Role of unusual CD4<Superscript>+</Superscript> CD28<Superscript>−</Superscript> T cells in acute coronary syndrome

Acute coronary syndrome (ACS) is a group of clinical symptoms that results from complete or partial occlusive thrombus, which is caused by coronary an atherosclerotic plaque rupture or erosion. According to a recent study, CD4⁺ CD28⁻ T cells are found in atherosclerotic plaques and the peripheral circulation blood in patients with ACS, these cells play an important role in plaque ruptures. CD4⁺ CD28⁻ T cells are an unusual subset of helper cells, which expand and have harmful effects in ACS. In this review, we discuss the current issues on the generation of CD4⁺ CD28⁻ T cells and focus on their phenotypic and functional characteristics relevant to the development of cardiovascular events. Targeting the CD4⁺ CD28⁻ T cells subset in ACS could provide novel therapeutic means to prevent acute life-threatening coronary events.     

The emerging role of thrombus aspiration in contemporary percutaneous coronary intervention practice

Coronary atherosclerosis may lead towards thrombogenesis, usually triggered by rupture or erosion of a vulnerable epicardial coronary artery plaque. Most acute coronary syndromes are caused by ruptured atherosclerotic plaques with superimposed thrombus.     

Oxysterols and symptomatic versus asymptomatic human atherosclerotic plaque

Atherosclerosis is the most common cause of mortality in the Western world, contributing to about 50% of all deaths. Atherosclerosis is characterized by deposition of lipids onto the coronary or carotid arterial wall and formation of an atherosclerotic plaque. Atherosclerotic plaques are categorized into two groups: symptomatic and asymptomatic. The symptomatic plaques tend to be unstable and prone to rupture, and are associated with an increase in ischemic events. Oxysterols, products of cholesterol oxidation, are cytotoxic materials. Their level and type may be associated with plaque formation, development and stability. Oxysterols stimulate the formation of foam cells, advance atherosclerotic plaque progression, and contribute to plaque vulnerability and instability due to their cytotoxicity and their ability to induce cell apoptosis. Studies indicate that plasma 7β-OH CH level can be used as a biomarker for detecting carotid and coronary artery disease. Further clinical studies are needed to evaluate the potential of oxysterols for use as biomarkers for plaque vulnerability and instability. The identification of biomarkers in the blood that can distinguish between symptomatic and asymptomatic plaques remains an unresolved issue.     

Plaque Image Characteristics, Hyperhomocysteinemia, and Gene Polymorphism of Homocysteine Metabolism-Related Enzyme (MTHFR C677T) in Acute Coronary Syndrome

This study aims to investigate the correlation between the different characteristics of plaques, plasma level of homocysteine (Hcy), and gene polymorphism of Hcy metabolism-related enzyme. In this consecutive case–control study, we measured the plasma Hcy level using fluorescence biochemistry method and examined the gene polymorphism of Hcy metabolism-related enzyme methylenetetrahydrofolate reductase (MTHFR) C677T using TaqMan probe technology. We also examined these using intravascular ultrasound. We studied the characteristics of the plaque, measured the cross-sectional areas of the external elastic membrane and the lumen, calculated the plaque area, plaque burden, and eccentricity index, and examined the remodeling index. Hard plaques were more dominant in the (SPA) group, whereas soft plaques were more dominant in the acute coronary syndrome (ACS) group (P < 0.001). The risk of plaque rupture and thrombus is higher in the ACS group (P < 0.05). Compared with SPA group, plaque burden was heavier in the ACS group (P < 0.05), but the eccentricity index is significantly higher in SPA group than in the ACS group (P < 0.001). Positive remodeling was more frequent in ACS group, whereas negative remodeling was more frequent in the SPA group (P < 0.001). Plasma Hcy levels were higher in the unstable than in the stable plaque group (P < 0.001). The constituent ratio of MTHFR C677T genotype were different in stable plaque group and vulnerable plaque group (P < 0.05). The T genotype can increase the incidence rate of vulnerable plaque. Hcy and MTHFR C677T gene polymorphism were found to be risk factors for vulnerable plaque. Therefore, these can be used as indices to predict the instability of atherosclerotic plaque.     

The nature of the problem: an overview of acute coronary syndromes and myocardial infarction

The leading cause of death worldwide is coronary heart disease (CHD). This often presents with atherosclerotic plaque rupture, leading to a partial or complete obstruction of coronary artery flow, and resulting ischemia or infarction of myocardial tissue. There are risk factors which can predict CHD risk, and the treatment of some risk factors can reduce the likelihood of developing an acute coronary syndrome (ACS). While the incidence of CHD may be decreasing in the developed world, significant increases are projected in the developing world. In addition to the immediate adverse events associated with ACS, these patients have long-term increases in morbidity and mortality, which make the worldwide epidemic of CHD a leading public health issue.     

Phenotype commitment in vascular smooth muscle cells derived from coronary atherosclerotic plaques: differential gene expression of endothelial nitric oxide synthase

Unstable angina and myocardial infarction are the clinical manifestations of the abrupt thrombotic occlusion of an epicardial coronary artery as a result of spontaneous atherosclerotic plaque rupture or fissuring, and the exposure of highly thrombogenic material to blood. It has been demonstrated that the proliferation of vascular smooth muscle cells (VSMCs) and impaired bioavailabilty of nitric oxide (NO) are among the most important mechanisms involved in the progression of atherosclerosis. It has also been suggested that a NO imbalance in coronary arteries may be involved in myocardial ischemia as a result of vasomotor dysfunction triggering plaque rupture and the thrombotic response. We used 5' nuclease assays (TaqMan PCRs) to study gene expression in coronary plaques collected by means of therapeutic directional coronary atherectomy from 15 patients with stable angina (SA) and 15 with acute coronary syndromes (ACS) without ST elevation. Total RNA was extracted from the 30 plaques and the cDNA was amplified in order to determine endothelial nitric oxide synthase (eNOS) gene expression. Analysis of the results showed that the expression of eNOS was significantly higher (p<0.001) in the plaques from the ACS patients. Furthermore, isolated VSMCs from ACS and SA plaques confirmed the above pattern even after 25 plating passages. In situ RT-PCR was also carried out to co-localize the eNOS messengers and the VSMC phenotype. The eNOS gene was more expressed in ACS plaques and VSMCs cultured from them, thus indicating that: a) the expression of the most important differentiation markers is retained under in vitro conditions; and b) NO may play a pivotal role in coronary artery disease. Our findings suggest a new cell system model for studying the pathophysiology of unstable angina and myocardial infarction.     

Alternatively spliced human tissue factor: a circulating,soluble, thrombogenic protein

Tissue factor (TF) is an essential enzyme activator that forms a catalytic complex with FVII(a) and initiates coagulation by activating FIX and FX, ultimately resulting in thrombin formation. TF is found in adventitia of blood vessels and the lipid core of atherosclerotic plaques. In unstable coronary syndromes, plaque rupture initiates coagulation by exposing TF to blood. Biologically active TF has been detected in vessel walls and circulating blood. Elevated intravascular TF has been reported in diverse pro-thrombotic syndromes such as myocardial infarction, sepsis, anti-phospholipid syndrome and sickle-cell disease. It is unclear how TF circulates, although it may be present in pro-coagulant microparticles. We now report identification of a form of human TF generated by alternative splicing. Our studies indicate that alternatively spliced human tissue factor (asHTF) contains most of the extracellular domain of TF but lacks a transmembrane domain and terminates with a unique peptide sequence. asHTF is soluble, circulates in blood, exhibits pro-coagulant activity when exposed to phospholipids, and is incorporated into thrombi. We propose that binding of asHTF to the edge of thrombi contributes to thrombus growth by creating a surface that both initiates and propagates coagulation.     

Impaired modulation of circadian rhythms in patients with diabetes mellitus: a risk factor for cardiac thrombotic events?

Serious adverse cardiovascular events, including myocardial infarction, sudden cardiac death, and stroke, frequently result from rupture of atherosclerotic plaques with superimposed thrombosis and exhibit a pronounced circadian rhythmicity, peaking in the morning hours. Two potentially synergistic mechanisms play a pathogenic role in the circadian variation of arterial thrombotic events. A morning surge in sympathetic activity alters hemodynamic forces and predisposes vulnerable coronary atherosclerotic plaques to rupture. Day-night variations of hemostatic and fibrinolytic factors result in morning hypercoagulability and hypofibrinolysis, promoting intraluminal thrombus formation at the same time when the risk for plaque rupture is highest. Diabetic patients have a very high cardiac event rate but fail to show normal circadian fluctuations in the occurrence of myocardial infarction. Alterations in the circadian variation autonomic tone, blood pressure, and the thrombotic-thrombolytic equilibrium have been documented in diabetic patients. These include reduced or absent 24-h periodicity in autonomic tone, fibrinolytic activity, and thrombotic tendency, and a blunted decline in nocturnal blood pressure. Disruption of these circadian rhythms explains the lack of significant circadian distribution of cardiac events in diabetic patients. Moreover, the loss of these normal biorhythms results in a continuous susceptibility to thrombotic events throughout the day and may contribute to the excess cardiovascular mortality and morbidity in these patients. (Chronobiology International, 18(1), 109-121, 2001)     

MicroRNA-9 overexpression suppresses vulnerable atherosclerotic plaque and enhances vascular remodeling through negative regulation of the p38MAPK pathway via OLR1 in acute coronary syndrome

Acute coronary syndrome (ACS) is characterized by atherosclerotic plaque rupture with a high incidence of recurrent ischemic events. Several microRNAs are found to be aberrantly expressed in atherosclerotic plaques. This study aims to investigate the effects of microRNA-9 (miR-9) on vulnerable atherosclerotic plaque and vascular remodeling in ACS and underlying mechanisms. Microarray-based gene expression profiling was used to identify differentially expressed genes related to ACS and regulatory miRNAs. Oxidized low-density lipoprotein (lectin-like) receptor 1 (OLR1) was identified to be aberrantly activated in ACS and regulated by miR-9. OLR1 was verified as a target gene of miR-9 by bioinformatics prediction and dual luciferase reporter gene assay. The atherosclerotic models were induced in ApoE^−/− mice, in which the agomir or antagomir of miR-9, or small interfering RNA (siRNA) against OLR1 were separately introduced. Serum lipid levels and expression of vascular remodeling and inflammatory response-related factors were determined, respectively. On the basis of the obtained results, in the atherosclerosis mice treated with the agomir of miR-9 and siRNA against OLR1, the p38-mitogen-activated protein kinase (p38MAPK) pathway was inhibited; levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol, tumor necrosis factor-α, interleukin-6, and vascular endothelial growth factor were reduced, but the high-density lipoprotein cholesterol level was increased, along with decreased vulnerable atherosclerotic plaque area and enhanced vascular remodeling. Taken together, these findings suggested an inhibitory role miR-9 acts in the formation of vulnerable atherosclerotic plaques in ACS mice, along with a promoted vascular remodeling, via a negative feedback regulation of OLR1-mediated p38MAPK pathway.     

External triggers of onset of myocardial infarction-an update

Coronary heart disease is one of the leading causes of death in both industrialised and developing countries. About two thirds of all coronary deaths occur outside the hospital and before any medical care can be reached. Therefore, the prevention of coronary events appears to be of utmost importance. Rupture of an atherosclerotic plaque and subsequent coronary thrombosis is the most common underlying pathophysiological mechanism of coronary events. External stresses or 'triggers' imposing on coronary plaques may precipitate plaque rupture. External triggers include physical activity, various emotional stresses, eating, environmental factors, and sexual activity. The increased relative risk of myocardial infarction may be induced by external triggers via the activation of internal triggering mechanisms such as biomechanical and hemodynamic stresses and changes in platelet aggregability and blood viscosity. Recent prospective studies have confirmed the results of earlier retrospective studies and have, similarly, shown the importance of external triggers in increasing the risk of myocardial infarction and other coronary events. Particularly, sedentary individuals with underlying coronary heart disease appear to be at risk when exposed to external triggers. Regular physical activity, on the other hand, is a protective factor against the increased risk associated with external triggers. However, health education needs to be provided about the risks associated with strenuous exercise in untrained individuals. Apart from lifestyle factors, pharmacological protection of the population at risk during vulnerable periods plays an important role as well. Medication such as beta-blockers and aspirin may lower the increased risk of coronary events during exposure to external triggers. Also, further research is needed with regard to psychosocial stressors and their potential role as external triggers of myocardial infarction and other coronary events.     

24-Hour Assessment of Performance on a Palmtop Computer: Validating a Self-Constructed Test Battery

Serious adverse cardiovascular events, including myocardial infarction, sudden cardiac death, and stroke, frequently result from rupture of atherosclerotic plaques with superimposed thrombosis and exhibit a pronounced circadian rhythmicity, peaking in the morning hours. Two potentially synergistic mechanisms play a pathogenic role in the circadian variation of arterial thrombotic events. A morning surge in sympathetic activity alters hemodynamic forces and predisposes vulnerable coronary atherosclerotic plaques to rupture. Day–night variations of hemostatic and fibrinolytic factors result in morning hypercoagulability and hypofibrinolysis, promoting intraluminal thrombus formation at the same time when the risk for plaque rupture is highest. Diabetic patients have a very high cardiac event rate but fail to show normal circadian fluctuations in the occurrence of myocardial infarction. Alterations in the circadian variation autonomic tone, blood pressure, and the thrombotic–thrombolytic equilibrium have been documented in diabetic patients. These include reduced or absent 24-h periodicity in autonomic tone, fibrinolytic activity, and thrombotic tendency, and a blunted decline in nocturnal blood pressure. Disruption of these circadian rhythms explains the lack of significant circadian distribution of cardiac events in diabetic patients. Moreover, the loss of these normal biorhythms results in a continuous susceptibility to thrombotic events throughout the day and may contribute to the excess cardiovascular mortality and morbidity in these patients. (Chronobiology International, 18(1), 109–121, 2001)     

冠状动脉易损斑块影像学最新研究进展

冠心病(CAD)是世界上致死率最高的疾病之一,其中,以急性冠状动脉综合征(ACS)病情最为凶险,而近70%的急性冠脉事件并不是由显著地冠状动脉狭窄引起,而是由冠状动脉易损斑块(vulnerable plaque)破裂造成的急性狭窄,以及其后血栓形成所致,因此冠状动脉易损斑块是导致急性冠状动脉综合征的主要元凶,因此需要早期发现易损斑块并积极进行干预。近两年来,CT、MRI、血管内超声(IVUS)和光学相干断层成像(OCT)广泛应用于易损斑块的评估并取得显著进展,而分子影像学能从分子层面揭示易损斑块形成机制以及更加早期识别斑块进行。本文简要总结近两年影像学方法对易损斑块的最新研究进展及热点。     

Inflammatory markers: linking unstable plaques to coronary event, an interventional perspective

Abundant data links inflammatory mechanisms to atheromatous plaque destabilization leading to plaque rupture and coronary events. The discovery of inflammatory cells and inflammatory mediators within atherosclerotic plaques prone to rupture led to a series of studies demonstrating an association between various markers of inflammation and future coronary events. Inflammatory markers have also been used in patients undergoing coronary angioplasty in an attempt to predict restenosis and risk for post-procedural coronary events. This review article provides an overview on the potential use of inflammatory markers in the context of coronary interventions.     

Shear strain in the adventitial layer of the arterial wall facilitates development of vulnerable plaques

Myocardial infarction and stroke are two of the leading causes of death and primarily triggered by destabilization of atherosclerotic plaques. Fatty streaks are known to develop at sites in the arterial wall where shear stress is low. These fatty streaks can develop into more advanced plaques that are prone to rupture. Rupture leads to thrombus formation, which may subsequently result in a myocardial infarction or stroke. The relation between shear stress on the inner (endothelial) layer of the arterial wall in relation to plaque development has been studied extensively. However, a causal relation between adventitial shear forces and atherosclerosis development has never been considered.Arterial stiffening increases with age and may facilitate an increase in shear strain in the adventitial layer, an axial shear between artery and surrounding tissue. In the adventitial layer, a large number of inflammatory cells and perivascular structures are present that are subjected to shear strain. Cyclic strain applied to endothelial cells stimulates neovascularisation via different pathways. The conduit arteries in the human body (e.g. coronary and carotid artery) have their own nutrition supply: the vasa vasorum, which is located in the adventitial layer and sprouts into the intimal layer when atherosclerotic plaque develops. Increased plaque neovascularisation makes the plaques more prone to rupture. Therefore we hypothesize that increased shear strain facilitates the development of vulnerable plaques by stimulation of atherosclerotic plaque neovascularisation that sprouts from the adventitial vasa vasorum. Validation of this hypothesis paves the road to the use of adventitial shear strain (measured using a noninvasive ultrasound technique) as risk assessment in plaque.     

The importance of defining serum MMP-9 concentration in diabetics as an early marker of the rupture of atheromatous plaque in acute coronary syndrome

Acute coronary syndrome (ACS) is the main cause of mortality in diabetics. Acute myocardial infarction (AMI) in diabetics is much more often than in non-diabetics. MMP-9 activity could ease the formation of atherosclerosis, destabilization and plaque rupture as well as thrombocyte aggregation. THE AIM OF THIS STUDY IS TO EXAMINE: MMP-9 defining in serum in diabetics; the impact of diabetes mellitus on atherosclerosis and MMP-9 level; relation between serum values of MMP-9 and markers of glycoregulation and lipid status, respectively. RESULTS: The greatest concentration of both total and active MMP-9 serum has been noted in diabetics group with ACS. Both total and active MMP-9 values, in group with diabetes and ACS showed significantly important difference regarding the values in control group. Total and active MMP-9 showed statistically important correlation between the values of glycated hemoglobine A1c (HbA1c) and inverse correlations with values of subfraction HDL3.Active MMP-9 showed statistically important inverse correlation with value of HDL cholesterol. IN CONCLUSION: According to the results, it has been thought that active MMP-9 shows a certain degree of atherosclerotic changes on blood vessels better than total MMP-9. MMP-9, active one, could present an early marker of atherosclerosis, especially on coronary blood vessels, in diabetics with type 2.     

Role of plaque inflammation in acute and recurrent coronary syndromes

Inflammation plays an important role in the initiation, development, progression and complications of atherosclerotic vascular disease. Our present knowledge of the elementary role of inflammation for the onset of plaque rupture in atherosclerotic coronary lesions primarily stems from autopsy studies. However, the introduction of directional coronary atherectomy catheters has provided a unique opportunity to directly investigate the role of inflammation in coronary syndromes. In this report we describe the role of coronary plaque inflammation, as determined by immunohistochemistry, on the presentation of coronary syndromes and on the clinical outcome following percutaneous interventions.     

Apoptosis and acute coronary syndromes

Atherosclerosis is an inflammatory disease of the arterial wall. Ischemic manifestations of atherosclerosis are mainly due to thrombus formation upon a superficially eroded (denudation of luminal endothelium, 40% of cases) or deeply ruptured (fibrous cap rupture, 60% of cases) plaques. Recent studies have unraveled potentially critical roles for both inflammatory and apoptotic processes in plaque destabilization leading to thrombus formation. Pro-inflammatory mediators have been particularly implicated in the loss of smooth muscle cell and the promotion of collagen degradation that are responsible for fibrous cap rupture, whereas apoptosis has been identified as one of the major determinants of plaque thrombogenicity.     

Assessment of serum tenascin-C and growth differentiation factor-15 among type 2 diabetes mellitus patients with and without acute coronary syndrome

BackgroundHigh prevalence of type 2 diabetes mellitus (T2DM) is associated with a higher prevalence of acute coronary syndrome (ACS). Inflammation is one of the important contributors to the pathogenesis and complications of coronary atherosclerotic plaque. Growth Differentiation Factor-15 (GDF-15) and Tenascin-C (TNC) play an important role in the initiation of atherosclerotic plaque as well as its rupture. The aim of the study was to evaluate the association between serum GDF-15, TNC, and the risk of ACS among T2DM patients.MethodsAnthropometric parameters, routine biochemical investigations like liver and renal function tests, lipid profile, and Creatine Kinase-Total (CK-T), Creatine Kinase-MB (CK-MB) were measured in 42 T2DM patients with ACS and 42 T2DM patients. Serum GDF-15 and TNC were measured by Human Sandwich-ELISA kits.ResultsSerum GDF-15 and TNC levels were significantly higher in T2DM patients with ACS as compared to T2DM patients. Serum GDF-15 was significantly correlated with waist circumference, diastolic blood pressure, pulse, serum CK-T, and CK-MB. Serum TNC was significantly correlated with the pulse, serum CK-T, CK-MB, high-density lipoprotein-cholesterol, and blood urea nitro GEN. Multivariate linear regression analysis showed that waist circumference was independently positively associated with serum GDF-15.ConclusionsT2DM patients with higher serum GDF-15 and TNC levels were at higher risk of acute coronary syndrome independent of other cardiovascular risk factors.     

Antibody Phage Display Assisted Identification of Junction Plakoglobin as a Potential Biomarker for Atherosclerosis

To date, no plaque-derived blood biomarker is available to allow diagnosis, prognosis or monitoring of atherosclerotic vascular diseases. In this study, specimens of thrombendarterectomy material from carotid and iliac arteries were incubated in protein-free medium to obtain plaque and control secretomes for subsequent subtractive phage display. The selection of nine plaque secretome-specific antibodies and the analysis of their immunopurified antigens by mass spectrometry led to the identification of 22 proteins. One of them, junction plakoglobin (JUP-81) and its smaller isoforms (referred to as JUP-63, JUP-55 and JUP-30 by molecular weight) were confirmed by immunohistochemistry and immunoblotting with independent antibodies to be present in atherosclerotic plaques and their secretomes, coronary thrombi of patients with acute coronary syndrome (ACS) and macrophages differentiated from peripheral blood monocytes as well as macrophage-like cells differentiated from THP1 cells. Plasma of patients with stable coronary artery disease (CAD) (n = 15) and ACS (n = 11) contained JUP-81 at more than 2- and 14-fold higher median concentrations, respectively, than plasma of CAD-free individuals (n = 13). In conclusion, this proof of principle study identified and verified JUP isoforms as potential plasma biomarkers for atherosclerosis. Clinical validation studies are needed to determine its diagnostic efficacy and clinical utility as a biomarker for diagnosis, prognosis or monitoring of atherosclerotic vascular diseases.     

Retracted: Downregulated microRNA-224 aggravates vulnerable atherosclerotic plaques and vascular remodeling in acute coronary syndrome through activation of the TGF-β/Smad pathway

Recent studies have shown that circulating microRNAs (miRNA) play a critical role in diagnosing acute coronary syndrome (ACS). This study aims to investigate the effect of miR-224 on atherosclerotic plaques forming and vascular remodeling in ACS and its relationship with TGF-β/Smad pathway. Myocardial infarction (MI) rat model was established and lentivirus vector of miR-224 inhibitor was prepared for investigating the effect of downregulated miR-224 on the contents of nitric oxide (NO) and endothelin-1 (ET-1), blood lipid levels and inflammatory factor levels in serum as well as the TGF-β/Smad pathway. The rats suffering from MI had decreased survival rates and exhibited reduced levels of NO, high-density lipoprotein cholesterol, and lumen diameter, and Smad7 messenger RNA (mRNA) and protein expression; while had significantly increased ratio of heart weight or body weight, levels of ET-1, inflammatory factors, blood lipid indexes, vascular remodeling indexes, collagen volume fraction, vulnerable atherosclerotic plaque area, VCAM-1 and MMP-2 protein expression, TGF-β, Smad2, Smad3, and Smad4 mRNA and protein expression. After inhibiting the TGF-β/Smad pathway, the rats suffering from MI showed notably opposite trend. In conclusion, downregulation of miR-224 expression promotes the formation of vulnerable atherosclerotic plaques and vascular remodeling in ACS through activation of the TGF-β/Smad pathway. Therefore, this study provides a new therapeutic target for ACS.