[Anti-myocardial ischemic injury effects and mechanisms of cryptotanshinone in regulating macrophage polarisation through Dectin-1 signalling pathway].

The aim of this study was to investigate the potential mechanism by which cryptotanshinone(CTS) may exert its anti-myo-cardial ischemic effect through the regulation of macrophage polarization via the dendritic cell-associated C-type lectin 1(Dectin-1) signaling pathway. Male C57BL/6 mice, aged six weeks, were utilized to establish myocardial ischemia models and were subsequently divided into five groups: sham, model, CTS low-dose(21 mg·kg~(-1)·d~(-1)), CTS high-dose(84 mg·kg~(-1)·d~(-1)), and dapagliflozin(0.14 mg·kg~(-1)·d~(-1)). The cardiac function, serum enzyme levels, Dectin-1 expression, macrophage polarization, and neutrophil infiltration in the myocardial infarction area were assessed in each group. An in vitro model of M1-type macrophages was constructed using lipopolysaccharide/interfe-ron-γ(LPS/IFN-γ) stimulated RAW264.7 cells to investigate the impact of CTS on macrophage polarization and to examine alterations in key proteins within the Dectin-1 signaling pathway. In the CTS group, compared to the model group mice, there was a significant improvement in the cardiac function and myocardial injury, along with a notable increase in the ratio of M2/M1-type macrophages in the myocardial infarcted area and a decrease in neutrophil infiltration. Additionally, Dectin-1 exhibited low expression. The results of in vitro experiments demonstrated that CTS can decrease the expression of M1-type marker genes and increase the expression of M2-type marker genes. Besides, it can decrease the levels of Dectin-1 and the phosphorylation of its associated proteins, including spleen tyrosine kinase(Syk), protein kinase B(Akt), nuclear factor-kappaB p65(NF-κB p65), and extracellular signal-regulated protein kinases(ERK1/2). Additionally, CTS was found to enhance the phosphorylation of signal transducer and activator of transcription-6(STAT6). The above results suggest that CTS exerts its anti-myocardial ischemic injury effect by regulating macrophage polarization through the Dectin-1 signaling pathway.

Immuno-inflammatory pathogenesis in ischemic heart disease: perception and knowledge for neutrophil recruitment.

Ischemic heart disease (IHD) can trigger responses from the innate immune system, provoke aseptic inflammatory processes, and result in the recruitment and accumulation of neutrophils. Excessive recruitment of neutrophils is a potential driver of persistent cardiac inflammation. Once recruited, neutrophils are capable of secreting a plethora of inflammatory and chemotactic agents that intensify the inflammatory cascade. Additionally, neutrophils may obstruct microvasculature within the inflamed region, further augmenting myocardial injury in the context of IHD. Immune-related molecules mediate the recruitment process of neutrophils, such as immune receptors and ligands, immune active molecules, and immunocytes. Non-immune-related molecular pathways represented by pro-resolving lipid mediators are also involved in the regulation of NR. Finally, we discuss novel regulating strategies, including targeted intervention, agents, and phytochemical strategies. This review describes in as much detail as possible the upstream molecular mechanism and external intervention strategies for regulating NR, which represents a promising therapeutic avenue for IHD.

Identification of diagnostic signature and immune infiltration for ischemic cardiomyopathy based on cuproptosis-related genes through bioinformatics analysis and experimental validation.

BACKGROUND: Ischemic cardiomyopathy (IC) is primarily due to long-term ischemia/hypoxia of the coronary arteries, leading to impaired cardiac contractile or diastolic function. A new form of cell death induced by copper, called "cuproptosis" is related to the development and progression of multiple diseases. The cuproptosis-related gene (CuGs) plays an important role in acute myocardial infarction, while the specific mechanisms of CuGs in ischemic cardiomyopathy remain unclear. METHODS: The expressions of CuGs and their immune characteristics were analyzed with the IC datasets obtained from the Gene Expression Omnibus, namely GSE5406 and GSE57338, identifying core genes associated with IC development. By comparing RF, SVM, GLM and XGB models, the optimal machine learning model was selected. The expression of marker genes was validated based on the GSE57345, GSE48166 and GSE42955 datasets. Construct a CeRNA network based on core genes. Therapeutic chemiacals targeting core genes were acquired using the CTD database, and molecular docking was performed using Autodock vina software. By ligating the left anterior descending (LAD) coronary artery, an IC mouse model is established, and core genes were experimentally validated using Western blot (WB) and immunohistochemistry (IHC) methods. RESULTS: We identified 14 CuGs closely associated with the onset of IC. The SVM model exhibited superior discriminative power (AUC = 0.914), with core genes being DLST, ATP7B, FDX1, SLC31A1 and DLAT. Core genes were validated on the GSE42955, GSE48166 and GSE57345 datasets, showing excellent performance (AUC = 0.943, AUC = 0.800, and AUC = 0.932). The CeRNA network consists of 218 nodes and 264 lines, including 5 core diagnostic genes, 52 miRNAs, and 161 lncRNAs. Chemicals predictions indicated 8 chemicals have therapeutic effects on the core diagnostic genes, with benzo(a)pyrene molecular docking showing the highest affinity (-11.3 kcal/mol). Compared to the normal group, the IC group,which was established by LAD ligation, showed a significant decrease in LVEF as indicated by cardiac ultrasound, and increased fibrosis as shown by MASSON staining, WB results suggest increased expression of DLST and ATP7B, and decreased expression of FDX1, SLC31A1 and DLAT in the myocardial ischemic area (p < 0.05), which was also confirmed by IHC in tissue sections. CONCLUSION: In summary, this study comprehensively revealed that DLST, ATP7B, FDX1, SLC31A1 and DLAT could be identified as potential immunological biomarkers in IC, and validated through an IC mouse model, providing valuable insights for future research into the mechanisms of CuGs and its diagnostic value to IC.

Resident and recruited macrophages differentially contribute to cardiac healing after myocardial ischemia.

Cardiac macrophages are heterogenous in phenotype and functions, which has been associated with differences in their ontogeny. Despite extensive research, our understanding of the precise role of different subsets of macrophages in ischemia/reperfusion (I/R) injury remains incomplete. We here investigated macrophage lineages and ablated tissue macrophages in homeostasis and after I/R injury in a CSF1R-dependent manner. Genomic deletion of a fms-intronic regulatory element (FIRE) in the Csf1r locus resulted in specific absence of resident homeostatic and antigen-presenting macrophages, without affecting the recruitment of monocyte-derived macrophages to the infarcted heart. Specific absence of homeostatic, monocyte-independent macrophages altered the immune cell crosstalk in response to injury and induced proinflammatory neutrophil polarization, resulting in impaired cardiac remodeling without influencing infarct size. In contrast, continuous CSF1R inhibition led to depletion of both resident and recruited macrophage populations. This augmented adverse remodeling after I/R and led to an increased infarct size and deterioration of cardiac function. In summary, resident macrophages orchestrate inflammatory responses improving cardiac remodeling, while recruited macrophages determine infarct size after I/R injury. These findings attribute distinct beneficial effects to different macrophage populations in the context of myocardial infarction.

The effect of macrophages and their exosomes in ischemic heart disease.

Ischemic heart disease (IHD) is a leading cause of disability and death worldwide, with immune regulation playing a crucial role in its pathogenesis. Various immune cells are involved, and as one of the key immune cells residing in the heart, macrophages play an indispensable role in the inflammatory and reparative processes during cardiac ischemia. Exosomes, extracellular vesicles containing lipids, nucleic acids, proteins, and other bioactive molecules, have emerged as important mediators in the regulatory functions of macrophages and hold promise as a novel therapeutic target for IHD. This review summarizes the regulatory mechanisms of different subsets of macrophages and their secreted exosomes during cardiac ischemia over the past five years. It also discusses the current status of clinical research utilizing macrophages and their exosomes, as well as strategies to enhance their therapeutic efficacy through biotechnology. The aim is to provide valuable insights for the treatment of IHD.

Meta-analysis of the association between interleukin-17 and ischemic cardiovascular disease.

BACKGROUND: Interleukin-17 (IL-17) has been hypothesized to be involved in ischemic cardiovascular disease (ICVD). However, the association of IL-17 with ICVD remained unclear. The aim of this study was to systematically analyze the available evidence regarding the association between IL-17 and ICVD. METHODS: We searched the PubMed, Web of Science, Cochrane Library, and Embase databases up to October 2023 to identify publications on the association between IL-17 and ICVD. The merged results were analyzed using a random effects model for meta-analysis and subgroup analysis. RESULTS: A total of 955 publications were initially identified in our search and screened; six studies were eventually included in the analysis. The average age of study participants was 60.3 ± 12.6 years and 65.5% were men. There was a high degree of heterogeneity among studies. The results showed that IL-17 level were higher in the case group than those in the control group (standardized mean difference, SMD = 1.60, 95% confidence interval (95% CI): 0.53-2.66, P = 0.003). In sensitivity analysis, the merged results showed good robustness. Additionally, subgroup analysis showed that race and ethnicity, sample size, and detection methods were significant factors influencing heterogeneity in the published studies. CONCLUSION: Our finding revealed that increased IL-17 level contributed to the development of ICVD, suggesting IL-17 as a potential risk marker. Further research is needed to establish IL-17 as a therapeutic biomarker of ICVD.

Regulatory T-Cell Response to Low-Dose Interleukin-2 in Ischemic Heart Disease.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease of the artery wall. Regulatory T cells (Tregs) limit inflammation and promote tissue healing. Low doses of interleukin (IL)-2 have the potential to increase Tregs, but its use is contraindicated for patients with ischemic heart disease. METHODS: In this randomized, double-blind, placebo-controlled, dose-escalation trial, we tested low-dose subcutaneous aldesleukin (recombinant IL-2), given once daily for 5 consecutive days. In study part A, the primary end point was safety, and patients with stable ischemic heart disease were randomly assigned to receive placebo or to one of five dose groups (range, 0.3 to 3.0 × 106 IU daily). In study part B, patients with acute non-ST elevation myocardial infarction or unstable angina were randomly assigned to receive placebo or to one of two dose groups (1.5 and 2.5 × 106 IU daily). The coprimary end points were safety and the dose required to increase circulating Tregs by 75%. Single-cell RNA-sequencing of circulating immune cells was used to provide a mechanistic assessment of the effects of aldesleukin. RESULTS: Forty-four patients were randomly assigned to either study part A (n=26) or part B (n=18). In total, 3 patients withdrew before dosing, 27 received active treatment, and 14 received placebo. The majority of adverse events were mild. Two serious adverse events occurred, with one occurring after drug administration. In parts A and B, there was a dose-dependent increase in Tregs. In part B, the estimated dose to achieve a 75% increase in Tregs was 1.46 × 106 IU (95% confidence interval, 1.06 to 1.87). Single-cell RNA-sequencing demonstrated the engagement of distinct pathways and cell­cell interactions. CONCLUSIONS: In this phase 1b/2a study, low-dose IL-2 expanded Tregs without adverse events of major concern. Larger trials are needed to confirm the safety and to further evaluate the efficacy of low-dose IL-2 as an anti-inflammatory therapy for patients with ischemic heart disease. (Funded by the Medical Research Council, the British Heart Foundation, and others; ClinicalTrials.gov number, NCT03113773)

Soluble fibrinogen­like protein 2 levels are decreased in patients with ischemic heart failure and associated with cardiac function.

Soluble fibrinogen­like protein 2 (sFGL2), as a novel effector of regulatory T cells (Tregs), exhibits immune regulatory activity in several inflammatory diseases. Immune activation and persistent inflammation participate in the progression of ischemic heart failure (IHF). The present study aimed to determine serum sFGL2 levels in patients with IHF and explore the relationship between sFGL2 levels and cardiac function. A total of 104 patients with IHF and 32 healthy controls were enrolled. patients with IHF were further split into subgroups according to the New York Heart Association functional classification or left ventricular ejection fraction (LVEF). Serum sFGL2 levels and peripheral Tregs frequencies were analyzed by ELISA and flow cytometry, respectively. The suppressive function of Tregs was measured by proliferation and functional suppression assays. Serum levels of sFGL2 and circulating Tregs frequencies were significantly decreased in patients with IHF compared with healthy controls. In patients with IHF, sFGL2 levels and Tregs frequencies were decreased with the deterioration of cardiac function. Tregs from patients with IHF exhibited compromised ability to suppress CD4+CD25­ T cells proliferation and inflammatory cytokines secretion. Specifically, sFGL2 levels and Tregs frequencies positively correlated with LVEF, whereas negatively correlated with left ventricular end­diastolic dimension and N­terminal pro­brain natriuretic peptide. sFGL2 levels were positively correlated with Tregs frequencies. In conclusion, the reduction of serum sFGL2 levels are associated with the progression of IHF and sFGL2 could be used as a potential indicator for predicting disease severity.

Cardiac Dysfunction in Rheumatoid Arthritis: The Role of Inflammation.

Rheumatoid arthritis is a chronic, systemic inflammatory disease that carries an increased risk of mortality due to cardiovascular disease. The link between inflammation and atherosclerotic disease is clear; however, recent evidence suggests that inflammation may also play a role in the development of nonischemic heart disease in rheumatoid arthritis (RA) patients. We consider here the link between inflammation and cardiovascular disease in the RA community with a focus on heart failure with preserved ejection fraction. The effect of current anti-inflammatory therapeutics, used to treat RA patients, on cardiovascular disease are discussed as well as whether targeting resolution of inflammation might offer an alternative strategy for tempering inflammation and subsequent inflammation-driven comorbidities in RA.

The evolving cardiac lymphatic vasculature in development, repair and regeneration.

The lymphatic vasculature has an essential role in maintaining normal fluid balance in tissues and modulating the inflammatory response to injury or pathogens. Disruption of normal development or function of lymphatic vessels can have severe consequences. In the heart, reduced lymphatic function can lead to myocardial oedema and persistent inflammation. Macrophages, which are phagocytic cells of the innate immune system, contribute to cardiac development and to fibrotic repair and regeneration of cardiac tissue after myocardial infarction. In this Review, we discuss the cardiac lymphatic vasculature with a focus on developments over the past 5 years arising from the study of mammalian and zebrafish model organisms. In addition, we examine the interplay between the cardiac lymphatics and macrophages during fibrotic repair and regeneration after myocardial infarction. Finally, we discuss the therapeutic potential of targeting the cardiac lymphatic network to regulate immune cell content and alleviate inflammation in patients with ischaemic heart disease.

Expression of Paracrine Effectors in Human Adipose-Derived Mesenchymal Stem Cells Treated With Plasma From Brown Bears (Ursus arctos).

Adipose-derived mesenchymal stem cells (ADSCs) are promising candidates for novel cell therapeutic applications. Hibernating brown bears sustain tissue integrity and function via unknown mechanisms, which might be plasma borne. We hypothesized that plasma from hibernating bears may increase the expression of favorable factors from human ADSCs. In an experimental study, ADSCs from patients with ischemic heart disease were treated with interventional media containing plasma from hibernating and active bears, respectively, and with control medium. Extracted RNA from the ADSCs was sequenced using next generation sequencing. Statistical analyses of differentially expressed genes were performed using fold change analysis, pathway analysis, and gene ontology. As a result, we found that genes associated with inflammation, such as IGF1, PGF, IL11, and TGFA, were downregulated by > 10-fold in ADSCs treated with winter plasma compared with control. Genes important for cardiovascular development, ADM, ANGPTL4, and APOL3, were upregulated in ADSCs when treated with winter plasma compared with summer plasma. ADSCs treated with bear plasma, regardless if it was from hibernating or active bears, showed downregulation of IGF1, PGF, IL11, INHBA, IER3, and HMOX1 compared with control, suggesting reduced cell growth and differentiation. This can be summarized in the conclusion that plasma from hibernating bears suppresses inflammatory genes and activates genes associated with cardiovascular development in human ADSCs. Identifying the involved regulator(s) holds therapeutic potential.

Immature Platelets and Risk of Cardiovascular Events among Patients with Ischemic Heart Disease: A Systematic Review.

BACKGROUND: Immature platelets are larger and may be more thrombogenic than mature platelets. This systematic review included studies on the association between mean platelet volume (MPV), immature platelet count (IPC), and immature platelet fraction (IPF) and the risk of major cardiovascular events (MACEs) in patients with acute coronary syndrome (ACS) or stable coronary artery disease (CAD). METHODS: The literature search included studies in PubMed, Embase, Web of Science, and Cochrane Library. The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Effect estimates that included multivariate adjusted odds ratios, relative risks, or hazard ratios were extracted. RESULTS: Forty-two studies were identified. High MPV was positively associated with MACE in 20 of 26 studies of patients with ACS, four of five studies in patients with stable CAD, and in all six studies comprising a combined population with ACS and stable CAD. Using continuous models of MPV in patients with ACS, effect estimates varied from 0.90 (95% confidence interval [CI]: 0.95-1.03) to 1.66 (95% CI: 1.32-2.09). The strength of these associations was broadly similar among patients with stable CAD and in combined populations. Five studies investigated IPC or IPF as exposures and all reported positive associations with MACE among patients with ACS, stable CAD, or in combined populations. CONCLUSION: This review demonstrated clear evidence for positive associations between measures of immature platelets and subsequent risk of MACE in acute and stable ischemic heart disease patients.

Lipid Mediators in Critically Ill Patients: A Step Towards Precision Medicine.

A dysregulated response to systemic inflammation is a common pathophysiological feature of most conditions encountered in the intensive care unit (ICU). Recent evidence indicates that a dysregulated inflammatory response is involved in the pathogenesis of various ICU-related disorders associated with high mortality, including sepsis, acute respiratory distress syndrome, cerebral and myocardial ischemia, and acute kidney injury. Moreover, persistent or non-resolving inflammation may lead to the syndrome of persistent critical illness, characterized by acquired immunosuppression, catabolism and poor long-term functional outcomes. Despite decades of research, management of many disorders in the ICU is mostly supportive, and current therapeutic strategies often do not take into account the heterogeneity of the patient population, underlying chronic conditions, nor the individual state of the immune response. Fatty acid-derived lipid mediators are recognized as key players in the generation and resolution of inflammation, and their signature provides specific information on patients' inflammatory status and immune response. Lipidomics is increasingly recognized as a powerful tool to assess lipid metabolism and the interaction between metabolic changes and the immune system via profiling lipid mediators in clinical studies. Within the concept of precision medicine, understanding and characterizing the individual immune response may allow for better stratification of critically ill patients as well as identification of diagnostic and prognostic biomarkers. In this review, we provide an overview of the role of fatty acid-derived lipid mediators as endogenous regulators of the inflammatory, anti-inflammatory and pro-resolving response and future directions for use of clinical lipidomics to identify lipid mediators as diagnostic and prognostic markers in critical illness.

Potential Therapeutic Role of Purinergic Receptors in Cardiovascular Disease Mediated by SARS-CoV-2.

Novel coronavirus disease 2019 (COVID-19) causes pulmonary and cardiovascular disorders and has become a worldwide emergency. Myocardial injury can be caused by direct or indirect damage, particularly mediated by a cytokine storm, a disordered immune response that can cause myocarditis, abnormal coagulation, arrhythmia, acute coronary syndrome, and myocardial infarction. The present review focuses on the mechanisms of this viral infection, cardiac biomarkers, consequences, and the possible therapeutic role of purinergic and adenosinergic signalling systems. In particular, we focus on the interaction of the extracellular nucleotide adenosine triphosphate (ATP) with its receptors P2X1, P2X4, P2X7, P2Y1, and P2Y2 and of adenosine (Ado) with A2A and A3 receptors, as well as their roles in host immune responses. We suggest that receptors of purinergic signalling could be ideal candidates for pharmacological targeting to protect against myocardial injury caused by a cytokine storm in COVID-19, in order to reduce systemic inflammatory damage to cells and tissues, preventing the progression of the disease by modulating the immune response and improving patient quality of life.

Regulatory T cells in ischemic cardiovascular injury and repair.

Ischemic injury triggers a heightened inflammatory response that is essential for tissue repair, but excessive and chronic inflammatory responses contribute to the pathogenesis of ischemic cardiovascular disease. Regulatory T cells (Tregs), a major regulator of self-tolerance and immune suppression, control innate and adaptive immune responses, modulate specific immune cell subsets, prevent excessive inflammation, and participate in tissue repair after ischemia. Herein, we summarize the multiple potential mechanisms by which Tregs exert suppressor functions including modulation of cytokine production, alteration of cell-cell interactions, and disruption of metabolic pathways. Furthermore, we review the role of Tregs implicated in ischemic injury and repair including myocardial, limb, and cerebral ischemia. We conclude with a perspective on the therapeutic opportunities and future challenges of Treg biology in understanding the pathogenesis of ischemic cardiovascular disease states.

Artemisinin suppresses myocardial ischemia-reperfusion injury via NLRP3 inflammasome mechanism.

Artemisinin is known for its pharmaceutical effect against malaria and received increased attention for its other potential function. Mounting evidence suggest that artemisinin could also exert cardioprotective effects while the understanding of its regulatory mechanism is still limited. This study is designed to investigate the role of artemisinin in myocardial ischemia/reperfusion (I/R) injury and the involvement of NLRP3 inflammasome. Artemisinin was administrated for 14 consecutive days intragastrically before I/R injury. Cardiac function was assessed by echocardiography. Infarct area was observed through HE and TTC staining. Apoptosis and autophagy were assessed by TUNEL and Western blotting. The artemisinin-treated myocardial I/R rats demonstrated less severe myocardial I/R injury (smaller infarct size and lower CK-MB, LDH), significant inhibition of cardiac autophagy (decreased LC3II/I and increased p62), improved mitochondrial electron transport chain activity, concomitant with decreased activation of NLRP3 inflammasome (decreased NLRP3, ASC, cleaved caspase-1, IL-1ß). In conclusion, our findings further confirmed that activation of the NLRP3 inflammasome pathway is involved in myocardial I/R injury, whereas artemisinin preconditioning could effectively protect against myocardial I/R injury through suppression of NLRP3 inflammasome activation. Therefore, the NLRP3 inflammasome might serve as a promising therapeutic target providing new mechanisms for understanding the effect of artemisinin during the evolution of myocardial infarction.

[Effects of electroacupuncture pretreatment on cardiac function and immune inflammatory response in mice with acute myocardial ischemia].

OBJECTIVE: To observe the effects of electroacupuncture (EA) pretreatment on the cardiac ejection fraction (EF), the number of macrophages in spleen and heart, and the expression of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) and interleukin-1ß (IL-1ß) in myocardium in mice with acute myocardial ischemia, and to explore the possible mechanism of EA pretreatment on promoting myocardial protection. METHODS: A total of 30 male C57BL/6J mice were randomly divided into a control group, a model group and an EA pretreatment group, 10 rats in each group. The acute myocardial ischemia model was established by ligating the left anterior descending branch of the coronary artery in the model group and EA pretreatment group, while threading but no ligating at left anterior descending branch of the coronary artery was applied in the control group. In the EA pretreatment group, mice were intervented with EA at bilateral "Neiguan" (PC 6), disperse-dense wave, frequency of 2 Hz/15 Hz, intensity of 2 mA; each EA treatment last for 20 min, once a day, and 3-day treatment was given before model establishment. The EF value was evaluated by ultrasonic cardiogram; the number of macrophages in spleen and heart was measured by flow cytometry; the expression level of NLRP3 and IL-1ß in myocardium was measured by Western blot. RESULTS: Compared with the control group, the EF value was decreased in the model group (P<0.001), the number of macrophages in the heart and spleen was increased (P<0.001), and the expression level of NLRP3 and IL-1ß in the myocardium was increased (P<0.001, P<0.01). Compared with the model group, the EF value was increased in the EA pretreatment group (P<0.01), the number of macrophages in the heart and spleen was decreased (P<0.01), and the expression level of NLRP3 and IL-1ß in the myocardium was decreased (P<0.01, P<0.05). CONCLUSION: EA pretreatment could reduce the number of macrophages in spleen and heart, down-regulate the expression of NLRP3 and IL-1ß in myocardial tissue in mice with acute myocardial ischemia, which could relieve the local inflammatory response and achieve the myocardial protective effect.

Cleavage of cyclic AMP-responsive element-binding protein H aggravates myocardial hypoxia reperfusion injury in a hepatocyte-myocardial cell co-culture system.

OBJECTIVE: This study aimed to determine whether proinflammatory cytokines have an effect on myocardial cells (MCs) and hepatocytes during myocardial ischemia to induce cyclic AMP-responsive element-binding protein H (CREBH) cleavage, activate the acute phase response in the liver, and cause a superimposed injury in MCs. METHODS: In this study, a hepatocyte-MC transwell co-culture system was used to investigate the relationship between myocardial hypoxia/reperfusion injury and CREBH cleavage. MCs and hepatocytes of neonatal rats were obtained from the ventricles and livers of Sprague-Dawley rats, respectively. MCs were inoculated into the lower chamber of transwell chambers for 12 hours under hypoxia. Levels of the endoplasmic reticulum stress protein glucose-regulated protein 78 in MCs, CREBH in hepatocytes, inflammatory factor (tumor necrosis factor-α and interleukin-6) levels, and cell viability were evaluated. The effect of CREBH knockdown was also studied using a CREBH-specific short hairpin RNA (Ad-CREBHi). RESULTS: We found that proinflammatory cytokines affect MCs and hepatocytes during myocardial ischemia to induce CREBH cleavage, activate the acute phase response in the liver, and cause superimposed injury in MCs. CONCLUSIONS: Expression of CREBH aggravates myocardial injury during myocardial ischemia.

The Prognostic Impact of Circulating Regulatory T Lymphocytes on Mortality in Patients with Ischemic Heart Failure with Reduced Ejection Fraction.

BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) constitutes a global health issue. While proinflammatory cytokines proved to have a pivotal role in the development and progression of HFrEF, less attention has been paid to the cellular immunity. Regulatory T lymphocytes (Tregs) seem to have an important role in the induction and maintenance of immune homeostasis. Therefore, we aimed to investigate the impact of Tregs on the outcome in HFrEF. METHODS: We prospectively enrolled 112 patients with HFrEF and performed flow cytometry for cell phenotyping. Individuals were stratified in ischemic (iHFrEF, n = 57) and nonischemic etiology (niHFrEF, n = 57) and nonischemic etiology (niHFrEF. RESULTS: Comparing patients with iHFrEF to niHFrEF, we found a significantly lower fraction of Tregs within lymphocytes in the ischemic subgroup (0.42% vs. 0.56%; p = 0.009). After a mean follow-up time of 4.5 years, 32 (28.6%) patients died due to cardiovascular causes. We found that Tregs were significantly associated with cardiovascular survival in the entire study cohort with an adjusted HR per one standard deviation (1-SD) of 0.60 (95% CI: 0.39-0.92; p = 0.009). After a mean follow-up time of 4.5 years, 32 (28.6%) patients died due to cardiovascular causes. We found that Tregs were significantly associated with cardiovascular survival in the entire study cohort with an adjusted HR per one standard deviation (1-SD) of 0.60 (95% CI: 0.39-0.92; p = 0.009). After a mean follow-up time of 4.5 years, 32 (28.6%) patients died due to cardiovascular causes. We found that Tregs were significantly associated with cardiovascular survival in the entire study cohort with an adjusted HR per one standard deviation (1-SD) of 0.60 (95% CI: 0.39-0.92; p = 0.009). After a mean follow-up time of 4.5 years, 32 (28.6%) patients died due to cardiovascular causes. We found that Tregs were significantly associated with cardiovascular survival in the entire study cohort with an adjusted HR per one standard deviation (1-SD) of 0.60 (95% CI: 0.39-0.92. CONCLUSION: Our results indicate a potential influence of Tregs in the pathogenesis and progression of iHFrEF, fostering the implication of cellular immunity in iHFrEF pathophysiology and proving Tregs as a predictor for long-term survival among iHFrEF patients. A preview of this study has been presented at a meeting of the European Society of Cardiology earlier this year.