scholarly journals Expansion of CD14+HLA-DRneg/low monocytes and CD10neg neutrophils driving proinflammatory responses in patients with acute myocardial infarction

2020 ◽  
Author(s):  
Daniela Fraccarollo ◽  
Jonas Neuser ◽  
Julian Möller ◽  
Paolo Galuppo ◽  
Johann Bauersachs
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
T Cells ◽  
Immune Responses ◽  
Ischemia Reperfusion ◽  
Characteristic Curve ◽  
Normal Density ◽  
Cardiac Damage ◽  
Hla Dr ◽  
St Elevation

ABSTRACTBackgroundImmature myeloid cells expand in cancer, autoimmune diseases and viral infection, but their appearance and function after acute myocardial infarction (AMI) remain underexplored.Methods and ResultUsing flow cytometry, cell sorting and a mouse model of ischemia/reperfusion we investigated the role of immature granulocytic/monocytic cells in immune responses post-AMI. Seventy-one patients were categorized into unstable angina (n=11), Non-ST-elevation MI (NSTEMI, n=16), and ST-elevation MI (STEMI, n=44). Circulating CD14+HLA-DRneg/low monocytes and normal-density CD16+CD66b+CD10neg neutrophils are expanded in patients with large AMI and strongly correlated with cardiac damage, function and serum levels of S100A9/S100A8, MMP-9 and IL-1ß. Receiver operating characteristic curve analysis highlighted ability of CD14+HLA-DRneg/low and CD16+CD66b+CD10neg cells in discriminating acute coronary syndromes. CD14+HLA-DRneg/low monocytes did not suppress T-cell proliferation but expressed high amounts of IL1R1 and S100A9. Mechanistically, macrophages differentiated from CD14+HLA-DRneg/low monocytes produced more proinflammatory cytokines upon IFNγ stimulation as CD14+HLA-DRhigh monocyte-derived macrophages. CD10neg neutrophils expressed MMP9 and S100A9 at higher levels compared to CD10pos neutrophils. IFNγ production by CD4+ T-cells was increased in presence of CD10neg neutrophils. Remarkably, elevated circulating IFNγ levels were detected in cytomegalovirus-seropositive patients with expanded CD10neg neutrophils and increased frequency of CD4+CD28null T-cells. Lastly, we showed that murine homologs of human CD10neg neutrophils are Ly6GposCXCR2posCD11bdimCD101neg cells. CD101neg neutrophils are rapidly released into the bloodstream after AMI and migrate to ischemic sites, displaying increased expression of MMP-9 at 3 hours and of IL-1ß at 24 hours after reperfusion.ConclusionCD14+HLA-DRneg/low monocytes and normal-density CD10neg neutrophils inducing proinflammatory immune responses expand in patients with AMI.

scholarly journals Expansion of CD10neg neutrophils and HLA-DRneg/low monocytes driving inflammatory responses after myocardial infarction

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Daniela Fraccarollo ◽  
Jonas Neuser ◽  
Julian Möller ◽  
Christian Riehle ◽  
Paolo Galuppo ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
T Cells ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Myeloid Cell ◽  
Damage Function ◽  
Cardiac Damage ◽  
Bioinformatic Tools ◽  
Hla Dr ◽  
Ifn Γ

Background: Immature neutrophils and HLA-DRneg/low monocytes expand in cancer, autoimmune diseases and viral infections, but their appearance and immunoregulatory effects on T-cells after acute myocardial infarction (AMI) remain underexplored.Methods and Results: We found an expansion of circulating immature CD16+CD66b+CD10neg neutrophils and CD14+HLA-DRneg/low monocytes in AMI patients, correlating with cardiac damage, function and levels of immune-inflammation markers. Immature CD10neg neutrophils expressed high amounts of MMP-9 and S100A9, and displayed resistance to apoptosis. Moreover, we found that increased frequency of CD10neg neutrophils and elevated circulating IFN-γ levels were linked, mainly in patients with expanded CD4+CD28null T-cells. Notably, the expansion of circulating CD4+CD28null T-cells was associated with cytomegalovirus (CMV) seropositivity. Using bioinformatic tools we identified a tight relationship among the peripheral expansion of immature CD10neg neutrophils, CMV IgG titers, and circulating levels of IFN-γ and IL-12 in patients with AMI. At a mechanistic level, CD10neg neutrophils enhanced IFN-γ production by CD4+ T-cells through a contact-independent mechanism involving IL-12. In vitro experiments also highlighted that HLA-DRneg/low monocytes do not suppress T-cell proliferation but secrete high levels of pro-inflammatory cytokines after differentiation to macrophages and IFN-γ stimulation. Lastly, using a mouse model of AMI, we showed that immature neutrophils (CD11bposLy6GposCD101neg cells) are recruited to the injured myocardium and migrate to mediastinal lymph nodes shortly after reperfusion.Conclusions: Immunoregulatory functions of CD10neg neutrophils play a dynamic role in mechanisms linking myeloid cell compartment dysregulation, Th1-type immune responses and inflammation after AMI.

scholarly journals Cytotoxic CD8+ T cells promote granzyme B-dependent adverse post-ischemic cardiac remodeling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Icia Santos-Zas ◽  
Jeremie Lemarié ◽  
Ivana Zlatanova ◽  
Marine Cachanado ◽  
Jean-Christophe Seghezzi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
T Cells ◽  
T Lymphocytes ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Granzyme B ◽  
Acute Ischemia ◽  
Risk Of Death ◽  
Increased Risk

AbstractAcute myocardial infarction is a common condition responsible for heart failure and sudden death. Here, we show that following acute myocardial infarction in mice, CD8+ T lymphocytes are recruited and activated in the ischemic heart tissue and release Granzyme B, leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8+ T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8+ T cells. The protective effect of CD8 depletion on heart function is confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of GRANZYME B in patients with acute myocardial infarction predict increased risk of death at 1-year follow-up. Our work unravels a deleterious role of CD8+ T lymphocytes following acute ischemia, and suggests potential therapeutic strategies targeting pathogenic CD8+ T lymphocytes in the setting of acute myocardial infarction.

scholarly journals CCR6 Deficiency Increases Infarct Size after Murine Acute Myocardial Infarction

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1532
Author(s):  
David Schumacher ◽  
Elisa A. Liehn ◽  
Anjana Singh ◽  
Adelina Curaj ◽  
Erwin Wijnands ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Bone Marrow ◽  
Coronary Artery ◽  
Reperfusion Injury ◽  
Bone Marrow Cells ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Cardiac Damage

Ischemia-reperfusion injury after the reopening of an occluded coronary artery is a major cause of cardiac damage and inflammation after acute myocardial infarction. The chemokine axis CCL20-CCR6 is a key player in various inflammatory processes, including atherosclerosis; however, its role in ischemia-reperfusion injury has remained elusive. Therefore, to gain more insight into the role of the CCR6 in acute myocardial infarction, we have studied cardiac injury after transient ligation of the left anterior descending coronary artery followed by reperfusion in Ccr6-/- mice and their respective C57Bl/6 wild-type controls. Surprisingly, Ccr6-/- mice demonstrated significantly reduced cardiac function and increased infarct sizes after ischemia/reperfusion. This coincided with a significant increase in cardiac inflammation, characterized by an accumulation of neutrophils and inflammatory macrophage accumulation. Chimeras with a bone marrow deficiency of CCR6 mirrored this adverse Ccr6-/- phenotype, while cardiac injury was unchanged in chimeras with stromal CCR6 deficiency. This study demonstrates that CCR6-dependent (bone marrow) cells exert a protective role in myocardial infarction and subsequent ischemia-reperfusion injury, supporting the notion that augmenting CCR6-dependent immune mechanisms represents an interesting therapeutic target.

The gut hormone GLP-2 predicts cardiovascular risk in patients with acute myocardial infarction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
F Kahles ◽  
R.W Mertens ◽  
M.V Rueckbeil ◽  
M.C Arrivas ◽  
J Moellmann ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
Acute Myocardial Infarction ◽  
Receiver Operating Characteristic Curve ◽  
Operating Characteristic ◽  
Characteristic Curve ◽  
Funding Source ◽  
Cardiovascular Prognosis ◽  
Operating Characteristic Curve ◽  
Hs Crp

Abstract Background GLP-1 and GLP-2 (glucagon-like peptide-1/2) are gut derived hormones that are co-secreted from intestinal L-cells in response to food intake. While GLP-1 is known to induce postprandial insulin secretion, GLP-2 enhances intestinal nutrient absorption and is clinically used for the treatment of patients with short bowel syndrome. The relevance of the GLP-2 system for cardiovascular disease is unknown. Purpose The aim of this study was to assess the predictive capacity of GLP-2 for cardiovascular prognosis in patients with myocardial infarction. Methods Total GLP-2 levels, NT-proBNP concentrations and the Global Registry of Acute Coronary Events (GRACE) score were assessed at time of admission in 918 patients with myocardial infarction, among them 597 patients with NSTEMI and 321 with STEMI. The primary composite outcome of the study was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (3-P-MACE) with a median follow-up of 311 days. Results Kaplan-Meier survival plots (separated by the median of GLP-2 with a cut-off value of 4.4 ng/mL) and univariable cox regression analyses found GLP-2 values to be associated with adverse outcome (logarithmized GLP-2 values HR: 2.87; 95% CI: 1.75–4.68; p<0.0001). Further adjustment for age, sex, smoking, hypertension, hypercholesterolemia, diabetes mellitus, family history of cardiovascular disease, hs-Troponin T, NT-proBNP and hs-CRP levels did not affect the association of GLP-2 with poor prognosis (logarithmized GLP-2 values HR: 2.96; 95% CI: 1.38–6.34; p=0.0053). Receiver operating characteristic curve (ROC) analyses illustrated that GLP-2 is a strong indicator for cardiovascular events and proved to be comparable to other established risk markers (area under the curve of the combined endpoint at 6 months; GLP-2: 0.72; hs-Troponin: 0.56; NT-proBNP: 0.70; hs-CRP: 0.62). Adjustment of the GRACE risk estimate by GLP-2 increased the area under the receiver-operating characteristic curve for the combined triple endpoint after 6 months from 0.70 (GRACE) to 0.75 (GRACE + GLP-2) in NSTEMI patients. Addition of GLP-2 to a model containing GRACE and NT-proBNP led to a further improvement in model performance (increase in AUC from 0.72 for GRACE + NT-proBNP to 0.77 for GRACE + NT-proBNP + GLP-2). Conclusions In patients admitted with acute myocardial infarction, GLP-2 levels are associated with adverse cardiovascular prognosis. This demonstrates a strong yet not appreciated crosstalk between the heart and the gut with relevance for cardiovascular outcome. Future studies are needed to further explore this crosstalk with the possibility of new treatment avenues for cardiovascular disease. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): German Society of Cardiology (DGK), German Research Foundation (DFG)

The effect of preloading statins prior to primary reperfusion on in-hospital mortality risk in a contemporary large-scale cohort of patients with ST-elevation myocardial infarction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R Fu ◽  
C.X Song ◽  
X.D Li ◽  
Y.J Yang
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Hospital Mortality ◽  
Mortality Risk ◽  
Large Scale ◽  
Reperfusion Therapy ◽  
St Elevation Myocardial Infarction ◽  
Control Group ◽  
Funding Source ◽  
St Elevation

Abstract Background The benefit of statins in secondary prevention of patients stabilized after acute coronary syndrome (ACS) has been well established. However, the benefit of preloading statins, i.e. high-intensity statins prior to reperfusion therapy remains unclear. Most previous studies included all types of ACS patients, and subgroup analysis indicated the benefit of preloading statins was only seen in ST-elevation myocardial infarction (STEMI) patients who underwent percutaneous coronary intervention (PCI). However, the sample size of subgroup population was relatively small and such benefit requires further validation. Objective To investigate the effect of loading dose of statins before primary reperfusion on 30-mortality in patients with STEMI. Methods We enrolled patients in China Acute Myocardial Infarction (CAMI) registry from January 2013 to September 2014. CAMI registry was a prospective multicenter registry of patients with acute acute myocardial infarction in China. Patients were divided into two groups according to statins usage: preloading group and control group. Patients in preloading group received loading does of statins before primary reperfusion and during hospitalization. Patients in control group did not receive statins during hospitalization or at discharge. Primary outcome was in-hospital mortality. Baseline characteristics, angiographic characteristics and outcome were compared between groups. Propensity score (PS) matching was used to mitigate baseline differences between groups and examine the association between preloading statins on in-hospital mortality risk. The following variables were used to establish PS matching score: age, sex, classification of hospitals, clinical presentation (heart failure at presentation, cardiac shock, cardiac arrest, Killip classification), hypertension, diabetes, prior angina, prior myocardial infarction history, prior stroke, initial treatment. Results A total of 1169 patients were enrolled in control group and 6795 in preloading group. A total of 833 patients (334 in control group and 499 in preloading group) died during hospitalization. Compared with control group, preloading group were younger, more likely to be male and present with Killip I classification. The proportion of hypertension and diabetes were higher in preloading group. After PS matching, all the variables used to generate PS score were well balanced. In the PS-matched cohort, 30-day mortality risk was 26.3% (292/1112) in the control group and 11.9% (132/1112) in the preloading group (p<0.0001). Conclusions The current study found preloading statins treatment prior to reperfusion therapy reduced in-hospital mortality risk in a large-scale contemporary cohort of patients with STEMI. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Chinese Academy of Medical Sciences

scholarly journals Reducing Cardiac Injury during ST-Elevation Myocardial Infarction: A Reasoned Approach to a Multitarget Therapeutic Strategy

2021 ◽  
Vol 10 (13) ◽  
pp. 2968
Author(s):  
Alessandro Bellis ◽  
Giuseppe Di Gioia ◽  
Ciro Mauro ◽  
Costantino Mancusi ◽  
Emanuele Barbato ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Reperfusion Injury ◽  
Therapeutic Strategy ◽  
Ventricular Remodeling ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
St Elevation Myocardial Infarction ◽  
Ischemic Time ◽  
St Elevation

The significant reduction in ‘ischemic time’ through capillary diffusion of primary percutaneous intervention (pPCI) has rendered myocardial-ischemia reperfusion injury (MIRI) prevention a major issue in order to improve the prognosis of ST elevation myocardial infarction (STEMI) patients. In fact, while the ischemic damage increases with the severity and the duration of blood flow reduction, reperfusion injury reaches its maximum with a moderate amount of ischemic injury. MIRI leads to the development of post-STEMI left ventricular remodeling (post-STEMI LVR), thereby increasing the risk of arrhythmias and heart failure. Single pharmacological and mechanical interventions have shown some benefits, but have not satisfactorily reduced mortality. Therefore, a multitarget therapeutic strategy is needed, but no univocal indications have come from the clinical trials performed so far. On the basis of the results of the consistent clinical studies analyzed in this review, we try to design a randomized clinical trial aimed at evaluating the effects of a reasoned multitarget therapeutic strategy on the prevention of post-STEMI LVR. In fact, we believe that the correct timing of pharmacological and mechanical intervention application, according to their specific ability to interfere with survival pathways, may significantly reduce the incidence of post-STEMI LVR and thus improve patient prognosis.

scholarly journals Use of Circulating MicroRNAs to Diagnose Acute Myocardial Infarction

2012 ◽  
Vol 58 (3) ◽  
pp. 559-567 ◽  
Author(s):  
Yvan Devaux ◽  
Mélanie Vausort ◽  
Emeline Goretti ◽  
Petr V Nazarov ◽  
Francisco Azuaje ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Chest Pain ◽  
Troponin T ◽  
Correct Diagnosis ◽  
Patient Treatment ◽  
Healthy Controls ◽  
Clinical Model ◽  
Acute Mi ◽  
St Elevation

Abstract BACKGROUND Rapid and correct diagnosis of acute myocardial infarction (MI) has an important impact on patient treatment and prognosis. We compared the diagnostic performance of high-sensitivity cardiac troponin T (hs-cTnT) and cardiac enriched microRNAs (miRNAs) in patients with MI. METHODS Circulating concentrations of cardiac-enriched miR-208b and miR-499 were measured by quantitative PCR in a case-control study of 510 MI patients referred for primary mechanical reperfusion and 87 healthy controls. RESULTS miRNA-208b and miR-499 were highly increased in MI patients (>105-fold, P < 0.001) and nearly undetectable in healthy controls. Patients with ST-elevation MI (n= 397) had higher miRNA concentrations than patients with non–ST-elevation MI (n = 113) (P < 0.001). Both miRNAs correlated with peak concentrations of creatine kinase and cTnT (P < 10−9). miRNAs and hs-cTnT were already detectable in the plasma 1 h after onset of chest pain. In patients who presented <3 h after onset of pain, miR-499 was positive in 93% of patients and hs-cTnT in 88% of patients (P= 0.78). Overall, miR-499 and hs-cTnT provided comparable diagnostic value with areas under the ROC curves of 0.97. The reclassification index of miR-499 to a clinical model including several risk factors and hs-cTnT was not significant (P = 0.15). CONCLUSION Circulating miRNAs are powerful markers of acute MI. Their usefulness in the establishment of a rapid and accurate diagnosis of acute MI remains to be determined in unselected populations of patients with acute chest pain.

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