Cells In Acute Coronary Syndrome Research Articles

Characteristics, prognostic determinants of monocytes, macrophages and T cells in acute coronary syndrome: protocol for a multicenter, prospective cohort study

BackgroundAcute coronary syndrome(ACS) is the leading cause of mortality and disability worldwide. Immune response has been confirmed to play a vital role in the occurrence and development of ACS. The objective of this prospective, multicenter, observational study is to define immune response and their relationship to the occurrence and progressive of ACS.MethodsThis is a multicenter, prospective, observational longitudinal cohort study. The primary outcome is the incidence of major adverse cardiovascular events (MACE) including in-stent restenosis, severe ventricular arrhythmia, heart failure, recurrent angina pectoris, and sudden cardiac death, and stroke one year later after ACS. Demographic characteristics, clinical data, treatments, and outcomes are collected by local investigators. Furthermore, freshly processed samples will be stained and assessed by flow cytometry. The expression of S100A4, CD47, SIRPα and Tim-3 on monocytes, macrophages and T cells in ACS patients were collected. Follow-up: during hospitalization, 3, 6 and 12 months after discharge.DiscussionIt is expected that this study will reveal the possible targets to improve the prognosis or prevent from occurrence of MACE in ACS patients. Since it’s a multicenter study, the enrollment rate of participants will be accelerated and it can ensure that the collected data are more symbolic and improve the richness and credibility of the test basis.Ethics and disseminationThis study has been registered in Chinese Clinical Trial Registry Center. Ethical approval was obtained from the Affiliated Hospital of Guizhou Medical University. The dissemination will occur through the publication of articles in international peer-reviewed journals.Trial RegistrationChinese Clinical Trial Registry: ChiCTR2200066382.

Downregulation of TIGIT Expression in FOXP3+Regulatory T Cells in Acute Coronary Syndrome.

ObjectiveLittle is currently known on the role of T-cell immunoglobulin and ITIM domain (TIGIT) expression in Foxp3+ regulatory T cells (TIGIT+Tregs) in acute coronary syndrome (ACS) patients. The aim of this study was to investigate the role and alterations of TIGIT+Tregs in ACS patients.MethodsWe enrolled 117 subjects, including 61 ACS patients, 26 chronic coronary syndrome (CCS) patients, and 30 control subjects without coronary artery disease. The quantification of TIGIT+Tregs was determined by flow cytometry; serum interleukin-6 (IL-6) and transforming growth factor-β (TGF-β) were also measured.ResultsTIGIT+Tregs expression was significantly lower in ACS patients compared with CCS and control patients (P<0.05). The expression of TIGIT+Tregs was comparable in patients with and without traditional risk factors (P>0.05). Logistic regression analysis revealed that TIGIT+Tregs levels are independent predictors of ACS (P<0.01). Receiver-operating characteristic (ROC) curve analysis showed the expression levels of TIGIT+Tregs had a discriminative power for ACS (P<0.01). IL-6 levels were increased (P<0.01), while TGF-β was decreased in ACS patients compared with CCS and control patients (P<0.01). Meanwhile, an inverse correlation between IL-6 and TIGIT+Tregs was observed (P<0.01), while a positive correlation between TGF-β and TIGIT+Tregs was found (P<0.05).ConclusionTIGIT+Tregs levels are significantly reduced in ACS, accompanied by upregulated IL-6 and downregulated TGF-β expression. The downregulated TIGIT+Tregs are independent predictors of ACS. These findings suggest that TIGIT+Tregs may have an anti-inflammatory and protective effect on ACS, and its decreased expression may be associated with atherosclerotic plaque destabilization.

Role of IL-37- and IL-37-Treated Dendritic Cells in Acute Coronary Syndrome.

As a chronic inflammatory disease, atherosclerosis is a leading cause of morbidity and mortality in most countries. Inflammation is responsible for plaque instability and the subsequent onset of acute coronary syndrome (ACS), which is one of the leading causes of hospitalization. Therefore, exploring the potential mechanism underlying ACS is of considerable concern, and searching for alternative therapeutic targets is very urgent. Interleukin-37 (IL-37) inhibits the production of proinflammatory chemokines and cytokines and acts as a natural inhibitor of innate and adaptive immunity. Interestingly, our previous study with murine models showed that IL-37 alleviated cardiac remodeling and myocardial ischemia/reperfusion injury. Of note, our clinical study revealed that IL-37 is elevated and plays a beneficial role in patients with ACS. Moreover, dendritic cells (DCs) orchestrate both immunity and tolerance, and tolerogenic DCs (tDCs) are characterized by more secretion of immunosuppressive cytokines. As expected, IL-37-treated DCs are tolerogenic. Hence, we speculate that IL-37- or IL-37-treated DCs is a novel therapeutic possibility for ACS, and the precise mechanism of IL-37 requires further study.

Activated phenotype, altered migration and enhanced suppressive ability characterize regulatory T cells in acute coronary syndrome

Activated phenotype, altered migration and enhanced suppressive ability characterize regulatory T cells in acute coronary syndrome

The Role of Natural Killer (NK) Cells in Acute Coronary Syndrome: A Comprehensive Review.

With poor outcomes and an immense financial burden, acute coronary syndrome (ACS) and its ischemic repercussions still present a major global health problem. Unfavorable outcomes seem to be mainly due to adverse cardiac remodeling. Since the inflammatory response takes an important role in remodeling secondary to myocardial infarction (MI), and as inflammation in this manner has not been completely elucidated, we attempted to give rise to a further understanding of ACS pathophysiology. Hence, in this review, we integrated current knowledge of complex communication networks between natural killer (NK) cells and immune and resident heart cells in the context of ACS. Based on available data, the role of NK cells seems to be important in the infarcted myocardium, where it affects heart remodeling. On the other hand, in atherosclerotic plaque, NK cells seem to be mere passers-by, except in the case of chronic infections by atherogenic pathogens. In that case, NK cells seem to support proinflammatory milieu. NK cell research is challenging due to ethical reasons, convergent evolution, and phenotypic diversity among individuals. Therefore, we argue that further research of NK cells in ACS is valuable, given their therapeutic potential in improving postischemic heart remodeling.

Changes of peripheral blood immune cells in acute coronary syndrome

The objective of this study is to explore changes in main immune cells during acute coronary syndrome (ACS), including changes in subsets of monocytes, T cells, and inhibitory myeloid-derived suppressor cells (MDSCs), and to evaluate possible mechanisms. A total of 50 patients suffering from ACS were divided into two subgroups based on attacks of acute infarction, acute myocardial infarction (AMI) with infarction including ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina (UA). Third, the subgroup of 19 healthy subjects was labeled the normal group (NG). CD14, CD16, and CD45 were used as markers of the subset of monocytes. CD4, CD8, and CD3 were used as markers of the subset of T cells and CD14, human leukocyte antigen—DR isotype (HLA-DR), and CD45 were used as markers of inhibitory MDSCs. Both CD11b+ CD206+ and CD11b+ CD68+ cells were also assayed. Our data indicated that lymphocytes/karyocytes and monocytes/karyocytes as well as those of CD3+ CD4+ T cells, CD14+ CD16– monocytes, CD14+ CD16+ monocytes, and CD11b+ CD68+ monocytes were significant in all three groups ( P &lt; 0.05). The ratio of T-cell subtypes to total lymphocytes among the three subgroups can be represented as AMI &gt; UA &gt; NG ( P &lt; 0.05). The ratios of CD14+ monocytes to total karyocytes among the three subgroups can be represented as NG &gt; UA &gt; AMI ( P &lt; 0.05). The ratios of CD14+ CD16– monocytes to total karyocytes among the three subgroups can be represented as NG &gt; UA &gt; AMI ( P &lt; 0.05). The ratios of CD14+ CD16+ monocytes to total karyocytes among the three subgroups can be represented as AMI &gt; UA &gt; NG ( P &lt; 0.05). There were no significant differences in the proportion of MDSCs ( P &gt; 0.05). Certain subsets of monocytes are closely associated with ACS, of which CD14+ CD16– monocytes present a negative association, while CD14+ CD16+ monocytes show a positive association. In addition, adaptive immunity is associated with unstable plaques of ACS, and CD3+ CD4+ T cells may play a role in early stages of ACS.

Intrinsic Vascular Repair by Endothelial Progenitor Cells in Acute Coronary Syndromes: an Update Overview.

Bone marrow-derived endothelial progenitor cells (EPCs) play a key role in the maintenance of endothelial homeostasis and endothelial repair at areas of vascular damage. The quantification of EPCs in peripheral blood by flow cytometry is a strategy to assess this reparative capacity. The number of circulating EPCs is inversely correlated with the number of cardiovascular risk factors and to the occurrence of cardiovascular events. Therefore, monitoring EPCs levels may provide an accurate assessment of susceptibility to cardiovascular injury, greatly improving risk stratification of patients with high cardiovascular risk, such as those with an acute myocardial infarction. However, there are many issues in the field of EPC identification and quantification that remain unsolved. In fact, there have been conflicting protocols used to the phenotypic identification of EPCs and there is still no consensual immunophenotypical profile that corresponds exactly to EPCs. In this paper we aim to give an overview on EPCs-mediated vascular repair with special focus on acute coronary syndromes and to discuss the different phenotypic profiles that have been used to identify and quantify circulating EPCs in several clinical studies. Finally, we will synthesize evidence on the prognostic role of EPCs in patients with high cardiovascular risk.

Decreased Helios Expression in Regulatory T Cells in Acute Coronary Syndrome.

Regulatory T cells (Tregs) play an essential role in acute coronary syndrome (ACS). However, there is debate about which Treg subsets are truly critical to ACS. Helios, a transcription factor, was recently reported to be a bona fide marker for natural Tregs or activated Tregs with a suppression function, but little is known about its role in ACS. We therefore examined Helios+ Tregs in patients with ACS, patients with stable angina, and control subjects. 73 patients with ACS, 30 patients with stable angina, and 48 control subjects were enrolled. The frequencies and estimated absolute numbers of different Treg subsets in peripheral blood were measured by flow cytometry. Plasma cytokine level was measured by ELISA. The mRNA expression of Foxp3 and Helios in purified CD4+ T cells was determined by RT-PCR. Helios+ Tregs was decreased significantly in patients with ACS. The frequency and estimated absolute numbers of CD4+Foxp3+Helios+ Tregs were negatively correlated with IL-6 and positively correlated with circulating level of TGF-beta1 and HDL-C. The mRNA expression of Foxp3 and Helios was decreased in CD4+ T cells from patients with ACS. In summary, Helios+ Tregs was downregulated in patients with ACS and may play a role in ACS.

The reduced soluble fibrinogen-like protein 2 and regulatory T cells in acute coronary syndrome.

Soluble fibrinogen-like protein 2, sfgl2, is the new effector of CD4(+)CD25(+)FOXP3(+) regulatory T cell (Treg) and exerts immunosuppressive activity. We design this study to investigate the possible role of sfgl2 in atherosclerosis. A total of 58 acute coronary syndrome (ACS) patients, together with 22 stable angina (SA) patients and 31 normal coronary artery (NCA) people were enrolled in our study. Serum level of sfgl2 and plasma level of Treg were respectively measured. In line with the change of Treg, serum level of sfgl2 in ACS (8.70 ng/mL) was significantly decreased (P = 0.003), compared with that in SA (11.86 ng/mL) and NCA (17.55 ng/mL). Both sfgl2 and Treg level were obviously decreased in ACS; Sfgl2 may play a protective role in atherosclerosis.

CD4+CD28null T cells in acute coronary syndrome: lower with ST-elevation myocardial infarction

>Objectives. We explored any possible difference in the percentage of CD4 + CD28null T cells between patients with ST-segment-elevation myocardial infarction (STEMI) and those with non-ST-segment-elevation acute coronary syndrome. Design. We enrolled 55 consecutive patients admitted with acute coronary syndrome, and 16 healthy control subjects. CD4 + CD28null T cell percentage was assayed by flow cytometry from blood samples withdrawn at the time of enrollment. Results. Mean age was 55.2 ± 10.8 years (69.1% males). Mean CD4 + CD28null T cell percentage was 5.9 ± 3.8% in the study cohort versus 0.8 ± 0.7% in controls (p < 0.001). Mean CD4 + CD28null T cell percentage was higher in patients presenting with non-ST-segment-elevation acute coronary syndrome versus those presenting with STEMI: 7.3 ± 4.1% versus 4.6 ± 3.1%, respectively (p = 0.008). Multivariable regression analysis identified the category of acute coronary syndrome as the only variable independently associated with CD4 + CD28null T cell percentage (p = 0.007). Conclusions. In patients presenting with acute coronary syndrome, the CD4 + CD28null T cell percentage was higher in patients with non-ST-segment-elevation acute coronary syndrome versus those with STEMI. The category of acute coronary syndrome was the only variable independently associated with the CD4 + CD28null T cell percentage in multivariable regression analysis.

Modulation of STAT3 and STAT5 activity rectifies the imbalance of Th17 and Treg cells in patients with acute coronary syndrome

The signal transducer and activator of transcription (STAT) activity plays an important role in the differentiation and imbalance of Th17 and Treg cells in acute coronary syndrome (ACS) patients. We determined that the basal STAT3 phosphorylation level was significantly increased and exhibited a positive relationship with Th17 cells but was negatively correlated with Treg cells in ACS patients. Opposite effects were observed for STAT5 activity. Using the pharmaceutical inhibitor TG101348 or knockdown of STAT3 reduced the number of Th17 cells while promoting the number and function of Treg cells via the Janus kinase2 (JAK2)/STAT3 pathway in ACS patients. Significantly more STAT5 bound to the Foxp3 locus when STAT3 was knocked down, and overexpression of STAT5 led to an increased number of Treg cells but a decreased number of Th17 cells in ACS patients. Our findings demonstrate that modulation of STAT3/STAT5 activity rectifies the imbalance of Th17/Treg cells in ACS patients.

Antioxidant status and glutathione redox potential of erythrocytes in patients with acute coronary syndrome

Indicators of oxidative stress (OS), systemic inflammation, metabolism and redox status of glutathione (GSH) were investigated and compared in patients with ST-segment elevation myocardial infarction on electrocardiograms (STEMI), and patients with unstable angina (UA). The elevated and decreased myeloperoxidase level, superoxide dismutase activity, and moderate increased plasma levels of interleukin-6, while maintaining the antioxidant potential, were found in Group 1. Disorders in pro-/antioxidant balance and systemic inflammatory response were manifested in UA. Increased GSH concentration (and total GSH) in erythrocytes has been established for STEMI patients and the decreased GSH for UA patients. Thus, a significant shift of erythrocytes redox to oxidization and increase (unlike STEMI patients) of glutathione peroxidase activity were recorded. Mechanisms of the pro- and antioxidant functions of red blood cells in acute coronary syndrome are considered. The role of red blood cell glutathione to provide more oxidized intravascular environment for S-glutathionylation and optimization of redox signaling in target cells is pronounced.

FRI0521 Cd28null T Cells Kill Autologous Muscle Cells from Polymyositis Patients in Vitro by Perforin-Dependent Mechanisms

BackgroundInflammatory infiltrates of muscles in polymyositis are dominated by CD4+CD28null and CD8+CD28null T cells1. In contrast to conventional CD28+ T cells, these cells have a restricted T cell-receptor repertoire, rapidly...

Functional deficiency of natural killer cells in acute coronary syndrome is related to ineffective degranulation

pressure, and (2) to the impairment of the LV longitudinal function by reducing coronary flow reserve. In asymptomatic patients with moderate to severe AS and preserved LV ejection fraction, BNP release is mainly determined by LV end-diastolic volume, LV filling pressure estimation (diastolic burden) and exercise LV longitudinal strain (subclinical LV dysfunction). Further studies are needed to clarify the role of those determinants in risk stratification of asymptomatic patients with AS. P.L. This work was supported by the Belgian National Fund for Scientific Research (F.R.S-FNRS T.0028.14). C.H. received grants from the Montreal Heart Institute Foundation (Bourse du Bal du Cœur), and the Department of Medicine of the University of Montreal and the Association des Cardiologues du Quebec.

Imbalanced Frequencies of Th17 and Treg Cells in Acute Coronary Syndromes Are Mediated by IL-6-STAT3 Signaling

AimsExtensive evidence suggests inflammatory components participate in the pathogenic processes of acute coronary syndromes (ACS). In this study, we aimed to elucidate the role and mechanism underlying the imbalance of Th17 and Treg cell peripheral populations in the pathogenesis of ACS.Methods and ResultsUsing a flow cytometric analysis, we observed a significantly increased frequency of Th17 cells and a concurrently decreased CD4+CD25+Foxp3+ Treg cells in patients with ACS. To elucidate the mechanism of Th17/Treg imbalance in ACS, 22 inflammatory cytokines were measured using multiplexed immunobead-based assays. Of six elevated cytokines in ACS patients, only IL-6 was positively correlated with a higher Th17 cell level (r = 0.39, P<0.01). Relying on IL-6 stimulating and neutralizing studies, we demonstrated a direct role for IL-6 in sera from ACS patients with an increased frequency of Th17 cells. IL-6 induces the differentiation of Th17 cells from naïve CD4+ T cells through STAT3 activation and RORγt induction. However, we observed that high levels of TGF-β1 inhibited IL-6-dependent Th17 cell differentiation, indicating a complex interplay between the two cytokines in the control of Th17 and Treg cell populations.ConclusionsOur results demonstrate the role of IL-6-STAT3 signaling in ACS through increased Th17 cell differentiation. These findings indicate that IL-6 neutralizing strategies could present novel therapeutic avenues in the treatment of ACS.

FOXP3 demethylation as a means of identifying quantitative defects in regulatory T cells in acute coronary syndrome

FOXP3 demethylation as a means of identifying quantitative defects in regulatory T cells in acute coronary syndrome

GW24-e1722 FOXP3 demethylation as a means of identifying quantitative defects in regulatory T cells in acute coronary syndrome

ObjectivesThe contribution of regulatory T cells (Tregs) to the pathogenesis of acute coronary syndrome (ACS) remains poorly understood. One core obstacleis the lack of Treg-specific markers. A highly conserved CpG...

FOXP3 demethylation as a means of identifying quantitative defects in regulatory T cells in acute coronary syndrome

ObjectiveThe contribution of regulatory T cells (Tregs) to the pathogenesis of acute coronary syndrome (ACS) remains poorly understood. One core obstacle is the lack of Treg-specific markers. A highly conserved CpG enriched element in forkhead box P3 intron 1 (FOXP3 i l) is unmethylated only in Tregs, and measuring the unmethylation of FOXP3 i l can be used to identify the role of Tregs in clinical diseases. This study investigated whether analyzing the demethylation status of FOXP3 i 1 is a more reliable means than using Treg-specific surface markers in ACS. Methods and resultsWe evaluated circulating Tregs percentages on different levels including cell frequencies (CD4+CD25hiFOXP3+Tregs and CD4+CD25hiCD45+naïve Tregs) or FOXP3 mRNA, FOXP3 i 1 demethylation status and related cytokine secretion in 89 patients with ACS and 35 controls. FOXP3 i 1 demethylation assay showed that the amount of Tregs in ACS patients was significantly reduced than that in controls (p = 0.0005). However, flow cytometry analysis did not identify any reduction of CD4+CD25hiFOXP3+Tregs in ACS patients. Notably, younger patients had higher percentage of CD4+CD25hiFOXP3+Tregs but decreased percentage of CD4+CD25hiCD45+naïve Tregs than either controls or older patients. Furthermore, a DNA hypomethylation agent increased the amount of CD4+CD25hiFOXP3+Tregs and Tregs related cytokine IL-10 and suppressed the production of pro-inflammatory cytokine interferon-γ by inducing FOXP3 i 1 demethylation in vitro. ConclusionsA quantitative defect of Tregs, suggestive of decreased peripheral tolerance, could be a potential hallmark of ACS disease. Targeting FOXP3 i l demethylation might elevate the inhibitory activity of Tregs in ACS.

ASSA13-01-13 FOXP3 Demethylation as a Means of Identifying Quantitative Defects in Regulatory T Cells in Acute Coronary Syndrome

<h3>Background</h3> The contribution of regulatory T cells (Tregs) to the pathogenesis of acute coronary syndrome (ACS) remains poorly understood. One core obstacle is the lack of Treg-specific markers that distinguish Tregs and activated conventional T cells. A highly conserved CpG enriched element in forkhead boxP3intron 1 (FOXP3 i l) is unmethylated only in Tregs, and measuring the unmethylation of FOXP3 i l can be used to identify the role of Tregs in clinical diseases. For this reason, we investigated whether analysing the demethylation status of FOXP3 i 1 is a more reliable means than using Treg-specific surface markers. <h3>Methods and Results</h3> Circulating Tregs percentages, cytokine (anti-inflammatory cytokines, IL-10 and TGF-β1; pro-inflammatory cytokine, interferon-γ) production profile in subjects with acute coronary syndrome (ACS) were correlated to the amount of FOXP3 protein expression measured by flow cytometry or FOXP3 mRNA expression measured by RT-PCR or FOXP3 i 1 demethylation status measured by pyrosequencing. Activated T cells were treated in vitro with a DNA demethylation agent to study the effect of DNA methylation on FOXP3 expression, FOXP3 i l demethylation and Treg cytokine production. FOXP3 i 1 demethylation assay showed that the amount of Tregs in ACS patients was significantly reduced than that in healthy controls (<i>p</i> = 0.0005). This test displayed a sensitivity of 94.7% and specificity of 80% in distinguishing ACS patients from healthy controls, as indicated by analysis of the receiver operating characteristic (ROC) curve (AUC = 0.916; <i>p</i> &lt; 0.001). However, flow cytometry analysis did not identify any reductions in total percentage of CD4⁺CD25⁺FOXP3⁺Tregs, indicating that CD4⁺CD25⁺FOXP3⁺Tregs in ACS patients were highly variable. Notably, younger patients with ACS had higher percentage of total CD4⁺CD25⁺FOXP3⁺Tregs but decreased percentage of CD4⁺CD25⁺CD45⁺naïve Tregs, higher amounts of interferon-γ, and lower amounts of high-density lipoprotein than either healthy controls or older patients with ACS. Furthermore, 5-aza-2′-deoxycytidine, a DNA hypomethylation agent, increased the amount of CD4⁺CD25⁺FOXP3⁺Tregs and IL-10 and suppressed the production of interferon-γ by inducing FOXP3 i 1 demethylation in vitro. <h3>Conclusions</h3> Our findings showed that a quantitative defect of Tregs, suggestive of decreased peripheral tolerance, could be a potential hallmark of ACS disease. Targeting FOXP3 i l demethylation might elevate the inhibitory activity of Tregs in ACS.

Pathophysiological role of neutrophils in acute myocardial infarction

The pathogenesis of acute myocardial infarction is known to be mediated by systemic, intraplaque and myocardial inflammatory processes. Among different immune cell subsets, compelling evidence now indicates a pivotal role for neutrophils in acute coronary syndromes. Neutrophils infiltrate coronary plaques and the infarcted myocardium and mediate tissue damage by releasing matrix-degrading enzymes and reactive oxygen species. In addition, neutrophils are also involved in post-infarction adverse cardiac remodelling and neointima formation after angioplasty. The promising results obtained in preclinical modelswith pharmacological approaches interfering with neutrophil recruitment or function have confirmed the pathophysiological relevance of these immune cells in acute coronary syndromes and prompted further studies of these therapeutic interventions. This narrative review will provide an update on the role of neutrophils in acute myocardial infarction and on the pharmacological means that were devised to prevent neutrophil-mediated tissue damage and to reduce post-ischaemic outcomes.