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. Summary: 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.

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.

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. 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. 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. 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. Gal-3, a marker of fibrosis, is associated with new-onset cancer and new-onset HF in males, but not in females.

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.

Cardiomyopathies (CMP) are a diverse group of myocardial diseases that cause structural, functional, and pathological changes to the heart. Alterations at the molecular level associated with the clinical phenotype and progression of CMPs cannot be solely explained by the genetic mutations, even in inherited cardiomyopathies. Epigenetics and environmental factors are likely to significantly modify the clinical manifestations of CMPs, resulting in variable clinical expression and different age-related penetrance. This review examines the role of dysfunctional DNA methylation, histone modifications, chromatin remodelling, and noncoding RNAs in the development and exacerbation of CMPs, highlighting their potential as diagnostic markers and therapeutic targets, including the use of histone deacetylase inhibitors. Additionally, it explores how environmental exposures can influence epigenetic changes and potentially be used for preventive strategies and personalized care in CMP patients. Monozygotic twin studies and intergenerational studies are discussed as valuable tools for understanding the interplay between genetics, epigenetics, and environmental factors. Lastly, this review addresses current challenges and future perspectives, such as the need for greater specificity in epigenetic therapies, minimizing off-target effects, and investigating sex differences in CMP research and treatment.

Immune checkpoints are understudied in cardiovascular disease. We investigated the TIM-3 pathway in human serum, peripheral blood mononuclear cells (PBMCs) and cardiac tissue following myocardial infarction (MI). First, TIM-3 ligands in serum, galectin-9 and HMGB-1, were associated with cardiac remodelling 4 months post-MI (n = 357). Next, post-hoc single-cell RNA-sequencing of PBMCs from MI patients (n = 38) and controls (n = 38) revealed acute downregulation of TIM-3 in lymphocytes 24 h post-MI, which occurred after 8 weeks in myeloid cells. In the heart, single-nucleus RNA-sequencing and spatial transcriptomics of MI tissue demonstrated cardiomyocyte HMGB-1 upregulation which could communicate with myeloid TIM-3. Pro-inflammatory macrophages specifically showed significant TIM-3 expression and NLRP3 inflammasome activity. On the protein level, HMGB-1 was also upregulated in the infarcted heart and actively translocated throughout the cells. Finally, in vitro macrophage stimulation with HMGB-1 induced pro-inflammatory polarization (e.g. NLRP3 pathway activation), which was prevented by blocking TIM-3. Thus, TIM-3/HMGB-1 interaction presents as a target in cardiac inflammation following MI.