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The regulation of bone vasculature by chronic diseases, such as heart failure is unknown. Here, we describe the effects of myocardial infarction and post-infarction heart failure on the bone vascular cell composition. We demonstrate an age-independent loss of type H endothelium in heart failure after myocardial infarction in both mice and humans. Using single-cell RNA sequencing, we delineate the transcriptional heterogeneity of human bone marrow endothelium, showing increased expression of inflammatory genes, including IL1B and MYC , in ischemic heart failure. Endothelial-specific overexpression of MYC was sufficient to induce type H bone endothelial cells, whereas inhibition of NLRP3-dependent IL-1β production partially prevented the post-myocardial infarction loss of type H vasculature in mice. These results provide a rationale for using anti-inflammatory therapies to prevent or reverse the deterioration of bone vascular function in ischemic heart disease. Hematopoiesis influences the progression of cardiovascular disease, yet the influence of cardiovascular disease on the bone vasculature is unknown. Hoffmann, Luxán, Abplanalp et al. describe the response of the bone cell composition to myocardial infarction and provide a rationale for using anti-inflammatory therapies to prevent the deterioration of the bone vascular niche

Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A), play a pivotal role in driving clonal hematopoiesis of indeterminate potential (CHIP), and are associated with unfavorable outcomes in patients suffering from heart failure (HF). However, the precise interactions between CHIP-mutated cells and other cardiac cell types remain unknown. Here, we identify fibroblasts as potential partners in interactions with CHIP-mutated monocytes. We used combined transcriptomic data derived from peripheral blood mononuclear cells of HF patients, both with and without CHIP, and cardiac tissue. We demonstrate that inactivation of DNMT3A in macrophages intensifies interactions with cardiac fibroblasts and increases cardiac fibrosis. DNMT3A inactivation amplifies the release of heparin-binding epidermal growth factor-like growth factor, thereby facilitating activation of cardiac fibroblasts. These findings identify a potential pathway of DNMT3A CHIP-driver mutations to the initiation and progression of HF and may also provide a compelling basis for the development of innovative anti-fibrotic strategies. This study uncovers a critical link between DNMT3A-driven CHIP and heart failure and, in particular, it shows that DNMT3A inactivation in monocytes boosts the release of HB-EGF, which activates fibroblasts inducing diffuse fibrosis in the heart.

The aim of this study was to evaluate the subclinical patterns and evolution of cardiac abnormalities via transthoracic echocardiography (TTE) in patients with mild initial COVID-19 illness. A total of 343 infected individuals (163 males; age 44 (interquartile range, IQR 35–52) years) years) underwent serial TTE assessments at a median of 109 (interquartile range (IQR), 77–177) and 327 (276–379) days after infection. Compared with those of non-COVID-19-infected controls ( n  = 94, male n  = 49), baseline systolic (LVEF, TAPSE) and diastolic function (eʹ, aʹ, E/eʹ) were significantly different in infected participants ( p  < 0.05 for all). Compared with baseline assessments, there was a reduction in global longitudinal strain (GLS) and an increase in the E wave, E/A ratio and E/eʹ at follow-up. At baseline, symptomatic participants had a lower LVEF and TAPSE and increased IVRT, eʹ and E/eʹ. At follow-up, symptomatic patients had a lower LV end-diastolic diameter (LVEDd). Symptoms were independently associated with E/eʹ at baseline (OR (95% CI) 1.45 (1.12–1.87), p  = 0.005). Symptoms at follow-up were associated with LVEDd, measured either at baseline (OR: 0.91 (0.86, 0.96), p  < 0.001) or follow-up (OR (95% CI) 0.91 (0.86–0.96), p  < 0.001). There were significant associations for GLS and troponin and E/eʹ with CRP and NTproBNP at baseline. In the present cohort of COVID-19-infected individuals with mild initial illness, echocardiographic measurements revealed significant yet subclinical differences in systolic and diastolic function compared with controls, as well as between individuals with cardiac symptoms and those without. All the measured differences were small in magnitude and thus unlikely to be detectable clinically at the individual level.

Aims: The aim of the present study was to investigate the inhibition of classically activated macrophages in myocardial infarction (MI) under the influence of the chemokine (C‐C motif) receptor 2 (CCR2) antagonist propagermanium (PPG). Methods and Results: Mice (C57BL/6; n = 121) were subjected to occlusion of the left anterior descending artery and were randomized to the following groups: (a) MI with daily oral administration of 0.9% sodium chloride (“MI”), (b) MI with oral administration of 8 mg/kg PPG (“MI + PPG”), and (c) sham‐operated mice served as control. Mice were euthanized 2, 5, 10, or 21 days after MI for isolation of total RNA, protein, and immunofluorescence measurements. Flow cytometry was performed to investigate peripheral blood leucocytes. Scar size and cardiac function were determined by MRI on Day 7 after surgery and by trichrome staining on Day 21. PPG administration led to a significantly improved ejection fraction (MI + PPG: 38.5 % ± 3.4 % vs. MI: 23.8 % ± 3.0 % ; p < 0.05) after MI. MRI also revealed improved wall thickness (34.7 % ± 3.2 % vs. 21.8 % ± 2.9 % ; p < 0.05) associated with a diminished akinetic area (13.8 % ± 4.0 % vs. 37.3 % ± 5.6 % ; p < 0.01). Trichrome staining confirmed less collagen scar formation in the PPG‐treated group (12.7 % ± 1.4 % vs. 21.9 % ± 3.9 % ; p < 0.05). Flow cytometry showed fewer peripheral blood monocytes in MI + PPG than in MI 2 days after treatment (4.0 % ± 0.7 % vs. 12.7 % ± 1.2 % of total leucocytes; p < 0.05). Immunostaining and western blotting using activation type‐specific markers CCR2 and MRC1 demonstrated that the number of alternatively activated macrophages within the infarct zone increased, whereas the overall number was reduced after PPG treatment. PPG led to increased expression of VEGF‐ α and VEGF‐ β in THP‐1 cells in vitro and increased capillary density in vivo 2 days after MI (MI‐PPG: 1071 ± 81/mm 2 vs. MI: 648 ± 79/mm 2 ( p < 0.05)). Conclusion: Our results suggest that altering the activation type and distribution of invading macrophages in favor of alternative activation improves cardiac remodeling and function following MI.

Progressive deterioration of innate and adaptive immune functions, a status termed ＇immunosenescence＇, is associated with the higher frequency and severity of diseases in the elderly, such as chronic infections, cancer and autoimmune disorders.1 Age-related immunosenescence can be characterized by a decrease in adaptive immunity and increase in low-grade chronic inflam- mation, also referred to as ＇inflamm- aging＇.2 This dysfunctional immunity is characterized by perturbations of the T- lymphocyte compartment, largely attrib- uted to thymus involution, shrinkage of the naive T-cell repertoire and oligoclonal expansions of memory T cells, particu- larly of CD8＋ effector memory subsets.3 Age and latent viral infections, especially human cytomegalovirus （CMV）, are both considered a driving force ofCD8＋ T-cell expansion and senescence, which is char- acterized by shortened telomeres, pro- gressive loss of costimulatory receptors, CD28 and CD27, and expression of sen- escence-associated surface markers, such as KLRG1 and the glycoepitope CD57, which also reflects the proliferative his- tory of cells.

Aims Systemic inflammatory response, identified by increased total leucocyte counts, was shown to be a strong predictor of mortality after transcatheter aortic valve implantation (TAVI). Yet the mechanisms of inflammation‐associated poor outcome after TAVI are unclear. Therefore, the present study aimed at investigating individual inflammatory signatures and functional heterogeneity of circulating myeloid and T‐lymphocyte subsets and their impact on 1 year survival in a single‐centre cohort of patients with severe aortic stenosis undergoing TAVI. Methods and results One hundred twenty‐nine consecutive patients with severe symptomatic aortic stenosis admitted for transfemoral TAVI were included. Blood samples were obtained at baseline, immediately after, and 24 h and 3 days after TAVI, and these were analysed for inflammatory and cardiac biomarkers. Myeloid and T‐lymphocyte subsets were measured using flow cytometry. The inflammatory parameters were first analysed as continuous variables; and in case of association with outcome and area under receiver operating characteristic (ROC) curve (AUC) ≥ 0.6, the values were dichotomized using optimal cut‐off points. Several baseline inflammatory parameters, including high‐sensitivity C‐reactive protein (hsCRP; HR = 1.37, 95% CI: 1.15–1.63; P < 0.0001) and IL‐6 (HR = 1.02, 95% CI: 1.01–1.03; P = 0.003), lower counts of Th2 (HR = 0.95, 95% CI: 0.91–0.99; P = 0.009), and increased percentages of Th17 cells (HR = 1.19, 95% CI: 1.02–1.38; P = 0.024) were associated with 12 month all‐cause mortality. Among postprocedural parameters, only increased post‐TAVI counts of non‐classical monocytes immediately after TAVI were predictive of outcome (HR = 1.03, 95% CI: 1.01–1.05; P = 0.003). The occurrence of SIRS criteria within 48 h post‐TAVI showed no significant association with 12 month mortality (HR = 0.57, 95% CI: 0.13–2.43, P = 0.45). In multivariate analysis of discrete or dichotomized clinical and inflammatory variables, the presence of diabetes mellitus (HR = 3.50; 95% CI: 1.42–8.62; P = 0.006), low left ventricular (LV) ejection fraction (HR = 3.16; 95% CI: 1.35–7.39; P = 0.008), increased baseline hsCRP (HR = 5.22; 95% CI: 2.09–13.01; P < 0.0001), and low baseline Th2 cell counts (HR = 8.83; 95% CI: 3.02–25.80) were significant predictors of death. The prognostic value of the linear prediction score calculated of these parameters was superior to the Society of Thoracic Surgeons score (AUC: 0.88; 95% CI: 0.78–0.99 vs. 0.75; 95% CI: 0.64–0.86, respectively; P = 0.036). Finally, when analysing LV remodelling outcomes, ROC curve analysis revealed that low numbers of Tregs (P = 0.017; AUC: 0.69) and increased Th17/Treg ratio (P = 0.012; AUC: 0.70) were predictive of adverse remodelling after TAVI. Conclusions Our findings demonstrate an association of specific pre‐existing inflammatory phenotypes with increased mortality and adverse LV remodelling after TAVI. Distinct monocyte and T‐cell signatures might provide additive biomarkers to improve pre‐procedural risk stratification in patients referred to TAVI for severe aortic stenosis.

With the advent of primary PCI (PPCI), reperfusion is achieved in almost all patients presenting with acute myocardial infarction. However, despite multiple trials, reperfusion injury has not been successfully dealt with so far. In mouse models, CD4(+) T lymphocytes (T cells) have been shown to be crucial instigators of reperfusion injury. Our goal was to investigate the role of CD4(+) T cells during myocardial reperfusion following PPCI by developing a protocol for high-throughput multiplexed flow cytometric analysis and multivariate flow clustering. 13-parameter immunophenotyping and hierarchical cluster analysis (HCA) identified a unique CD4(+)CD57(+) T-cell population in PPCI patients that reflected acute proliferation in the CD4(+) T-cell compartment. CD4(+)CCR7(+) T cells were specifically depleted from peripheral blood during the first 30 min of myocardial reperfusion after PPCI, suggesting a potential role for the chemokine receptor CCR7 in T-cell redistribution to either peripheral tissues or migration to the infarcted heart during ischemia/reperfusion following PPCI. High-throughput polychromatic flow cytometry and HCA are capable of objective, time and cost efficient assessment of the individual T-cell immune profile in different stages of coronary heart disease and have broad applications in clinical trials.

Mouse models of myocardial infarction (MI) are commonly used to explore the pathophysiological role of the monocytic response in myocardial injury and to develop translational strategies. However, no study thus far has examined the potential impact of inter-individual variability and sham surgical procedures on monocyte subset kinetics after experimental MI in mice. Our goal was to investigate determinants of systemic myeloid cell subset shifts in C57BL/6 mice following MI by developing a protocol for sequential extensive flow cytometry (FCM). Following cross-sectional multiplex FCM analysis we provide for the first time a detailed description of absolute quantities, relative subset composition, and biological variability of circulating classical, intermediate, and non-classical monocyte subsets in C57BL/6 mice. By using intra-individual longitudinal measurements after MI induction, a time course of classical and non-classical monocytosis was recorded. This approach disclosed a significant reduction of monocyte subset dispersion across all investigated time points following MI. We found that in the current invasive model of chronic MI the global pattern of systemic monocyte kinetics is mainly determined by a nonspecific inflammatory response to sham surgery and not by the extent of myocardial injury. Application of sequential multiplexed FCM may help to reduce the impact of biological variability in C57BL/6 mice. Furthermore, the confounding influence of sham surgical procedures should always be considered when measuring monocyte subset kinetics in a murine model of MI.

Cardiac symptoms are increasingly recognized as late complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in previously well individuals with mild initial illness, but the underlying pathophysiology leading to long-term cardiac symptoms remains unclear. In this study, we conducted serial cardiac assessments in a selected population of individuals with Coronavirus Disease 2019 (COVID-19) with no previous cardiac disease or notable comorbidities by measuring blood biomarkers of heart injury or dysfunction and by performing magnetic resonance imaging. Baseline measurements from 346 individuals with COVID-19 (52% females) were obtained at a median of 109 days (interquartile range (IQR), 77–177 days) after infection, when 73% of participants reported cardiac symptoms, such as exertional dyspnea (62%), palpitations (28%), atypical chest pain (27%) and syncope (3%). Symptomatic individuals had higher heart rates and higher imaging values or contrast agent accumulation, denoting inflammatory cardiac involvement, compared to asymptomatic individuals. Structural heart disease or high levels of biomarkers of cardiac injury or dysfunction were rare in symptomatic individuals. At follow-up (329 days (IQR, 274–383 days) after infection), 57% of participants had persistent cardiac symptoms. Diffuse myocardial edema was more pronounced in participants who remained symptomatic at follow-up as compared to those who improved. Female gender and diffuse myocardial involvement on baseline imaging independently predicted the presence of cardiac symptoms at follow-up. Ongoing inflammatory cardiac involvement may, at least in part, explain the lingering cardiac symptoms in previously well individuals with mild initial COVID-19 illness. In individuals with long-term cardiac symptoms after an initially mild course of COVID-19 illness, magnetic resonance imaging and measurement of cardiac injury biomarkers commonly detected ongoing cardiac inflammation but not structural heart disease.

Cytomegalovirus (CMV) seropositivity in adults has been linked to increased cardiovascular disease burden. Phenotypically, CMV infection leads to an inflated CD8 T-lymphocyte compartment. We employed a 8-colour flow cytometric protocol to analyse circulating T cells in 597 octogenarians from the same birth cohort together with NT-proBNP measurements and followed all participants over 7 years. We found that, independent of CMV serostatus, a high number of CD27−CD28+ CD8 EMRA T-lymphocytes (TEMRA) protected from all-cause death after adjusting for known risk factors, such as heart failure, frailty or cancer (Hazard ratio 0.66 for highest vs lowest tertile; confidence interval 0.51–0.86). In addition, CD27−CD28+ CD8 EMRA T-lymphocytes protected from both, non-cardiovascular (hazard ratio 0.59) and cardiovascular death (hazard ratio 0.65). In aged mice treated with the senolytic navitoclax, in which we have previously shown a rejuvenated cardiac phenotype, CD8 effector memory cells are decreased, further indicating that alterations in T cell subpopulations are associated with cardiovascular ageing. Future studies are required to show whether targeting immunosenescence will lead to enhanced life- or healthspan.