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1.
Clin Res Cardiol ; 112(9): 1263-1277, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37004526

ABSTRACT

BACKGROUND: Mechanisms of myocardial ischemia in obstructive and non-obstructive coronary artery disease (CAD), and the interplay between clinical, functional, biological and psycho-social features, are still far to be fully elucidated. OBJECTIVES: To develop a machine-learning (ML) model for the supervised prediction of obstructive versus non-obstructive CAD. METHODS: From the EVA study, we analysed adults hospitalized for IHD undergoing conventional coronary angiography (CCA). Non-obstructive CAD was defined by a stenosis < 50% in one or more vessels. Baseline clinical and psycho-socio-cultural characteristics were used for computing a Rockwood and Mitnitski frailty index, and a gender score according to GENESIS-PRAXY methodology. Serum concentration of inflammatory cytokines was measured with a multiplex flow cytometry assay. Through an XGBoost classifier combined with an explainable artificial intelligence tool (SHAP), we identified the most influential features in discriminating obstructive versus non-obstructive CAD. RESULTS: Among the overall EVA cohort (n = 509), 311 individuals (mean age 67 ± 11 years, 38% females; 67% obstructive CAD) with complete data were analysed. The ML-based model (83% accuracy and 87% precision) showed that while obstructive CAD was associated with higher frailty index, older age and a cytokine signature characterized by IL-1ß, IL-12p70 and IL-33, non-obstructive CAD was associated with a higher gender score (i.e., social characteristics traditionally ascribed to women) and with a cytokine signature characterized by IL-18, IL-8, IL-23. CONCLUSIONS: Integrating clinical, biological, and psycho-social features, we have optimized a sex- and gender-unbiased model that discriminates obstructive and non-obstructive CAD. Further mechanistic studies will shed light on the biological plausibility of these associations. CLINICAL TRIAL REGISTRATION: NCT02737982.


Subject(s)
Coronary Artery Disease , Frailty , Myocardial Ischemia , Adult , Humans , Female , Middle Aged , Aged , Male , Coronary Artery Disease/diagnosis , Artificial Intelligence , Coronary Angiography/methods , Machine Learning , Cytokines , Risk Factors , Predictive Value of Tests
2.
Res Pract Thromb Haemost ; 7(8): 102262, 2023 Nov.
Article in English | MEDLINE | ID: mdl-38193050

ABSTRACT

Background: Severe COVID-19 is associated with an excessive immunothrombotic response and thromboinflammatory complications. Vaccinations effectively reduce the risk of severe clinical outcomes in patients with COVID-19, but their impact on platelet activation and immunothrombosis during breakthrough infections is not known. Objectives: To investigate how preemptive vaccinations modify the platelet-immune crosstalk during COVID-19 infections. Methods: Cross-sectional flow cytometry study of the phenotype and interactions of platelets circulating in vaccinated (n = 21) and unvaccinated patients with COVID-19, either admitted to the intensive care unit (ICU, n = 36) or not (non-ICU, n = 38), in comparison to matched SARS-CoV-2-negative patients (n = 48), was performed. Results: In the circulation of unvaccinated non-ICU patients with COVID-19, we detected hyperactive and hyperresponsive platelets and platelet aggregates with adaptive and innate immune cells. In unvaccinated ICU patients with COVID-19, most of whom had severe acute respiratory distress syndrome, platelets had high P-selectin and phosphatidylserine exposure but low capacity to activate integrin αIIbß3, dysfunctional mitochondria, and reduced surface glycoproteins. In addition, in the circulation of ICU patients, we detected microthrombi and platelet aggregates with innate, but not with adaptive, immune cells. In vaccinated patients with COVID-19, who had no acute respiratory distress syndrome, platelets had surface receptor levels comparable to those in controls and did not form microthrombi or platelet-granulocyte aggregates but aggregated avidly with adaptive immune cells. Conclusion: Our study provides evidence that vaccinated patients with COVID-19 are not associated with platelet hyperactivation and are characterized by platelet-leukocyte aggregates that foster immune protection but not excessive immunothrombosis. These findings advocate for the importance of vaccination in preventing severe COVID-19.

3.
Cardiovasc Res ; 2022 Dec 13.
Article in English | MEDLINE | ID: mdl-36508576

ABSTRACT

AIM: The functional capacity of the immune cells is strongly dependent on their metabolic state and inflammatory responses are characterized by a greater use of glucose in immune cells. This study is aimed to establish the role of glucose metabolism and its players [glucose transporter-1 (GLUT-1) and pyruvate kinase isozyme M2 (PKM2)] in the dysregulation of adaptive immunity and inflammation observed in patients with non-ST-segment elevation myocardial infarction (NSTEMI). METHODS AND RESULTS: We enrolled 248 patients allocated to three groups: NSTEMI patients, chronic coronary syndromes (CCS) patients, healthy subjects (HS). NSTEMI patients showed higher expression of GLUT-1 and an enhanced glucose uptake in T cells as compared to CCS patients (p < 0.0001; p = 0.0101, respectively) and HS (p = 0.0071; p = 0.0122, respectively). PKM2 had a prevalent nuclear localization in T lymphocytes in NSTEMI (p = 0.0005 for nuclear versus cytoplasm localization), while in CCS and HS was equally distributed in both compartments. In addition, the nuclear fraction of PKM2 was significantly higher in NSTEMI compared to HS (p = 0.0023). In NSTEMI patients, treatment with Shikonin and Fasentin, which inhibits PKM2 enzyme activity and GLUT-1 mediated glucose internalization, respectively, led to a significant reduction in GLUT-1 expression along with the downregulation of pro-inflammatory cytokine expression. CONCLUSIONS: NSTEMI patients exhibit dysregulation of the GLUT-1/PKM2 metabolic loop characterized by nuclear translocation of PKM2, where it acts as a transcription regulator of pro-inflammatory genes. This detrimental loop might represent a new therapeutic target for personalized medicine.

4.
J Thromb Haemost ; 20(4): 961-974, 2022 04.
Article in English | MEDLINE | ID: mdl-35032087

ABSTRACT

BACKGROUND: A rapid immune response is critical to ensure effective protection against COVID-19. Platelets are first-line sentinels of the vascular system able to rapidly alert and stimulate the immune system. However, their role in the immune response to vaccines is not known. OBJECTIVE: To identify features of the platelet-immune crosstalk that would provide an early readout of vaccine efficacy in adults who received the mRNA-based COVID-19 vaccine (BNT162b2). METHODS: We prospectively enrolled 11 young healthy volunteers (54% females, median age: 28 years) who received two doses of BNT162b2, 21 days apart, and we studied their platelet and immune response before and after each dose of the vaccine (3 and 10 ± 2 days post-injection), in relation to the kinetics of the humoral response. RESULTS: Participants achieving an effective level of neutralizing antibodies before the second dose of the vaccine (fast responders) had a higher leukocyte count, mounted a rapid cytokine response that incremented further after the second dose, and an elevated platelet turnover that ensured platelet count stability. Their circulating platelets were not more reactive but expressed lower surface levels of the immunoreceptor tyrosine-based inhibitory motif (ITIM)-coupled receptor CD31 (PECAM-1) compared to slow responders, and formed specific platelet-leukocyte aggregates, with B cells, just 3 days after the first dose, and with non-classical monocytes and eosinophils. CONCLUSION: We identified features of the platelet-immune crosstalk that are associated with the development of a rapid humoral response to an mRNA-based vaccine (BNT162b2) and that could be exploited as early biomarkers of vaccine efficacy.


Subject(s)
BNT162 Vaccine , Blood Platelets/immunology , COVID-19 , Immunity, Humoral , Vaccine Efficacy , Adult , Antibodies, Viral/blood , BNT162 Vaccine/immunology , COVID-19/prevention & control , Female , Humans , Male , SARS-CoV-2
6.
Front Cardiovasc Med ; 8: 741221, 2021.
Article in English | MEDLINE | ID: mdl-35146002

ABSTRACT

Despite the recent innovations in cardiovascular care, atherothrombosis is still a major complication of acute coronary syndromes (ACS). We evaluated the involvement of the CD31 molecule in thrombotic risk through the formation of monocyte-platelet (Mo-Plt) aggregates in patients with ACS with no-ST-segment elevation myocardial infarction (NSTEMI) on top of dual anti-platelet therapy (DAPT). We enrolled 19 control (CTRL) subjects, 46 stable angina (SA), and 86 patients with NSTEMI, of which, 16 with Intact Fibrous Cap (IFC) and 19 with Ruptured Fibrous Cap (RFC) as assessed by the Optical Coherence Tomography (OCT). The expression of CD31 on monocytes and platelets was measured. Following the coronary angiography, 52 NSTEMIs were further stratified according to thrombus grade (TG) evaluation. Finally, a series of ex vivo experiments verified whether the CD31 participates in Mo-Plt aggregate formation. In patients with NSTEMI, CD31 was reduced on monocytes and was increased on platelets, especially in NSTEMI presented with RFC plaques compared to those with IFC lesions, and in patients with high TG compared to those with zero/low TG. Ex vivo experiments documented an increase in Mo-Plt aggregates among NSTEMI, which significantly decreased after the CD31 ligation, particularly in patients with RFC plaques. In NSTEMI, CD31 participates in Mo-Plt aggregate formation in spite of optimal therapy and DAPT, suggesting the existence of alternative thrombotic pathways, as predominantly displayed in patients with RFC.

7.
Int J Cardiol ; 276: 289-292, 2019 Feb 01.
Article in English | MEDLINE | ID: mdl-30217424

ABSTRACT

BACKGROUND: A sizeable proportion of patients with Acute Coronary Syndromes (ACS) shows a unique adaptive immune system profile, associated to a worse outcome, characterized by higher CD4+CD28null T-cells, lower regulatory T-cells (Treg) and increased CD4+CD28null/Treg ratio. We sought to investigate the correlation between CD4+CD28null T-cells, Treg, CD4+CD28null/Treg ratio and plaque phenotype as assessed by Optical Coherence Tomography (OCT). METHODS: Peripheral blood mononuclear cells (PBMC) were collected from 30 Non-ST Elevation Myocardial Infarction (NSTEMI) patients, sub-grouped according to OCT analysis of culprit lesions into two cohorts: Ruptured Fibrous Cap (NSTEMI-RFC, n = 12) and Intact Fibrous Cap (NSTEMI-IFC, n = 18). Stable Angina patients (SA, n = 18) were used as controls. We examined the frequency of CD4+CD28null and Treg (defined as CD4+CD25highCD127lowFoxp3+ T-cells) by flow-cytometry. RESULTS: CD4+CD28null frequency (median, range) was significantly higher in NSTEMI-RFC patients (17.3%, 12.5-33.8) as compared with NSTEMI-IFC (3.8%, 0.3-14.1) and SA (3%, 0.6-17.7) (P < 0.001 for all comparisons). We also found a higher CD4+CD28null/Treg ratio in NSTEMI-RFC patients (6.6%, 3.7-13.9) than in NSTEMI-IFC (1.6%, 0.3-5.2) and SA (1.2%, 0.3-8.7) (P < 0.001 for all comparisons). Finally, there was an inverse correlation between CD4+CD28null/Treg ratio and cap-thickness (R = -0.44; P = 0.002). CONCLUSION: Patients with NSTEMI presenting with RFC as culprit lesion at OCT evaluation have a specific perturbation of adaptive immunity, mostly involving CD4+CD28null T- cells and Tregs, as compared with patients with IFC and SA. This specific imbalance of T-cells might play a key role in fibrous cap thinning, predisposing atherosclerotic plaque to rupture.


Subject(s)
Acute Coronary Syndrome/diagnosis , CD28 Antigens/immunology , CD4 Antigens/immunology , Coronary Vessels/pathology , Plaque, Atherosclerotic/diagnosis , T-Lymphocytes, Regulatory/immunology , Tomography, Optical Coherence/methods , Acute Coronary Syndrome/etiology , Acute Coronary Syndrome/immunology , Follow-Up Studies , Immunity, Cellular , Plaque, Atherosclerotic/complications , Plaque, Atherosclerotic/immunology , Prospective Studies , Rupture, Spontaneous , T-Lymphocytes/immunology , T-Lymphocytes/pathology , T-Lymphocytes, Regulatory/pathology
8.
J Am Coll Cardiol ; 72(13): 1490-1503, 2018 09 25.
Article in English | MEDLINE | ID: mdl-30236312

ABSTRACT

BACKGROUND: Superficial erosion currently causes at least one-third of acute coronary syndromes (ACS), and its incidence is increasing. Yet, the underlying mechanisms in humans are still largely unknown. OBJECTIVES: The authors sought to assess the role of hyaluronan (HA) metabolism in ACS. METHODS: Peripheral blood mononuclear cells were collected from ACS (n = 66), stable angina (SA) (n = 55), and control (CTRL) patients (n = 45). The authors evaluated: 1) gene expression of hyaluronidase 2 (HYAL2) (enzyme degrading high-molecular-weight HA to its proinflammatory 20-kDa isoform) and of CD44v1, CD44v4, and CD44v6 splicing variants of HA receptor; and 2) HYAL2 and CD44 protein expression. Moreover, they compared HYAL2 and CD44 gene expression in ACS patients with plaque erosion (intact fibrous cap and thrombus) and in ACS patients with plaque rupture, identified by optical coherence tomography analysis. RESULTS: Gene expression of HYAL2, CD44v1, and CD44v6 were significantly higher in ACS as compared with SA (p = 0.003, p < 0.001, and p = 0.033, respectively) and CTRL subjects (p < 0.001, p < 0.001, and p = 0.009, respectively). HYAL2 protein expression was significantly higher in ACS than in SA (p = 0.017) and CTRL (p = 0.032), whereas no differences were found in CD44 protein expression. HYAL2 and CD44v6 gene expression was significantly higher in patients with plaque erosion than in those with plaque rupture (p = 0.015 and p = 0.029, respectively). CONCLUSIONS: HYAL2 and CD44v6 splicing variants seem to play an important role in ACS, in particular when associated with plaque erosion. After further validation, HYAL2 might represent a potentially useful biomarker for the noninvasive identification of this mechanism of coronary instability.


Subject(s)
Acute Coronary Syndrome/metabolism , Cell Adhesion Molecules/genetics , Hyaluronoglucosaminidase/genetics , Plaque, Atherosclerotic/diagnostic imaging , Acute Coronary Syndrome/genetics , Aged , Case-Control Studies , Cell Adhesion Molecules/metabolism , Female , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , Gene Expression , Humans , Hyaluronan Receptors/genetics , Hyaluronan Receptors/metabolism , Hyaluronoglucosaminidase/metabolism , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , Protein Splicing , RNA, Messenger/metabolism , Tomography, Optical Coherence
9.
Eur Heart J ; 39(13): 1089-1097, 2018 04 01.
Article in English | MEDLINE | ID: mdl-29211854

ABSTRACT

Aims: In patients with acute coronary syndrome (ACS), the higher activity of effector T-cells suggests that mechanisms involving adaptive immunity dysregulation might play a role in coronary instability. The shedding of the functional CD31 domain 1-5 leads to uncontrolled lymphocyte activation. In experimental models, matrix metalloproteinase-9 (MMP-9) has been implicated in endothelial CD31 cleavage. Interestingly, higher serum levels of MMP-9 have been observed in ACS. We aim to investigate the mechanisms underlying CD31 dysregulation in ACS. Methods and results: To assess CD31 cleavage on CD4+ T-cells, we analysed by flow cytometry CD4+ T-cells of 30 ACS, 25 stable angina (SA) patients, and 28 controls (CTRL) using two different CD31 antibodies that specifically recognize domain 1-5 or the non-functional membrane-proximal domain 6. The ratio between the domains was significantly lower in ACS than in SA and CTRL (P = 0.002 ACS vs. SA; P = 0.002 ACS vs. CTRL). After stimulation with anti-CD3/CD28, the 1-5/6 domain ratio was significantly lower in ACS than in SA (P = 0.005). ELISA of supernatants obtained from T-cell receptor-stimulated CD4+ T-cells showed higher production of MMP-9 in ACS than in SA (P < 0.001). CD31 domain 1-5 expression in activated CD4+ T-cells from ACS patients increased after treatment with a specific MMP-9 inhibitor (P = 0.042). Conclusion: Our study suggest that enhanced MMP-9 release plays a key role in determining the cleavage and shedding of the functional CD31 domain 1-5 in CD4+ T-cells of ACS patients. This mechanism might represent an important therapeutic target to modulate T-cell dysregulation in ACS.


Subject(s)
Acute Coronary Syndrome/immunology , Adaptive Immunity , CD4-Positive T-Lymphocytes/immunology , Matrix Metalloproteinase 9/blood , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Acute Coronary Syndrome/enzymology , Down-Regulation , Humans , Prospective Studies , RNA Cleavage , RNA, Messenger/metabolism
10.
Int J Mol Sci ; 19(1)2017 Dec 26.
Article in English | MEDLINE | ID: mdl-29278387

ABSTRACT

Atherosclerosis is a chronic inflammatory disease characterized by a complex interplay between innate and adaptive immunity. Dendritic cells (DCs) play a key role in T-cell activation and regulation by promoting a tolerogenic environment through the expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme involved in tryptophan catabolism. IDO expression and activity was analyzed in monocytes derived DCs (MDDCs) from non-ST segment elevation myocardial infarction (NSTEMI) patients, stable angina (SA) patients and healthy controls (HC) by real-time quantitative polymerase chain reaction (RT-qPCR) before and after in vitro maturation with lipopolysaccharide (LPS). The amount of tryptophan catabolite; kynurenine; was evaluated in the culture supernatants of mature-MDDCs by ELISA assay. Autologous mixed lymphocyte reaction (MLR) between mature-MDDCs and naïve T-cells was carried out to study the differentiation towards T-helper 1 (Th1) and induced regulatory T-cells (iTreg). Analysis of IDO mRNA transcripts in mature-MDDCs revealed a significant reduction in cells isolated from NSTEMI (625.0 ± 128.2; mean ± SEM) as compared with those from SA (958.5 ± 218.3; p = 0.041) and from HC (1183.6 ± 231.6; p = 0.034). Furthermore; the concentration of kynurenine was lower in NSTEMI patients (2.78 ± 0.2) and SA (2.98 ± 0.25) as compared with HC (5.1 ± 0.69 ng/mL; p = 0.002 and p = 0.016; respectively). When IDO-competent mature-MDDCs were co-cultured with allogeneic naïve T-cells, the ratio between the percentage of generated Th1 and iTreg was higher in NSTEMI (4.4 ± 2.9) than in SA (1.8 ± 0.6; p = 0.056) and HC (0.9 ± 0.3; p = 0.008). In NSTEMI, the tolerogenic mechanism of the immune response related to IDO production by activated MDDCs is altered, supporting their role in T-cell dysregulation.


Subject(s)
Acute Coronary Syndrome/immunology , Immunity, Innate , Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology , Non-ST Elevated Myocardial Infarction/immunology , T-Lymphocyte Subsets/immunology , Acute Coronary Syndrome/pathology , Adult , Aged , Aged, 80 and over , Cell Differentiation , Cells, Cultured , Dendritic Cells/immunology , Dendritic Cells/pathology , Female , Humans , Lymphocyte Activation , Male , Middle Aged , Monocytes/immunology , Monocytes/pathology , Non-ST Elevated Myocardial Infarction/pathology , T-Lymphocyte Subsets/pathology
11.
Oncotarget ; 8(11): 17529-17550, 2017 Mar 14.
Article in English | MEDLINE | ID: mdl-28407684

ABSTRACT

Background- Adaptive immune-response is associated with a worse outcome in acute coronary syndromes. Statins have anti-inflammatory activity beyond lowering lipid levels. We investigated the effects of ex-vivo and in-vivo atorvastatin treatment in acute coronary syndromes on CD4+T-cells, and the underlying molecular mechanisms.Approach and results- Blood samples were collected from 50 statin-naïve acute coronary syndrome patients. We assessed CD4+T-cell activation by flow-cytometry, the expression of 84 T-helper transcription-factors and 84 T-cell related genes by RT-qPCR, and protein expression by Western-blot, before and after 24-hours incubation with increasing doses of atorvastatin: 3-10-26 µg/ml (corresponding to blood levels achieved with doses of 10-40-80 mg, respectively). After incubation, we found a significant decrease in interferon-γ-producing CD4+CD28nullT-cells (P = 0.009) and a significant increase in interleukin-10-producing CD4+CD25highT-cells (P < 0.001). Atorvastatin increased the expression of 2 genes and decreased the expression of 12 genes (in particular, EGR1, FOS,CCR2 and toll like receptor-4; >3-fold changes).The in-vivo effects of atorvastatin were analyzed in 10 statin-free acute coronary syndrome patients at baseline, and after 24h and 48h of atorvastatin therapy (80 mg/daily): EGR1-gene expression decreased at 24h (P = 0.01) and 48h (P = 0.005); EGR1-protein levels decreased at 48h (P = 0.03).Conclusions-In acute coronary syndromes, the effects of atorvastatin on immune system might be partially related to the inhibition of the master regulator gene EGR1. Our finding might offer a causal explanation on why statins improve the early outcome in acute coronary syndromes.


Subject(s)
Acute Coronary Syndrome/immunology , Atorvastatin/therapeutic use , CD4-Positive T-Lymphocytes/drug effects , Early Growth Response Protein 1/biosynthesis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Lymphocyte Activation/drug effects , Acute Coronary Syndrome/drug therapy , Blotting, Western , Cells, Cultured , Female , Flow Cytometry , Gene Expression/drug effects , Gene Expression Profiling , Humans , Male , Middle Aged , Polymerase Chain Reaction
12.
Int J Cardiol ; 236: 95-99, 2017 Jun 01.
Article in English | MEDLINE | ID: mdl-28268083

ABSTRACT

BACKGROUND: Epicardial adipose tissue (EAT) has a close functional and anatomic relationship with epicardial coronary arteries. Accumulating evidence suggests that host microbiome alterations may play a role in several inflammatory/immune disorders, triggering a robust proinflammatory response also involving interleukin-1ß (IL-1ß) and the NALP3 inflammasome. In the current study, we explore the hypothesis that in patients with non-ST elevation acute coronary syndrome (ACS), EAT contains potentially pro-atherosclerotic bacteria that might elicit inflammasome activation. METHODS: EAT samples were obtained during coronary artery bypass grafting from ACS (n=18) and effort stable angina (SA; n=16) patients, and as controls, from patients with angiographically normal coronary arteries undergoing surgery for mitral insufficiency (MVD; n=13). In all patients, NALP3 and proIL-1ß mRNA expressions were evaluated with qRT-PCR. In 3 patients from each group, EAT microbiota composition was determined using next-generation sequencing technologies. RESULTS: In EAT, mRNA expression of both NALP3 and pro-IL1ß was significantly higher in ACS than in SA and MVD (P=0.028 and P=0.005, respectively). A broad range of bacterial species (n=76) was identified in both ACS and SA, with different predominant species. In contrast, microbial DNA was barely observed in MVD. CONCLUSIONS: Our study demonstrated the presence of bacterial DNA directly into EAT, surrounding diseased coronary arteries, of patients with ACS. Furthermore, ACS is associated with NALP3/inflammasome pathway activation in EAT. Our data suggest that the EAT environment is susceptible to microbial colonization that might stimulate a proinflammatory response. These findings add new elements to the pathogenesis of ACS and suggest novel therapeutic targets.


Subject(s)
Acute Coronary Syndrome , Adipose Tissue , Coronary Artery Bypass/methods , Inflammasomes/physiology , Microbiota/physiology , Pericardium , Acute Coronary Syndrome/diagnosis , Acute Coronary Syndrome/immunology , Acute Coronary Syndrome/surgery , Adipose Tissue/immunology , Adipose Tissue/microbiology , Adipose Tissue/pathology , Aged , Colony Count, Microbial/methods , Coronary Vessels/pathology , DNA, Bacterial/isolation & purification , Female , Humans , Interleukin-1beta/analysis , Italy , Male , Middle Aged , NLR Family, Pyrin Domain-Containing 3 Protein/analysis , Pericardium/immunology , Pericardium/microbiology , Pericardium/pathology , Statistics as Topic
13.
J Am Coll Cardiol ; 68(19): 2107-2117, 2016 11 08.
Article in English | MEDLINE | ID: mdl-27810051

ABSTRACT

Although the early outcome of acute coronary syndrome (ACS) has considerably improved in the last decade, cardiovascular diseases still represent the main cause of morbidity and mortality worldwide. This is mainly because recurrence of ACS eventually leads to the pandemics of heart failure and sudden cardiac death, thus calling for a reappraisal of the mechanisms responsible for coronary instability. This review discusses recent advances in our understanding of how adaptive immunity contributes to the pathogenesis of ACS and the clinical implications that arise from these new pathogenic concepts.


Subject(s)
Acute Coronary Syndrome , Adaptive Immunity , B-Lymphocytes/immunology , T-Lymphocytes/immunology , Acute Coronary Syndrome/immunology , Acute Coronary Syndrome/metabolism , Acute Coronary Syndrome/pathology , Animals , Humans
14.
Am J Cardiol ; 117(3): 359-65, 2016 Feb 01.
Article in English | MEDLINE | ID: mdl-26739396

ABSTRACT

In this study, we aim to assess whether remote ischemic preconditioning (RIPC) reduces platelet activation during coronary angiography (CA) and/or percutaneous coronary interventions. We studied 30 patients who underwent CA because of a suspect of stable angina. Patients were randomized to RIPC (3 short episodes of forearm ischemia) or sham RIPC (controls) before the procedure. Blood samples were collected at baseline, at the end of the procedure, and 24 hours later. Monocyte-platelet aggregate (MPA) formation and platelet CD41 in the MPA gate and CD41 and CD62 expression in the platelet gate were assessed by flow cytometry, in the absence and in the presence of adenosine diphosphate (ADP) stimulation. A significant increase in platelet activation occurred during the invasive procedure in controls, which persisted at 24 hours. However, compared with controls, RIPC group showed no or a lower increase in platelet variables, including MPA formation (p <0.0001) and CD41 (p = 0.002) in the MPA gate and CD41 (p <0.0001) and CD62 (p = 0.002) in the platelet gate. ADP increased platelet activation at baseline, but did not further increase platelet reactivity during the invasive procedure in either groups. Percutaneous coronary interventions, performed in 10 patients (6 in the RIPC group and 4 in controls), did not have any further significant effect on platelet activation and reactivity compared with CA alone. In conclusion, RIPC reduces platelet activation occurring during CA. In contrast, no effects were observed on platelet response to ADP stimulation, probably related to the administration of an ADP antagonist in all patients.


Subject(s)
Coronary Angiography/adverse effects , Ischemic Preconditioning, Myocardial/methods , Myocardial Ischemia/therapy , Percutaneous Coronary Intervention/adverse effects , Platelet Activation/physiology , Telemetry/methods , Aged , Female , Flow Cytometry , Follow-Up Studies , Humans , Male , Myocardial Ischemia/blood , Myocardial Ischemia/etiology , Platelet Aggregation , Treatment Outcome
16.
Circ Cardiovasc Interv ; 8(8): e002554, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26243785

ABSTRACT

BACKGROUND: The role of allergic inflammation in acute coronary syndromes (ACS) has not been clearly defined to date. Aim of this study was to assess eosinophil and basophil activation in ACS and the prognostic role of eosinophil cationic protein in ST-segment-elevation myocardial infarction. METHODS AND RESULTS: In a cross-sectional study, we prospectively enrolled 51 patients undergoing percutaneous coronary intervention (60.8% patients with ACS and 39.2% with stable angina). Flow cytometry analysis assessed CD66b, CD69, and CD203c median fluorescence intensity expression. In a follow-up study, 181 patients presenting with ST-segment-elevation myocardial infarction, undergoing primary percutaneous coronary intervention, were prospectively enrolled with a follow-up of 24 months. Eosinophil activation (CD66b) was similar in patients with ACS and stable angina (6.61 [4.91-7.72] versus 6.62 [5.27-8.73], P=0.63), whereas eosinophil degranulation (CD69) and basophil activation (CD203c) were higher in ACS patients compared with stable angina patients (1.38 [1.16-1.52] versus 1.17 [1-1.31], P=0.01); 0.97 [0.89-1.11] versus 0.92 [0.87-0.95], P=0.03, respectively). Eosinophil cationic protein serum levels were significantly higher in ST-segment-elevation myocardial infarction patients with major adverse cardiac events as compared with those without (21.1 [10.37-25.65] versus 7.83 [3.37-12.8] µg/L, P=0.01) and in patients with thrombus score >3 compared with those with thrombus score ≤3 (15.0 [9.8-24.7] versus 5.2 [3.5-22.9] µg/L, P=0.006). Eosinophil cationic protein serum levels predicted major adverse cardiac events during follow-up (odds ratio =1.041, 95% confidence interval 1.012-1.071, P=0.005). C-reactive protein serum levels showed a borderline statistical significance (odds ratio =0.904, 95% confidence interval 0.806-1.014, P=0.085). CONCLUSIONS: These findings are the first demonstration of in vivo eosinophil degranulation and basophil activation during ACS and of the prognostic role of eosinophil cationic protein in ST-segment-elevation myocardial infarction.


Subject(s)
Basophils/immunology , Eosinophils/immunology , Inflammation/blood , Myocardial Infarction/blood , Acute Coronary Syndrome/immunology , Aged , Aged, 80 and over , Angina, Stable/immunology , C-Reactive Protein/metabolism , Coronary Angiography , Cross-Sectional Studies , Echocardiography , Eosinophil Cationic Protein/blood , Female , Flow Cytometry , Humans , Male , Middle Aged , Myocardial Infarction/diagnosis , Prognosis , Prospective Studies
17.
J Am Coll Cardiol ; 65(12): 1175-1186, 2015 Mar 31.
Article in English | MEDLINE | ID: mdl-25814225

ABSTRACT

BACKGROUND: Critical impairment of adaptive immune response has been observed in patients with acute coronary syndromes (ACS) with reduced expansion of regulatory T cells (Treg) and enhanced effector T-cell responsiveness, both associated with poorer outcomes. OBJECTIVES: This study investigated the mechanisms underlying T-cell dysregulation in ACS. METHODS: We evaluated both early and downstream T-cell receptor activation pathways after ex vivo stimulation with anti-CD3 and anti-CD28 crosslink in CD4(+) T cells from 20 patients with non-ST-segment elevation myocardial infarction (NSTEMI), 20 with stable angina (SA), and 20 controls. We reassessed 10 NSTEMI and 10 SA patients after 1 year. RESULTS: Phospho-flow analysis revealed reduced phosphorylation of the zeta-chain-associated protein kinase of 70 kDa at the inhibitory residue tyrosine 292, enhancing T-cell activation, in NSTEMI helper T cells versus SA and controls (each, p < 0.001), resulting from increased expression of the protein tyrosine phosphatase, nonreceptor type, 22 (PTPN22) (p < 0.001 for both comparisons), persisting at follow-up. We also observed reduced phosphorylation (p < 0.001 versus controls) and lower levels of binding to interleukins 2 and 10 core promoter regions of the transcription factor cyclic adenosine monophosphate response element-binding protein (CREB) in NSTEMI (p < 0.05 vs. controls), which recovered at 1 year. Finally, in NSTEMI patients, helper T cells had a reduced ability in T-cell receptor-induced Treg generation (p = 0.002 vs. SA; p = 0.001 vs. controls), partially recovered at 1 year. Restoring CREB activity and silencing PTPN22 enhanced NSTEMI patients' ability to generate Treg. CONCLUSIONS: The persistent overexpression of PTPN22 and the transient reduction of CREB activity, associated with impaired Treg differentiation, might play a role in ACS.


Subject(s)
Acute Coronary Syndrome/genetics , Acute Coronary Syndrome/immunology , Adaptive Immunity/immunology , CREB-Binding Protein/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics , T-Lymphocytes, Regulatory/immunology , Acute Coronary Syndrome/diagnostic imaging , Acute Coronary Syndrome/mortality , Aged , Analysis of Variance , Angina Pectoris/genetics , Angina Pectoris/immunology , Angina Pectoris/mortality , Case-Control Studies , Coronary Angiography , Electrocardiography , Female , Gene Expression Regulation , Humans , Male , Middle Aged , Myocardial Infarction/genetics , Myocardial Infarction/immunology , Myocardial Infarction/mortality , Prognosis , Reference Values , Risk Assessment , Signal Transduction , Survival Rate , T-Lymphocytes, Regulatory/metabolism
18.
Basic Res Cardiol ; 109(6): 448, 2014.
Article in English | MEDLINE | ID: mdl-25344833

ABSTRACT

In acute coronary syndrome (ACS), T cell abnormalities are associated to a worse outcome. Loss of inhibitory activity of CD31, an Ig-like adhesion molecule, on peripheral leukocytes has been found to enhance atherosclerosis in experimental models. In this study, we examined the expression of CD31 on T cells, and its role on TCR signaling in 35 patients with non-ST elevation ACS, in 35 patients with stable angina (SA), and in 35 controls. Furthermore, 10 ACS and 10 SA patients were re-analyzed at 1-year follow-up. Flow-cytometry analysis showed that in ACS patients, CD31 expression was reduced on total CD4(+) and CD4(+)CD28(null) (P < 0.001, ACS vs. SA), on naïve (P < 0.001, ACS vs. SA) and on central-memory and effector-memory CD4(+) T cells (P < 0.05, ACS vs. SA and controls). The immunomodulatory effect of CD31 on TCR signaling of CD4(+) and CD4(+)CD28(null) T cells, was lower in ACS than SA patients (P < 0.05, for both comparisons). At 1-year follow-up, CD31 expression and function increased in ACS becoming similar to that found in SA. CD31 recruitment in the immunological synapse was lower in ACS than controls (P = 0.012). Moreover, CD31 modulated MAPK signaling and reduced the expression of T bet and Rorγ-t, necessary for Th1 and Th17 differentiation. Finally, we studied TCR signaling in CD31(+) naïve and primed T cell subsets observing a different pattern of protein phosphorylation. A CD31-mediated regulatory pathway is enhanced in SA and temporarily downregulated in ACS. As CD31 modulates both T cell activation, by increasing the threshold for TCR stimulation, and T cell differentiation, it might represent a novel molecular target to treat T cell abnormalities in ACS.


Subject(s)
Acute Coronary Syndrome/immunology , Platelet Endothelial Cell Adhesion Molecule-1/physiology , T-Lymphocytes, Helper-Inducer/physiology , Acute Coronary Syndrome/metabolism , Aged , Female , Humans , Lymphocyte Activation , Male , Middle Aged , Platelet Endothelial Cell Adhesion Molecule-1/biosynthesis , Prospective Studies
19.
Microbes Infect ; 15(2): 105-14, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23164610

ABSTRACT

Chlamydia pneumoniae is a respiratory pathogen involved in the onset of chronic inflammatory pathologies. Dendritic cells (DC), are major players in spreading of C. pneumoniae from the lungs, a crucial step leading to disseminated infections. Less is known concerning modulation of DC functions consequent to encounter with the bacterium. In order to address this aspect, human monocyte-derived (MD)DC were infected with C. pneumoniae. After internalization bacterial counts increased in MDDC, as well as the expression of CPn1046, a gene involved in bacterial metabolism, with a peak 48 h after the infection. Infected MDDC switched to the mature stage, produced IL-12p70, IL-1ß, IL-6, and IL-10, and drove a mixed Type 1/Type 17 polarization. Intracellular pathways triggered by C. pneumoniae involved Toll-like receptor (TLR) 2. Indeed, TLR2 was activated by C. pneumoniae in transfected HEK 293 cells, and C. pneumoniae-mediated phosphorylation of ERK1/2 was inhibited by an anti-TLR2 antibody in MDDC. When an ERK1/2 inhibitor was used, IL-12p70 and IL-10 release by MDDC was reduced and T cell polarization shifted towards a Type 2 profile. Overall, our findings unveiled the role played by TLR2 and ERK1/2 induced by C. pneumoniae to affect DC functions in a way that contributes to a Type 1/Type 17 pro-inflammatory response.


Subject(s)
Chlamydophila pneumoniae/immunology , Dendritic Cells/microbiology , Interleukin-17/immunology , Interleukin-1/immunology , Monocytes/cytology , Antibodies/immunology , Apoptosis , Bacterial Load , Cell Polarity , Cells, Cultured , Chlamydophila Infections/immunology , Chlamydophila Infections/microbiology , Dendritic Cells/immunology , Flavonoids/pharmacology , Gene Expression Regulation , HEK293 Cells , Humans , Interleukin-12/immunology , Lymphocyte Activation , MAP Kinase Signaling System , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 1/immunology , Monocytes/immunology , Phagocytosis , Phosphorylation , Signal Transduction , T-Lymphocytes/immunology , T-Lymphocytes/microbiology , Time Factors , Toll-Like Receptor 2/immunology , Transfection
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