Do We Know Enough About The Immune Pathogenesis of Acute Coronary Syndromes To Improve Clinical Practice?

Theme Issue Article
Schattauer 2012
443
Do we know enough about the immune pathogenesis of acute coronary syndromes to improve clinical practice?
Pawel Matusik1; Bartlomiej Guzik1; Christian Weber2,3; Tomasz J. Guzik1
1Translational
Medicine Laboratory, Department of Internal and Agricultural Medicine, Jagiellonian University School of Medicine, Kracow, Poland; 2Institut fr Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Klinikum der Universitt Mnchen, Munich, Germany; 3Munich Heart Alliance, Munich, Germany
Summary
Morbidities related to atherosclerosis, such as acute coronary syndromes (ACS) including unstable angina and myocardial infarction, remain leading causes of mortality. Unstable plaques are inflamed and infiltrated with macrophages and T lymphocytes. Activated dendritic cells interact with T cells, yielding predominantly Th1 responses involving interferon-gamma (IFN-) and tumour necrosis factor-alpha (TNF-), while the role of interleukin 17 (IL-17) is questionable. The expansion of CD28nullCD4 or CD8 T cells as well as pattern recognition receptors activation (especially Toll-like receptors; TLR2 and TLR4) is characteristic for unstable plaque. Inflammation modifies platelet and fibrin clot characteristics, which are critical for ACS. Understanding of the inflammatory mechanisms of atherothrombosis, bridging inflammation, oxidative stress and immune regulation, will allow for the detection of subjects at risk, through the use of novel biomarkers and imaging techniques including intravascular ultrasound, molecular targeting, mag-
netic resonance imaging (MRI) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET). Moreover, understanding the specific inflammatory pathways of plaque rupture and atherothrombosis may allow for immunomodulation of ACS. Statins and anti-platelet drugs are anti-inflammatory, but importance of immune events in ACS warrants the introduction of novel, specific treatments directed either on cytokines, TLRs or inflammasomes. While the prime time for the introduction of immunologically inspired diagnostic tests and treatments for atherosclerosis have not come yet, we are closer than ever before to finally being able to benefit from this vast body of experimental and clinical evidence. This paper provides a comprehensive review of the role of the immune system and inflammation in ACS.
Keywords
Acute myocardial infarction, atherothrombosis, inflammation, atherosclerosis, immunity
Correspondence to: Prof. Tomasz J. Guzik, MD, PhD Translational Medicine Laboratory Department of Internal and Agricultural Medicine Jagiellonian University School of Medicine J Dietl Hospital, Ul. Skarbowa 1 31121 Cracow, Poland E-mail: tguzik@cm-uj.krakow.pl
Received: May 23, 2012 Accepted after minor revision: July 17, 2012 Prepublished online: August 7, 2012 doi:10.1160/TH12-05-0341 Thromb Haemost 2012; 108: 443456
Note: The review process for this manuscript was fully handled by G. Y. H. Lip, Editor in Chief.
Introduction
The role of the immune system and inflammation in the pathogenesis of atherosclerosis and coronary artery disease has been well established during the past two decades (1, 2). In spite of this, morbidities related to atherosclerosis remain the leading cause of mortality worldwide. In particular, acute coronary syndromes (ACSs) represent life-threatening conditions during the natural history of coronary atherosclerosis including unstable angina (UA) and acute myocardial infarction (AMI). Unraveling the immune mechanisms of atherosclerotic plaques has led to attempts to treat atherosclerotic plaque progression using immunomodulation. Immune mechanisms are also involved in the pathogenesis of risk factors such as hypertension or hypercholesterolaemia (3, 4). Much less is known about the immune mechanisms of acute events, as the majority of studies have focused on their thrombotic
nature (5). Thus, most of the therapies for ACS modulate coagulation and platelet function (6). These therapies have greatly improved clinical outcomes in ACS. While it is very important to develop effective new therapies to limit the consequences of acute coronary events, it is much more important to prevent them. However, we are still unable to effectively predict and prevent ACS occurrence. The term vulnerable plaque has been introduced indicating the high risk of plaque rupture or erosion, which subsequently leads to ACS. The vulnerable plaque is, however, difficult to detect, and no biomarkers have been identified so far to allow for early detection of the disease. Recent advances in the understanding of the role of inflammation in ACS give promise for more forthcoming progress in this field. This review will focus on the immune pathogenesis of ACSs and will address possible clinical (either diagnostic or therapeutic) applications of this knowledge.
Thrombosis and Haemostasis 108.3/2012
Downloaded from www.thrombosis-online.com on 2012-12-18 | IP: 77.239.85.129 For personal or educational use only. No other uses without permission. All rights reserved.
EVBM 2011 (Part 1)
444
Matusik et al. Clinical immunology of ACS
Immune events in ACS

While thrombus formation is the most critical step in ACS, it has been known for over a decade now that inflammation is exacerbated during both UA and MI (7). Gene arrays performed on unstable plaques have very often pointed to various immune associated genes alongside matrix metalloproteinases and tissue factor (TF) (8, 9). This inflammatory response has been initially thought to be induced by tissue damage in ACS. While there is no doubt that immunological response to damage is critical in modulating long term consequences of ACS such as heart failure (1012), recent studies point to the fact that specific immune mechanisms may underlie plaque instability, and may even modulate platelet function and thrombus formation (13, 14). Immunopathogenetic studies of atherosclerotic plaques from patients with ACS as well as studies in animal models show activated macrophages, T cells and dendritic cells at sites prone to plaque rupture or erosion (1517). Studies of platelet transcriptome, which give insight into events directly preceding acute coronary events in humans, also revealed several changes in immune related genes, such as CD69 and myeloid-related protein-14 (MRP14) (18). Thus, inflammatory responses in ACS include systemic immune activation, local inflammation in the vulnerable plaque and immune reactions associated with the thrombotic event itself.
EVBM 2011 (Part 1)
Systemic inflammation is associated with altered cytokine profiles in plasma in acute coronary events. While smaller studies demonstrate increased IFN- or IL-17 levels, and decreased inhibitory TGF-1 (31), many larger studies attempting to link specific cytokine or chemokine levels to ACS have been inconclusive (32). For instance, while RANTES is increased in vulnerable and unstable plaques, the plasma levels do not seem to adequately reflect the risk (32), although the jury is still out on this particular issue (33). One explanation might be that inflammatory responses occur locally in the plaques, which may not be transferred to the peripheral blood level measurements sufficiently. Thus, we must focus on local immune events within the unstable plaque or coronary thrombus.
A vulnerable plaque is an inflamed plaque

Sites of atherothrombosis leading to ACS are associated with plaque rupture (60%), plaque erosion (30%), calcified nodules (27%) or very rarely with isolated intra-plaque haemorrhage (34, 35). Plaque rupture has been initially considered predominantly mechanical, as it occurs at sites of turbulent blood flow (5). Very soon several distinct biological features of rupturing plaques became apparent. They are characterised by the presence of a thin fibrous cap, overlying a necrotic core (thin-cap fibroatheromas; TCFA) which is heavily infiltrated by macrophages (density up to 26%) and T lymphocytes, pointing the attention to the critical role of the immune system in plaque vulnerability ( Fig. 1) (5, 36, 37). Recent studies also point to the important role of perivascular adipose tissue in this process (38, 39). These inflammatory characteristics of plaque are related to the immune nature of atherosclerosis itself (which has been expertly reviewed elsewhere [2, 40]). However, culprit lesions in ACS show particularly strong immune activation, characterised by, for example, a high level of human leukocyte antigen (HLA)-DR (17) or Toll-like receptor (TLR1, 2 and 4) expression (41) ( Table 1). Interestingly, both M1 and M2 type macrophages were identified in vulnerable plaque regions, although it is now disputed how the functional balance between them relates to plaque instability (42). Matrix metalloproteinases (MMP-7, MMP-8, MMP-12, MMP-13, MMP-14 and particularly MMP-9) have been implicated in plaque rupture (43), as they decrease collagen content by degradation and suppression of its production by apoptotic smooth muscle cells (44) leading to a thinning of the fibrous cap and a generation of necrotic core. MMPs are released from activated macrophages and foam cells at the most vulnerable, shoulder regions of plaques (13, 43). Activated macrophages and neutrophils in vulnerable plaque also produce reactive oxygen species (ROS), which inhibit tissue derived inhibitors of metalloproteinases (TIMPs), further activate MMPs (43, 45) and exacerbate endothelial dysfunction. This may link up with recent discoveries of predictive role of myeloperoxidase in ACS to inflammation (46). This link between matrix metalloproteinases activation and inflammation is the critical step in atherothrombosis (36).
Schattauer 2012
Systemic inflammation in ACS

High C-reactive protein (CRP) levels, as indicators of systemic inflammation are accepted risk factors for acute coronary events (19). Moreover, ACS is associated with increased counts of total leukocytes, and in particular with an increased proportion of T lymphocytes (2022). Increased CD4+CD28null T cells [23] and decreased CD4+CD25+Foxp3+ T regulatory (Treg) cells producing anti-inflammatory interleukin (IL)-10 and transforming growth factor (TGF)- were identified in the peripheral blood of ACS patients (24, 25). At the same time, increased Th1 (interferon [IFN]-; IL-1beta, IL-12 p70 and regulated upon activation, normal T-cell expressed, and secreted (RANTES)) and decreased Th2 cytokines and expression of C-C chemokine receptor type 3 (CCR3) were identified (26). Th17 cells (CD4+ T-cells producing IL-17) are increased in ACS (27). However, there is no consensus regarding changes of lymphocyte subpopulations in the peripheral blood in ACS (27). Increased levels of CD14+ monocytes were found in ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) patients, when compared with unstable angina (28). Monocyte subpopulations in ACSs appear to be altered as well. Peak CD14+CD16+ monocyte levels are increased in AMI patients (29). Moreover, circulating and localised at culprit site CD14+CD16+ monocytes were identified to show largest expression of TLR4 and suggested to be involved in AMI pathogenesis (30).
445
Alongside macrophages, CD4+ and to a lesser extent CD8+ T cells are abundantly present in unstable regions of atherosclerotic plaques. In particular, Th1 lymphocytes, producing IFN- and tumour necrosis factor (TNF)-, have been abundant in unstable plaques (36, 47), while anti-inflammatory, T regulatory cells secreting IL-10 and TGF- attenuate atherosclerosis and stabilise plaque morphology (36, 48). Some studies confirm lower numbers of forkhead box P3 (FoxP3)+ T regulatory cells in unstable plaques (49), but others show their abundance (50). However, it is not the number of T regulatory cells, but their function that matters. Autoimmune diseases are often associated with increased numbers of dysfunctional T regulatory cells, which fail to provide inhibitory effects. Interestingly, while IL-17 has been found to play a pro-inflammatory role in numerous autoimmune diseases, a recent study has demonstrated that a lack of IL-17 is associated with an increased formation of unstable, vulnerable plaques (51). Moreover clinical studies show that activation of Th17/Th1 and Th1, but not of Th17 cells, is associated with ACS (52).
CD28null CD4 and CD8 T cells are very important players in the immunopathogenesis of plaque instability. Clonally expanded CD4+CD28null T cells with strong pro-inflammatory properties were found in unstable coronary plaques, and may amplify and sustain inflammatory processes (23). The CD4+CD28null T cells in ACS are characterised by an overexpression of alternative costimulatory receptors (OX40 inducible co-stimulator and 41BB cytotoxic T lymphocyte associated antigen-4, programmed death-1) (53), indicating mechanisms of their activation in ACS. Recent studies point particular attention to the role of dendritic cells (DCs) in cardiovascular disease (54) as well as unstable plaques. Their interactions with plaque residing T cells is the primary feature of rupture-prone plaque, even in the absence of thincap fibroatheromas (55). These DCs form clusters at the ruptureprone plaque regions with frequent DC-T cell contacts (55). They show markers of DC activation such as HLA-DR and CD83, and produce chemokines like CC chemokine ligands (CCL) 19 and CCL21 (56). Moreover, plasmacytoid dendritic cells in unstable regions produce INF-, which further stimulates inflammatory
Figure 1: Role of immune system in atherosclerotic plaque rupture. Infiltration with macrophages, T cells, B cells and neutrophils occurs at all vessel wall layers (including perivascular adipose tissue; PVAT) and thrombus itself and is especially strong at the site of plaque rupture. Activated leukocytes produce matrix metalloproteinases (MMPs), which degrade collagen leading to fibrous cap thinning and plaque rupture or erosion. Immune cells are also present and modulate thrombus formation. A white, platelet-rich, thrombus forms at the rupture site, while a red, erythrocyte-rich, thrombus Schattauer 2012
propagates both proximally and distally and may lead to total vessel occlusion. Based on [20, 23, 125]. TLR Toll-like receptor; PVAT perivascular adipose tissue; IL interleukin; IFN interferon; MIF macrophage migration inhibitory factor; MIP-1 macrophage inflammatory protein-1; MCP-1 monocyte chemoattractant protein-1; tPAI tissue plasminogen activator inhibitor; IP-10 interferon-gamma-inducible protein-10; GM-CSF granulocyte-macrophage colony-stimulating factor; HLA-DR human leukocyte antigen-DR;
EVBM 2011 (Part 1)
446
reaction in the plaque (57, 58). IFN- also induces TNF-related apoptosis-inducing ligand (TRAIL) on CD4+ T lymphocytes. TRAIL binds to its receptors, TRAIL-R1 and TRAIL-R2 which can be expressed on vascular smooth muscle cells (VSMCs) and leads to the activation of Fas-associated death domain (FADD), caspase-8 and subsequently caspase-3 activation, which results in VSMC death (57, 58). Apoptosis of VSMCs, immune cells and endothelium can be induced also by oxidative stress, oxidized lipoprotein (oxLDL), hypoxia or IFN- (59) and is a very important factor in plaque destabilisation (59). Various proinflammatory stimuli may activate inflammasomes (molecular platforms, which assemble multiple factors to provide caspase-1 activation) (60). To summarise, activated DC in shoulder regions and instability-prone areas of plaques produce chemokines, and thus regulate immune cell traffic into these regions of plaques. They may also augment T-cell stimulation and provide optimal conditions for T lymphocyte activation, resembling the microenvironment in organised lymphoid tissues in the vulnerable regions of atherosclerotic plaques (56). Mast cells have also been identified in atherosclerotic plaques, especially at sites of plaque rupture, erosion or haemorrhage (61). Pro-inflammatory cytokines, histamine, tryptase, leukotriens, thromboxane and chymase, secreted by mast cells can induce MMPs while proteases such as tryptase and chymase can cleave extracellular matrix, causing plaque destabilisation and/or intraplaque haemorrhage (61, 62). Mast cells can also contribute in macrophage apoptosis and leukocyte migration (61). Finally, much less is known about the role of activated B cells and neutrophils in plaque instability, although this is now a very active area of research which will likely bring many valuable new findings in the near future. Cells involved in immune regulation of ACS have been summarised in Table 2. While vulnerable, hot plaque is a major risk factor for the causation of an acute coronary event, it must be remembered that plaque rupture is not always associated with ACS. Some ruptured plaques can even be clinically silent, indicating that other, most likely pro-thrombotic mechanisms must coincide with plaque rupture.
Inflammation modifies thrombus formation

Thrombosis is also the most critical mechanism for ACS including STEMI (36). The local microenvironment, including inflammatory milieu, is critical for thrombus formation. Intracoronary ACS levels of cytokines [IL-1ra, IL-6, IL-8, IL-12, IL-17, IFN-, macrophage migration inhibitory factor (MIF), macrophage inflammatory protein (MIP)-1alpha, monocyte chemoattractant protein (MCP)-1, tissue plasminogen activator inhibitor (tPAI)-1, interferon-gamma-inducible protein (IP)-10, eotaxin and granulocytemacrophage colony-stimulating factor (GM-CSF)] are increased when compared with aortic blood (2022). While this may be a marker of unstable plaque inflammation, it will certainly affect platelet function as well as fibrin generation. Coronary thrombi
differ, both in architecture and composition (2022) from other circulatory thrombi (20, 63). Fibrin accounts for 55 18%, platelets for 17 18%, red blood cells for 11 9%, crystals of cholesterol for 5 8%, while leukocytes for 1.3 2.0% of ACS intracoronary thrombi (21). While leukocyte content is not predominant, they may play an important modulatory role. Leukocytes include an increased content of CD14+ monocytes and a decreased content of CD66b+ granulocytes, B cells and T cells, compared to aortic blood (20). The Toll-like receptors, TLR2 and TLR4, were overexpressed on monocytes and granulocytes (TLR2) in the intracoronary thrombi and play a functional role (20). Leukocytes are activated in the thrombus as is indicated by the elevated number of proinflammatory cytokines presence (64). An increasing body of evidence suggests that inflammation in the thrombus is not just a bystander, but actively modifies the thrombosis. Activated inflammatory cells, such as macrophages in the plaque or thrombus, release pro-thrombotic TF and plasminogen activator inhibitor (PAI)-1 (65, 66). Cytokines such as TNF- or IL-1 as well as CD154 (CD40L), a ligand binding to CD40 on the leukocytes, induce TF expression (66, 67). All of the following, activated CD4+ T lymphocytes, neutrophils and macrophages as well as non-immune platelets, endothelial cells and smooth muscle cells, produce CD40L (66, 68). Cytokines produced by leukocytes including IFN- and IL-4 are associated with residual platelet reactivity in patients with ACS on dual antiplatelet therapy (14). Importantly, TLR1 and TLR6 are expressed on platelets although their role in ACS has not been well established yet (69). The interaction between leukocytes and platelets is, however, two-directional, as platelets produce inflammatory modulators which may differentially modulate and traffic monocytes or T cells into the thrombus. These include RANTES, TGF-, plateletderived growth factor, platelet factor 4, trombospondin or nitric oxide (66). RANTES may be especially important as it triggers monocyte or neutrophil accumulation on inflamed or atherosclerotic endothelium, initiating acute coronary events (70). Circulating neutrophil-platelet and monocyte-platelet aggregates in ACS have also been reported (7173). Finally, inflammation may also alter fibrin structure, generating abnormally dense fibrin networks that resist fibrinolysis (74). This is particularly important as fibrin contributes to the majority of intracoronary thrombi. Taking into account the above-mentioned examples of leukocyte-platelet interface it is reasonable to assume with some degree of confidence that thrombosis activates inflammation and that inflammation can amplify thrombosis. However the exact mechanisms of these interactions and possible therapeutic implications are still unclear.
EVBM 2011 (Part 1)
Immune system in myocardial injury

Myocardial injury and heart failure are the main consequences of ACS (75). However, injured myocardium by inducing severe immune responses may also play modulating role in the natural his Schattauer 2012
447
tory of the disease. Ischaemia-reperfusion injury or necrosis to the myocardium leads to the generation of alarmins or danger-associated molecular patterns (DAMPs) from the cells or the extracellular matrix (61, 76) ( Fig. 2). They elicit innate immune reactions similar to immune activation induced via pathogen-associated molecular patterns (PAMPs), through TLRs. TLRs include at least 13 molecules, expressed by various cell types including leukocytes as well as vascular cells. These molecules can be either expressed on the cell membrane (TLR12, TLR46 and TLR11) or in the internal cellular compartments (TLR3, TLR79 and murine TLR13) (61). TLR2 and TLR4 have been the most intensely studied in the context of atherosclerosis and ACS and are summarised in Table 1. A role of other TLRs in cardiovascular diseases, such as the contribution of TLR3 and TLR7/8 in viral cardiomyopathy and/or myocarditis was reported (77). On the other hand TLR4, TLR5 and TLR9 are involved in adverse myocardial remodelling and/or contractile dysfunction (77). A more detailed description of TLRs function and role in cardiovascular diseases has been reviewed recently elsewhere (61, 7779). The importance of infiltrating neutrophils, monocytes and macrophages in ischaemia-reperfusion injury is very well defined ( Fig. 2) (80). Several chemoattractants including IL-8 (chemokine (C-X-C motif) ligand (CXCL)-8), CXCL-1, MCP-1 or fractalkine and adhesion molecules (L- and P-selectin; intercellular adhesion molecule (ICAM)-1) are implicated in leukocyte recruitment into the damaged myocardium during ACS (81). Neutrophils and monocytes release multiple inflammatory mediators such as TNF-, proteases or ROS which contribute to myocardial
Are ACS driven by acute and chronic infections?

Taking into account the profound involvement of immune activation in ACS, infections or other systemic inflammatory reactions could be associated with increased ACS risk. Indeed, up to 30% of MIs occur after upper respiratory tract infection (83), and the risk of ACS is greatly increased following respiratory, but not urinary, infections (84). The risk of MI or stroke is at its highest for the few days after infection (85) and remains elevated for over 21 days (86). Several other acute infections have been linked to ACS. These include gastroenteritis, N. meningitidis, C. canimorsus and S. aureus infections (85). Chronic infectious agents such as Ch. pneumoniae or P. gingivalis, initially linked to atherosclerosis, may increase risk of acute coronary events (8789). However, their direct role in ACS is controversial and has not been supported by strong evidence.
Figure 2: Myocardial infiltration by immune cells during the course of

myocardial infarction. Neutrophils and monocytes migrate into myocardial tissue attracted by IL-8, MCP-1 and other chemokines. Augmented release of inflammatory mediators, proteases and reactive oxygen species contributes to enhanced myocardial damage. Immune cells also contribute to proper healing and remodelling after myocardial infarction. Activated mono-
cytes/macrophages also migrate from infarcted myocardium and may elicit systemic inflammatory response (82). DC dendritic cell; TLRs Toll-like receptors; DAMPs danger-associated molecular patterns; Hsp heat shock proteins; HMGB-1 high-mobility group box-1; IL-8 interleukin-8; CXCL-1 chemokine (C-X-C motif) ligand 1; MCP-1 monocyte chemoattractant protein-1; monocytes/macrophages and T cells are presented as in Figure 1.
Schattauer 2012
EVBM 2011 (Part 1)
injury. Myocardial injury characterised by impaired ejection fraction recovery was recently linked to increased CD14+CD16 monocyte subset during ACS (29). Moreover, monocytes/macrophages activated within myocardial infarct can efflux to the periphery (10%/24 hours) to blood, liver, and spleen and abrogation of this was deleterious for infarct healing, and accelerated heart failure (82). Modulating the immune mechanisms of myocardial damage may be a promising drug target for its prevention during ACS.
448
Table 1: Toll-like receptors 2 and 4 (TLRs) and their ligands involvement in atherosclerosis and ACS (61, 7779). TLR Pathogen-associ- Danger-associ- Atherosclerosis ated molecular ated molecular patterns patterns
2

Acute coronary syndromes
EVBM 2011 (Part 1)
Peptidoglycans Lipoproteins
HMGB-1 Hyaluronic acid Fibronectin-EDA Cardiac myosin
TLR2 found in human coronary arteries and primary adventitial fibroblasts, TLR2 ligands enhance neointima formation and increases atherosclerosis in ApoE-/- mice [126]. TLR2 mRNA, its ligands (EDA and hsp60), and regulators like IRAK-M are increased in advanced plaques in ApoE-/-. TLR4 found in human coronary artery plaques and adventitia, Periadventitial application of lipopolysaccharide augmented neointima formation; TLR4-/-protected [129] TLR4 mRNA, its endogenous ligands (EDA and hsp60) as well as regulating mediators, (IRAK-M) are increased in advanced plaques in ApoE-/-.
Overexpressed on monocytes and granulocytes in coronary thrombi [20] TLR2-/- mice or anti-TLR-2 treatment [127] reduces myocardial ischemia/reperfusion injury. TLR2 -/- mice improved remodelling after MI [128]. Overexpressed on monocytes in coronary thrombi [20] TLR4 -/- reduced the LV remodeling and preserved systolic function [130] Smaller myocardial infarctions in TLR4-/-. Attenuated I/R-induced myocardial apoptosis and cytokine expression in TLR-4 -/- mice [120]
Cell surface lipopoly-saccharides [129]
Hsp60 HMGB-1 Hyaluronic acid Fibronectin-EDA
TLR Toll-like receptor; ds-RNA double-stranded RNA; ss-RNA single-stranded RNA; CpG cytosine-phosphate-guanine dinucleotide; Hsp heat shock protein; HMGB-1 high mobility group box 1; EDA extra domain A.
Infections may contribute to atherosclerosis and ACS development through diverse mechanisms, including direct effects on cells in the vascular wall, circulating cytokines and inflammatory mediators, TLRs activation as well as initiation of autoimmune reactions (90). DC numbers, as well as perivascular macrophage and T cell content, increased in the coronary artery intima and media of patients with systemic infections (85, 91) who died as a result of ACS (91). Infections enhance hypercoagulable states (92) and promote endothelial dysfunction (85, 93) also through the innate immunity, by TLRs activation. Thus we must remember that patients with severe coronary disease, admitted to hospital or in ambulatory practice with upper respiratory tract infection should be considered at high risk of ACS. This knowledge is, however, underestimated in current clinical management, possibly due to the lack of effectiveness of antimicrobial therapies in preventing ACS. The latter results most likely from the presence of some specific pathogen-related characteristic, host susceptibility to infection or concomitant viral infections (89, 90) and should not overshadow epidemiological evidence linking infections to ACS. Annual influenza vaccination, with inactivated vaccine decreases ACS risk (94) for coronary artery disease (CAD) patients and seems more cost-effective than primary and secondary statin prevention and beta-blocker use after MI (83). Moreover, pneumococcal vaccination also decreases MI rate (95). It may therefore, be worth considering if the vaccinations for CAD patients should be as widely used as they are for subjects with chronic obstructive pulmonary disease?
Increased ACS risk in autoimmune diseases

Several systemic autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), antiphospholipid syndrome (APS) or primary Sjgren syndrome (pSS), are associated with enhanced atherosclerosis development and with an increased cardiovascular risk of ACS (96). The underlying mechanisms, which involve both unspecific immune activation and molecular mimicry, are still under intense investigation. Particular interest has focused on APS, which is characterised by recurrent thrombosis and pregnancy loss with antiphospholipid antibodies (aPL) like anticardiolipin (aCL), anti-beta2-glycoprotein-I (antibeta2GPI), or lupus anticoagulant presence. Atherosclerotic events in APS can be mediated by the procoagulant and proinflammatory effects of aPL on endothelium or via autoantibody-mediated thrombosis. Systemic lupus erythematosus (SLE) is associated with a four- to eight-times increase in the risk of CAD and MI, independently of traditional risk factors, and which is also attributed to the presence of auto-antibodies as novel risk factors for ACS (96). Similarly, RA is associated with increased CAD, and the occurrence of ischaemic events of atypical presentation. Moreover, mortality and recurrence of ACS is greater in RA patients (96). Interestingly, in this group of patients a particularly high expansion of CD4+CD28null T cells was found (97). Th17/Treg imbalance, type 1 IFN and TRAIL are among important potential mechanisms linking autoimmune diseases and ACS (97). Moreover, autoimmune mechanisms appear to play a role in ACS even in the absence of autoimmune disease. For example, aCL profile (high IgG and low IgM) is associated with a three-fold increase of the risk of the recurrence of an acute coronary event even in the absence of SLE (98). Further understanding of the mechanisms linking auto Schattauer 2012
449
Immune system markers in the diagnosis and prediction of ACS

Immune-based biomarkers of vulnerable plaque
The primary diagnostic aim in ACS is to identify patients at risk, prior to the event. This is the only way to successfully limit the number of adverse outcomes, but is currently not possible. The taking into account of high CRP levels in addition to traditional risk factors can improve cardiovascular risk prediction (99). However, even the use of an extended biomarker panel, including the use of inflammatory markers such as CRP and fibrinogen, only modestly altered the final results of the risk prediction for the first cardiovascular event in the large Framingham Heart Study population (100). Assessment of specific components of the immune system, such as selected cellular markers, may aid in ACS risk stratification in future. This may include T cell repertoire, characterised by CD4+CD28null T lymphocyte expansion (101) or soluble CD40 ligand determination in patients at risk. CD40L has been used to identify patients for antiplatelet treatment with abciximab to reduce cardiovascular event rate (102). Similarly, pro-inflammatory lipoprotein-associated phospholipase A2 (103) or myeloperoxidase have been shown to predict imminent ACS (104, 105). Finally, microRNA markers as well as metabolomic approaches, partially related to the immunopathogenesis, may in future increase the sensitivity and specificity of prediction of ACS. However, at the moment we do not seem to have a ready prospect for the quick and affordable detection of vulnerable plaque.
Molecular imaging of inflamed plaques

Much greater progress has been made in the possibilities of invasive and non-invasive imaging of hot, unstable spots within atherosclerotic plaques. The majority of these techniques are based on the detection of plaque inflammation in conjunction with assessment of fibrous cap thickness and necrotic core determination. So far the most widely clinically assessed optical coherence tomography (OCT) and virtual histology intravascular ultrasound (VH-IVUS) or hybrid imaging using computed tomography coronary angiography (CTCA) allow for visualisation of thin fibrous cap and necrotic core. New modalities will base more on visualising specific inflammation such as 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET), or magnetic resonance imaging (MRI) and myocardial perfusion imaging tech Schattauer 2012
Immune system targeting in ACS

Animal models
Animal models of atherosclerosis and plaque rupture, such as ApoE-/- mice, have been extensively used to investigate therapeutic approaches to limit plaque instability (40). However, there are no perfect animal models for ACS. Firstly, immunosuppressive
EVBM 2011 (Part 1)
immune disorders and ACS will provide vital proof for the role of immune mechanisms of ACS. We need to better understand if the immune reactions increasing risk of ACS are of a more unspecific nature or whether they are associated with specific antigen stimulations related to these infections or autoimmune reactions.
niques, like single photon emission computed tomography (SPECT) (36, 106). Particular interest has been raised by 18F-FDG positron emission tomography. It is a gold standard for the detection of cancer metastasis, but has been successfully used to image metabolically active atherosclerotic plaques. 18F-FDG accumulation is directly correlated with plaque macrophage content (107). The anti-inflammatory effect of treatments such as statins can also be visualised (108). Increased coronary uptake of 18F-sodium fluoride (18F-NaF) and 18F-FDG by PET is associated with plaque inflammation, prior cardiovascular events (109). Authors of a recent review even posed the question are we ready for the prime time? (108). While this approach is very promising its costs and usefulness need to be verified by large clinical trials before we will be able to pronounce it a success. More recently Gaemperli et al. proposed the use of 11C-labelled PK11195 (the selective ligand for the translocator protein characteristic for macrophages), which may in turn, prove itself to be more specific for imaging plaque inflammation than FDG by PET/ CTA (110). High-resolution MRI allows us to discriminate plaque composition, including lipid core, intraplaque haemorrhage, fibrosis, calcifications or arterial thrombus age (111). Moreover, MRI using magnetic contrast agents targeted for macrophages or other inflammatory cells and molecules, neovascularisation, thrombotic material, high-density lipoprotein (HDL) or fibrin have all been tested at the pre-clinical level (111). Moreover, MRI detection of areas with high MMP activity has been proposed (112). Ultrasmall superparamagnetic iron oxides (USPIOs) targeted for adhesion molecules such as vascular cell adhesion molecule (VCAM)-1 or for molecules involved in apoptosis have been effectively used in ApoE-/- mice for vulnerable plaque identification (113). Electric impedance spectroscopy (EIS) imaging shows that impedance values differ depending on the cellular composition of plaque, in particular in relation to the presence of CD31 (neovascularisation), CD36 (scavenger cells) and MMP-3 (114). This may create new opportunities for vulnerable plaque imaging in the clinical setting. Further development of these approaches, will be enabled by a better understanding of the role individual cells of the immune system play in the pathogenesis of plaque instability, as this will identify the molecular targets we need to image to identify atherothrombosis-prone sites.
450
Table 2: Cellular involvement in ACS in humans. Cell Lymphocytes Acute coronary syndrome

EVBM 2011 (Part 1)
CD3+ CD4+CD28null
HLA-DR expression on both CD4+ and CD8+ T cells in UA patients [131] Increased CD3+CD4+HLA-DR+ T cells presence in AMI and SA patients [132] Expanded in patients with UA, clonally multiplied found in culprit, but not non-culprit lesions [23] Associated with ACS recurrence [101] Increased in DM patients and correlate with first cardiovascular event, as well as with worse ACS outcome [133] Increased in ACS patients [24] Increased in ACS (Th17/Th1 subset) but no difference between AMI, UA, SA [52] High IL-17 transcoronary gradient is associated with higher troponin I [134] Decreased in ACS patients as compared to SA and controls [24] Compromised functional properties in ACS subjects [25] Lower Treg cells in NSTACS, than in STEMI, SA or in controls, highest levels in STEMI patients [135] Increased in AMI and SA [125] HLA-DR+TEM and CXCR3+TEM increased in AMI and SA [125]
Th17 T cells
T regulatory (Treg) CD4+CD25+ high/ Foxp3+ Effector memory T cells (TEM: CD3+CD4+ CD45RACD45RO+CCR7- ) T-cell receptor zetachaindim CD4+ T cells Cytokines producing
Increased in ACS patients, Enhanced transendothelial migratory capacity [136] Increased IFN CD4+ and CD8+ T cells in UA than in SA or controls [11] Increased IFN producing CD4+ (Th1) T cells in ACS, than in SA [137] 12 weeks after UA increase in CD4+ T cell IL-2 and IL-4 with decrease in CD4+ and CD8+ IFN production, rebound to the original levels at three months [11] Reduced TGF-1 producing cells (Th3) in ACS [31] Lower prevalence in AMI patients, than in control subjects [138] Reduced (CD56(dim)) in ACS and SA patients as compared to controls, concomitant loss of function Reduced invariant NK (iNK) T cells in AMI patients, iNK T cells as restenosis predictors [138] Reduction of circulating precursors of mDC in SA, UA and AMI [139] Inverse correlation between mDC and hsCRP or IL-6 [139] Increased mDC in vulnerable carotid plaques [139] No change in circulating precursors of pDC presence in SA, UA, AMI [139] IFN-alpha production by pDC in vulnerable plaque [57, 58] Increased in STEMI and NSTEMI when compared with unstable angina [28] Higher CD11b/CD18 on monocytes in coronary than in aortic blood in UA [140] Increased monocyte LFA-1 (CD11a/CD18), Mac-1, VLA-4, ICAM-1 expression in myocardial infarction patients as compared to controls [141] Peak levels after AMI (on day 3) negatively associated with myocardial salvage and ejection fraction recovery [29] No significant changes during three days after UA event [29] Decreased in AMI patients on admission as compared to UA and SA subjects [29] Peak values after AMI (on day 5) higher than in SA patients [29] Show largest expression of TLR4 [30] Reduced myeloperoxidase intracellular index in ACS patients [142] Higher CD11b/CD18(Mac-1) on Neu in coronary than in aortic blood UA [140] Increased Mac-1 expression in MI [141] Increased activity (histamine; tryptase; leukotriens; thromboxane) in ACS [62] Higher ACS risk of atopic individuals [62] Links between allergic reactions, mast cells and ACSs occurrence Hypereosinophilia presenting as ACS with normal coronaries Cases of eosinophilia and ACSs recurrence, lower rate of ACSs on prednisone treatment [143]
Natural killer cells (NK)
Dendritic cells (DC)

Myeloid DC (mDC)

Plasmacytoid DC (pDC)
Monocytes
CD14+

CD14+CD16CD14+CD16+
Other leukocytes
Neutrophils

Mast cells
Eosinophils
(NSTE) ACS (nonST segment elevation) acute coronary syndrome; STEMI ST segment elevation myocardial infarction; AMI acute myocardial infarction; UA unstable angina; SA stable angina; NCA normal coronary artery; TLR toll-like receptor; TGF-1 transforming growth factor beta-1; IFN interferon ; IL interleukin; NK natural killer; CRP C-reactive protein; IFN interferon; LFA-1 lymphocyte function-associated antigen-1 (CD11a/CD18); VLA-4 very late activation antigen-4; ICAM-1 intercellular adhesion molecule-1.
Schattauer 2012
451
treatment using low-dose (lacking systemic immunosuppressive complications) FK506 decreased inflammatory cell density and reduced necrotic core, while increasing collagen content, indicating a more stable plaque morphology. 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) and antiplatelet drugs have pleiotropic effects reducing plaque inflammation. Simvastatin stabilises plaques across a variety of species including humans, and is associated with an increase in T regulatory lymphocytes in atherosclerotic plaques (115). Non-selective cyclooxygenase (COX)-1 and 2 inhibition, using low dose aspirin in LDL-receptor deficient mice on a high fat diet, decreases circulating ICAM-1, MCP-1, TNF- and stabilises atherosclerotic plaques (116). The similar effects of a selective COX-2 blockade, stabilising plaques, have been described in a pig model of atherosclerosis (117). More specific approaches include the use of immunomodulating cytokines such as TGF-1, which limits plaque instability and
reduces other complications of atherosclerosis (118). As Toll-like receptors have been shown to play a very important role in plaque inflammation ( Table 1), the combined inactivation of TLR2 and TLR4 attenuated inflammation and increased plaque stability in a ApoE -/- mice model (119). Finally the blocking of certain immunogenic epitopes may also prove useful. For example, the use of the anti-Hsp60 antibody attenuated ischaemia-reperfusion-induced myocardial apoptosis and cytokine expression in mice (120). The use by subjects of experiments of various non-pharmacological approaches, such as being subjected to regimens of constant exercise, have been shown to strongly inhibit the presence of both oxidative stress and inflammation in the plaque (121). The aspects described above are selected from a large body of evidence. We need to be careful when translating these findings directly to human disease and treatment. The use of larger animals such as pigs would seem the appropriate choice in a selection of valuable clinical interventions.
Table 3: Selected interventional clinical studies or meta-analyses (if present, described preferentially) of interventions targeted at immune
system in ACS. Clinically relevant approaches using antithrombotic agents e.g. aspirin, lipid lowering drugs e.g. statins or blood pressure lowering treatments e.g. ACE-I with known anti-inflammatory properties are not listed.
Clinical study
Giugliano et al. (meta-analysis)
Intervention Systemic
Corticosteroids
Population
AMI patients
Effect
Associated with 26% decrease in mortality (11 trials). However analysis limited to studies > 100 patients and RCTs shows no benefit. No harm and possible beneficial effects on mortality. Reduced CRP, but trend toward worse event-free survival noticed. No improvement of short-term (30-day) outcome. Trend to lower mortality, lower reinfarction and major cardiac events. Lower rate of recurrent angina, myocardial infarction or death as well as secondary composite variable (coronary revascularisation, MI and death). Did not reduce infarct size (CK-MB assessment) or adverse clinical outcomes. Did not reduce infarct size (determined by CK-MB assessment), but lowered 90-day mortality rate. Did not affect mortality rate. Induced transient leukocytosis, but did not affect coronary blood flow, infarct size or ST-segment elevation resolution. Possible interference of heparin.
Ref.
[144]
MUNA trial DAVIT II study NUT-2
Methyl-prednisolone (48 h course) NSAIDs (randomisation in the 2nd week after AMI). Addition of meloxicam (COX-2 inhibitor) to aspirin and heparin for 30 days. Pexelizumab (an anti-C5 complement mAb) 2 mg/kg bolus < 6 h after onset and 0.05 mg/kg/h for 20 h Pexelizumab 2 mg/kg bolus 0.05 mg/kg per h for 20 h infusion Pexelizumab 2 mg/kg bolus < 6 h after onset and 0.05 mg/kg/h for 20 h Recombinant, humanised anti-CD18 mAb (subunit of beta2 integrin adhesion receptor) intravenous bolus 0.5 or 2 mg/kg, added to recombinant tissue plasminogen activator Antibody against CD11/CD18 (Hu23F2G, 0.3 or 1 mg/kg) within 6 hours of chest pain onset, before angioplasty Recombinant P-selectin glycoprotein ligand-immunoglobulin (75 or 150 mg rPSGL-Ig i.v., P-selectin antagonist), within 6 h of onset
Unstable angina patients AMI patients Non-ST-segment elevation acute coronary syndrome patients STEMI patients undergoing fibrinolysis STEMI patients undergoing primary PCI STEMI patients undergoing primary PCI STEMI patients <12 h from onset
[145] [146] [147]
COMPLY
[148]
COMMA Armstrong et al. LIMIT AMI
[149] [150] [151]
HALT-MI study
STEMI patients
No infarct size decrease. No differences according in corrected TIMI frame and clinical events. High doses increased in minor infections.
[152]
PSALM
Alteplase treated STEMI No benefits in coronary vessel patency, myocardial tissue patients reperfusion or function recovery. Prematurely stopped after 88 patients, due to no efficacy in larger trial (RAPSODY).
[153]
Schattauer 2012
EVBM 2011 (Part 1)
452
Table 3: Continued Clinical study Intervention Local

Dexamethasone-eluting stent (0.5 g/ mm2 of stent, BiodivYsio Matrix Lo)
Population
De novo diagnosed SA or UA Primary PCI patients
Effect
Ref.
EVBM 2011 (Part 1)
STRIDE
Six-month MACE was observed in 3.3%, while binary reste- [154] nosis in 13.3% of patients. Safe, demonstrated the feasibility and effect on in-stent neointimal hyperplasia. Decreased target lesion and vessel revascularisation and major cardiac events compared with BMS. No increase in mortality, recurrent MI or stent thrombosis. [122]
DES (first generation) Wallace et al. (meta-analysis of 8 RCTs and five observational studies, 3 years follow-up). Sakurai et al. (meta-analysis of four RCTs). Hannan et al. LEADERS trial Kim et al. Sirolimus-eluting stents
STEMI patients
Reduced target lesion revascularisation and long-term mor- [155] tality (up to 4 years) compared with BMS. No significant effects on MI recurrence or in-stent thrombosis. Median follow-up of 3.7 years -- lower mortality, TVR and total repeat revascularisation, than BMS treated subjects. [156]
DES (first generation)
Patients with NSTEMI
Biolimus-eluting stents with biodegrad- ACS or SA patients able polymer Sirolimus-eluting stents STEMI patients
Not inferior to sirolimus-eluting stents with durable polymer, [157] endpoints: cardiac death, MI, TVR Associated with lower major cardiac events incidence as [158] well as with decreased target lesion and vessel revascularisation, when compared to zotarolimus-eluting stents during one-year follow-up. Non-inferior to new generation zotarolimus-eluting stents [159] according to primary endpoint (combined: cardiac death, target vessel MI or target lesion revascularisation) and stent thrombosis at one-year follow-up. No differences in in-segment binary restenosis or in-stent late luminal loss. Lower TVR rate, lower stent thrombosis and trend toward lower MI risk, than in sirolimus-eluting stent treated patients in three-year follow-up. As compared to Xience V everolimus-eluting stents (EES) shown non-inferiority according to primary end point (target-lesion failure: death from cardiac causes, any MI, TLR within 12 months) and degree of in-stent stenosis at 13 months. No differences in death from cardiac causes, any MI, revascularisation, stent thrombosis or adverse events rate. [123]
ISAR-TEST 5 trial
Polymer-free sirolimus- and probucoleluting stents
Patients with ischaemic symptoms or myocardial ischaemia evidence (spontaneous or inducible) ACS patients
Kalesan et al.
Implantation of everolimus-eluting stents Resolute zotarolimus-eluting stents (ZES)
Resolute All Comers trial
Patients with SA or ACS
[124]
DES drug-eluting stent; BMS bare metal stent; TVR target vessel revascularisation; TLR target lesion revascularisation; AMI acute myocardial infarction; RCT randomised clinical trial; SA stable angina; UA unstable angina; NSAIDs non-steroidal antiinflammatory drugs; CRP C-reactive protein; PCI percutaneous coronary intervention; h hour; COX cyclooxygenase; MUNA Methylprednisolone in Unstable Angina; DAVIT II Danish Verapamil Infarction Trial II; NUT-2 the Non-steroidal anti-inflammatory Drugs In Unstable Angina Treatment-2; COMPLY COMPlement inhibition in myocardial infarction treated with thromboLYtics; COMMA COMplement inhibition in Myocardial infarction treated with Angioplasty; LIMIT AMI The Limitation of Myocardial Infarction following Thrombolysis in Acute Myocardial Infarction Study; HALT-MI Hu23F2G Anti-Adhesion to Limit Cytotoxic Injury Following AMI; PSALM P-Selectin Antagonist Limiting Myonecrosis; STRIDE STudy of anti-Restenosis with BlodivYsio Dexamethsone-Eluting stent; LEADERS trial Limus Eluted from A Durable versus ERodable Stent coating trial; ISAR-TEST 5 the Intracoronary Stenting and Angiographic Results Test 5; other abbreviations as in Table 2.
Clinical studies
It is much more difficult to assess the effects of anti-inflammatory treatments on plaque stability in humans. Imaging modalities such as intravascular ultrasound or FDG-PET have been used in small to moderate-size studies. Both systemic anti-inflammatory treatments as well as the local delivery of drugs, particularly through drug-eluting stents (DES), have been used to stabilise plaques. The major studies are summarised in Table 3. In particular, statin use
has been recommended for plaque stabilisation. Moreover several studies which are testing the use of anti-cytokine and immunomodulating treatments in humans are currently under way. Local delivery of anti-proliferative and anti-inflammatory molecules on DES is valuable, as DES are clinically used. DES have been associated with superior features of plaque stabilisation, although the possible anti-endothelial effects of some of the drugs available on stents must be considered ( Table 3) (122). Anti-inflammatory drugs such as sirolimus (rapamycin), a calcineurin inhibitor,
Schattauer 2012
453
which inhibits T cell activation by interfering with IL-2 actions, shows superiority over paclitaxel a pure antimitotic agent, which stabilises intracellular polymers of microtubules. Use of other, newer immunosuppressant agents on stents such as zotarolimus or everolimus appears very promising in clinical trials (123, 124). Local delivery of anti-inflammatory medications may be also provided by direct, one shot drug delivery to the area of high risk plaque during angiography or PCI. Among other anti-inflammatory approaches photodynamic therapy, cooling, heating and sonotherapy of vulnerable plaques have been proposed (35). In summary, several methods, including statins, aspirin and other antiplatelet treatments have anti-inflammatory effects and induce plaque stabilisation. However, we are now close to introducing specific treatments targeting the various individual immune mechanisms of ACS.
Conclusions
Immune mechanisms are critical for the development of plaque rupture and atherothrombosis. The understanding of these specific mechanisms brings us closer to the ability to successfully detect unstable atherosclerotic plaques and identify patients at high risk of ACS. Moreover, attempts are made to employ immunomodulating therapies in the treatment of atherothrombosis and prevention of ACS. However, before we can achieve that we need to further uncover the very specific mechanisms of immune involvement in ACS, so that novel therapies are free of strong immunosuppressant activities, which are associated with significant adverse clinical outcomes. While the prime time for the clinical use of the results of many years of research into the immune mechanisms of atherosclerosis is not there yet, we are closer than ever before to being in a state of finally benefiting from this vast body of experimental and clinical evidence.
Acknowledgements
TJG and PM are supported by European Union Structural Grant for the Foundation for Polish Science/Welcome/2009/02 and The Wellcome Trust International Senior Research Fellowship.
Conflicts of interest
None declared.
References
1. Lutgens E, Binder CJ. Immunology of atherosclerosis. Thromb Haemost 2011; 106: 755756. 2. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature 2011; 473: 317325. 3. Lob HE, Marvar PJ, Guzik TJ, et al. Induction of hypertension and peripheral inflammation by reduction of extracellular superoxide dismutase in the central nervous system. Hypertension 2010; 55: 277283.
4. Guzik TJ, Hoch NE, Brown KA, et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med 2007; 204: 24492460. 5. Arbab-Zadeh A, Nakano M, Virmani R, et al. Acute coronary events. Circulation 2012; 125: 11471156. 6. Boden H, van der Hoeven BL, Karalis I, et al. Management of acute coronary syndrome: achievements and goals still to pursue. Novel developments in diagnosis and treatment. J Intern Med 2012; 271: 521-536. 7. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364: 937952. 8. Randi AM, Biguzzi E, Falciani F, et al. Identification of differentially expressed genes in coronary atherosclerotic plaques from patients with stable or unstable angina by cDNA array analysis. J Thromb Haemost 2003; 1: 829835. 9. Razuvaev A, Ekstrand J, Folkersen L, et al. Correlations between clinical variables and gene-expression profiles in carotid plaque instability. Eur J Vasc Endovasc Surg 2011; 42: 722730. 10. Liuzzo G, Baisucci LM, Gallimore JR, et al. Enhanced inflammatory response in patients with preinfarction unstable angina. J Am Coll Cardiol 1999; 34: 16961703. 11. Liuzzo G, Kopecky SL, Frye RL, et al. Perturbation of the T-cell repertoire in patients with unstable angina. Circulation 1999; 100: 21352139. 12. De Palma R, Del Galdo F, Abbate G, et al. Patients with acute coronary syndrome show oligoclonal T-cell recruitment within unstable plaque: evidence for a local, intracoronary immunologic mechanism. Circulation 2006; 113: 640646. 13. Finn AV, Nakano M, Narula J, et al. Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol 2010; 30: 12821292. 14. Gori AM, Cesari F, Marcucci R, et al. The balance between pro- and anti-inflammatory cytokines is associated with platelet aggregability in acute coronary syndrome patients. Atherosclerosis 2009; 202: 255262. 15. Manthey HD, Zernecke A. Dendritic cells in atherosclerosis: functions in immune regulation and beyond. Thromb Haemost 2011; 106: 772778. 16. Shah PK. Inflammation and plaque vulnerability. Cardiovasc Drugs Ther 2009; 23: 3140. 17. van der Wal AC, Becker AE, van der Loos CM, et al. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994; 89: 3644. 18. Healy AM, Pickard MD, Pradhan AD, et al. Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular events. Circulation 2006; 113: 22782284. 19. Calabro P, Golia E, Yeh ET. CRP and the risk of atherosclerotic events. Semin Immunopathol 2009; 31: 7994. 20. Wyss CA, Neidhart M, Altwegg L, et al. Cellular actors, Toll-like receptors, and local cytokine profile in acute coronary syndromes. Eur Heart J 2010; 31: 14571469. 21. Silvain J, Collet JP, Nagaswami C, et al. Composition of coronary thrombus in acute myocardial infarction. J Am Coll Cardiol 2011; 57: 13591367. 22. Yunoki K, Naruko T, Sugioka K, et al. Erythrocyte-rich thrombus aspirated from patients with ST-elevation myocardial infarction: association with oxidative stress and its impact on myocardial reperfusion. Eur Heart J 2012; 33: 1480-1490. 23. Liuzzo G, Goronzy JJ, Yang H, et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation 2000; 101: 28832888. 24. Cheng X, Yu X, Ding YJ, et al. The Th17/Treg imbalance in patients with acute coronary syndrome. Clin Immunol 2008; 127: 8997. 25. Mor A, Luboshits G, Planer D, et al. Altered status of CD4(+)CD25(+) regulatory T cells in patients with acute coronary syndromes. Eur Heart J 2006; 27: 25302537. 26. Steppich BA, Moog P, Matissek C, et al. Cytokine profiles and T cell function in acute coronary syndromes. Atherosclerosis 2007; 190: 443451. 27. Butcher M, Galkina E. Current views on the functions of interleukin-17A-producing cells in atherosclerosis. Thromb Haemost 2011; 106: 787795. 28. Ozdogru I, Inanc MT, Eryol NK, et al. CD14+ monocyte levels in subgroups of acute coronary syndromes. Coron Artery Dis 2007; 18: 519522. 29. Tsujioka H, Imanishi T, Ikejima H, et al. Impact of heterogeneity of human peripheral blood monocyte subsets on myocardial salvage in patients with primary acute myocardial infarction. J Am Coll Cardiol 2009; 54: 130138. 30. Kashiwagi M, Imanishi T, Ozaki Y, et al. Differential expression of Toll-like receptor 4 and human monocyte subsets in acute myocardial infarction. Atherosclerosis 2012; 221: 249253.
Schattauer 2012
EVBM 2011 (Part 1)
454
31. Ji QW, Guo M, Zheng JS, et al. Downregulation of T helper cell type 3 in patients with acute coronary syndrome. Arch Med Res 2009; 40: 285293. 32. Herder C, Peeters W, Illig T, et al. RANTES/CCL5 and risk for coronary events: results from the MONICA/KORA Augsburg case-cohort, Athero-Express and CARDIoGRAM studies. PLoS One 2011; 6: e25734. 33. Winnik S, Klingenberg R, Matter CM. Plasma RANTES: a molecular fingerprint of the unstable carotid plaque? Eur Heart J 2011; 32: 393395. 34. Virmani R, Burke AP, Farb A, et al. Pathology of the vulnerable plaque. J Am Coll Cardiol 2006; 47: C1318. 35. Waxman S, Ishibashi F, Muller JE. Detection and treatment of vulnerable plaques and vulnerable patients: novel approaches to prevention of coronary events. Circulation 2006; 114: 23902411. 36. Yla-Herttuala S, Bentzon JF, Daemen M, et al. Stabilisation of atherosclerotic plaques. Position paper of the European Society of Cardiology (ESC) Working Group on atherosclerosis and vascular biology. Thromb Haemost 2011; 106: 119. 37. Virmani R, Kolodgie FD, Burke AP, et al. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000; 20: 12621275. 38. Guzik TJ, Mangalat D, Korbut R. Adipocytokines novel link between inflammation and vascular function? J Physiol Pharmacol 2006; 57: 505528. 39. Harrison DG, Guzik TJ, Lob HE, et al. Inflammation, immunity, and hypertension. Hypertension 2011; 57: 132140. 40. Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 2011; 17: 14101422. 41. Edfeldt K, Swedenborg J, Hansson GK, et al. Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation 2002; 105: 11581161. 42. Zacharias DG, Kim SG, Massat AE, et al. Humanin, a cytoprotective peptide, is expressed in carotid artherosclerotic plaques in humans. PLoS One 2012; 7: e31065. 43. Newby AC. Matrix metalloproteinase inhibition therapy for vascular diseases. Vascul Pharmacol 2012; 56: 232-244. 44. Libby P. Molecular and cellular mechanisms of the thrombotic complications of atherosclerosis. J Lipid Res 2009; 50 (Suppl): S352357. 45. Schramm A, Matusik P, Osmenda G, et al. Targeting NADPH oxidases in vascular pharmacology. Vascul Pharmacol 2012; 56: 216231. 46. Tavora FR, Ripple M, Li L, et al. Monocytes and neutrophils expressing myeloperoxidase occur in fibrous caps and thrombi in unstable coronary plaques. BMC Cardiovasc Disord 2009; 9: 27. 47. Han SF, Liu P, Zhang W, et al. The opposite-direction modulation of CD4+CD25+ Tregs and T helper 1 cells in acute coronary syndromes. Clin Immunol 2007; 124: 9097. 48. Ait-Oufella H, Salomon BL, Potteaux S, et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med 2006; 12: 178180. 49. de Boer OJ, van der Wal AC. FOXP3+ regulatory T cells in vulnerable atherosclerotic plaques. Int J Cardiol 2010; 145: 161. 50. Patel S, Chung SH, White G, et al. The atheroprotective mediators apolipoprotein A-I and Foxp3 are over-abundant in unstable carotid plaques. Int J Cardiol 2010; 145: 183187. 51. Danzaki K, Matsui Y, Ikesue M, et al. Interleukin-17A deficiency accelerates unstable atherosclerotic plaque formation in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2012; 32: 273280. 52. Zhao Z, Wu Y, Cheng M, et al. Activation of Th17/Th1 and Th1, but not Th17, is associated with the acute cardiac event in patients with acute coronary syndrome. Atherosclerosis 2011; 217: 518524. 53. Dumitriu IE, Baruah P, Finlayson CJ, et al. High levels of costimulatory receptors OX40 and 41BB characterize CD4+CD28null T cells in patients with acute coronary syndrome. Circ Res 2012; 110: 857869. 54. Vinh A, Chen W, Blinder Y, et al. Inhibition and genetic ablation of the B7/CD28 T-cell costimulation axis prevents experimental hypertension. Circulation 2010; 122: 25292537. 55. Yilmaz A, Lochno M, Traeg F, et al. Emergence of dendritic cells in rupture-prone regions of vulnerable carotid plaques. Atherosclerosis 2004; 176: 101110. 56. Erbel C, Sato K, Meyer FB, et al. Functional profile of activated dendritic cells in unstable atherosclerotic plaque. Basic Res Cardiol 2007; 102: 123132. 57. Niessner A, Sato K, Chaikof EL, et al. Pathogen-sensing plasmacytoid dendritic cells stimulate cytotoxic T-cell function in the atherosclerotic plaque through interferon-alpha. Circulation 2006; 114: 24822489.
58. Doring Y, Manthey HD, Drechsler M, et al. Auto-antigenic protein-DNA complexes stimulate plasmacytoid dendritic cells to promote atherosclerosis. Circulation 2012; 125: 16731683. 59. Van Vre EA, Ait-Oufella H, Tedgui A, et al. Apoptotic cell death and efferocytosis in atherosclerosis. Arterioscler Thromb Vasc Biol 2012; 32: 887893. 60. Zheng Y, Gardner SE, Clarke MC. Cell death, damage-associated molecular patterns, and sterile inflammation in cardiovascular disease. Arterioscler Thromb Vasc Biol 2011; 31: 27812786. 61. Seneviratne AN, Sivagurunathan B, Monaco C. Toll-like receptors and macrophage activation in atherosclerosis. Clin Chim Acta 2012; 413: 314. 62. Kounis NG. Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigm? Int J Cardiol 2006; 110: 714. 63. Matusik P, Mazur P, Stepien E, et al. Architecture of intraluminal thrombus removed from abdominal aortic aneurysm. J Thromb Thrombolysis 2010; 30: 79. 64. Kato K, Matsubara T, Iida K, et al. Elevated levels of pro-inflammatory cytokines in coronary artery thrombi. Int J Cardiol 1999; 70: 267273. 65. Sakai T, Inoue S, Takei M, et al. Activated inflammatory cells participate in thrombus size through tissue factor and plasminogen activator inhibitor-1 in acute coronary syndrome: Immunohistochemical analysis. Thromb Res 2011; 127: 443449. 66. Libby P, Simon DI. Inflammation and thrombosis: the clot thickens. Circulation 2001; 103: 17181720. 67. Shebuski RJ, Kilgore KS. Role of inflammatory mediators in thrombogenesis. J Pharmacol Exp Ther 2002; 300: 729735. 68. Mach F, Schonbeck U, Sukhova GK, et al. Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci USA 1997; 94: 19311936. 69. Shiraki R, Inoue N, Kawasaki S, et al. Expression of Toll-like receptors on human platelets. Thromb Res 2004; 113: 379385. 70. von Hundelshausen P, Weber KS, Huo Y, et al. RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation 2001; 103: 17721777. 71. Ostrovsky L, King AJ, Bond S, et al. A juxtacrine mechanism for neutrophil adhesion on platelets involves platelet-activating factor and a selectin-dependent activation process. Blood 1998; 91: 30283036. 72. Ott I, Neumann FJ, Gawaz M, et al. Increased neutrophil-platelet adhesion in patients with unstable angina. Circulation 1996; 94: 12391246. 73. Sarma J, Laan CA, Alam S, et al. Increased platelet binding to circulating monocytes in acute coronary syndromes. Circulation 2002; 105: 21662171. 74. Campbell RA, Overmyer KA, Selzman CH, et al. Contributions of extravascular and intravascular cells to fibrin network formation, structure, and stability. Blood 2009; 114: 48864896. 75. Matusik P, Dubiel M, Wizner B, et al. Age-related gap in the management of heart failure patients. The National Project of Prevention and Treatment of Cardiovascular Diseases POLKARD. Cardiol J 2012; 19: 146152. 76. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 2007; 81: 15. 77. Arslan F, de Kleijn DP, Pasterkamp G. Innate immune signaling in cardiac ischemia. Nat Rev Cardiol 2011; 8: 292300. 78. Timmers L, Pasterkamp G, de Hoog VC, et al. The innate immune response in reperfused myocardium. Cardiovasc Res 2012; 94: 276-283. 79. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004; 4: 499511. 80. Monassier JP. Reperfusion injury in acute myocardial infarction. From bench to cath lab. Part I: Basic considerations. Arch Cardiovasc Dis 2008; 101: 491500. 81. Liao YH, Xia N, Zhou SF, et al. Interleukin-17A contributes to myocardial ischemia/reperfusion injury by regulating cardiomyocyte apoptosis and neutrophil infiltration. J Am Coll Cardiol 2012; 59: 420429. 82. Leuschner F, Rauch PJ, Ueno T, et al. Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. J Exp Med 2012; 209: 123137. 83. Madjid M, Naghavi M, Litovsky S, et al. Influenza and cardiovascular disease: a new opportunity for prevention and the need for further studies. Circulation 2003; 108: 27302736. 84. Dong M, Liu T, Li G. Association between acute infections and risk of acute coronary syndrome: a meta-analysis. Int J Cardiol 2011; 147: 479482. 85. Corrales-Medina VF, Madjid M, Musher DM. Role of acute infection in triggering acute coronary syndromes. Lancet Infect Dis 2010; 10: 8392.
EVBM 2011 (Part 1)
Schattauer 2012
455
86. Clayton TC, Thompson M, Meade TW. Recent respiratory infection and risk of cardiovascular disease: case-control study through a general practice database. Eur Heart J 2008; 29: 96103. 87. Tiirola T, Sinisalo J, Nieminen MS, et al. Chlamydial lipopolysaccharide is present in serum during acute coronary syndrome and correlates with CRP levels. Atherosclerosis 2007; 194: 403407. 88. Shah PK, Plaque disruption and thrombosis: potential role of inflammation and infection. Cardiol Rev 2000; 8: 3139. 89. Rosenfeld ME, Campbell LA. Pathogens and atherosclerosis: update on the potential contribution of multiple infectious organisms to the pathogenesis of atherosclerosis. Thromb Haemost 2011; 106: 858867. 90. Epstein SE, Zhu J, Najafi AH, et al. Insights into the role of infection in atherogenesis and in plaque rupture. Circulation 2009; 119: 31333141. 91. Madjid M, Vela D, Khalili-Tabrizi H, et al. Systemic infections cause exaggerated local inflammation in atherosclerotic coronary arteries: clues to the triggering effect of acute infections on acute coronary syndromes. Tex Heart Inst J 2007; 34: 1118. 92. Fitzgerald JR, Foster TJ, Cox D. The interaction of bacterial pathogens with platelets. Nat Rev Microbiol 2006; 4: 445457. 93. Vallance P, Collier J, Bhagat K. Infection, inflammation, and infarction: does acute endothelial dysfunction provide a link? Lancet 1997; 349: 13911392. 94. Davis MM, Taubert K, Benin AL, et al. Influenza vaccination as secondary prevention for cardiovascular disease: a science advisory from the American Heart Association/American College of Cardiology. Circulation 2006; 114: 15491553. 95. Lamontagne F, Garant MP, Carvalho JC, et al. Pneumococcal vaccination and risk of myocardial infarction. CMAJ 2008; 179: 773777. 96. Lopez-Pedrera C, Perez-Sanchez C, Ramos-Casals M, et al. Cardiovascular risk in systemic autoimmune diseases: epigenetic mechanisms of immune regulatory functions. Clin Dev Immunol 2012; 2012: 97469748. 97. Shoenfeld Y, Gerli R, Doria A, et al. Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation 2005; 112: 33373347. 98. Bili A, Moss AJ, Francis CW, et al. Anticardiolipin antibodies and recurrent coronary events: a prospective study of 1150 patients. Thrombogenic Factors, and Recurrent Coronary Events Investigators. Circulation 2000; 102: 12581263. 99. Ridker PM, Everett BM. Letter by Ridker and Everett regarding article, The inflammatory hypothesis: any progress in risk stratification and therapeutic targets?. Circulation 2007; 115: e475; author reply e476. 100. Wang TJ, Gona P, Larson MG, et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med 2006; 355: 26312639. 101. Liuzzo G, Biasucci LM, Trotta G, et al. Unusual CD4+CD28null T lymphocytes and recurrence of acute coronary events. J Am Coll Cardiol 2007; 50: 14501458. 102. Heeschen C, Dimmeler S, Hamm CW, et al. Soluble CD40 ligand in acute coronary syndromes. N Engl J Med 2003; 348: 11041111. 103. Packard CJ, O'Reilly DS, Caslake MJ, et al. Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group. N Engl J Med 2000; 343: 11481155. 104. Sawicki M, Sypniewska G, Kozinski M, et al. Diagnostic efficacy of myeloperoxidase for the detection of acute coronary syndromes. Eur J Clin Invest 2011; 41: 667671. 105. Ferrante G, Nakano M, Prati F, et al. High levels of systemic myeloperoxidase are associated with coronary plaque erosion in patients with acute coronary syndromes: a clinicopathological study. Circulation 2010; 122: 25052513. 106. Matter CM, Stuber M, Nahrendorf M. Imaging of the unstable plaque: how far have we got? Eur Heart J 2009; 30: 25662574. 107. Rudd JH, Warburton EA, Fryer TD, et al. Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography. Circulation 2002; 105: 27082711. 108. Rudd JH, Narula J, Strauss HW, et al. Imaging atherosclerotic plaque inflammation by fluorodeoxyglucose with positron emission tomography: ready for prime time? J Am Coll Cardiol 2010; 55: 25272535. 109. Dweck MR, Chow MW, Joshi NV, et al. Coronary Arterial 18F-Sodium Fluoride Uptake: A Novel Marker of Plaque Biology. J Am Coll Cardiol 2012; 59: 15391548. 110. Gaemperli O, Shalhoub J, Owen DR, et al. Imaging intraplaque inflammation in carotid atherosclerosis with 11C-PK11195 positron emission tomography/computed tomography. Eur Heart J 2012; 33: 1902-1910. 111. Corti R, Fuster V. Imaging of atherosclerosis: magnetic resonance imaging. Eur Heart J 2011; 32: 170919b.
112. Hermann S, Starsichova A, Waschkau B, et al. Non-FDG imaging of atherosclerosis: Will imaging of MMPs assess plaque vulnerability? J Nucl Cardiol 2012; 19: 609-617. 113. Burtea C, Ballet S, Laurent S, et al. Development of a Magnetic Resonance Imaging Protocol for the Characterization of Atherosclerotic Plaque by Using Vascular Cell Adhesion Molecule-1 and Apoptosis-Targeted Ultrasmall Superparamagnetic Iron Oxide Derivatives. Arterioscler Thromb Vasc Biol 2012; 32: 36-48. 114. Streitner I, Goldhofer M, Cho S, et al. Cellular imaging of human atherosclerotic lesions by intravascular electric impedance spectroscopy. PLoS One 2012; 7: e35405. 115. Meng X, Zhang K, Li J, et al. Statins Induce the Accumulation of Regulatory T Cells in the Atherosclerotic Plaque. Mol Med 2012; 18: 598-605. 116. Cyrus T, Sung S, Zhao L, et al. Effect of low-dose aspirin on vascular inflammation, plaque stability, and atherogenesis in low-density lipoprotein receptordeficient mice. Circulation 2002; 106: 12821287. 117. Timmers L, Sluijter JP, Verlaan CW, et al. Cyclooxygenase-2 inhibition increases mortality, enhances left ventricular remodeling, and impairs systolic function after myocardial infarction in the pig. Circulation 2007; 115: 326332. 118. Frutkin AD, Otsuka G, Stempien-Otero A, et al. TGF-[beta]1 limits plaque growth, stabilizes plaque structure, and prevents aortic dilation in apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol 2009; 29: 12511257. 119. Yang JM, Wang Y, Qi LH, et al. Combinatorial interference of toll-like receptor 2 and 4 synergistically stabilizes atherosclerotic plaque in apolipoprotein E-knockout mice. J Cell Mol Med 2011; 15: 602611. 120. Li Y, Si R, Feng Y, et al. Myocardial ischemia activates an injurious innate immune signaling via cardiac heat shock protein 60 and Toll-like receptor 4. J Biol Chem 2011; 286: 3130831319. 121. Pellegrin M, Miguet-Alfonsi C, Bouzourene K, et al. Long-term exercise stabilizes atherosclerotic plaque in ApoE knockout mice. Med Sci Sports Exerc 2009; 41: 21282135. 122. Wallace EL, Abdel-Latif A, Charnigo R, et al. Meta-Analysis of Long-Term Outcomes for Drug-Eluting Stents Versus Bare-Metal Stents in Primary Percutaneous Coronary Interventions for ST-Segment Elevation Myocardial Infarction. Am J Cardiol 2012; 109: 932940. 123. Kalesan B, Stefanini GG, Raber L, et al. Long-term comparison of everolimusand sirolimus-eluting stents in patients with acute coronary syndromes. JACC Cardiovasc Interv 2012; 5: 145154. 124. Serruys PW, Silber S, Garg S, et al. Comparison of zotarolimus-eluting and everolimus-eluting coronary stents. N Engl J Med 2010; 363: 136146. 125. 125.Alfonso F and Virmani R, New morphological insights on coronary plaque rupture: bridging the gap from anatomy to clinical presentation? JACC Cardiovasc Interv 2011; 4: 836. 126. Schoneveld AH, Oude Nijhuis MM, van Middelaar B, et al. Toll-like receptor 2 stimulation induces intimal hyperplasia and atherosclerotic lesion development. Cardiovasc Res 2005; 66: 162169. 127. Arslan F, Smeets MB, O'Neill LA, et al. Myocardial ischemia/reperfusion injury is mediated by leukocytic toll-like receptor-2 and reduced by systemic administration of a novel anti-toll-like receptor-2 antibody. Circulation 2010; 121: 8090. 128. Shishido T, Nozaki N, Yamaguchi S, et al. Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction. Circulation 2003; 108: 29052910. 129. Vink A, Schoneveld AH, van der Meer JJ, et al. In vivo evidence for a role of tolllike receptor 4 in the development of intimal lesions. Circulation 2002; 106: 19851990. 130. Timmers L, Sluijter JP, van Keulen JK, et al. Toll-like receptor 4 mediates maladaptive left ventricular remodeling and impairs cardiac function after myocardial infarction. Circ Res 2008; 102: 257264. 131. Neri Serneri GG, Prisco D, Martini F, et al. Acute T-cell activation is detectable in unstable angina. Circulation 1997; 95: 18061812. 132. Ammirati E, Cianflone D, Vecchio V, et al. Effector Memory T cells Are Associated With Atherosclerosis in Humans and Animal Models. J Am Heart Assoc 2012; 1: 2741. 133. Giubilato S, Liuzzo G, Brugaletta S, et al. Expansion of CD4+CD28null T-lymphocytes in diabetic patients: exploring new pathogenetic mechanisms of increased cardiovascular risk in diabetes mellitus. Eur Heart J 2011; 32: 12141226. 134. Cirillo P, Golino P, Piscione F, et al. Transcoronary Th-17 lymphocytes and acute coronary syndromes: new evidence from the crime scene? Int J Cardiol 2011; 153: 215216.
Schattauer 2012
EVBM 2011 (Part 1)
456
135. Ammirati E, Cianflone D, Banfi M, et al. Circulating CD4+CD25hiCD127lo regulatory T-Cell levels do not reflect the extent or severity of carotid and coronary atherosclerosis. Arterioscler Thromb Vasc Biol 2010; 30: 18321841. 136. Ammirati E, Vermi AC, Cianflone D, et al. Expansion of T-cell receptor zeta dim effector T cells in acute coronary syndromes. Arterioscler Thromb Vasc Biol 2008; 28: 23052311. 137. Methe H, Brunner S, Wiegand D, et al. Enhanced T-helper-1 lymphocyte activation patterns in acute coronary syndromes. J Am Coll Cardiol 2005; 45: 19391945. 138. Liu LL, Lu JL, Chao PL, et al. Lower prevalence of circulating invariant natural killer T (iNKT) cells in patients with acute myocardial infarction undergoing primary coronary stenting. Int Immunopharmacol 2011; 11: 480484. 139. Yilmaz A, Weber J, Cicha I, et al. Decrease in circulating myeloid dendritic cell precursors in coronary artery disease. J Am Coll Cardiol 2006; 48: 7080. 140. Mazzone A, De Servi S, Ricevuti G, et al. Increased expression of neutrophil and monocyte adhesion molecules in unstable coronary artery disease. Circulation 1993; 88: 358363. 141. Meisel SR, Shapiro H, Radnay J, et al. Increased expression of neutrophil and monocyte adhesion molecules LFA-1 and Mac-1 and their ligand ICAM-1 and VLA-4 throughout the acute phase of myocardial infarction: possible implications for leukocyte aggregation and microvascular plugging. J Am Coll Cardiol 1998; 31: 120125. 142. Biasucci LM, D'Onofrio G, Liuzzo G, et al. Intracellular neutrophil myeloperoxidase is reduced in unstable angina and acute myocardial infarction, but its reduction is not related to ischemia. J Am Coll Cardiol 1996; 27: 611616. 143. Wong CW, Luis S, Zeng I, et al. Eosinophilia and coronary artery vasospasm. Heart Lung Circ 2008; 17: 488496. 144. Giugliano GR, Giugliano RP, Gibson CM, et al. Meta-analysis of corticosteroid treatment in acute myocardial infarction. Am J Cardiol 2003; 91: 10551059. 145. Azar RR, Rinfret S, Theroux P, et al. A randomized placebo-controlled trial to assess the efficacy of antiinflammatory therapy with methylprednisolone in unstable angina (MUNA trial). Eur Heart J 2000; 21: 20262032. 146. Sajadieh A, Wendelboe O, Hansen JF, et al. Nonsteroidal anti-inflammatory drugs after acute myocardial infarction. DAVIT Study Group. Danish Verapamil Infarction Trial. Am J Cardiol 1999; 83: 12631265, A9. 147. Altman R, Luciardi HL, Muntaner J, et al. Efficacy assessment of meloxicam, a preferential cyclooxygenase-2 inhibitor, in acute coronary syndromes without ST-segment elevation: the Nonsteroidal Anti-Inflammatory Drugs in Unstable Angina Treatment-2 (NUT-2) pilot study. Circulation 2002; 106: 191195. 148. Mahaffey KW, Granger CB, Nicolau JC, et al. Effect of pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to fibrinolysis in acute myocardial infarction: the COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) trial. Circulation 2003; 108: 11761183. 149. Granger CB, Mahaffey KW, Weaver WD, et al. Pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to primary percutaneous coronary inter-
vention in acute myocardial infarction: the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial. Circulation 2003; 108: 11841190. 150. Armstrong PW, Granger CB, Adams PX, et al. Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: a randomized controlled trial. J Am Med Assoc 2007; 297: 4351. 151. Baran KW, Nguyen M, McKendall GR, et al. Double-blind, randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction: limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study. Circulation 2001; 104: 27782783. 152. Faxon DP, Gibbons RJ, Chronos NA, et al. The effect of blockade of the CD11/CD18 integrin receptor on infarct size in patients with acute myocardial infarction treated with direct angioplasty: the results of the HALT-MI study. J Am Coll Cardiol 2002; 40: 11991204. 153. Mertens P, Maes A, Nuyts J, et al. Recombinant P-selectin glycoprotein ligandimmunoglobulin, a P-selectin antagonist, as an adjunct to thrombolysis in acute myocardial infarction. The P-Selectin Antagonist Limiting Myonecrosis (PSALM) trial. Am Heart J 2006; 152: 125 e18. 154. Liu X, Huang Y, Hanet C, et al. Study of antirestenosis with the BiodivYsio dexamethasone-eluting stent (STRIDE): a first-in-human multicenter pilot trial. Catheter Cardiovasc Interv 2003; 60: 172179. 155. Sakurai R, Inajima T, Kaneda H, et al. Sirolimus-eluting stents reduce long-term mortality compared with bare metal stents in ST-segment elevation myocardial infarction: A meta-analysis of randomized controlled trials. Int J Cardiol 2012; epub ahead of print. 156. Hannan EL, Samadashvili Z, Walford G, et al. Comparison of outcomes for patients receiving drug-eluting versus bare metal stents for non-ST-segment elevation myocardial infarction. Am J Cardiol 2011; 107: 13111318. 157. Windecker S, Serruys PW, Wandel S, et al. Biolimus-eluting stent with biodegradable polymer versus sirolimus-eluting stent with durable polymer for coronary revascularisation (LEADERS): a randomised non-inferiority trial. Lancet 2008; 372: 11631173. 158. Kim HK, Jeong MH, Ahn YK, et al. Comparison of outcomes between Zotarolimus- and sirolimus-eluting stents in patients with ST-segment elevation acute myocardial infarction. Am J Cardiol 2010; 105: 813818. 159. Massberg S, Byrne RA, Kastrati A, et al. Polymer-free sirolimus- and probucoleluting versus new generation zotarolimus-eluting stents in coronary artery disease: the Intracoronary Stenting and Angiographic Results: Test Efficacy of Sirolimus- and Probucol-Eluting versus Zotarolimus-eluting Stents (ISAR-TEST 5) trial. Circulation 2011; 124: 624632.
EVBM 2011 (Part 1)
Schattauer 2012

Do We Know Enough About The Immune Pathogenesis of Acute Coronary Syndromes To Improve Clinical Practice?

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Do We Know Enough About The Immune Pathogenesis of Acute Coronary Syndromes To Improve Clinical Practice?

Uploaded by

Copyright:

Available Formats

Theme Issue Article

EVBM 2011 (Part 1)

Matusik et al. Clinical immunology of ACS

Immune events in ACS

A vulnerable plaque is an inflamed plaque

Systemic inflammation in ACS

Thrombosis and Haemostasis 108.3/2012

Matusik et al. Clinical immunology of ACS

Thrombosis and Haemostasis 108.3/2012

EVBM 2011 (Part 1)

Matusik et al. Clinical immunology of ACS

Inflammation modifies thrombus formation

EVBM 2011 (Part 1)

Immune system in myocardial injury

Matusik et al. Clinical immunology of ACS

Are ACS driven by acute and chronic infections?

Figure 2: Myocardial infiltration by immune cells during the course of

Thrombosis and Haemostasis 108.3/2012

EVBM 2011 (Part 1)

Matusik et al. Clinical immunology of ACS

Acute coronary syndromes

EVBM 2011 (Part 1)

HMGB-1 Hyaluronic acid Fibronectin-EDA Cardiac myosin

Cell surface lipopoly-saccharides [129]

Hsp60 HMGB-1 Hyaluronic acid Fibronectin-EDA

Increased ACS risk in autoimmune diseases

Thrombosis and Haemostasis 108.3/2012

Matusik et al. Clinical immunology of ACS

Immune system markers in the diagnosis and prediction of ACS

Molecular imaging of inflamed plaques

Immune system targeting in ACS

EVBM 2011 (Part 1)

Matusik et al. Clinical immunology of ACS

EVBM 2011 (Part 1)

Natural killer cells (NK)

Dendritic cells (DC)

Thrombosis and Haemostasis 108.3/2012

Matusik et al. Clinical immunology of ACS

MUNA trial DAVIT II study NUT-2

[145] [146] [147]

COMMA Armstrong et al. LIMIT AMI

[149] [150] [151]

Thrombosis and Haemostasis 108.3/2012

EVBM 2011 (Part 1)

Matusik et al. Clinical immunology of ACS

Table 3: Continued Clinical study Intervention Local

EVBM 2011 (Part 1)

DES (first generation)

Patients with NSTEMI

Polymer-free sirolimus- and probucoleluting stents

Implantation of everolimus-eluting stents Resolute zotarolimus-eluting stents (ZES)

Resolute All Comers trial

Patients with SA or ACS

Matusik et al. Clinical immunology of ACS

Thrombosis and Haemostasis 108.3/2012

EVBM 2011 (Part 1)

Matusik et al. Clinical immunology of ACS

EVBM 2011 (Part 1)

Thrombosis and Haemostasis 108.3/2012

Matusik et al. Clinical immunology of ACS

Thrombosis and Haemostasis 108.3/2012

EVBM 2011 (Part 1)