Role In Plaque Rupture Research Articles

Correlation of CRP level with intermediate and high Syntax Score in patients with acute coronary syndrome

In patients with acute coronary syndromes, inflammation has a major role in plaque rupture, which results in acute coronary artery obstruction. This vascular process is not limited only to the site of plaque destabilisation but also in the systemic level. So, it may be detected by determining plasma inflammatory markers. C-reactive protein (CRP) has been frequently studied in recent years and considered to be one of the most important markers. The SYNTAX score (SXscore) is a useful angiographic scoring system that has been developed to assess and quantify the extent, severity and complexity of coronary artery disease. In our study, we investigated whether baseline high-sensitivity CRP levels are associated with burden of coronary atherosclerosis assessed by SYNTAX score (SXScore). We enrolled 128 patients with ACS who underwent coronary angiography between January 2022 and November 2022. The patients were divided according to the SXScore: low SXScore (≤ 22), and intermediate-high SXScore (≥ 23). A total of 128 patients met the inclusion criteria and was included in the study. Among those 128 patients, 98 (76%) were males and 30 (23%) were females. The mean age of patients in the intermediate-high SXScore (61 ± 12 years) group was significantly higher than the low SXScore group (57 ± 10 years) with a P-value: 0.003. Coronary risk factor frequencies such as hypertension were present in 45%, type 2 diabetes mellitus in 42% and dyslipidemia in 83% of patients with no significant difference between both groups except for diabetes with a significant P-value: 0.008. Subjects with an intermediate-high SXScore had higher values of serum glucose, creatinine, peak troponin, and uric acid levels compared to the low SXScore subjects. In addition, the intermediate-high SXScore group showed significantly higher values of high sensibility CRP than the lower SXScore (17.8 ± 6.4 mg/L versus 10.2 ± 5.3 mg/L, P < 0.001). One of the most important results in this study was that serum hs-CRP levels on admission in patients with ACS could predict the severity and complexity of coronary atherosclerosis together with multivessel disease.

Abstract 9530: Plaque Rupture, Compared to Plaque Erosion, is Associated With Higher Level of Pan-Coronary Inflammation, Measured by Peri-Coronary Adipose Tissue Attenuation on Coronary Computed Tomography Angiography

Introduction: Vascular inflammation plays a key role in plaque rupture, while the role of inflammation in plaque erosion remains less well defined. Peri-coronary adipose tissue attenuation (PCATA) has emerged as a marker specific for coronary artery inflammation. Direct comparison of the level of vascular inflammation between plaque rupture and plaque erosion has not been reported. Objectives: To compare the level of coronary inflammation between plaque rupture and plaque erosion using PCATA. Methods: Patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) who underwent pre-intervention coronary computed tomography angiography and optical coherence tomography (OCT) culprit lesion imaging were enrolled. PCATA was measured in the culprit lesion and in the proximal 40mm segment of the coronary arteries. The relationship between OCT culprit plaque characteristics and PCATA was also examined. Results: Out of 198 patients, plaque rupture was the underlying mechanism in 107 patients (54.0%) and plaque erosion in 91 (46.0%) patients. Plaque rupture had higher PCATA than plaque erosion both at the culprit plaque level (-65.8 ± 7.5 vs. -69.5 ± 11.4 Hounsfield unit [HU], p = 0.010) and at the culprit vessel level (-67.1 ± 7.1 vs. -69.6 ± 8.2 HU, p = 0.024). The mean PCATA of all 3 coronary arteries was also significantly higher in plaque rupture than in plaque erosion indicating a higher level of inflammation (-67.9 ± 5.7 vs. -69.9 ± 6.8 HU, p = 0.030). In the multivariable analysis, plaque rupture was significantly associated with high PCATA at all 3 levels: culprit plaque, culprit vessel, and pan-coronary arteries. Conclusions: PCATA in culprit plaque, culprit vessel, and all 3 coronary arteries was higher in plaque rupture than in plaque erosion. The results indicate pan-coronary inflammation plays a more significant role in plaque rupture than in plaque erosion.

Plaque Rupture, Compared With Plaque Erosion, Is Associated With a Higher Level of Pancoronary Inflammation

ObjectivesThe aim of this study was to compare the level of coronary inflammation between plaque rupture and plaque erosion using pericoronary adipose tissue (PCAT) attenuation. BackgroundVascular inflammation plays a key role in plaque rupture, while the role of inflammation in plaque erosion remains less well defined. PCAT attenuation determined using computed tomography has emerged as a marker specific for coronary artery inflammation. MethodsPatients with non–ST-segment elevation acute coronary syndromes who underwent preintervention coronary computed tomographic angiography and optical coherence tomographic culprit lesion imaging were enrolled. PCAT attenuation was measured around the culprit lesion and in the proximal 40 mm of all coronary arteries. ResultsAmong 198 patients, plaque rupture was the underlying mechanism in 107 (54.0%) and plaque erosion in 91 (46.0%). Plaque rupture had higher PCAT attenuation than plaque erosion both at the culprit plaque level (−65.8 ± 7.5 HU vs −69.5 ± 11.4 HU; P = 0.010) and at the culprit vessel level (−67.1 ± 7.1 HU vs −69.6 ± 8.2 HU; P = 0.024). The mean PCAT attenuation of all 3 coronary arteries was also significantly higher in patients with plaque rupture than in plaque erosion, indicating a higher level of inflammation (−67.9 ± 5.7 HU vs −69.9 ± 6.8 HU; P = 0.030). In multivariable analysis, plaque rupture was significantly associated with high PCAT attenuation. ConclusionsPCAT attenuation in culprit plaque, culprit vessel, and all 3 coronary arteries was higher in plaque rupture than in plaque erosion. The results suggest that pancoronary inflammation plays a more significant role in plaque rupture than in plaque erosion. (Massachusetts General Hospital and Tsuchiura Kyodo General Hospital Coronary Imaging Collaboration; NCT04523194)

Impact of wall shear stress affected by anatomical difference between acute and chronic coronary syndrome in patients with LAD proximal disease

Abstract Recent hemodynamic studies have demonstrated that progression of coronary atherosclerosis occurs at low wall share-stress site, whereas plaque rupture frequently occurs at high share stress site. It is well recognized that wall shear stress is relatively low along the outer walls of the bifurcation. We investigated consecutive 140 patients (77 with acute coronary syndrome (ACS) and 63 with chronic coronary syndrome (CCS) performed PCI for LAD proximal lesions (AHA seg.6) from January 2016 to December 2019. In CCS group, entry criteria included stenosis of at least 90% in the LAD proximal lesion or at least 70% in the LAD proximal lesion and objective evidence of myocardial ischemia (inducible ischemia with either exercise or pharmacologic vasodilator stress or with pressure wire). Exclusion criteria were patients with maintenance dialysis, chronic total occlusion lesions, in-stent restenosis, and clinically diagnosed unstable angina without troponin I elevation. We measured the distance from LMT distal carina to the culprit site (Distance) and plaque location (Location) with intravascular ultrasound and angle between LMT and LAD with cardiovascular angiography analysis system (CAAS) (Angle). The two groups were generally well balanced with regard to baseline clinical characteristics. The mean (±SD) age of the patients was 69.0±11.8 years, and 75% were men. Medication at baseline was also similar between two groups except higher prevalence of statin prescription in CCS group. The Distance was shorter and Angle was steeper in CCS group than in ACS group. The number of patients with Angle less than 150 degrees and with Location in the lateral wall side was much more in CCS group. In this study, plaques in CCS were frequently observed at low shear stress site, whereas those in ACS at high shear stress site. Plaque progression in CCS may be associated with low wall shear stress, and high shear stress may play key role in plaque rupture in ACS. This anatomical difference can partly explain the different mechanisms of onset between of ACS and CCS. Funding Acknowledgement Type of funding sources: None. Anatomical differenceCharacteristics and results

Human monocyte-derived macrophages: Pathogenetic role in plaque rupture associated to systemic inflammation

BackgroundMacrophages play a key role in coronary plaque destabilization. In-vitro human monocyte-derived macrophages (MDMs) are used to study macrophages infiltrating tissue. Optical coherence tomography (OCT) provides an in-vivo insight of the coronary arteries. We compared the MDMs morpho-phenotype and culprit plaque features at OCT in acute coronary syndrome (ACS) patients according to the underlying plaque pathobiology. MethodsSixty-six patients undergoing coronary angiography and pre-angioplasty OCT of the culprit vessel were allocated to three groups according to mechanism of ACS at OCT and C-reactive protein levels (cut-off: 2 mg/Ll): 1) plaque rupture with systemic inflammation; 2) plaque rupture without systemic inflammation, 3) plaque with intact fibrous cap. A blood sample was collected to obtain MDMs, categorized as having “round” or “spindle” morphology. ResultsThirty-two patients (48.5%) were assigned to Group 1, 10 (15.2%) to Group 2 and 24 (36.4%) to Group 3. The “round” MDMs were significantly more frequent in Group 1 (39.25 ± 4.98%) than in Group 2 (23.89 ± 3.10%) and Group 3 (23.02 ± 7.89%), p = 0.008. MDMs in Group 1 as compared to Groups 2 and 3 showed lower efferocytosis (8.74 ± 1.38 vs 9.74 ± 2.15 vs 11.41 ± 2.41; p = 0.012), higher tissue factor levels (369.84 ± 101.13 vs 301.89 ± 59.78 vs 231.74 ± 111.47; p = 0.001) and higher heme oxygenase-1 expression (678.78 ± 145.43 vs 419.12 ± 74.44 vs 409.78 ± 64.33; p = 0.008). ConclusionsMDMs of ACS patients show morpho-phenotypic heterogeneity with prevalence of pro-thrombotic and pro-oxidative properties in case of plaque rupture and systemic inflammation. Such MDMs subpopulation may take part to the cellular pathways leading to fibrous cap rupture with the subsequent thrombus formation.

Morphometric and Mechanical Analyses of Calcifications and Fibrous Plaque Tissue in Carotid Arteries for Plaque Rupture Risk Assessment.

Atherosclerotic plaque rupture in carotid arteries is a major source of cerebrovascular events. Calcifications are highly prevalent in carotid plaques, but their role in plaque rupture remains poorly understood. This work studied the morphometric features of calcifications in carotid plaques and their effect on the stress distribution in the fibrous plaque tissue at the calcification interface, as a potential source of plaque rupture and clinical events. A comprehensive morphometric analysis of 65 histology cross-sections from 16 carotid plaques was performed to identify the morphology (size and shape) and location of plaque calcifications, and the fibrous tissue fiber organization around them. Calcification-specific finite element models were constructed to examine the fibrous plaque tissue stresses at the calcification interface. Statistical correlation analysis was performed to elucidate the impact of calcification morphology and fibrous tissue organization on interface stresses. Hundred-seventy-one calcifications were identified on the histology cross-sections, which showed great variation in morphology. Four distinct patterns of fiber organization in the plaque tissue were observed around the calcification. They were termed as attached, pushed-aside, encircling and random patterns. The stress analyses showed that calcifications are correlated with high interface stresses, which might be comparable to or even above the plaque strength. The stress levels depended on the calcification morphology and fiber organization. Thicker calcification with a circumferential slender shape, located close to the lumen were correlated most prominently to high interface stresses. Depending on its morphology and the fiber organization around it, a calcification in an atherosclerotic plaque can act as a stress riser and cause high interface stresses. This study demonstrated the potential of calcifications in atherosclerotic plaques to cause elevated stresses in plaque tissue and provided a biomechanical explanation for the histopathological findings of calcification-associated plaque rupture.

Numerical study of biomechanical characteristics of plaque rupture at stenosed carotid bifurcation: a stenosis mechanical property-specific guide for blood pressure control in daily activities

Acute stress concentration plays an important role in plaque rupture and may cause stroke or myocardial infarction. Quantitative evaluation of the relation between in vivo plaque stress and variations in blood pressure and flow rates is valuable to optimize daily monitoring of the cardiovascular system for high-risk patients as well as to set a safe physical exercise intensity for better quality of life. In this study, we constructed an in vivo stress model for a human carotid bifurcation with atherosclerotic plaque, and analyzed the effects of blood pressure, flow rates, plaque stiffness, and stenosis on the elastic stress and fluid viscous stress around the plaque. According to the maximum values of the mechanical stress, we define a risk index to predict the risk level of plaque rupture under different exercise intensities. For a carotid bifurcation where the blood flow divides, the results suggest that the stenosis ratio determines the ratio of the contributions of elastic shear stress and viscous shear stress to plaque rupture. An increase of the plaque stiffness enhances the maximum elastic shear stress in the plaque, indicating that a high-stiffness plaque is more prone to rupture for given stenosis ratio. High stress co-localization at the shoulder of plaques agrees with the region of plaque injury in clinical observations. It is demonstrated that, due to the stress-shield effect, the rupture risk of a high-stiffness plaque tends to decrease under high-stenosis conditions, suggesting the existence of a specific stenosis corresponding to the maximum risk. This study may help to complement risk stratification of vulnerable plaques in clinical practice and provides a stenosis mechanical property-specific guide for blood pressure control in cardiovascular health management.

Role of Monocyte Chemoattractant Protein-1 for Diagnosing Acute Myocardial Infarction

Background: Acute myocardial infarction (AMI) controlled and promoted by inflammation within the coronary plaque. Monocyte chemoattractant protein-1 (MCP-1) is a pro-inflammatory mediator, that’s playing a major role in plaque rupture. This study aimed to assess the diagnostic performance of MCP-1 for early diagnosis of AMI among chest pain (CP) patients. Methods: MCP-1 and cardiac Troponin I (cTnI) were performed for all studied patients. The receiver operating characteristic (ROC) curve was used to assess the diagnostic accuracy of biomarkers. Results: The baseline level of MCP-1 has a good capacity for discriminating patients with AMI from non-coronary chest pain (NCCP), stable angina (SA), and unstable angina (UA) patients with efficiency 91%, 91%, and 83%; respectively. Area under the curves (AUCs) of MCP-1 for diagnosis AMI patients at 0-6 hours and > 6-12 hours after onset time of CP were 0.69 (P 12-24 hours, cTnI has AUC 0.93 (P < 0.0001) compared with MCP-1 0.74 (P < 0.0001). In conclusion: Independent early baseline MCP-1 has given sufficient diagnostic information for patients with AMI.

3D Fiber Orientation in Atherosclerotic Carotid Plaques.

Atherosclerotic plaque rupture is the primary trigger of fatal cardiovascular events. Fibrillar collagen in atherosclerotic plaques and their directionality are anticipated to play a crucial role in plaque rupture. This study aimed assessing 3D fiber orientations and architecture in atherosclerotic plaques for the first time. Seven carotid plaques were imaged ex-vivo with a state-of-the-art Diffusion Tensor Imaging (DTI) technique, using a high magnetic field (9.4Tesla) MRI scanner. A 3D spin-echo sequence with uni-polar diffusion sensitizing pulsed field gradients was utilized for DTI and fiber directions were assessed from diffusion tensor measurements. The distribution of the 3D fiber orientations in atherosclerotic plaques were quantified and the principal fiber orientations (circumferential, longitudinal or radial) were determined. Overall, 52% of the fiber orientations in the carotid plaque specimens were closest to the circumferential direction, 34% to the longitudinal direction, and 14% to the radial direction. Statistically no significant difference was measured in the amount of the fiber orientations between the concentric and eccentric plaque sites. However, concentric plaque sites showed a distinct structural organization, where the principally longitudinally oriented fibers were closer to the luminal side and the principally circumferentially oriented fibers were located more abluminally. The acquired unique information on 3D plaque fiber direction will help understanding pathobiological mechanisms of atherosclerotic plaque progression and pave the road to more realistic biomechanical plaque modeling for rupture assessment.

Role of Cholesterol Crystals During Acute Myocardial Infarction and Cerebrovascular Accident

Cholesterol crystals have long been recognized as part of atherosclerotic plaques. They have been visualized by light microscopy as empty spaces or imprints where crystals were once present and then dissolved by tissue processing. Thus, until now, their role in atherosclerosis and plaque rupture had been considered to be inert. However, by the processing of tissue without ethanol it was possible to visualize their extensiveness and potential role in tissue injury. Also, it was demonstrated that cholesterol expands in volume when crystallizing from the liquid to the solid state, which is the presumed cause of plaque rupture by sharp-tipped crystals growing out of the plaque’s necrotic core. Specifically, in patients who died of myocardial infarction, all culprit coronary lesions had extensive cholesterol crystals perforating the fibrous cap and intima, while those patients who died of other causes and had plaques did not have crystals perforating the cap and intima. Additionally, cholesterol crystals traveling downstream from the plaque rupture site can scrape the endothelium and promote vasospasm. Moreover, cholesterol crystals lodging into the muscle can trigger an inflammation with necrosis independent of circulatory compromise or ischemia. These findings suggest that cholesterol crystals could play a critical role in plaque rupture, as well as vascular and myocardial injury.

358 - Pharmacological Inhibition of Myeloperoxidase Improves Endothelial Function and Stabilizes Atherosclerotic Lesions in a Mouse Model of Vulnerable Plaque

The involvement of myeloperoxidase (MPO) in human atherosclerotic plaque progression is well documented, including its potential role in plaque rupture that can cause acute myocardial infarction. Despite this, establishing a causal relationship between MPO and atherosclerosis-associated complications has proven difficult in mouse models. In the present study we employed a mouse model of atherosclerotic plaque instability (Circ Res 113:252) to examine the role of MPO in endothelial dysfunction and atherosclerotic plaque vulnerability. Unstable plaques were introduced in apolipoprotein E gene knockout (Apoe–/–) mice fed a Western diet for 13 weeks by placing a tandem stenosis around the right carotid artery after 6 weeks of diet, and MPO activity was partially blocked by oral administration of a 2-thioxanthine (AZM198). Unstable carotid plaques, but not stable plaques in the aortic root and arch, contained measurable MPO activity as assessed by the in vivo conversion of hydroethidine to 2-chloroethidium and non-invasive magnetic resonance imaging using MPO-gadolinium (bis-5-hydroxytryptamine-DTPA-Gd). Administration of AZM198 did not change circulating white blood cell counts, plasma concentrations of pro-inflammatory cytokines and lipids, nor did it affect atherosclerotic lesion size in the aortic root. In contrast, AZM198 significantly attenuated arterial MPO activity in unstable plaques and endothelial dysfunction in the abdominal aorta. Inhibition of MPO activity was associated with increased plaque stability in the carotid artery, as indicated by the increase in cap thickness and the cap-to-lesion ratio, without affecting necrotic core size and arterial monocytes. Together, these data indicate that vulnerable but not stable atherosclerotic lesions in Apoe–/– mice exhibit MPO activity, and that pharmacological inhibition of MPO stabilizes vulnerable plaques.

Metalloproteinases in the pathogenesis and progression of metabolic syndrome: potential targets for improved outcomes

Matrix metalloproteinases (MMPs) constitute a family of more than 25 calcium- dependent, zinc-containing endopeptidases, synthesized by multiple cell types. These enzymes play an important role during physiological tissue development and remodeling and angiogenesis, as well as in pathophysiological conditions such as obesity and atherosclerotic process. Moreover, circulating levels of MMPs have emerged as potential biomarkers of cardiovascular disease. MMPs are regulated by different factors such as insulin resistance and obesity. Different components of the metabolic syndrome have been identified as possible stimulus for the synthesis and activity of MMPs. On the other hand, pro-inflammatory and anti-inflammatory cytokines, such as leptin and adiponectin, respectively, are associated with the regulation of MMPs. Leptin induces expression of MMP-2 activators as well as expression of MMP-2, MMP-9, and tis- sue inhibitor of metalloproteinase (TIMP)-1 in different human cells. Adiponectin may play a protective role in plaque rupture through selectively increasing TIMP expression. The hepatic manifestation of metabolic syndrome is nonalcoholic fatty liver disease (NAFLD). MMPs may remodel the liver parenchyma during the process of liver fibrosis. MMP-2 and MT1-MMP have been considered to be fibrogenic enzymes.There are few studies analyzing the role of MMPs in NAFLD, and most of them include study on mRNA expression, but even the results on their expression pattern remains controversial. MMPs could be considered as possible therapeutic targets. Different studies demonstrated that metformin, thiazolidinediones, and antibiotics could have inhibitory effects on the expression of MMPs; however, a rational study of lifestyle modifications as well as further studies of pharmacological therapies that influence MMPs are necessary to generate the information that physicians will probably need to improve the treatment of patients. The aim of this revision is to update the data about MMPs in the pathogenesis and progression of metabolic syndrome and the possible effect of different drugs on the behavior of these enzymes.

Circulating and adipose tissue matrix metalloproteinases in cardiometabolic risk environments: pathophysiological aspects.

Matrix metalloproteinases (MMPs) play an important role during physiological tissue remodeling in embryonic development and angiogenesis, as well as in pathophysiological conditions such as obesity and development and vulnerability of atherosclerotic plaque. Moreover, MMP circulating levels have emerged as potential biomarkers of cardiovascular disease. MMP expression and activity are regulated by different factors such as insulin resistance and obesity. Expanded fat tissue has been demonstrated to be an active organ, where MMPs also exert a role in adipogenesis, angiogenesis, and proliferation of extracellular matrix (ECM). However, the lack of association between adipose tissue and plasma levels of some MMPs, specifically MMP-2 and MMP-9, suggests that this tissue is not a major contributor to circulating gelatinases. MMPs are also co-expressed or co-repressed in response to inflammatory adipocytokines, like adiponectin and leptin. Adiponectin may also play a protective role in plaque rupture through selectively increasing the tissue inhibitor of metalloproteinase (TIMP) expression. Leptin induces the expression of MMP-2 activators as well as the expression of MMP-2, MMP-9, and TIMP-1 in different human cells. Furthermore, sex hormones also participate in MMP regulation. In postmenopausal women, hormone replacement therapy produces an increase in MMP activity, leading to a breakdown in ECM homeostasis and accelerated progression of vascular pathologies. Besides, in men, an inverse relationship between testosterone levels and MMP-2 activity has been described. It is still necessary to go forward in the study of MMPs in different metabolic situations to corroborate their role as vulnerable plaque biomarkers.

Association between P-selectin glycoprotein ligand-1 and pathogenesis in acute coronary syndrome assessed by optical coherence tomography

ObjectiveAlthough monocytes appear to be actively involved in the onset of acute coronary syndrome (ACS), they are heterogenous in human peripheral blood. How up-regulation of monocyte subsets leads to coronary plaque rupture followed by thrombus formation remains unclear. Recent studies have shown that P-selectin glycoprotein ligand-1 (PSGL-1) is involved in monocyte activation in patients with thrombus formation. We therefore investigated the relationship between the expression of PSGL-1 on monocyte subsets and thrombus formation using frequency-domain optical coherence tomography (FD-OCT) in patients with ACS. MethodsWe enrolled a total of 100 individuals in this study: patients with acute myocardial infarction (AMI, n = 25), unstable angina pectoris (UAP, n = 20), or stable angina pectoris (n = 35) who underwent coronary angiography, and control subjects (n = 20). Three monocyte subsets (CD14++CD16−, CD14++CD16+, and CD14+CD16+) and the expression of PSGL-1 were measured by flow cytometry. In patients with AMI and UAP, FD-OCT was performed before percutaneous coronary intervention. ResultsCirculating peripheral CD14++CD16+ monocytes expressed PSGL-1 more frequently than CD14++CD16− and CD14+CD16+ monocytes in patients with ACS. The expression of PSGL-1 on circulating peripheral CD14++CD16+ monocytes was significantly elevated in patients with AMI compared with the other 3 groups. Moreover, the expression levels of PSGL-1 on CD14++CD16+ monocytes were significantly higher in patients with plaque rupture or intracoronary thrombus assessed by FD-OCT. ConclusionUp-regulation of PSGL-1 on CD14++CD16+ monocytes may be a crucial role in plaque rupture and thrombus formation.

Tumor necrosis factor superfamily molecules in acute coronary syndromes

Accumulating evidence suggests that inflammatory pathways play an essential role in all stages of atherogenesis. Inflammatory processes are not only involved in plaque progression, but seem also to play a critical role in plaque rupture. Members of the tumor necrosis factor (TNF) superfamiliy are potent regulators of inflammation and cell survival and consist of 20 ligands that signal through 29 different receptors. Several lines of evidence suggest that TNF-related molecules are involved in the development of acute coronary syndromes (ACS). Most, convincing evidence exists for CD40 ligand-CD40 interaction, but several other members of the TNF superfamily seem also to be involved in this immune-mediated promotion of plaque instability, including LIGHT, receptor activator of nuclear factor κB ligand, and TNF-α. These plaque destabilization pathways involve the bidirectional interaction between platelets and endothelial cells/monocytes, activation of vascular smooth muscle cells, and co-stimulatory effects on T cells, promoting inflammation, thrombus formation, matrix degradation, and apoptosis. TNF-related pathways could contribute to the non-resolving inflammation that characterizes atherosclerosis, representing pathogenic loops that are operating during plaque rupture and the development of ACS. These TNF-related molecules could also represent attractive new targets for therapy in this disorder.

Level of circulating CD4+ 28null cells in chronic inflammatory diseases: an important marker in predicting acute coronary events?

Emerging and established evidence in the last decade has clearly established that atherosclerosis is an inXammatory disease. InXammation not only plays an important role in the development of the atherosclerotic plaque but also in the rupture of the plaque leading to critical ischaemia [1]. There is an increasing interest in identifying the immunological mediators that play an important role in plaque rupture. A subset of CD4 T cells lacking the surface expression of CD28 (CD4+ 28 cells) has been identiWed as potential culprits in driving this process. CD4+ 28 cells are the type of lymphocytes not usually found in young individuals. They have been identiWed in the peripheral circulation of elderly individuals and in patients with chronic inXammatory diseases and they diVer from other T cells in their ability to resist apoptosis [2]. Interestingly, they are found in higher numbers in patients with acute coronary syndromes when compared with patients with stable angina [3] and their appearance is strongly associated with the recurrence of acute coronary events suggesting an important role in plaque rupture [4]. These cells are also identiWed in patients with rheumatoid arthritis (RA), Wegener’s granulomatosis and Crohn’s disease [5–7]. In patients with RA, their presence is signiWcantly associated not only with extraarticular features and severe joint destruction but also with preclinical atherosclerotic changes, including arterial endothelial dysfunction and carotid artery wall thickening [5, 8]. In contrast, although patients with primary Sjogren’s syndrome (PSS) have an increased incidence of subclinical atherosclerosis, there is no evidence that mortality due to cardiovascular events is increased [9, 10]. This might be due to the fact that in patients with PSS the number of CD4+ 28 cells in peripheral circulation is not high when compared with healthy controls [10]. Interestingly until now no research is done to look at the role of these cells in patients with systemic lupus erythematosus (SLE). In my opinion, monitoring the levels of these cells in patients with chronic inXammatory diseases will help in identifying an important group of patients who are at a very high risk of developing ischaemic events, thereby allowing aggressive modiWcation of cardiovascular risk factors and initiating further investigations and treatment. More studies are needed to look at the role of these very important T cells in the pathogenesis of atherosclerosis in SLE.

Role of MCP-1 in cardiovascular disease: molecular mechanisms and clinical implications

Many of the major diseases, including cardiovascular disease, are widely recognized as inflammatory diseases. MCP-1 (monocyte chemotactic protein-1) plays a critical role in the development of cardiovascular diseases. MCP-1, by its chemotactic activity, causes diapedesis of monocytes from the lumen to the subendothelial space where they become foam cells, initiating fatty streak formation that leads to atherosclerotic plaque formation. Inflammatory macrophages probably play a role in plaque rupture and the resulting ischaemic episode as well as restenosis after angioplasty. There is strong evidence that MCP-1 plays a major role in myocarditis, ischaemia/reperfusion injury in the heart and in transplant rejection. MCP-1 also plays a role in cardiac repair and manifests protective effects under certain conditions. Such protective effects may be due to the induction of protective ER (endoplasmic reticulum) stress chaperones by MCP-1. Under sustained ER stress caused by chronic exposure to MCP-1, the protection would break down resulting in the development of heart failure. MCP-1 is also involved in ischaemic angiogenesis. The recent advances in our understanding of the molecular mechanisms that might be involved in the roles that MCP-1 plays in cardiovascular disease are reviewed. The gene expression changes induced by the signalling events triggered by MCP-1 binding to its receptor include the induction of a novel zinc-finger protein called MCPIP (MCP-1-induced protein), which plays critical roles in the development of the pathophysiology caused by MCP-1 production. The role of the MCP-1/CCR2 (CC chemokine receptor 2) system in diabetes, which is a major risk factor for cardiovascular diseases, is also reviewed briefly. MCP-1/CCR2- and/or MCPIP-targeted therapeutic approaches to intervene in inflammatory diseases, including cardiovascular diseases, may be feasible.

The HDL proteome: a marker–and perhaps mediator–of coronary artery disease

One important cardioprotective function of HDL is to remove cholesterol from lipid-laden macrophages in the artery wall. HDL also exerts anti-inflammatory effects that might inhibit atherogenesis. However, HDL has been proposed to be dysfunctional in humans with established coronary artery disease (CAD), though the underlying mechanisms are unclear. Therefore, we used mass spectrometry to investigate the roles of HDL proteins in inflammation and cardiovascular disease. Shotgun proteomic analysis identified multiple complement regulatory proteins, protease inhibitors, and acute-phase response proteins in HDL, strongly implicating the lipoprotein in inflammation and the innate immune system. Moreover, mass spectrometry and biochemical analyses demonstrated that HDL3 from subjects with clinically significant CAD was selectively enriched in apolipoprotein E, suggesting that it carries a distinctive protein cargo in humans with atherosclerosis. HDL from CAD subjects also contained markedly elevated levels of chlorotyrosine and nitrotyrosine, two characteristic products of myeloperoxidase, indicating that oxidative damage might generate dysfunctional HDL. Aggressive lipid therapy with a statin and niacin remodeled the HDL proteome to resemble that of apparently healthy subjects. Collectively, our observations indicate that quantifying the HDL proteome by mass spectrometry should help identify novel anti-inflammatory and cardioprotective actions of HDL and provide insights into lipid therapy.

Potential implications of matrix metalloproteinase-9 in assessment and treatment of coronary artery disease

Background: Matrix metalloproteinase (MMP)-9, a member of the MMP superfamily is consistently implicated in the pathophysiology of atherosclerosis and plaque rupture, the most common mechanism responsible for acute coronary syndrome (ACS).Aim: To summarize the role of MMP-9 in atherosclerosis and its potential implications in assessment and treatment of coronary artery disease (CAD).Methods: We reviewed the PubMed database for relevant data regarding the role of MMP-9 in the pathophysiology of atherosclerosis. In the light of these data, we postulate potential implications of MMP-9 in the management and treatment of CAD.Results and conclusions: Existing data strongly support the role of MMP-9 in plaque destabilization and rupture. Based on the current knowledge, MMP-9 can potentially serve as a diagnostic biomarker in ACS and a prognostic biomarker in ACS and chronic CAD patients. MMP-9 is reduced by therapies that are associated with favourable outcome in atherosclerosis and thus may serve as a surrogate biomarker of treatment efficacy. However, large morbidity and mortality trials are still required to confirm that MMP-9 reduction is associated with improved outcome independent of the traditional risk factors (i.e. low-density lipoprotein cholesterol). Given its role in plaque rupture, inhibition of MMP-9 may promote plaque stabilization and consequently reduce cardiovascular events. Yet, the efficacy and safety of MMPs inhibitors should be first studied in preclinical models of atherosclerosis.

A Magnetic Resonance Iron Oxide Imaging Agent Targeting Activated GPIIb/IIIa on Platelets Allows In vivo Detection of Thrombosis and Monitoring of Thrombolysis

Background: Platelets are the key to thrombus formation and play a major role in plaque rupture. Here, we evaluate theabilityof amagnetic resonance imaging (MRI) contrast agent consisting of microparticles of iron oxide (MPIO) and a single-chain antibody targeting ligandinduced binding sites (LIBS) on activated GPIIb/IIIa to image carotid artery thrombi. Methods and results: Anti-LIBS or control antibody were conjugated to 1 m-sized MPIOs (LIBS–MPIO/control–MPIO). Non-occlusive mural thrombi were induced in BL/6 mice using 6% ferricchloride. MRI (9.4 T) of the carotid artery was performed once before and repeatedly in 12min long sequences after LIBS–MPIO/control–MPIO injection. After 36min, a significant signal void, which is the typical effect of iron oxide-based contrast agents and which notably extends beyond the particle size, was observed with LIBS–MPIO, but not control–MPIO (P< 0.01) and corresponded to LIBS–MPIO binding as confirmed by histology. After thrombolysis, in LIBS–MPIO injectedmice the signal void subsided, indicating successful thrombolysis. On histology, MPIO-content of thrombus, as well as thrombus size, correlated significantly with LIBS–MPIO-induced signal void (both P< 0.01). Conclusions: We describe a novel approach for molecular imaging allowing in vivo targeting of magnetic resonance contrast agents to activated platelets. Thereby, thrombi canbedetectedwithexcellent resolutionandcontrast properties, which are suitable for coronary artery imaging in humans. Furthermore, success or failure of thrombolytic therapy can be monitored. This novel non-invasive technique provides rapid detection and quantification of thrombi, such as found in myocardial infarction, pulmonary embolism and on the surface of ruptured or rupture-prone atherosclerotic plaques.