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While the advent of drug-eluting stents has been clinically effective in substantially reducing the rates of major stent-related adverse events compared with bare metal stents, vascular biological problems such as neointimal hyperplasia, delayed re-endothelialization, late stent thrombosis are not eliminated and, increasingly, neoatherosclerosis is the underlying mechanism for very late stent failure. Further understanding regarding the mechanisms underlying the biological responses to stent deployment is therefore required so that new and improved therapies can be developed. This review will discuss the accumulating evidence that the chemokines, small inflammatory proteins, play a role in each key biological process of stent biocompatibility. It will address the chemokine system in its specialized roles in regulating the multiple facets of vascular biocompatibility including neointimal hyperplasia, endothelial progenitor cell (EPC) mobilization and re-endothelialization after vascular injury, platelet activation and thrombosis, as well as neoatherosclerosis. The evidence in this review suggests that chemokine-targeting strategies may be effective in controlling the pathobiological processes that lead to stent failure. Preclinical studies provide evidence that inhibition of specific chemokines and/or broad-spectrum inhibition of the CC-chemokine class prevents neointimal hyperplasia, reduces thrombosis and suppresses the development of neoatherosclerosis. In contrast, however, to these apparent deleterious effects of chemokines on stent biocompatibility, the CXC chemokine, CXCL12, is essential for the mobilization and recruitment of EPCs that make important contributions to re-endothelialization post-stent deployment. This suggests that future chemokine inhibition strategies would need to be correctly targeted so that all key stent biocompatibility areas could be addressed, without compromising important adaptive biological responses., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Kounis syndrome was recognized as the concurrence of acute cardiovascular events with hypersensitivity reactions. We report a case of Kounis syndrome type III (coronary thrombosis) variant in a 48-year-old man who had experienced recurrent acute myocardial infarctions after scallion-induced hypersensitivity reactions. After appropriate antithrombotic, antihistamine, and reperfusion strategies, the patient was found to have elevated levels of immunoglobulin E and chronic urticaria. Upon administration of omalizumab, there was an improvement of chronic urticaria, a decrease in immunoglobulin E levels, and resolution of the ischemic attacks., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Persons with HIV infection (PWH) have increased risk for cardiovascular disease (CVD), but the underlying mechanisms remain unclear. Coronary thrombosis is known to provoke myocardial infarctions, but whether PWH have elevated thrombotic propensity is unknown. We compared thrombogenicity of PWH on antiretroviral therapy versus matched controls using the Badimon chamber. Measures of inflammation, platelet reactivity, and innate immune activation were simultaneously performed. Enrolled PWH were then randomized to placebo, aspirin (81 mg), or clopidogrel (75 mg) for 24 weeks to assess treatment effects on study parameters. Thrombogenicity was significantly higher in PWH and correlated strongly with plasma levels of D-dimer, soluble TNF receptors 1 and 2, and circulating classical and nonclassical monocytes in PWH. Clopidogrel significantly reduced thrombogenicity and sCD14. Our data suggest that higher thrombogenicity, interacting with inflammatory and immune activation markers, contributes to the increased CVD risk observed in PWH. Clopidogrel exhibits an anti-inflammatory activity in addition to its antithrombotic effect in PWH.

Kounis syndrome (KS) consists of an association between hypersensitivity reactions triggered by various environmental and pharmacological factors and acute coronary syndromes. Blood supply may be compromised by either vasospasm (type I), native plaque destabilization (type II) or stent thrombosis (type III). Although the prognosis is generally favorable, treatment should include aggressive anti-thrombotic and anti-allergic therapies. A case compatible with type III KS, manifested as a macular rash followed by two episodes of stent thrombosis after primary angioplasty (PCI) of the right coronary artery is presented, and complemented by a review on the topic., (Copyright © 2018. Published by Elsevier Inc.)

Kawasaki disease (KD) is the commonest vasculitic syndrome. It affects medium-sized arteries, principally the coronary arteries. Histologically, coronary arteritis begins at 6 to 8 days after the onset of KD and the inflammation rapidly involves all layers of the artery. This results in severe damage to the structural components of the artery leading to arterial dilation. The inflammatory infiltrate in KD arteritis is characterized predominantly by infiltration of monocytes and macrophages. Activated neutrophils, monocytes and macrophages are believed to be involved in the initial stage of coronary arteritis. Inflammatory cell infiltration may continue for up to 25 days of disease following which the inflammatory cells gradually decline in number. Inflammatory lesions in the arteries are relatively synchronous as they evolve from an acute to the chronic stage. If a giant aneurysm remains or vessel recanalization occurs after thrombotic occlusion of an aneurysm, the remodeling of vascular structures may continue for a much longer time., (© 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Recent studies have demonstrated that inflammatory cells are a component that plays a role in thrombus formation in ST-elevation myocardial infarction (STEMI). 3-nitrotyrosine (3-NO2-Tyr), a specific marker for protein modification by nitric oxide-derived oxidants, is increased in human atherosclerotic lesions. The purpose of this study was to determine the possible association of inflammatory markers of coronary thrombi with nitroxidative stress. Intracoronary thrombus (n=51) and blood from the systemic circulation were obtained by thromboaspiration in 138 consecutive STEMI patients presenting for primary percutaneous coronary intervention (PCI). Each blood and intracoronary thrombus were measured simultaneously the following biomarkers: C-reactive protein (CRP), 3-NO2-Tyr, soluble CD 40 ligand (sCD40L), vascular cellular adhesion molecule-1 (VCAM-1) and haemoglobin content (only in coronary thrombus). Time delay in minutes from symptom onset to PCI was 244 ± 324. Serum CRP was positively correlated to CRP content in the thrombus (r= 0.395; p = 0.02) and serum sCD40L was negatively correlated to sCD40L in the thrombus (r= -0.394; p = 0.02). Patients were divided into tertiles according to thrombi 3-NO2-Tyr concentration: 1(st)tertile (<0.146ng/mg), 2(nd)tertile (0.146-0.485ng/mg) and 3(rd)tertile (>0.485ng/mg). Thus, thrombus in the highest tertile had significantly higher levels of CRP (p=0.002), VCAM-1 (p=0.003) and haemoglobin (p=0.002). In conclusion, the present study demonstrated that coronary thrombi with higher levels of 3-NO2-Tyr content often contain more inflammatory markers which could have a direct impact on the efficacy of drugs or devices used for coronary reperfusion.

Background: IFN-γ-producing Th17 cells have been implicated in autoimmune disorders, but their properties in humans are known only partially. The molecular mechanisms and external factors that govern IFN-γ-producing Th17-cell bias are incompletely understood. The present work was to clarify whether (i) IFN-γ-producing Th17 cells are present in the peripheral circulation of patients with coronary atherosclerosis (CA); (ii) high mobility group box (HMGB)1 in circulation is associated with IFN-γ-producing Th17-cell bias., Methods: Thirty-six patients (17 females and 19 males; 45-84 years) diagnosed as having atherosclerosis after coronary angiography for suspected or known CA were included the study cohort. Samples of peripheral blood were collected from healthy volunteers and patients, and classical tests (flow cytometry, RT-qPCR) were used to measure blood components., Results and Conclusion: Our results clearly demonstrated that HMGB1 were up-regulated in different progressive CA patients: 5.38 ± 1.48 ng/ml, 6.30 ± 1.53 ng/ml and 5.86 ± 1.12 ng/ml vs1.45 ± 0.65 ng/ml for only atherosclerotic plaque (AP), atherosclerotic plaque and some plaque rupture, no thrombosis (PR), plaque rupture and accompanying thrombosis (TH) and volunteers, respectively, p < 0.05. The frequency of IFN-γ-producing Th17 cells was 2.33 ± 0.58%, 1.93 ± 0.2% and 2.21 ± 0.65% vs 0.38 ± 0.21% for AP, PR, TH and volunteers, p < 0.05, respectively. Furthermore, HMGB1 contributed to IFN-γ-producing Th17-cell bias by controlling expression of T-bet and RUNX3. We demonstrated, for the first time, that HMGB1 is a potential inducer of IFN-γ-producing Th17-cell bias, and that IFN-γ-producing Th17 cells might be one of the pathogenic factors in atherosclerosis., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

We investigated whether the neutrophil to lymphocyte ratio (NLR) can predict stent thrombosis (STh) and high mortality rate in patients with ST-segment elevation myocardial infarction (STEMI). We analyzed data of 102 patients with STh and 450 patients with STEMI admitted to 2 high volume hospitals. Preprocedural NLR was significantly higher in patients with STh (P < .001). There was a significantly higher mortality rate in patients with high NLR during hospitalization (P < .001). Also, in the STh group there was a significantly higher mortality rate in patients with high NLR (P < .001). In receiver-operating characteristic analysis, NLR >4.8 had 56% sensitivity and 68% specificity for predicting STh. The NLR >4.9 had 70% sensitivity and 65% specificity for predicting in-hospital mortality. On multivariate regression analysis, NLR was found to be significantly related to STh. In patients with STEMI, preprocedural high NLR is associated with both STh and higher mortality rates., (© The Author(s) 2014.)

Aims: Regulatory T cells (Treg) exert anti-inflammatory and atheroprotective effects in experimental atherosclerosis. Treg can be induced against specific antigens using immunization strategies associated with clonal restriction. No data exist on Treg in combination with clonal restriction of T cells in patients with acute coronary syndromes (ACS)., Methods and Results: Among T cell subsets characterized by flow cytometry, Treg (CD4(+) CD25(+) CD127(low)) were twice as frequent in coronary thrombi compared with peripheral blood. Treg prevailed among T cell subsets identified in coronary thrombi. To evaluate clonal restriction, genomic DNA was extracted from coronary thrombi and peripheral blood in order to evaluate T cell receptor (TCR) β chain diversity by means of Multi-N-plex PCR using a primer specific for all TCR β V gene segments and another primer specific for TCR β J gene segments. T cell receptor diversity was reduced in thrombi compared with peripheral blood (intra-individual comparisons in 16 patients) with 8 gene rearrangements in the TCR common in at least 6 out of 16 analysed coronary thrombi. Compared with age-matched healthy controls (n = 16), TCR diversity was also reduced in peripheral blood of patients with ACS; these findings were independent of peripheral T cell numbers., Conclusion: We provide novel evidence for a perturbed T cell compartment characterized by clonal restriction in peripheral blood and coronary thrombi from patients with ACS. Our findings warrant further studies on Treg as novel therapeutic targets aimed at enhancing this anti-inflammatory component of adaptive immunity in human atherothrombosis., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Despite improvements in interventional and pharmacological therapy for atherosclerotic disease, it is still the leading cause of death in the developed world. Hence, there is a need for further development of more effective therapeutic approaches. This requires better understanding of the molecular mechanisms and pathophysiology of the disease. Recent research in the last decade has changed our view of acute coronary syndrome (ACS): from a mere lipid deposition to an inflammatory disease; from ACS exclusively due to plaque rupture to the novel definitions of plaque erosion or calcified nodule; from the notion of a superimposed thrombus with necessary lethal consequences to the concept of healed plaques and thrombus contributing to plaque progression. In the hope of improving our understanding of ACS, all these recently discovered concepts are reviewed in this article.

A 54-year-old male entered the emergency room in cardiorespiratory arrest after syncope at home. Resuscitation was attempted, but the patient died a few hours later. At necropsy, aneurysms were found at the right and left anterior descending coronary arteries. At microscopic examination, there was no significant coronary atherosclerosis, and a dense inflammatory infiltrate was detected, with a high number of igG4-positive cells (94.0 positive cells/hpf). The case illustrates that IgG4-related disease can cause coronary disease and sudden cardiac death., (Copyright © 2013 Elsevier Inc. All rights reserved.)

This manuscript reviews the studies performed with ALX-0081 (INN: caplacizumab), a Nanobody targeting von Willebrand factor, in the context of current antithrombotic therapy in coronary artery disease. ALX-0081 specifically inhibits platelet adhesion to the vessel wall, and may control platelet aggregation and subsequent clot formation without increasing bleeding risk. A substantial number of antithrombotics are aimed at this cascade; however, their generally indiscriminative mode of action can result in a narrow therapeutic window, defined by the risk for bleeding complications, and thrombotic events. Nonclinically, ALX-0081 compared favorably to several antithrombotics. In Phase I studies in healthy subjects and stable angina patients undergoing percutaneous coronary intervention (PCI), ALX-0081 was well tolerated, and effectively inhibited pharmacodynamic markers. Following these results, a phase II study was initiated in high-risk acute coronary syndrome patients undergoing PCI. Based on its mechanism of action, ALX-0081 is also being developed for acquired thrombotic thrombocytopenic purpura.

Pentraxin 3 (PTX3) plays cardioprotective and anti-atherogenic roles in murine models. PTX3 blood levels raise during early acute myocardial infarction (AMI). Neutrophils from healthy subjects physiologically contain PTX3 in secondary (also called specific) granules. In this study, we report that circulating neutrophils release preformed PTX3 in the early phase of AMI (within 6 h from the onset of clinical symptoms). Depletion of intracellular PTX3 correlates with increased plasma levels and with platelet-neutrophil heterotypic aggregates. Neutrophil PTX3 returns to normal values 48 h after the onset of symptoms; concentration does not vary in matched healthy controls or in patients with chronic stable angina. In vitro, recognition of activated P-selectin(+) platelets causes the formation of neutrophil-platelet heteroaggregates and the release of neutrophil PTX3. Purified or membrane-bound P-selectin triggers PTX3 release from resting neutrophils. Released PTX3 binds to activated platelets in vitro. Moreover, PTX3 binds to a substantial fraction of platelets from patients in the circulating blood. PTX3-bound activated platelets have a reduced ability to 1) form heterotypic aggregates with neutrophils and monocytes; 2) activate neutrophils, as evaluated assessing the upregulation of leukocyte β(2) integrins; 3) aggregate with other platelets; and 4) bind to fibrinogen. Our results suggest that neutrophils early release prestored PTX3 in patients undergoing AMI. PTX3 binds to activated circulating platelets and dampens their proinflammatory and prothrombotic action, thus possibly contributing to its cardioprotective effects.

Background: Intravascular ultrasound of drug-eluting stent (DES) thrombosis (ST) reveals a high incidence of incomplete stent apposition (ISA) and vessel remodeling. Autopsy specimens of DES ST show delayed healing and hypersensitivity reactions. The present study sought to correlate histopathology of thrombus aspirates with intravascular ultrasound findings in patients with very late DES ST., Methods and Results: The study population consisted of 54 patients (28 patients with very late DES ST and 26 controls). Of 28 patients with very late DES ST, 10 patients (1020+/-283 days after implantation) with 11 ST segments (5 sirolimus-eluting stents, 5 paclitaxel-eluting stents, 1 zotarolimus-eluting stent) underwent both thrombus aspiration and intravascular ultrasound investigation. ISA was present in 73% of cases with an ISA cross-sectional area of 6.2+/-2.4 mm(2) and evidence of vessel remodeling (index, 1.6+/-0.3). Histopathological analysis showed pieces of fresh thrombus with inflammatory cell infiltrates (DES, 263+/-149 white blood cells per high-power field) and eosinophils (DES, 20+/-24 eosinophils per high-power field; sirolimus-eluting stents, 34+/-28; paclitaxel-eluting stents, 6+/-6; P for sirolimus-eluting stents versus paclitaxel-eluting stents=0.09). The mean number of eosinophils per high-power field was higher in specimens from very late DES ST (20+/-24) than in those from spontaneous acute myocardial infarction (7+/-10), early bare-metal stent ST (1+/-1), early DES ST (1+/-2), and late bare-metal stent ST (2+/-3; P from ANOVA=0.038). Eosinophil count correlated with ISA cross-sectional area, with an average increase of 5.4 eosinophils per high-power field per 1-mm(2) increase in ISA cross-sectional area., Conclusions: Very late DES thrombosis is associated with histopathological signs of inflammation and intravascular ultrasound evidence of vessel remodeling. Compared with other causes of myocardial infarction, eosinophilic infiltrates are more common in thrombi harvested from very late DES thrombosis, particularly in sirolimus-eluting stents, and correlate with the extent of stent malapposition.

Integrins are heterodimeric adhesion receptors essential for metazoan life. In addition to mediating cell-extracellular matrix and cell-cell interactions, integrins are bona fide signalling receptors in that they transmit information in both directions across the plasma membrane. The affinity of integrins for extracellular ligands is regulated through a process termed integrin activation or "inside-out signalling". On the other hand, ligand binding to integrins can induce the recruitment and activation of a number of enzymes and adaptors such as pp125(FAK) and Src family kinases, to initiate "outside-in signalling". Intensive investigation into the mechanisms of integrin signalling has revealed many of the key players; amongst these, one of the most important is talin. Our understanding of how many of these molecules interact is now understood at the atomic level thanks to detailed structural studies. Indeed structural information and model cell systems have provided unique opportunities to dissect the molecular mechanisms of many aspects of integrin signalling. Recent studies have begun testing the biological significance of these mechanisms using in-vivo models, particular genetically modified mice. The generation and characterisation of in-vivo models to study integrin signalling has provided valuable information into the functional significance of integrin signalling in fundamental physiological processes as well as within the context of human disease. Here, I will review recent insights that have been gained into integrin signalling through the use of genetically modified mice focusing on integrin alphaIIbbeta3 (GPIIb-IIIa) and the regulation of its function in haemostasis and thrombosis.

Objective: During myocardial infarction, platelet activation and endothelial apoptosis are responsible for the release of procoagulant membrane-derived microparticles (MPs) in the bloodstream. Few data are available on the potential role played by MPs in coronary atherothrombosis. In the present study, we investigated the levels and cellular origins of MPs within the occluded coronary artery of patients with ST-segment elevation myocardial infarction (STEMI) treated by primary angioplasty (PCI)., Methods: A total of 12 patients with STEMI treated by primary PCI within 24h of symptom onset were included in this study. MPs procoagulant activity and cellular origin were characterized within the occluded coronary artery before PCI (C(0)), after restoration of the epicardial blood flow (C(1)), and in blood collected from the femoral artery (F)., Results: Levels of leukocyte-derived CD11a(+) MPs, endothelial-derived CD105(+) MPs, and tissue factor (TF)-bearing MPs were significantly higher within the occluded coronary artery than in peripheral blood samples. Restoration of the epicardial blood flow led to a significant reduction of procoagulant CD11a(+) and CD105(+) MPs by 30% and 42%, respectively (p<0.05)., Conclusions: Elevation of procoagulant MPs within the occluded coronary artery of patients with STEMI suggests their pathophysiological role in coronary atherothrombosis.

Thrombus aspiration therapy allows for the examination of thrombus and atheroma fragments in acute coronary syndrome (ACS). Inflammatory cells and platelet activation play key roles in thrombus formation in ACS. However, histopathologic evaluation of thrombi in ACS has not been adequately addressed. We performed histologic analysis of tissue samples obtained by thrombus aspiration therapy. We studied 165 samples from patients with ACS. The area of each sample, percentage of red thrombus, and percentage of white thrombus were measured. Samples were stained immunohistochemically with antibodies against macrophages, activated platelets, and interleukin (IL)-5. Seventy-six samples included atheroma fragments. Macrophages, neutrophils, and activated platelets were observed in thrombi and in atheroma fragments. Eosinophil infiltration was also observed predominantly in the area between white thrombus and red thrombus in 106 samples. We categorized all samples into 3 groups according to the grade of eosinophil infiltration (eos-, eos+, eos++ group). Sample area in the eos++ group was greater than that in the eos- group (P < 0.0001). In addition, the percentage of the red thrombus areas in the eos++ group and the eos+ group was greater than that in the eos- group (P < 0.009, P < 0.02, respectively). However, there was no difference in the percentage of white thrombus area between the 3 groups. Staining for IL-5 was identified in inflammatory cells within thrombi. Eosinophils may play an important role in coronary occlusion by promoting thrombus growth.

Disrupting the CD40-CD40L costimulation pathway promotes allograft acceptance in many settings. Herein, we demonstrate that stimulating OX40 overrides cardiac allograft acceptance induced by disrupting CD40-CD40L interactions. This effect of OX40 stimulation was dependent on CD4(+) T cells, which in turn provided help for CD8(+) T cells and B cells. Allograft rejection was associated with donor-reactive Th1 and Th2 responses and an unconventional granulocytic infiltrate and thrombosis of the arteries. Interestingly, OX40 stimulation induced a donor-reactive IgG class switch in the absence of CD40-CD40L interactions, and the timing of OX40 stimulation relative to transplantation affected the isotype of donor-reactive Ab produced. Inductive OX40 stimulation induced acute graft rejection, which correlated with both IgG1 and IgG2a deposition within the graft. Once graft acceptance was established following CD40-CD40L blockade, delayed OX40 stimulation did not induce acute allograft rejection despite priming of graft-reactive Th1 and Th2. Rather, chronic rejection was induced, which was characterized by IgG1 but not IgG2a deposition within the graft. These studies reveal both redundancy and key differences in function among costimulatory molecules that manifest in distinct pathologies of allograft rejection. These findings may help guide development of therapeutics aimed at promoting graft acceptance in transplant recipients.

Heterotopic cardiac xenotransplantation from alpha1,3-galactosyltransferase gene-knockout (GalT-KO) swine to baboons was performed to characterize immunological reaction to the xenograft in the absence of anti-Gal antibody-mediated rejection. Eight baboons received heterotopic cardiac xenografts from GalT-KO porcine donors. All baboons were treated with chronic immunosuppressive therapy. Both histological and immunohistochemical studies were performed on biopsy and graftectomy samples. No hyperacute rejection was observed. Three baboons were euthanized or died 16 to 56 days after transplantation. The other five grafts ceased beating between days 59 and 179 (median, 78 days). All failing grafts exhibited thrombotic microangiopathy (TM) with platelet-rich fibrin thrombi in the microvasculature, myocardial ischemia and necrosis, and focal interstitial hemorrhage. TM developed in parallel with increases in immunoglobulin (IgM and IgG) and complement (C3, C4d, and C5b-9) deposition, as well as with subsequent increases in both TUNEL(+) endothelial cell death and procoagulant activation (increased expression of both tissue factor and von Willebrand factor and decreased expression of CD39). CD3(+) T-cell infiltration occurred in all grafts and weakly correlated with the development of TM. In conclusion, although the use of GalT-KO swine donors prevented hyperacute rejection and prolonged graft survival, slowly progressive humoral rejection--probably associated with non-Gal antibodies to the xenograft--and disordered thromboregulation represent major immunological barriers to long-term xenograft survival.

Our understanding of the relationship between the proatherogenic activities of arterial mast cells (MCs) and the development of atherosclerotic lesions is advancing. Atherosclerosis is a chronic inflammatory disease in which cholesterol and other lipids of circulating low-density lipoprotein (LDL) particles accumulate both extracellularly and intracellularly in the innermost layer of the arterial wall, the intima. One prerequisite for the proatherogenic activity of the LDL particles is their retention and proteolytic modification within the extracellular matrix of the intima. Experimental studies with activated chymase-secreting MCs have provided us fundamental insights into the molecular mechanisms of these processes. High-density lipoprotein (HDL) particles, again, remove cholesterol from the intracellular stores and carry it back to the circulation. MC chymase and tryptase actively degrade HDL and thus generate functionally defective particles that are unable to initiate cholesterol efflux from the arterial wall. In advanced atherosclerotic plaques, the accumulated lipids are separated from the circulation by a collagenous cap. By inducing apoptosis of endothelial cells (ECs), subendothelial MCs may induce detachment of ECs from the cap (plaque erosion). Moreover, MCs may weaken the cap if they disturb local collagen turnover by inducing apoptosis of the collagen-secreting smooth muscle cells or when they promote collagen degradation by activating matrix metalloproteinases. Plaques with a weak cap are vulnerable to rupture. The exposed subendothelial tissue at eroded and ruptured sites of plaques triggers local development of a platelet-rich thrombus. As regulators of the collagen-induced platelet activation and fibrin formation/fibrinolysis, the MCs may retard or accelerate the growth of the plaque-associated thrombus and ultimately participate in the wound-healing response of the injured plaque. We propose that by promoting cholesterol accumulation and plaque vulnerability and by locally regulating hemostasis, MCs in atherosclerotic lesions have the potential to contribute to the clinical outcomes of atherosclerosis, such as myocardial infarction and stroke.

The present study aims to report a-20-year old girl with systemic lupus erythematosus (SLE) who developed myocardial infarction (MI) and also aims to review acute myocardial infarction (AMI) in young SLE cases (< or =35 years) reported in the literature. We conducted a comprehensive review of the English literature from 1975 to 2006 to analyse data on MI in SLE patients who had developed AMI either at 35 or earlier. In 32 English articles, we identified 49 SLE patients, plus our case, with AMI. They consist of 41 female and nine male patients, their mean age being 24 +/- 6.4 years (range of 5-35). Disease duration varied between 0 and 13 years. The lag time between the onset of the SLE manifestations and development of AMI was 7.7 +/- 5.4 year (range of 1 month to 20.5 years). We divided the patients into three subgroups according to their coronary involvement type (Group I: normal coronary artery or coronary thrombosis (n = 16); Group II: coronary aneurysm/arteritis (n = 12); Group III: coronary atherosclerosis (n = 22)). The lag time between the onset of the SLE manifestations and development of MI in the subgroups showed variations: Group I < Group II < Group III. Both prevalence of renal involvement and steroid therapy were higher in patients with coronary atherosclerosis than were in Group I. There were one or more risk factors for atherosclerosis in 39 SLE patients. AMI in young SLE patients may be seen, albeit rare. We suggest that clinicians should have a low threshold for cardiac evaluation in patients with SLE. Also, traditional risk factors could be managed through preventive measures.

Objectives: This study sought to investigate the relationship between multiple plaque ruptures, C-reactive protein (CRP), and clinical prognosis in acute myocardial infarction (AMI)., Background: Several studies have demonstrated that ruptured or vulnerable plaques exist not only at the culprit lesion but also in the whole coronary artery in some acute coronary syndrome (ACS) patients. Recent studies have reported that a ruptured plaque at the culprit lesion is associated with elevated CRP, which indicates a poor prognosis in patients with ACS., Methods: We performed intravascular ultrasound in 45 infarct-related arteries and another 84 major coronary arteries in 45 first AMI patients., Results: Plaque rupture was observed in 21 patients (47%) at the culprit site. Intravascular ultrasound revealed 17 additional plaque ruptures at remote sites in 11 patients (24%). Patients with multiple risk factors were more frequently found in our multiple-plaque rupture patients compared with single-plaque rupture or nonrupture patients (82% vs. 40% vs. 29%, p = 0.01). High-sensitive CRP levels had a positive correlation with the number of plaque ruptures (p < 0.01). All culprit lesions were successfully treated by percutaneous coronary intervention. Patients with multiple plaque rupture showed significantly poor prognosis compared with others (p = 0.01)., Conclusions: Multiple plaque rupture is associated with systemic inflammation, and patients with multiple plaque rupture can be expected to show a poor prognosis. Our results suggest that AMI treatment should focus not only on stabilization of the culprit site but also a systemic approach to systemic stabilization of the arteries.

P-selectin is a transmembrane protein present in the alpha granules of platelets and the Weibel-Palade bodies of endothelial cells. Following activation, it is rapidly translocated to the cell surface. P-selectin expression in platelets has been shown to be elevated in disorders associated with arterial thrombosis such as coronary artery disease, acute myocardial infarction, stroke, and peripheral artery disease. P-selectin mediates rolling of platelets and leukocytes on activated endothelial cells as well as interactions of platelets with leukocytes. Platelet P-selectin interacts with P-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes to form platelet-leukocyte aggregates. Furthermore, this interaction of P-selectin with PSGL-1 induces the upregulation of tissue factor, several cytokines in leukocytes and the production of procoagulant microparticles, thereby contributing to a prothrombotic state. P-selectin is also involved in platelet-platelet interactions, i. e. platelet aggregation which is a major factor in arterial thrombosis. P-selectin interacts with platelet sulfatides, thereby stabilizing initial platelet aggregates formed by GPIIb/IIIa-fibrinogen bridges. Inhibtion of the P-selectin-sulfatide interaction leads to a reversal of platelet aggregation. Thus, P-selectin plays a significant role in platelet aggregation and platelet- leukocyte interactions, both important mechanisms in the development of arterial thrombosis.

Cardiovascular diseases are the leading cause of morbidity and mortality in Western countries. Atherosclerosis, the background for many cardiovascular diseases, is characterized by the accumulation of lipid and fibrotic entities in large arteries and bears many similarities with chronic inflammatory diseases such as rheumatoid arthritis. Common features include extravasation of blood-derived leukocytes, as well as production of cytokines, chemokines and matrix-degrading enzymes. There are also many shared signaling pathways, including activation of the nuclear factor kappaB (NFkappaB) cascade. In the context of atherosclerosis, there are a range of candidate stimuli which can activate NFkappaB, including traditional risk factors, infectious agents, cytokines and cell-cell contact. Many inflammatory genes relevant to the pathogenesis of atherosclerosis are regulated by NFkappaB, the activated form of which is present in atherosclerotic plaques. Thus, it is essential to understand the role of this important signaling cascade in atherosclerosis, in a quest for more specific therapeutic targets.

Thrombosis of the coronary artery following plaque rupture is the commonest substrate of acute coronary events. The detection of atherosclerotic plaques prone to rupture would allow identifying patients at risk for acute coronary events and aggressive intervention. It has been assumed that the plaque morphology happens to be the major determinant for clinical outcome. The risk of plaque rupture depends upon the prevalence of plaques that have a large lipid core, a thin fibrous cap, and a dense inflammation of the fibrous cap. Evaluating monocytes and the lipid core and their proportions in the atherosclerotic lesion by novel radionuclide imaging strategies may predict a likelihood of an acute coronary event.

Rupture of atherosclerotic plaque has been identified as the proximate event in the majority of cases of acute ischemic syndromes. Plaque rupture exposes thrombogenic components of the plaque, activating the clotting cascade and promoting thrombus formation. Future culprit lesions are difficult to identify, however, and angiographic assessment of stenosis severity is prone to underestimation. Compared with plaques that cause severe luminal stenosis, vulnerable plaques may cause relatively minor stenosis, although they account for more cases of rupture and thrombosis. Such unstable, vulnerable plaques may be associated with outward remodeling of the vessel. Because severely stenotic plaques are more likely to stimulate collateral circulation to the post-stenotic segment, plaque rupture and thrombosis at such sites may be clinically silent. Characteristic histomorphologic features of vulnerable plaques include a high lipid content, increased numbers of inflammatory cells, and extensive adventitial and intimal neovascularity. The fibrous cap of an atherosclerotic plaque may become thin and rupture as a result of the depletion of matrix components through the activation of enzymes, such as matrix-degrading proteinases and cystine and aspartate proteases, and through the reduction in the number of smooth muscle cells. Activated T cells may also inhibit matrix synthesis through the production of interferon-gamma. A number of triggers of plaque rupture have been identified. Also, some thrombi may occur without rupture of the fibrous cap. Reducing the lipid component and inflammation in atherosclerotic plaques may help reduce the risk of plaque rupture. This may account for the clinical benefit of risk-factor reduction gained from changes in lifestyle and from drug therapy.

The propensity of plaque to disrupt is a major determinant of future ischemic events. Although they are distinct from one another, the atherosclerotic and thrombotic processes appear to be interdependent and may be integrated under the term "atherothrombosis." It is now clear that plaque composition, rather than the percent stenosis, is a major determinant of plaque vulnerability. Plaque disruption seems to depend on both passive and active phenomena and is not purely mechanical. Inflammation (activation of monocytes/macrophages) is a major determinant of both plaque vulnerability and thrombogenicity as they relate to plaque disruption. In one-third of acute coronary syndromes, there is, however, no plaque disruption but only superficial erosion of a markedly stenotic, fibrotic plaque. In these cases, thrombus formation may be exacerbated by a hyperthrombogenic state present in patients with certain systemic risk factors. The endothelium plays a pivotal role in vascular homeostasis and hemostasis. This dynamic organ regulates blood thrombogenicity as well as contractile, secretory, and mitogenic activities in the vessel wall. Some classic risk factors induce endothelial dysfunction by reducing the bioavailability of nitric oxide, increasing tissue endothelin-1, and activating pro-inflammatory signaling pathways. Vascular hemostasis, which is the maintenance of blood fluidity and vascular integrity, is achieved by counter-balancing the intrinsic clotting tendency of blood. As a consequence of the central role of endothelial cells in hemostatic control, a dysfunctional endothelium will generate a pro-thrombotic environment favoring development of atherosclerotic lesions and thrombotic complications.

Our perception of the mechanisms underlying the acute complications of atherosclerosis has significantly changed in the last decade. Most coronary thromboses result from a rupture or a fissure in the protective fibrous cap of atherosclerotic plaque, but less common from a superficial erosion. The extent of thrombosis is a determinant of the clinical picture of acute coronary syndromes. Until now, we held a high grade stenosis responsible for the vast majority of acute coronary syndromes. However, current findings establish the relevance of qualitative aspects of plaques as important determinants of the vulnerability of plaques, i.e. the risk to cause acute complications. Among morphologic and functional features of plaques, inflammation has emerged as a leading pathophysiologic mechanism. In addition to local effect of inflammation at the level of the unstable plaque itself, systemic factors of the inflammatory response may alter the thrombogenicity of a vulnerable plaque. Knowledge of the role of inflammation helps us to understand the mechanisms by which therapeutic efforts can reduce clinical events. The clinical benefits of dietary modifications, pharmacotherapy with statins, and ACE inhibitors may be due in part to an anti-inflammatory action.

We report a case of antiphospholipid syndrome (APS) which presented with clinical and laboratory signs of an autoimmune hemolytic anemia (AHA), in the absence of manifestations typically related to APS. The diagnosis of APS was made only after the occurrence of a sudden severe heart failure due to an intraventricular thrombus requiring a surgical approach. An accurate thrombophilic screening is warranted also in patients with apparently idiopathic AHA., (Copyright 2002 S. Karger AG, Basel)

A number of clinical studies have suggested that carriage of the low frequency allele (b) of the human platelet antigen 1 (HPA-1) system is a risk factor for coronary thrombosis. We have examined the effect of a series of HPA biallelic polymorphisms (systems -1, -2, -3 and -5) on the in vitro platelet aggregation in response to adrenaline and collagen in 30 healthy volunteers. There was a significantly higher prevalence (10 out of 18) of carriers of the HPA-1b polymorphism among subjects showing a > 50% aggregation response to adrenaline ('responders') than the prevalence (1/12) in 'non-responders' (P < 0.05). Platelets heterozygous for the HPA-1b polymorphism showed a significantly higher rate (slope) and greater extent (%) of adrenaline-induced aggregation than platelets not carrying the HPA-1b allele (P < 0.05). A greater extent of collagen-induced aggregation was also demonstrated in HPA-1ab platelets (P < 0.05). Inhibition of adrenaline-induced aggregation following incubation with aspirin was greater (P < 0.01) in HPA-1ab than in HPA-1aa platelets. Collagen-induced aggregation was slower in carriers of the HPA-5b allele than in HPA-5aa subjects (P < 0.05). Polymorphisms of the HPA-2 and HPA-3 systems were not associated with different aggregation responses to either adrenaline or collagen. These results support the clinical observation that polymorphism HPA-1b may predispose to increased platelet thrombogenicity and suggest that the presence of polymorphism HPA-5b might render the platelet less reactive to collagen.

We tested the hypothesis that selectin inhibition with blocking antibodies or a small-molecular-weight inhibitor of L-, P-, and E-selectin, methoxybenzoylpropionic acid (MBPA), prevents thrombus formation in a canine coronary Folts' model. Cyclic flow variations (CFVs) were induced by crush injury and constriction of the left anterior descending coronary artery in dogs. Systemic infusion of antibodies to P- and L-selectin abolished CFVs, respectively, in 50% and 17% of treated dogs [P = not significant (NS)]. The combination of P- and L-selectin antibodies suppressed CFVs in 60% of treated dogs (P = NS). In contrast, systemic selectin blockade by intravenous infusion or local adventitial application of MBPA markedly reduced CFVs and, in addition, reduced myocardial myeloperoxidase (MPO) activity. We conclude that inhibition of L-, P-, and E-selectin binding by a small-molecular-weight, noncarbohydrate compound markedly reduces arterial thrombosis, whereas systemic administration of antibodies to L- and P-selectin fail to reproduce this antithrombotic effect. These results underscore the role of selectins in the pathogenesis of arterial thrombosis under high shear stress and suggest that inhibition of P- and L- selectin may not suffice to prevent thrombus formation in this model. The role of E-selectin in thrombus formation in this model awaits further testing.

Objectives: To define the role of mast cells in plaque destabilization., Background: Inflammation is an essential feature of human coronary plaques. Macrophages and T lymphocytes are considered to contribute to destabilization of the plaques. The role of mast cells in this setting is less well studied. We therefore counted the mast cells in coronary atherectomy specimens from patients with chronic stable angina, unstable angina and severe unstable angina., Methods: Patients studied had chronic stable angina (group 1, n=11), "stabilized" unstable angina (group 2; Braunwald's class I and II, n=11) and "refractory" unstable angina (group 3; Braunwald's class III, n=7). Samples of culprit lesions (n=29) were obtained by directional atherectomy, snap-frozen and analyzed immunohistochemically. The numbers of mast cells and T lymphocytes per square millimeter squared were counted and the areas containing macrophages and smooth muscle cells were measured by computed planimetry., Results: We found that the numbers of mast cells and T lymphocytes increased from group 1 through groups 2 to 3. Specimens from group 3 also contained the largest numbers of tumor necrosis factor alpha (TNF-alpha)-positive mast cells and of matrix metalloproteinase (MMP)-9 (92 kD gelatinase)-positive macrophages., Conclusions: Unstable coronary syndromes are associated with increased numbers of mast cells in culprit lesions. Activated mast cells secrete neutral proteases capable of degrading the extracellular matrix and TNF-alpha, capable of stimulating macrophages to synthesize MMP-9. Our observations suggest that mast cells, in addition to macrophages, contribute to matrix degradation and, hence, to progression of coronary syndromes.

We tested the hypothesis of anaphylaxis as a pathogenic factor in acute myocardial infarction. Mast cells were counted in the myocardium, coronary arteries and airways. Total serum IgE, mast cell tryptase, complements C3, C4, and factor B, were measured in 29 cases of sudden death from coronary artery thrombosis and in 27 controls. We found increased numbers of mast cells in the coronary arteries following coronary death: 46 +/- 21 (SD) compared with 22 +/- 10 (SD) in the control group (P < 0.002). In the myocardium and airways there were no differences between the groups. The concentrations of tryptase and IgE in serum did not differ between the groups although 20% of the coronary deaths had elevated values (> 200 kU/l) compared with 8% in the control group. Of the complement factors, C3 was higher in the coronary deaths (P < 0.05) than in the controls. The results give no evidence of anaphylactic reaction in the pathogenesis of acute myocardial infarction.

To date, six families of cell adhesion molecules are known. These are cell surface receptors that mediate adhesion of cells to each other or to components of the extracellular matrix and include integrins, selectins, the immunoglobulin superfamily, cadherins, proteoglycans and mucins. These cell adhesion molecules play a key role in cell-cell interaction (such as among endothelium, monocytes, smooth muscle cells and platelets) and cell-extracellular matrix interaction (such as between leukocytes, platelets or fibroblasts and the extracellular matrix). The importance of these interactions has recently been demonstrated in clinical trials with the use of an antibody fragment directed against the platelet alpha IIb beta IIIa integrin, with reduction of arterial thrombosis and restenosis after percutaneous coronary interventions. A fundamental role for cell adhesion molecules has been suggested for several other relevant disease processes, including atherosclerosis, acute coronary syndromes, reperfusion injury and allograft vasculopathy. This review focuses on providing the clinically relevant biology of these families of adhesion molecules, setting the foundation for delineation of their emerging role in cardiovascular therapeutics.

We studied the frequency of antiphospholipid antibodies (aPL) in patients undergoing cardiac valve replacement, and present the results in the context of the pathology of the valve lesions. Forty-eight consecutive patients undergoing valve replacement were studied. Of the whole group, 15 (31%) had antibody levels greater than 2 SD above the mean for a control group of healthy persons and 11 (23%) had a level of greater than 3 SD. There was an increased frequency of elevated antibody levels in patients with valves showing fibrocalcific change and a significant association between aPL and valve thrombus. The possible role of these antibodies in the pathogenesis of the valve lesions is discussed.

Antiphospholipidsyndrome is a well-defined entity characterized by spontaneous abortion, thrombocytopenia and recurrent arterial and venous thromboses. The diagnosis is biochemically verified by the presence of antibodies binding to negatively charged phospholipids. A patient with recurrent thromboembolic complications over the years eventually developed a rapidly progressing dyspnoe. Two-dimensional echocardiography showed a large right atrial mass which at operation proved to be a thrombus. Coombs test was positive as were lupus anticoagulans and antibodies against cardiolipin, in addition to thrombocytopenia and prolonged bleeding time. The author reviews the literature and discusses problems regarding diagnostical criteria for antiphospholipidsyndrome, pathogenesis of the "procoagulopathy" and thrombembolic complications associated with the syndrome. Special consideration is given to non-invasive diagnostic methods for distinguishing between atrial myxom and floating thrombus.

A 28-year-old, 16 week primigravida presented with an acute anteroseptal myocardial infarction and a past history of recurrent venous thromboembolism and primary infertility. Although she lacked other clinical features of systemic lupus erythematosus, she had a circulating 'lupus' anticoagulant, anticardiolipin antibodies, a weakly positive anti-nuclear antibody and thrombocytopenia. She died suddenly despite corticosteroid therapy and autopsy revealed coronary arteritis and thrombosis.

Interactions between platelets with injured vascular endothelium contribute to thrombotic occlusion. A murine monoclonal antibody [7E3 F(ab')2] to the platelet GPIIb/IIIa receptor complex was used to inhibit platelet aggregation in an experimental model of coronary artery thrombosis. Prevention of thrombotic occlusion by 7E3 F(ab')2 (0.8 mg/kg bolus i.v.) was studied in dogs with direct current induced intimal injury (100 microA for 5 h) and critical stenosis of the left circumflex coronary artery (LCCA). Baseline LCCA blood flow (CBF) was similar in 7E3 F(ab')2 and control groups, but decreased in the controls [24 +/- 2 ml/min to 0 +/- 0 ml/min, n = 13 (mean +/- S.E.M.)] due to thrombotic occlusion in each case (time to thrombosis 136 +/- 15 min). In the group treated with 7E3 F(ab')2, CBF did not change significantly (27 +/- 3 ml/min to 22 +/- 3 ml/min, n = 6) and thrombotic occlusion did not occur during the 5-h observation period in which intimal injury was produced in the LCCA (P less than 0.001). Oscillations in CBF preceded thrombosis in the control group, but did not occur with 7E3 F(ab')2 treatment (2.2 +/- 0.7 vs. 0 +/- 0, P less than 0.05). The thrombus mass recovered from the LCCA 30 min after occlusion was 8.8 +- 1.3 mg in the controls compared to 2.2 +/- 1.2 mg determined 5 h after administration of 7E3 F(ab')2 (P less than 0.05). When studied ex vivo, before the administration of the test agents, platelets from both groups of dogs aggregated in response to ADP and arachidonic acid. However, after treatment, the ex vivo aggregation of platelets from 7E3 F(ab')2 animals was inhibited whereas platelets from the control animals continued to aggregate ex vivo throughout the period of the experimental protocol (P less than 0.05). The labeling of platelets with 111indium showed accumulation of radioactivity within the thrombus and upon the vascular endothelium which was less in 7E3 F(ab')2 treated dogs as compared to the control group (P less than 0.05). The murine monoclonal antibody 7E3 F(ab')2 did not affect hemodynamic values or the circulating platelet count during the experimental protocol. In conclusion, antibody to platelet GPIIb/IIIa receptors: (1) prevented thrombotic LCCA occlusion, (2) inhibited ex vivo platelet aggregation, (3) minimized platelet deposition on injured vascular endothelium and within formed thrombi, and (4) stabilized CBF during 5 h of continuous direct current induced intimal injury of the LCCA.