Increased ubiquitin immunoreactivity in unstable atherosclerotic plaques associated with acute coronary syndromes

OBJECTIVES: The current study was designed to examine whether ubiquitin expression is higher in unstable than in stable lesions of patients with acute coronary syndrome (ACS). BACKGROUND: The ubiquitin system has been identified as the nonlysosomal pathway of protein degradation; it is involved in a number of biologic processes crucial to cell and tissue integrity and therefore, might be potentially involved in the rupture of unstable coronary plaques. METHODS: We conducted an autopsy-based study of 25 consecutive patients with fatal ACS. Lesions of both infarct-related and noninfarct-related segments from the same patients were examined for the expression and localization of ubiquitin by use of immunohistochemistry and a semiquantitative grading scale. RESULTS: Ubiquitin immunoreactivity was higher in infarct-related than in noninfarct-related lesions (1.4 +/- 0.5 vs. 1.1 +/- 0.6, p = 0.03). Compared with areas adjacent to the plaque (0.6 +/- 0.7), ubiquitin immunoreactivity was higher in areas around the lipid core (2.5 +/- 0.8, p < 0.001), plaque shoulders (1.6 +/- 1.1, p < 0.001), and fibrous cap regions (1.6 +/- 1.1, p < 0.001). Within the plaque area, co-localization of ubiquitin immunoreactivity with T cells and macrophages was found. In areas adjacent to the plaque, ubiquitin immunoreactivity co-localized with neointima cells and media smooth muscle cells. CONCLUSIONS: In patients with ACS, ubiquitin immunoreactivity is enhanced in unstable, infarct-related lesions, predominantly in plaque regions of tissue degradation. Based on these findings, this study suggests a role for the ubiquitin system in the destabilization and rupture of coronary atherosclerotic plaques in humans.     

急性冠状动脉综合征与动脉粥样硬化血栓性脑梗死患者颈动脉斑块高频超声特征

目的通过高频超声对急性冠状动脉综合征(ACS)和动脉粥样硬化血栓性脑梗死(ACI)患者的颈动脉粥样硬化斑块特征进行研究。方法选择拟诊为ACS的患者100例(单支病变患者50例,多支病变患者50例)及ACI的患者56例,采用高频超声对以上两类患者的颈动脉斑块特征进行对比研究。结果 ACS及ACI患者的颈动脉斑块均以双侧颈动脉窦部多发,且以硬斑块多见;ACS中冠状动脉多支病变患者斑块发生率高于单支病变(P0.05),与ACI患者相似;ACS中多支病变患者与ACI患者的不稳定斑块及狭窄发生率均较单支病变患者高(P0.05)。结论高频超声发现ACS和ACI患者具有相似的颈动脉斑块特征,其中ACS中多支病变患者与ACI患者颈部斑块特征的相似度更为明显。     

Pathomorphological features of atherosclerotic plaques in acute coronary syndrome

We studied transverse cross-sections (5 mm apart) of coronary arteries of 45 men and women who died of acute myocardial infarction at the age of 41-79 years. Both stable and unstable atherosclerotic plaques were found in all cases. Stable plaques consisted of solid fibrous tissue with small amount of lipids and cellular elements. Unstable plaques were represented by 2 types: lipid (75.6%) and dystrophic necrotic (24.4%). Various degree of inflammatory cellular reaction was present in all lipid plaques. Factors associated with fibrous cap rupture were identified. Lipid plaques were more frequent in subjects with elevated while dystrophic-necrotic - with normal levels of blood lipids (measured during life).     

Identification of unstable coronary atherosclerotic plaques

The mechanisms of atherogenesis are better understood and the detection of atherosclerosis has improved with the different diagnostic methods currently available. However, it is almost impossible at present to differentiate high risk, unstable or vulnerable plaques from quiescent or stable plaques of atherosclerosis. This is a crucial problem given the banality of atherosclerosis on the one hand, and, on the other hand, the serious consequences (acute coronary syndromes, cerebrovascular accidents) of thrombotic occlusion at the site of an atherosclerotic plaque. It has now been established that the composition of the plaque is more important than the degree of stenosis, a fundamental concept in the risk of plaque rupture, precipitating the cascade of reactions leading to uncontrolled thrombosis. Consequently, new imaging techniques should address the problem of analysing the composition of atheromatous plaques. Endovascular ultrasonography, fast CT, angioscopy, nuclear imaging techniques and MRI are so many promising tools. However, non-invasive techniques should be distinguished from invasive ones. In all probability, it will be the former which will turn out to be the most useful diagnostic aid in pauci or asymptomatic patients. This article reviews the different imaging techniques under evaluation for the identification of risk of plaque rupture.     

Emerging importance of HDL cholesterol in developing high-risk coronary plaques in acute coronary syndromes

Cardiovascular disease is the principal cause of death in industrialized countries. Hyperlipidemia, with high low-density lipoprotein cholesterol and triglycerides, and low high-density lipoprotein cholesterol levels (<40 mg/dL in men and <45 mg/dL in women), is a known major cardiovascular risk factor. Statins are considered the most potent and effective agents to reduce low-density lipoprotein cholesterol, but they have a variable effect on high-density lipoprotein cholesterol and triglycerides. Different clinical trials with statins have shown a decrease in low-density lipoprotein cholesterol by 35% and a reduction of the incidence of coronary events by as much as 30%. However, 60 to 70% of events still occur, despite remarkable reduction of low-density lipoprotein cholesterol concentration. Recent National Cholesterol Education Program guidelines highlighted the importance of high-density lipoprotein cholesterol concentration in the prevention and treatment of cardiovascular disease. High-density lipoprotein cholesterol is considered an independent risk factor and has an inverse relation with coronary events. The association of low levels of high-density lipoprotein cholesterol with an increased incidence of cardiovascular events implies a critical role of high-density lipoprotein in the protection against atherosclerotic disease and in the progression of coronary atherosclerotic disease. High-density lipoprotein cholesterol appears to exert this protective effect through multiple mechanisms. High-density lipoprotein is not only involved in reverse cholesterol transport, but also prevents endothelial dysfunction; inhibits the homing of monocytes, apoptosis, platelet activation, and factor X activation; and has antioxidant properties. In this article the authors review the available experimental and clinical evidence supporting the importance of high-density lipoprotein cholesterol as a protective factor in coronary artery disease, and the strategies developed to increase high-density lipoprotein cholesterol.     

Recent activation of the plaque immune response in coronary lesions underlying acute coronary syndromes

Objective—To discriminate between chronic inflammation and acute activation of the plaque immune response in culprit lesions of patients with acute coronary syndromes.Design—Retrospective study.Setting—Tertiary referral centre.Subjects—71 patients having coronary atherectomy were classified according to their ischaemic syndrome: stable angina (n = 23); stabilised unstable angina (n = 18); refractory unstable angina (n = 11); and acute myocardial infarction (n = 19).Main outcome measures—Immunohistochemical measurement of interleukin 2 receptor (IL-2R) (CD25) positive cells expressed as a percentage of the total amount of (CD3 positive) T lymphocytes in frozen sections of atherectomy specimens.Results—The number of lesions containing IL-2R (CD25) positive T cells increased with severity of the ischaemic coronary syndrome (stable angina, 52%; stabilised unstable angina, 77.8%; refractory unstable angina, 90.9%; acute myocardial infarction, 89.4%). The percentage of activated T cells (CD25/CD3 ratios ×100) increased in lesions associated with refractory unstable angina (7.8%) and acute myocardial infarction (18.5%), compared with those in lesions associated with either chronic stable angina (2.2%) or stabilised unstable angina (3.3%).Conclusions—An increase in the percentage of IL-2R positive T lymphocytes in culprit lesions of patients with acute coronary syndromes indicates recent activation and amplification of the immune response within plaques. This may result in a burst of inflammatory products with tissue degrading and vasoactive properties and, hence, could initiate or accelerate the onset of an acute coronary event.     

Heat production of atherosclerotic plaques and inflammation assessed by the acute phase proteins in acute coronary syndromes

Several studies have shown that inflammation plays an important role in the pathogenesis of coronary heart disease (CHD). Serum amyloid A (SAA) and C-reactive protein (CRP) reactants of the acute phase of inflammation, have been shown to be increased in patients with CHD. Recently ex vivo studies demonstrated that some types of atherosclerotic plaques show substantially warmer regions. A catheter-based technique has been developed to measure the temperature of human arteries in vivo. Therefore, the aim of the present study was to measure the luminal surface temperature in patients with CHD and to correlate it with the acute phase proteins in order to discriminate the role of inflammation in heat production in acute coronary syndromes. Sixty patients were studied with CHD (20 with stable angina, 20 with unstable angina and 20 with acute myocardial infarction) and 20 sex- and age-matched controls without coronary artery disease, by measuring plasma levels of SAA, CRP, plasma lipids and intracoronary arterial luminal wall temperature. Intracoronary temperature was measured with a thermography catheter developed in our Institution: a thermistor probe with a temperature accuracy of 0.05 degrees C, was attached at the distal end of a long 3F polyurethane shaft. It was found that the median temperature differences at the site of the lesion from the core temperature was increased in patients with unstable angina (1.025 degrees C) and acute myocardial infarction (2.150 degrees C) compared with stable angina (0.300 degrees C), P<0.001 for each comparison. Furthermore, stable angina has increased temperature differences compared with controls (0.200 degrees C, P<0.001). There were very good correlations between CRP and SAA with the temperature (r=0.796, P=0.01 and r=0.848, P=0.01, respectively). Local heat at the site of lesion is increased in patients with acute coronary syndromes and may arise from an aggressive inflammatory response occurring in these situations. The sensitive measurement of plaque temperature as a prognostic marker may be useful in the management of coronary heart disease.     

Presence and severity of Chlamydia pneumoniae and Cytomegalovirus infection in coronary plaques are associated with acute coronary syndromes

Although an association between Chlamydia pneumoniae (Cpn) or Cytomegalovirus (CMV) infection and coronary atherosclerosis has been reported, such an association is less clear for acute coronary syndromes (ACS). The purpose of this study was to investigate the pathogenic roles of Cpn and CMV infection of coronary plaques in ACS. We divided 38 coronary plaque specimens obtained from 38 patients who underwent directional coronary atherectomy or thrombectomy into an ACS group (n = 21) and a non-ACS group (n = 17). Cpn and CMV in specimens were stained using immunohistochemical techniques and analyzed quantitatively. The detection rate for either Cpn- or CMV-positive cells in ACS patients was slightly higher compared with non-ACS patients. Detection rates for both Cpn- and CMV-positive cells were significantly higher in ACS patients than in non-ACS patients (P = 0.010). Furthermore, the density of Cpn- and CMV-positive cells in plaques was significantly higher in ACS patients than in non-ACS patients (P < 0.003). The results indicate that the presence and severity of Cpn and CMV infection in coronary plaques are greater in patients with ACS compared with non-ACS patients. We conclude that infection with Cpn and CMV in coronary plaques may be involved in the pathogenesis of ACS.     

Physiopathology of acute coronary syndromes

Coronary atherosclerosis and its thrombotic complications represent one of the leading causes of lesions usually consists of successive acute episodes, either silent or in the form of an acute coronary syndrome such as unstable angina, non-Q-wave myocardial infarctions, transmural myocardial infarctions or sudden death. This mode of progression does not exclude phases of regression, or more frequently stabilization of plaques, which, depending on their haemodynamic repercussions, are then responsible for chronic myocardial ischaemia. Acute coronary syndrome (ACS) correspond to the same pathophysiological process: rupture of an atheromatous plaque initiating harmful thrombotic, inflammatory and vasomotor phenomena. This is not a new concept, but progress over recent years suggests that the composition and biology of the plaque are factors involved more in the initiation of ACS than the size of the plaque. "Soft" lesions, rich in lipids, are clearly not only the most unstable lesions, but also the most thrombogenic because of their large tissue factor content. After describing the structure of vulnerable plaques, the authors discuss the causes of their rupture and the resulting cascade or events, responsible for life-threatening clinical situations.     

Proteomics of acute coronary syndromes

Acute coronary syndromes (ACS), such as unstable angina, acute myocardial infarction, and sudden cardiac death, are commonly associated with the presence of vulnerable plaques in coronary arteries. Rupture or erosion of vulnerable plaques results in the formation of luminal thrombi due to the physical contact between platelets and thrombogenic elements within the atherosclerotic lesions. Considering the socioeconomic burden of ACS, it is imperative that the scientific community achieves a clear understanding of the multifaceted pathophysiology of vulnerable atheroma to identify accurate prognostic biomarkers and therapeutic targets. The analytical power of modern proteomic technologies could facilitate our understanding of vulnerable plaques and lead to the discovery of novel therapeutic targets and diagnostic biomarkers.