lack of permanent positions for young medical specialists. In the current study, we present data on contemporary early career perspectives in the field of cardiology. We conducted a survey among 304 young cardiologists who completed their training between 2015 and 2020; the response rate was 91%. Our analysis revealed a low unemployment rate (0.3%). One, 3 and 5 years after registration, 81%, 41% and 18% of the respondents, respectively, had not gained a permanent position. Having conducted a fellowship significantly delayed the time to permanent position (hazard ratio (HR): 0.48; 95% confidence interval (CI): 0.34-0.67). For those who had conducted a fellowship, holding a PhD degree (HR: 1.95; 95% CI: 1.10-3.44), age (per year increase, HR: 0.90; 95% CI: 0.82-0.99) and training in an academic hospital (HR: 1.97; 95% CI: 1.10-3.52) were of significant influence on the likelihood of having a permanent position at 3 years of follow-up. These results showed a disturbing increase in time to permanent position compared with an earlier analysis. This trend justifies close monitoring of the labour market in the coming years. Solutions for this multifactorial problem in the field of cardiology and across the entire medical specialty spectrum should be explored., (© 2022. The Author(s).)

Background and Purpose: Immune checkpoint inhibitors (ICI), such as anti-PD-1 monoclonal antibodies, have revolutionized cancer therapy by enhancing the cytotoxic effects of T-cells against tumours. However, enhanced T-cell activity also may cause myocarditis and cardiotoxicity. Our understanding of the mechanisms of ICI-induced cardiotoxicity is limited. Here, we aimed to investigate the effect of PD-1 inhibition on cardiac function and explore the molecular mechanisms of ICI-induced cardiotoxicity., Experimental Approach: C57BL6/J and BALB/c mice were treated with isotype control or anti-PD-1 antibody. Echocardiography was used to assess cardiac function. Cardiac transcriptomic changes were investigated by bulk RNA sequencing. Inflammatory changes were assessed by qRT-PCR and immunohistochemistry in heart, thymus, and spleen of the animals. In follow-up experiments, anti-CD4 and anti-IL-17A antibodies were used along with PD-1 blockade in C57BL/6J mice., Key Results: Anti-PD-1 treatment led to cardiac dysfunction and left ventricular dilation in C57BL/6J mice, with increased nitrosative stress. Only mild inflammation was observed in the heart. However, PD-1 inhibition resulted in enhanced thymic inflammatory signalling, where Il17a increased most prominently. In BALB/c mice, cardiac dysfunction was not evident, and thymic inflammatory activation was more balanced. Inhibition of IL-17A prevented anti-PD-1-induced cardiac dysfunction in C57BL6/J mice. Comparing myocardial transcriptomic changes in C57BL/6J and BALB/c mice, differentially regulated genes (Dmd, Ass1, Chrm2, Nfkbia, Stat3, Gsk3b, Cxcl9, Fxyd2, and Ldb3) were revealed, related to cardiac structure, signalling, and inflammation., Conclusions: PD-1 blockade induces cardiac dysfunction in mice with increased IL-17 signalling in the thymus. Pharmacological inhibition of IL-17A treatment prevents ICI-induced cardiac dysfunction., (© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Previous studies have reported an association between ABO type blood group and cardiovascular (CV) events and outcomes. The precise mechanisms underpinning this striking observation remain unknown, although differences in von Willebrand factor (VWF) plasma levels have been proposed as an explanation. Recently, galectin-3 was identified as an endogenous ligand of VWF and red blood cells (RBCs) and, therefore, we aimed to explore the role of galectin-3 in different blood groups. Two in vitro assays were used to assess the binding capacity of galectin-3 to RBCs and VWF in different blood groups. Additionally, plasma levels of galectin-3 were measured in different blood groups in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study (2571 patients hospitalized for coronary angiography) and validated in a community-based cohort of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study (3552 participants). To determine the prognostic value of galectin-3 in different blood groups, logistic regression and cox regression models were used with all-cause mortality as the primary outcome. First, we demonstrated that galectin-3 has a higher binding capacity for RBCs and VWF in non-O blood groups, compared to blood group O. Additionally, LURIC patients with non-O blood groups had substantially lower plasma levels of galectin-3 (15.0, 14.9, and 14.0 μg/L in blood groups A, B, and AB, respectively, compared to 17.1 μg/L in blood group O, p < 0.0001). Finally, the independent prognostic value of galectin-3 for all-cause mortality showed a non-significant trend towards higher mortality in non-O blood groups. Although plasma galectin-3 levels are lower in non-O blood groups, the prognostic value of galectin-3 is also present in subjects with a non-O blood group. We conclude that physical interaction between galectin-3 and blood group epitopes may modulate galectin-3, which may affect its performance as a biomarker and its biological activity.

Aims: Ongoing adverse remodeling is a hallmark of heart failure (HF), which might be reflected by either focal or diffuse myocardial fibrosis. Therefore, in (pre)clinical settings, we used immunohistochemistry or cardiac magnetic resonance imaging (CMR) to investigate the association of (focal or diffuse) fibrosis with cardiac biomarkers and adverse events in HF., Methods and Results: In C57Bl/6J mice, we determined the presence and extent of myocardial fibrosis 6 weeks post-myocardial infarction (MI). Furthermore, we studied 159 outpatient HF patients who underwent CMR, and determined focal and diffuse fibrosis by late gadolinium enhancement (LGE) and post-contrast T1 time of the non-LGE myocardium, respectively. HF patients were categorized based on the presence of LGE, and by the median post-contrast T1 time. Kaplan-Meier and Cox regression analyses were used to determine the association of fibrosis with HF hospitalization and all-cause mortality. LGE was detected in 61 (38%) patients. Cardiac biomarker levels were comparable between LGE-positive and LGE-negative patients. LGE-positive patients with a short T1 time had elevated levels of both NT-proBNP and galectin-3 (1611 vs. 453 ng/L, p = 0.026 and 20 vs. 15 μg/L, p = 0.004, respectively). This was not observed in LGE-negative patients. Furthermore, a short T1 time in LGE-positive patients was associated with a higher risk of adverse events (log-rank p = 0.01)., Conclusion: This study implies that cardiac biomarkers reflect active remodeling of the non-infarcted myocardium of patients with focal myocardial scarring. Diffuse fibrosis, in contrast to focal scarring, might have a higher prognostic value regarding adverse outcomes in HF patients.

Background: Heart failure (HF) is the leading cause of morbidity and mortality worldwide, and there is an urgent need for more global studies and data mining approaches to uncover its underlying mechanisms. Multiple omics techniques provide a more holistic molecular perspective to study pathophysiological events involved in the development of HF., Methods: In this study, we used a label-free whole myocardium multi-omics characterization from three commonly used mouse HF models: transverse aortic constriction (TAC), myocardial infarction (MI), and homozygous Phospholamban-R14del (PLN-R14 Δ/Δ ). Genes, proteins, and metabolites were analysed for differential expression between each group and a corresponding control group. The core transcriptome and proteome datasets were used for enrichment analysis. For genes that were upregulated at both the RNA and protein levels in all models, clinical validation was performed by means of plasma level determination in patients with HF from the BIOSTAT-CHF cohort., Results: Cell death and tissue repair-related pathways were upregulated in all preclinical models. Fatty acid oxidation, ATP metabolism, and Energy derivation processes were downregulated in all investigated HF aetiologies. Putrescine, a metabolite known for its role in cell survival and apoptosis, demonstrated a 4.9-fold (p < 0.02) increase in PLN-R14 Δ/Δ , 2.7-fold (p < 0.005) increase in TAC mice, and 2.2-fold (p < 0.02) increase in MI mice. Four Biomarkers were associated with all-cause mortality (PRELP: Hazard ratio (95% confidence interval) 1.79(1.35, 2.39), p < 0.001; CKAP4: 1.38(1.21, 1.57), p < 0.001; S100A11: 1.37(1.13, 1.65), p = 0.001; Annexin A1 (ANXA1): 1.16(1.04, 1.29) p = 0.01), and three biomarkers were associated with HF-Related Rehospitalization, (PRELP: 1.88(1.4, 2.53), p < 0.001; CSTB: 1.15(1.05, 1.27), p = 0.003; CKAP4: 1.18(1.02, 1.35), P = 0.023)., Conclusions: Cell death and tissue repair pathways were significantly upregulated, and ATP and energy derivation processes were significantly downregulated in all models. Common pathways and biomarkers with potential clinical and prognostic associations merit further investigation to develop optimal management and therapeutic strategies for all HF aetiologies., Competing Interests: Declaration of Competing Interest The UMCG, which employs several of the authors, has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc., Novo Nordisk, and Roche. Dr. de Boer received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Within the aging population, the frequency of cancer is increasing dramatically. In addition, multiple genetic and environmental factors lead to common multifactorial diseases, including cardiovascular disease, chronic kidney disease, chronic obstructive pulmonary disease, and metabolic-associated fatty liver disease. In recent years, there has been a growing awareness of the connection between cancer and multifactorial diseases, as well as how one can affect the other, resulting in a vicious cycle. Although the exact mechanistic explanations behind this remain to be fully explored, some progress has been made in uncovering the common pathologic mechanisms. In this review, we focus on the nature of the link between cancer and common multifactorial conditions, as well as specific shared mechanisms, some of which may represent either preventive or therapeutic targets. Rather than organ-specific interactions, we herein focus on the shared mechanisms among the multifactorial diseases, which may explain the increased cancer risk. More research on this subject will highlight the significance of developing new drugs that target multiple systems rather than just one disease.

Aims: Management of comorbidities represents a critical step in optimal treatment of heart failure (HF) patients. However, minimal attention has been paid whether comorbidity burden and their prognostic value changes over time. Therefore, we examined the association between comorbidities and clinical outcomes in HF patients between 2002 and 2017., Methods and Results: The 2002-HF cohort consisted of patients from The Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH) trial (n = 1,032). The 2017-HF cohort were outpatient HF patients enrolled after hospitalization for HF in a tertiary referral academic hospital (n = 382). Kaplan meier and cox regression analyses were used to assess the association of comorbidities with HF hospitalization and all-cause mortality. Patients from the 2017-cohort were more likely to be classified as HF with preserved ejection fraction (24 vs 15%, p < 0.001), compared to patients from the 2002-cohort. Comorbidity burden was comparable between both cohorts (mean of 3.9 comorbidities per patient) and substantially increased with age. Higher comorbidity burden was significantly associated with a comparable increased risk for HF hospitalization and all-cause mortality (HR 1.12 [1.02-1.22] and HR 1.18 [1.05-1.32]), in the 2002- and 2017-cohort respectively. When assessing individual comorbidities, obesity yielded a statistically higher prognostic effect on outcome in the 2017-cohort compared to the 2002-HF cohort (p for interaction 0.026)., Conclusion: Despite major advances in HF treatment over the past decades, comorbidity burden remains high in HF and influences outcome to a large extent. Obesity emerges as a prominent comorbidity, and efforts should be made for prevention and treatment. Created with BioRender.com., (© 2022. The Author(s).)

Aim: We aimed to analyse the association of clonal haematopoiesis of indeterminate potential (CHIP) with incident heart failure (HF) in a European population cohort., Methods and Results: From the prospective Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort, we included all 374 participants with incident HF and selected 1:1 age- and sex-matched control subjects. Peripheral blood samples of 705 individuals were successfully analysed by error-corrected next generation sequencing for acquired mutations at a variant allele frequency ≥2% in 27 CHIP driver genes. The median age of the study population was 65 years (interquartile range 58-70) and 35.6% were female. CHIP mutations positively correlated with age, smoking, hypertension and cardiovascular biomarkers including N-terminal pro-B-type natriuretic peptide and mid-regional pro-A-type natriuretic peptide, but the frequency of CHIP was comparable in individuals with incident HF and in control participants (18.4% vs. 17.3%; p = 0.69). In multivariable Cox regression models, CHIP was not significantly associated with incident HF (hazard ratio [HR] 1.24, 95% confidence interval [CI] 0.93-1.65; p = 0.144). This association, however, was modified by age (p for CHIP-age interaction = 0.002). Among people younger than 65 years, CHIP mutations were more frequently detected in the case cohort compared to the control cohort (14.2% vs. 5.8%; p = 0.009), and were significantly associated with new-onset HF (HR 2.07, 95% CI 1.30-3.29; p = 0.002)., Conclusion: Clonal haematopoiesis of indeterminate potential correlates with HF risk factors and biomarkers, and is associated with incident HF in subjects <65 years of age., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Insulin like growth factor binding protein 7 (IGFBP7) is a marker of senescence secretome and a novel biomarker in patients with heart failure (HF). We evaluated the prognostic value of IGFBP7 in patients with heart failure and examined associations to uncover potential new pathophysiological pathways related to increased plasma IGFBP7 concentrations., Methods and Results: We have measured plasma IGFBP7 concentrations in 2250 subjects with new-onset or worsening heart failure (BIOSTAT-CHF cohort). Higher IGFBP7 plasma concentrations were found in older subjects, those with worse kidney function, history of atrial fibrillation, and diabetes mellitus type 2, and in subjects with higher number of HF hospitalizations. Higher IGFBP7 levels also correlate with the levels of several circulating biomarkers, including higher NT-proBNP, hsTnT, and urea levels. Cox regression analyses showed that higher plasma IGFBP7 concentrations were strongly associated with increased risk of all three main endpoints (hospitalization, all-cause mortality, and combined hospitalization and mortality) (HR 1.75, 95% CI 1.25-2.46; HR 1.71, 95% CI 1.39-2.11; and HR 1.44, 95% CI 1.23-1.70, respectively). IGFBP7 remained a significant predictor of these endpoints in patients with both reduced and preserved ejection fraction. Likelihood ratio test showed significant improvement of all three risk prediction models, after adding IGFBP7 (P < 0.001). A biomarker network analysis showed that IGFBP7 levels activate different pathways involved in the regulation of the immune system. Results were externally validated in BIOSTAT-CHF validation cohort., Conclusions: IGFPB7 presents as an independent and robust prognostic biomarker in patients with HF, with both reduced and preserved ejection fraction. We validate the previously published data showing IGFBP7 has correlations with a number of echocardiographic markers. Lastly, IGFBP7 pathways are involved in different stages of immune system regulation, linking heart failure to senescence pathways., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

In the Netherlands, concerns have been raised regarding the high unemployment rates and the lack of permanent positions for young medical specialists. In the current study, we present data on contemporary early career perspectives in the field of cardiology. We conducted a survey among 304 young cardiologists who completed their training between 2015 and 2020; the response rate was 91%. Our analysis revealed a low unemployment rate (0.3%). One, 3 and 5 years after registration, 81%, 41% and 18% of the respondents, respectively, had not gained a permanent position. Having conducted a fellowship significantly delayed the time to permanent position (hazard ratio (HR): 0.48; 95% confidence interval (CI): 0.34-0.67). For those who had conducted a fellowship, holding a PhD degree (HR: 1.95; 95% CI: 1.10-3.44), age (per year increase, HR: 0.90; 95% CI: 0.82-0.99) and training in an academic hospital (HR: 1.97; 95% CI: 1.10-3.52) were of significant influence on the likelihood of having a permanent position at 3 years of follow-up. These results showed a disturbing increase in time to permanent position compared with an earlier analysis. This trend justifies close monitoring of the labour market in the coming years. Solutions for this multifactorial problem in the field of cardiology and across the entire medical specialty spectrum should be explored., Supplementary Information: The online version of this article (10.1007/s12471-022-01736-1) contains supplementary material, which is available to authorized users., Competing Interests: Conflict of interestV.M.M. Vorselaars, M. Minneboo, W.C. Meijers, A.C. van der Heijden, D. Haroun, V.J.M. Baggen, W.R. Berger and G.P.J. van Hout declare that they have no competing interests., (© The Author(s) 2022.)

Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy 1 . The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1 -/- Ctla4 +/- mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration 2 . Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1 -/- Ctla4 +/- mice, we identify clonal effector CD8 + T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1 -/- Ctla4 +/- mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, which required CD8 + T cells. The cardiac-specific protein α-myosin, which is absent from the thymus 3,4 , was identified as the cognate antigen source for three major histocompatibility complex class I-restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from three patients with ICI-MC were expanded by α-myosin peptides. Moreover, these α-myosin-expanded T cells shared TCR clonotypes with diseased heart and skeletal muscle, which indicates that α-myosin may be a clinically important autoantigen in ICI-MC. These studies underscore the crucial role for cytotoxic CD8 + T cells, identify a candidate autoantigen in ICI-MC and yield new insights into the pathogenesis of ICI toxicity., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Immune checkpoint inhibitors (ICI) are monoclonal antibodies which bind to immune checkpoints (IC) and their ligands to prevent inhibition of T-cell activation by tumor cells. Currently, multiple ICI are approved targeting Cytotoxic T-lymphocyte antigen 4 (CTLA-4), Programmed Death Protein 1 (PD-1) and its ligand PD-L1, and Lymphocyte-activation gene 3 (LAG-3). This therapy has provided potent anti-tumor effects and improved prognosis for many cancer patients. However, due to systemic effects, patients can develop immune related adverse events (irAE), including possible life threatening cardiovascular irAE, like atherosclerosis, myocarditis and cardiomyopathy. Inhibition of vascular IC is associated with increased atherosclerotic burden and plaque instability. IC protect against atherosclerosis by inhibiting T-cell activity and cytokine production, promoting regulatory T-cell differentiation and inducing T-cell exhaustion. In addition, PD-L1 on endothelial cells might promote plaque stability by reducing apoptosis and increasing expression of tight junction molecules. In the heart, IC downregulate the immune response to protect against cardiac injury by reducing T-cell activity and migration. Here, inhibition of IC could induce life-threatening T-cell-mediated-myocarditis. One proposed purpose behind lymphocyte infiltration is reaction to cardiac antigens, caused by decreased self-tolerance, and thereby increased autoimmunity because of IC inhibition. In addition, there are several reports of ICI-mediated cardiomyopathy with immunoglobulin G expression on cardiomyocytes, indicating an autoimmune response. IC are mostly known due to their cardiotoxicity. However, t his review compiles current knowledge on mechanisms behind IC function in cardiovascular disease with the aim of providing an overview of possible therapeutic targets in prevention or treatment of cardiovascular irAEs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yousif, Tanja, de Boer, Teske and Meijers.)

Purpose of the Study: A major challenge in cardiology remains in finding a therapy for cardiac fibrosis. Inhibition of galectin-3 with pectins attenuates fibrosis in animal models of heart failure. The purpose of this study is to identify pectins with the strongest galectin-3 inhibitory capacity. We evaluated the in vitro inhibitory capacity, identified potent pectins, and tested if this potency could be validated in a mouse model of myocardial fibrosis., Methods: Various pectin fractions were screened in vitro. Modified rhubarb pectin (EMRP) was identified as the most potent inhibitor of galectin-3 and compared to the well-known modified citrus pectin (MCP). Our findings were validated in a mouse model of myocardial fibrosis, which was induced by angiotensin II (Ang II) infusion., Results: Ang II infusion was associated with a 4-5-fold increase in fibrosis signal in the tissue of the left ventricle, compared to the control group (0•22±0•10 to 1•08±0•53%; P < 0•001). After treatment with rhubarb pectin, fibrosis was reduced by 57% vs. Ang II alone while this reduction was 30% with the well-known MCP (P = NS, P < 0•05). Treatment was associated with a reduced cardiac inflammatory response and preserved cardiac function., Conclusion: The galectin-3 inhibitor natural rhubarb pectin has a superior inhibitory capacity over established pectins, substantially attenuates cardiac fibrosis, and preserves cardiac function in vivo. Bioactive pectins are natural sources of galectin-3 inhibitors and may be helpful in the prevention of heart failure or other diseases characterized by fibrosis., Funding: Dr. Meijers is supported by the Mandema-Stipendium of the Junior Scientific Masterclass 2020-10, University Medical Center Groningen and by the Netherlands Heart Foundation (Dekkerbeurs 2021)Dr. de Boer is supported by the Netherlands Heart Foundation (CVON SHE-PREDICTS-HF, grant 2017-21; CVON RED-CVD, grant 2017-11; CVON PREDICT2, grant 2018-30; and CVON DOUBLE DOSE, grant 2020B005), by a grant from the leDucq Foundation (Cure PhosphoLambaN induced Cardiomyopathy (Cure-PLaN), and by a grant from the European Research Council (ERC CoG 818715, SECRETE-HF)., Competing Interests: Declaration of Competing Interests The UMCG, which employs several of the authors, has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc., Novo Nordisk, and Roche.  Dr. de Boer received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche., (Copyright © 2021 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Improving cancer survival represents the most significant effect of precision medicine and personalized molecular and immunologic therapeutics. Cardiovascular health becomes henceforth a key determinant for the direction of overall outcomes after cancer. Comprehensive tissue diagnostic studies undoubtedly have been and continue to be at the core of the fight against cancer. Will a systemic approach integrating circulating blood-derived biomarkers, multimodality imaging technologies, strategic panomics, and real-time streams of digitized physiological data overcome the elusive cardiovascular tissue diagnosis in cardio-oncology? How can such a systemic approach be personalized for application in day-to-day clinical work, with diverse patient populations, cancer diagnoses, and therapies? To address such questions, this scientific statement approaches a broad definition of the biomarker concept. It summarizes the current literature on the utilization of a multitude of established cardiovascular biomarkers at the intersection with cancer. It identifies limitations and gaps of knowledge in the application of biomarkers to stratify the cardiovascular risk before cancer treatment, monitor cardiovascular health during cancer therapy, and detect latent cardiovascular damage in cancer survivors. Last, it highlights areas in biomarker discovery, validation, and clinical application for concerted efforts from funding agencies, scientists, and clinicians at the cardio-oncology nexus.

Introduction: Several lines of evidence reveal that cardiovascular disease (CVD) and cancer share similar common pathological milieus. The prevalence of the two diseases is growing as the population ages and the burden of shared risk factors increases. In this respect, we hypothesise that tumour biomarkers can be potential predictors of CVD outcomes in the general population. Methods: We measured six tumour biomarkers (AFP, CA125, CA15-3, CA19-9, CEA and CYFRA 21-1) and determined their predictive value for CVD in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study. A total of 8,592 subjects were enrolled in the study. Results: The levels of CEA significantly predicted CV morbidity and mortality, with hazard ratios (HRs) of HR 1.28 (95% CI 1.08-1.53), respectively. Two biomarkers (CA15-3 and CEA) showed statistical significance in predicting all-cause mortality, with HRs 1.58 (95% CI 1.18-2.12) and HR 1.60 (95% CI 1.30-1.96), when adjusted for shared risk factors and prevalent CVD. Furthermore, biomarkers seem to be sex specific. CYFRA 21-1 presented as an independent predictor of CV morbidity and mortality in female, but not in male gender, with HR 1.82 (95% CI 1.40-2.35). When it comes to all-cause mortality, both CYFRA and CEA show statistical significance in male gender, with HR 1.64 (95% CI 1.28-3.12) and HR 1.55 (95% CI 1.18-2.02), while only CEA showed statistical significance in female gender, with HR 1.64 (95% CI 1.20-2.24). Lastly, CA15-3 and CEA strongly predicted CV mortality with HR 3.01 (95% CI 1.70-5.32) and HR 1.82 (95% CI 1.30-2.56). On another hand, CA 15-3 also presented as an independent predictor of heart failure (HF) with HR 1.67 (95% CI 1.15-2.42). Conclusion: Several tumour biomarkers demonstrated independent prognostic value for CV events and all-cause mortality in a large cohort from the general population. These findings support the notion that CVD and cancer are associated with similar pathological milieus., Competing Interests: The UMCG, which employs several of the authors, has received research grants and/or fees from AstraZeneca, Abbott, Bristol-Myers Squibb, Novartis, Novo Nordisk, and Roche. RB received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bracun, Suthahar, Shi, de Wit, Meijers, Klip, de Boer and Aboumsallem.)

Importance: In the last decade, immune checkpoint inhibitors (ICIs) have been approved for the treatment of many cancer types. Immune checkpoint inhibitor-associated myocarditis has emerged as a significant and potentially fatal adverse effect. Recognizing, diagnosing, and treating ICI-associated myocarditis poses new challenges for the practicing clinician. Here, the current literature on ICI-associated myocarditis is reviewed., Observations: Clinical presentation and cardiac pathological findings are highly variable in patients with ICI-associated myocarditis. Although endomyocardial biopsy is the criterion standard diagnostic test, a combination of clinical suspicion, cardiac biomarkers (specifically troponin), and cardiac imaging, in addition to biopsy, is often needed to support the diagnosis. Importantly, the combination of a cytotoxic T-lymphocyte-associated protein 4 inhibitor with a programmed cell death protein 1 or programmed death-ligand 1 inhibitor increases the risk of developing ICI-associated myocarditis., Conclusion and Relevance: This review aims to provide a standardized diagnostic and therapeutic approach for patients with suspected ICI-associated myocarditis. A complete history of recent cancer treatments and physical examination in combination with cardiac biomarkers, cardiac imaging, and endomyocardial biopsy represent a pragmatic diagnostic approach for most cases of ICI-associated myocarditis. The addition of novel biomarkers or imaging modalities is an area of active research and should be evaluated in larger cohorts.

Circulating biomarkers and imaging techniques provide independent and complementary information to guide management of heart failure (HF). This consensus document by the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) presents current evidence-based indications relevant to integration of imaging techniques and biomarkers in HF. The document first focuses on application of circulating biomarkers together with imaging findings, in the broad domains of screening, diagnosis, risk stratification, guidance of treatment and monitoring, and then discusses specific challenging settings. In each section we crystallize clinically relevant recommendations and identify directions for future research. The target readership of this document includes cardiologists, internal medicine specialists and other clinicians dealing with HF patients., (© 2021 European Society of Cardiology.)

New biomarkers are being evaluated for their ability to advance the management of patients with heart failure. Despite a large pool of interesting candidate biomarkers, besides natriuretic peptides virtually none have succeeded in being applied into the clinical setting. In this review, we examine the most promising emerging candidates for clinical assessment and management of patients with heart failure. We discuss high-sensitivity cardiac troponins (Tn), procalcitonin, novel kidney markers, soluble suppression of tumorigenicity 2 (sST2), galectin-3, growth differentiation factor-15 (GDF-15), cluster of differentiation 146 (CD146), neprilysin, adrenomedullin (ADM), and also discuss proteomics and genetic-based risk scores. We focused on guidance and assistance with daily clinical care decision-making. For each biomarker, analytical considerations are discussed, as well as performance regarding diagnosis and prognosis. Furthermore, we discuss potential implementation in clinical algorithms and in ongoing clinical trials., (© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Accurate measurement of kidney function in patients with neuromuscular disorders is challenging. Cystatin C, a marker not influenced by skeletal muscle degradation, might be of clinical value in these patients. Methods: We consecutively enrolled 39 patients with neuromuscular disorders. We investigated the association of the eGFR, based on plasma creatinine and Cystatin C, with clinical and biochemical variables associated with kidney function, namely age and galectin-3. Results: Creatinine-based eGFR was 242 (±80) and Cystatin C-based eGFR was 110 (±23) mL/min/1.73 m 2 . Cystatin C-based eGFR was associated with age (β -0.63 p < 0.0001) and galectin-3 levels (β -0.43 p < 0.01), while creatinine-based eGFR was not (β -0.22 p = 0.20; β -0.28 p = 0.10). Sensitivity analyses in Duchenne and Becker patients revealed the same results: Cystatin C-based eGFR was associated with age (β -0.61 p < 0.01) and galectin-3 levels (β -0.43 p = 0.05), while creatinine-based eGFR was not (β -0.32 p = 0.13; β -0.34 p = 0.14). Conclusions: These data indicate that estimation of renal function in patients with neuromuscular disorders cannot reliably be achieved with creatinine, while Cystatin C appears a reasonable alternative. Since a large proportion of patients with neuromuscular disorders develops heart failure, and requires heart failure medication, adequate monitoring of renal function is warranted., Competing Interests: The UMCG, which employs the authors, has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc., Novo Nordisk, and Roche. RdB received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche., (Copyright © 2021 Screever, Kootstra-Ros, Doorn, Nieuwenhuis, Meulenbelt, Meijers and de Boer.)

Aims: Two key echocardiographic parameters that are currently used to diagnose heart failure (HF) with preserved ejection fraction (HFpEF) are left atrial volume index (LAVi) and left ventricular mass index (LVMi). We investigated whether patients' characteristics, biomarkers, and co-morbidities are associated with these parameters and whether the relationships differ between patients with HFpEF or HF with reduced ejection fraction (HFrEF)., Methods: We consecutively enrolled 831 outpatients with typical signs and symptoms of HF and elevated N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels and categorized patients based upon left ventricular ejection fraction (LVEF): LVEF < 40% (HFrEF), LVEF between 40% and 50% (HF with mid-range ejection fraction), and LVEF ≥ 50% (HFpEF). The study includes consecutively enrolled HF patients from an HF outpatient clinic at a tertiary medical centre in the Netherlands. All patients underwent baseline characterization, laboratory measurements, and echocardiography., Results: Four hundred sixty-nine patients had HFrEF, 189 HF with mid-range ejection fraction, and 173 HFpEF. The patients with HFrEF were rather male [HFrEF: 323 (69%); HFpEF: 80 (46%); P < 0.001], and the age was comparable (HFrEF 67 ± 13; HFpEF 70 ± 14; P = 0.069). In HFpEF, more patients had hypertension [190 (40.5%); 114 (65.9%); P < 0.001], higher body mass indices (27 ± 8; 30 ± 7; P < 0.001), and atrial fibrillation [194 (41.4); 86 (49.7); P = 0.029]. The correlation analyses showed that in HFrEF patients, LAVi was significantly associated with age (β 0.293; P < 0.001), male gender (β 0.104; P = 0.042), body mass index (β -0160; P = 0.002), diastolic blood pressure (β -0.136; P < 0.001), New York Heart Association (β 0.174; P = 0.001), atrial fibrillation (β 0.381; P < 0.001), galectin 3 (β 0.230; P < 0.001), NT-proBNP (β 0.183; P < 0.001), estimated glomerular filtration rate (β -0.205; P < 0.001), LVEF (β -0.173; P = 0.001), and LVMi (β 0.337; P < 0.001). In HFpEF patients, only age (β 0.326; P < 0.001), atrial fibrillation (β 0.386; P < 0.001), NT-proBNP (β 0.176; P = 0.036), and LVMi (β 0.213; P = 0.013) were associated with LAVi., Conclusions: Although LVMi and LAVi are hallmark parameters to diagnose HFpEF, they only correlate with a few characteristics of HF and mainly with atrial fibrillation. In contrast, in HFrEF patients, LAVi relates strongly to several other HF parameters. These findings underscore the complexity in visualizing the pathophysiology of HFpEF and question the relation between cardiac structural remodeling and the impact of co-morbidities., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objective: Recent studies have reported suboptimal up-titration of heart failure (HF) therapies in patients with heart failure and a reduced ejection fraction (HFrEF). Here, we report on the achieved doses after nurse-led up-titration, reasons for not achieving the target dose, subsequent changes in left ventricular ejection fraction (LVEF), and mortality., Methods: From 2012 to 2018, 378 HFrEF patients with a recent (< 3 months) diagnosis of HF were referred to a specialised HF-nurse led clinic for protocolised up-titration of guideline-directed medical therapy (GDMT). The achieved doses of GDMT at 9 months were recorded, as well as reasons for not achieving the optimal dose in all patients. Echocardiography was performed at baseline and after up-titration in 278 patients., Results: Of 345 HFrEF patients with a follow-up visit after 9 months, 69% reached ≥ 50% of the recommended dose of renin-angiotensin-system (RAS) inhibitors, 73% reached ≥ 50% of the recommended dose of beta-blockers and 77% reached ≥ 50% of the recommended dose of mineralocorticoid receptor antagonists. The main reasons for not reaching the target dose were hypotension (RAS inhibitors and beta-blockers), bradycardia (beta-blockers) and renal dysfunction (RAS inhibitors). During a median follow-up of 9 months, mean LVEF increased from 27.6% at baseline to 38.8% at follow-up. Each 5% increase in LVEF was associated with an adjusted hazard ratio of 0.84 (0.75-0.94, p = 0.002) for mortality and 0.85 (0.78-0.94, p = 0.001) for the combined endpoint of mortality and/or HF hospitalisation after a mean follow-up of 3.3 years., Conclusions: This study shows that protocolised up-titration in a nurse-led HF clinic leads to high doses of GDMT and improvement of LVEF in patients with new-onset HFrEF., (© 2021. The Author(s).)

Cardio-Oncology has blossomed as a new field in cardiovascular medicine, in large part due to new therapies, which may have cardiovascular sequelae. Despite this, anthracyclines still serve as cornerstone therapy for most pediatric cancers, several solid tumors and hematological malignancies. Cardiotoxicity is the main limiting concern with anthracyclines, and this is particularly an issue in patients in extremes of age (both young and old patients). Pediatric hearts are susceptible for cardiotoxicity, while in older patients, concomitant risk factors may contribute to lower threshold for cardiotoxic effects. With increasing patient survival, a significant increase in elderly cancer patients and long-term cardiotoxicity effects of anthracyclines, a better mechanistic understanding of age-dependent processes-that define cardiotoxicity-is needed. This review sheds light on how age affects underlying molecular pathways of anthracycline-associated cardiotoxicity and aims to provide preventive strategies that can be used in clinical practice.

Immune checkpoint inhibitors (ICI) targeting CTLA4 or PD-1/PD-L1 have transformed cancer therapy but are associated with immune-related adverse events, including myocarditis. Here, we report a robust preclinical mouse model of ICI-associated myocarditis in which monoallelic loss of Ctla4 in the context of complete genetic absence of Pdcd1 leads to premature death in approximately half of mice. Premature death results from myocardial infiltration by T cells and macrophages and severe ECG abnormalities, closely recapitulating the clinical and pathologic hallmarks of ICI-associated myocarditis observed in patients. Using this model, we show that Ctla4 and Pdcd1 functionally interact in a gene dosage-dependent manner, providing a mechanism by which myocarditis arises with increased frequency in the setting of combination ICI therapy. We demonstrate that intervention with CTLA4-Ig (abatacept) is sufficient to ameliorate disease progression and additionally provide a case series of patients in which abatacept mitigates the fulminant course of ICI myocarditis. SIGNIFICANCE: We provide a preclinical model of ICI-associated myocarditis which recapitulates this clinical syndrome. Using this model, we demonstrate that CTLA4 and PD-1 (ICI targets) functionally interact for myocarditis development and that intervention with CTLA4-Ig (abatacept) attenuates myocarditis, providing mechanistic rationale and preclinical support for therapeutic clinical studies. See related commentary by Young and Bluestone, p. 537 . This article is highlighted in the In This Issue feature, p. 521 ., (©2020 American Association for Cancer Research.)

Androgen deprivation therapy is a cornerstone of prostate cancer treatment. Pharmacological androgen deprivation includes gonadotropin-releasing hormone agonism and antagonism, androgen receptor inhibition, and CYP17 (cytochrome P450 17A1) inhibition. Studies in the past decade have raised concerns about the potential for androgen deprivation therapy to increase the risk of adverse cardiovascular events such as myocardial infarction, stroke, and cardiovascular mortality, possibly by exacerbating cardiovascular risk factors. In this review, we summarize existing data on the cardiovascular effects of androgen deprivation therapy. Among the therapies, abiraterone stands out for increasing risk of cardiac events in meta-analyses of both randomized controlled trials and observational studies. We find a divergence between observational studies, which show consistent positive associations between androgen deprivation therapy use and cardiovascular disease, and randomized controlled trials, which do not show these associations reproducibly.

Emerging evidence supports that cancer incidence is increased in patients with cardiovascular (CV) disease and heart failure (HF), and patients with HF frequently die from cancer. Recently, data have been generated showing that circulating factors in relation to HF promote tumour growth and development in murine models, providing proof that a causal relationship exists between both diseases. Several common pathophysiological mechanisms linking HF to cancer exist, and include inflammation, neuro-hormonal activation, oxidative stress and a dysfunctional immune system. These shared mechanisms, in combination with risk factors, in concert may explain why patients with HF are prone to develop cancer. Investigating the new insights linking HF with cancer is rapidly becoming an exciting new field of research, and we herein review the most recent data. Besides insights in mechanisms, we call for clinical awareness, that is essential to optimize treatment strategies of patients having developed cancer with a history of HF. Finally, ongoing and future trials should strive for comprehensive phenotyping of both CV and cancer end points, to allow optimal usefulness of data, and to better describe and understand common characteristics of these two lethal diseases., (© 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Natriuretic peptide [NP; B-type NP (BNP), N-terminal proBNP (NT-proBNP), and midregional proANP (MR-proANP)] concentrations are quantitative plasma biomarkers for the presence and severity of haemodynamic cardiac stress and heart failure (HF). End-diastolic wall stress, intracardiac filling pressures, and intracardiac volumes seem to be the dominant triggers. This paper details the most important indications for NPs and highlights 11 key principles underlying their clinical use shown below. NPs should always be used in conjunction with all other clinical information. NPs are reasonable surrogates for intracardiac volumes and filling pressures. NPs should be measured in all patients presenting with symptoms suggestive of HF such as dyspnoea and/or fatigue, as their use facilitates the early diagnosis and risk stratification of HF. NPs have very high diagnostic accuracy in discriminating HF from other causes of dyspnoea: the higher the NP, the higher the likelihood that dyspnoea is caused by HF. Optimal NP cut-off concentrations for the diagnosis of acute HF (very high filling pressures) in patients presenting to the emergency department with acute dyspnoea are higher compared with those used in the diagnosis of chronic HF in patients with dyspnoea on exertion (mild increase in filling pressures at rest). Obese patients have lower NP concentrations, mandating the use of lower cut-off concentrations (about 50% lower). In stable HF patients, but also in patients with other cardiac disorders such as myocardial infarction, valvular heart disease, atrial fibrillation or pulmonary embolism, NP concentrations have high prognostic accuracy for death and HF hospitalization. Screening with NPs for the early detection of relevant cardiac disease including left ventricular systolic dysfunction in patients with cardiovascular risk factors may help to identify patients at increased risk, therefore allowing targeted preventive measures to prevent HF. BNP, NT-proBNP and MR-proANP have comparable diagnostic and prognostic accuracy. In patients with shock, NPs cannot be used to identify cause (e.g. cardiogenic vs. septic shock), but remain prognostic. NPs cannot identify the underlying cause of HF and, therefore, if elevated, must always be used in conjunction with cardiac imaging., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Cardiovascular (CV) disease and cancer are the leading causes of death.1,2 Over the last decades, it has been appreciated that both CV disease and cancer are more common in individuals in whom risk factors for disease development accumulate, and preventative measures have been extremely important in driving down the incidence of disease.3-6 In general, the field of epidemiology, risk reduction, and preventative trials is divided into health care professionals who have an interest in either CV disease or cancer. As a result, the medical literature and medical practice has largely focused on the one disease, or the other. However, human individuals do not behave according to this dogma. Emerging data clearly suggest that identical risk factors may lead to CV disease in the one individual, but may cause cancer in another, or even both diseases in the same individual. This overlap exists between risk factors that are historically classified as 'CV risk factors' as these factors do equally strong predict cancer development. Therefore, we propose that a holistic approach might better estimate actual risks for CV disease and cancer. In this review, we summarize current insights in common behavioural risk factors for heart failure, being the most progressed and lethal form of CV disease, and cancer., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Galectin-3 (Gal-3) has been associated with heart failure (HF) and poor cardiovascular outcomes. However, the effect of longitudinal changes in Gal-3 on clinical outcomes remains unclear., Objectives: The authors sought to study clinical determinants of change in Gal-3 among community-dwelling individuals. Further, they sought to examine the role of serial Gal-3 measurements in predicting risk of future HF, cardiovascular disease (CVD), and mortality., Methods: A total of 2,477 participants in the Framingham Heart Study Offspring cohort underwent measurement of plasma Gal-3 levels at 2 examinations (1995 to 1998 and 2005 to 2008). Linear regression models were used to examine clinical correlates of change in Gal-3. Proportional hazards models were used to relate future clinical outcomes with change in Gal-3., Results: The following clinical correlates were associated with greater longitudinal increases in Gal-3 levels: age, female sex, hypertension, diabetes, body mass index, interim development of chronic kidney disease, and HF (p < 0.0001 for all in multivariable model). Change in Gal-3 was associated with future HF (hazard ratio [HR]: 1.39 per 1-SD increase; 95% confidence interval [CI]: 1.13 to 1.71), CVD (HR: 1.29; 95% CI: 1.11 to 1.51), and all-cause mortality (HR: 1.30; 95% CI: 1.17 to 1.46). Change in Gal-3 was associated with both HF with preserved as well as reduced ejection fraction (p < 0.05 for both)., Conclusions: Longitudinal changes in Gal-3 are associated with traditional cardiovascular risk factors and renal disease. In turn, change in Gal-3 predicts future HF, CVD, and mortality in the community. Future studies are needed to determine whether serial Gal-3 measures may be useful in disease prevention., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)