Dutch cardio-oncology cohort: Incident cardiovascular disease predisposes to a higher cancer mortality rate.

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.

Risk Factors for Immune Checkpoint Inhibitor-Mediated Cardiovascular Toxicities.

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.

LVEF by Multigated Acquisition Scan Compared to Other Imaging Modalities in Cardio-Oncology: a Systematic Review.

PURPOSE OF REVIEW: The prevalence of cancer therapy-related cardiac dysfunction (CTRCD) is increasing due to improved cancer survival. Serial monitoring of cardiac function is essential to detect CTRCD, guiding timely intervention strategies. Multigated radionuclide angiography (MUGA) has been the main screening tool using left ventricular ejection fraction (LVEF) to monitor cardiac dysfunction. However, transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (CMR) may be more suitable for serial assessment. We aimed to assess the concordance between different non-radiating imaging modalities with MUGA to determine whether they can be used interchangeably. RECENT FINDINGS: In order to identify relevant studies, a PubMed search was performed. We included cross-sectional studies comparing MUGA LVEF to that of 2D TTE, 3D TTE, and CMR. From 470 articles, 22 were selected, comprising 1017 patients in total. Among others, this included three 3D TTE, seven 2D harmonic TTE + contrast (2DHC), and seven CMR comparisons. The correlations and Bland-Altman limits of agreement varied for CMR but were stronger for 3D TTE and 2DHC. Our findings suggest that MUGA and CMR should not be used interchangeably whereas 3D TTE and 2DHC are appropriate alternatives following an initial MUGA scan. We propose a multimodality diagnostic imaging strategy for LVEF monitoring in patients undergoing cancer treatment.

Circulating immune checkpoints predict heart failure outcomes.

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 (ß = 0.230, ß = 0.283, and ß = 0.304, respectively). sPD-L1 and galectin-9 were also associated with hs-troponin-T (ß = 0.386 and ß = 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.

Fibrotic Marker Galectin-3 Identifies Males at Risk of Developing Cancer and Heart Failure.

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.

Characterization of immune checkpoint inhibitor-induced cardiotoxicity reveals interleukin-17A as a driver of cardiac dysfunction after anti-PD-1 treatment.

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.

Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T cells.

Invariant natural killer T (iNKT) cells act at the interface between lipid metabolism and immunity because of their restriction to lipid antigens presented on CD1d by antigen-presenting cells (APCs). How foreign lipid antigens are delivered to APCs remains elusive. Since lipoproteins routinely bind glycosylceramides structurally similar to lipid antigens, we hypothesized that circulating lipoproteins form complexes with foreign lipid antigens. In this study, we used 2-color fluorescence correlation spectroscopy to show, for the first time to our knowledge, stable complex formation of lipid antigens α-galactosylceramide (αGalCer), isoglobotrihexosylceramide, and OCH, a sphingosine-truncated analog of αGalCer, with VLDL and/or LDL in vitro and in vivo. We demonstrate LDL receptor-mediated (LDLR-mediated) uptake of lipoprotein-αGalCer complexes by APCs, leading to potent complex-mediated activation of iNKT cells in vitro and in vivo. Finally, LDLR-mutant PBMCs of patients with familial hypercholesterolemia showed impaired activation and proliferation of iNKT cells upon stimulation, underscoring the relevance of lipoproteins as a lipid antigen delivery system in humans. Taken together, circulating lipoproteins form complexes with lipid antigens to facilitate their transport and uptake by APCs, leading to enhanced iNKT cell activation. This study thereby reveals a potentially novel mechanism of lipid antigen delivery to APCs and provides further insight into the immunological capacities of circulating lipoproteins.

The role of immune checkpoints in cardiovascular disease.

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.

Triptych of the Hermit Saints: pneumococcal polysaccharide vaccines for the elderly.

Pneumococcal pneumonia is a serious disease with considerable morbidity and mortality in the elderly. Despite adequate antibiotic treatment, the long-term mortality of pneumococcal pneumonia remains high. Preventive measures in the form of vaccination, therefore, are warranted. Twenty-three-valent polysaccharide vaccines have a broad coverage but limited efficacy. Pneumococcal conjugate vaccines have been shown in children to be able to prevent invasive and mucosal pneumococcal diseases. It should be realized that the serotype composition of current pneumococcal conjugate vaccines is not tailored for the elderly, and that replacement disease can occur. Yet, the current 13-valent conjugate vaccine has been shown to protect against infections with vaccine serotypes. Long-term mortality of pneumococcal pneumonia should be included in policy making about the introduction of these vaccines for the elderly.