Association of fibrotic markers with diastolic function after STEMI.

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.

Hallmarks of cancer in patients with heart failure: data from BIOSTAT-CHF.

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.

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.

Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence.

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.

Heart failure-induced microbial dysbiosis contributes to colonic tumour formation in mice.

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.

Immune checkpoints in cardiac physiology and pathology: therapeutic targets for heart failure.

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.

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.

CTLA-4 Pathway Is Instrumental in Giant Cell Arteritis.

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.

Divergent effects of myostatin inhibition on cardiac and skeletal muscles in a mouse model of pressure overload.

The transforming growth factor-ß (TGF-ß) 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-ß signaling in mitigating cardiac dysfunction and remodeling. As myostatin belongs to the TGF-ß 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.

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.

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.

Galectin-3 and Blood Group: Binding Properties, Effects on Plasma Levels, and Consequences for Prognostic Performance.

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.

Diffuse Myocardial Fibrosis on Cardiac Magnetic Resonance Imaging Is Related to Galectin-3 and Predicts Outcome in Heart Failure.

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.

Multifactorial Diseases of the Heart, Kidneys, Lungs, and Liver and Incident Cancer: Epidemiology and Shared Mechanisms.

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.

Comorbidities complicating heart failure: changes over the last 15 years.

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.

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.