Unstable Atherosclerotic Plaques Research Articles

Рідкісний випадок спонтанного тромболізису у пацієнтки з гострим інфарктом міокарда з елевацією сеґмента ST

In the pathogenesis of acute myocardial infarction an important role belongs to coronary sclerosis and coronary artery thrombosis. Endothelium plays an important role in a regulation of vascular tone, local inflammation, hemostasis, neovascularisation. An impairment of endothelial barrier function occurs after direct damage of endothelial cells as a result of an atherosclerotic plaque destabilization, injury, chronic inflammation or exposure to hazardous substances. Breakage of the endothelial surface causes an exposure of subendothelial collagen and triggers expression of adhesive proteins (e.g. tissue factor and von Willebrand factor) and decreases synthesis of prostacyclin and nitric oxide. In case of its damage and activation, thrombocytes adhere and aggregate to each other which leads to thrombosis and can cause an acute myocardial infarction.  Aim. Our aim was to evaluate a cellular mechanisms of thrombosis as well as conditions that leads to spontaneous thrombolysis in acute myocardial infarction for treatment optimisation of acute coronary syndrome.   Material and Methods. The case of acute myocardial infarction with ST segment elevation in 79 years old patient is presented that showed spontaneous coronary blood flow recovery.  Results and Discussion. In described case in a patient with acute myocardial infarction a rapid regression of ECG changes were documented after medical treatment at home was provided. Those changes were most likely a results of spontaneous thrombolysis with subsequent recovery of coronary blood flow in infarct-related artery due to rarely occurring activation of fibrinolytic system. The fibrinolysis system was triggered by the release of plasminogen activator and affected newly formed thrombus. However unstable atherosclerotic plaque was thrombogenic enough and leaded to recurrence of myocardial infarction. Thus the patient received coronary artery stenting. Clinical and morphological data has shown that in those patients a major role in development of acute coronary syndrome plays not a coronary artery spasm but a coronary thrombosis with subsequent spontaneous thrombolysis and restoration of coronary blood flow which happened upon timely application of antiaggregants, anticoagulants and antianginals drugs. Coronary artery spasm typically occurs more distal from the obstruction place as a result of exposure to vasoconstrictors released after thrombocyte degranulation. Spontaneous thrombolysis by acute myocardial infarction is untypical, hence myocardial infarction with pathological Q wave develops.  Conclusions. Patients with acute coronary syndrome, which exhibit spontaneous thrombolysis require angiography and stenting of coronary arteries as soon as possible to prevent recurrence of coronary thrombosis and development of acute myocardial infarction.

Expression and Cellular Localization of CXCR4 and CXCL12 in Human Carotid Atherosclerotic Plaques.

The CXCR4/CXCL12 complex has already been associated with progression of atherosclerosis; however, its exact role is yet unknown. The aim of this study was to analyse the expression and cellular localization of CXCL12 and its receptor CXCR4 in human carotid atherosclerotic plaques. Carotid plaques (n = 58; 31 stable, 27 unstable, based on histological characterization of plaque morphology) were obtained during carotid endarterectomy, and 10 healthy vessels were used as a control. Expression of cxcr4, cxcr7, cxcl12, ccl2/ccr2 and csf1/csf1r was analysed at mRNA, and level expression of CXCR4, CXCR7 and CXCL12 was analysed at protein level. Cellular localization was determined using consecutive and double immunohistochemical (IHC) staining and microdissection. At mRNA level, cxcr4, cxcr7 and cxcl12 were significantly higher expressed in stable carotid plaques compared with controls (p = 0.011, p < 0.001 and p < 0.001). Cxcl12 mRNA expression was successively augmented toward unstable plaques (p < 0.001). At protein level, CXCR4, CXCR7 and CXCL12 expression was significantly increased in both stable (p = 0.001, p < 0.001 and p = 0.035, respectively) and unstable (p = 0.003, p < 0.001 and p = 0.045, respectively) plaques compared with controls. Using IHC, CXCR4 was particularly localized in macrophages and small neovessels. Microdissection confirmed strongest expression of cxcr4 in macrophages within atherosclerotic plaques. Leukocytes and smooth muscle cells showed cxcr4 expression as well. For cxcl12, only microdissected areas with macrophages were positive. Expression of CXCR4 and CXCL12 was significantly increased in both stable and unstable carotid atherosclerotic plaques compared with healthy vessels, both at mRNA and protein level. CXCR4 and CXCL12 were localized particularly in macrophages.

Contrast-enhanced ultrasonography as the most perspective diagnostic method for unstable atherosclerotic plaque of carotid artery

Problem of internal carotid artery disease diagnosis appears to be crucial today. Complications of this pathology are strokes and transient ischemic attacks. There is no technology for their prediction or at least stratifying risks. Some recent researches are devoted to a new diagnostic method. This new technology is called Contrast Enhanced Ultrasonography (CEUS) and followed by outstanding results in studying the morphological peculiarities of internal carotid artery plaques and predicting the probability of complications. CEUS is a new way for atherosclerotic process analysis because it is able to detect intraplaque neovascularization and vascular wall inflammation.

Pathological Quantification of Carotid Artery Plaque Instability in Patients Undergoing Carotid Endarterectomy.

Unstable atherosclerotic carotid plaques cause cerebral thromboemboli and ischemic events. However, this instability has not been pathologically quantified, so we sought to quantify it in patients undergoing carotid endarterectomy (CEA).Methods and Results:Carotid plaques were collected during CEA from 67 symptomatic and 15 asymptomatic patients between May 2015 and August 2016. The specimens were stained with hematoxylin-eosin and elastica-Masson. Immunohistochemistry was performed using an endothelial-specific antibody to CD31, CD34 and PDGFRβ. The histopathological characteristics of the plaques were studied. By multiple-variable logistic regression analysis, plaque instability correlated with the presence of plaque rupture [odds ratio (OR), 9.75; P=0.013], minimum fibrous cap thickness (OR per 10 μm 0.70; P=0.025), presence of microcalcifications in the fibrous cap (OR 7.82; P=0.022) and intraplaque microvessels (OR 1.91; P=0.043). Receiver-operating characteristics analyses showed that these factors combined into a single score diagnosed symptomatic carotid plaques in patients with carotid artery stenosis with a high level of accuracy (area under the curve 0.92; 95% confidence interval 0.85-0.99 vs. asymptomatic). This analysis of carotid plaque instability strongly suggested that the diagnostic scoring of carotid plaque instability improves the understanding and treatment of carotid artery disease in patients undergoing CEA.

Novel molecular imaging ligands targeting matrix metalloproteinases 2 and 9 for imaging of unstable atherosclerotic plaques.

Molecular imaging of matrix metalloproteinases (MMPs) may allow detection of atherosclerotic lesions vulnerable to rupture. In this study, we develop a novel radiolabelled compound that can target gelatinase MMP subtypes (MMP2/9) with high selectivity and inhibitory potency. Inhibitory potencies of several halogenated analogues of MMP subtype-selective inhibitors (N-benzenesulfonyliminodiacetyl monohydroxamates and N-halophenoxy-benzenesulfonyl iminodiacetyl monohydroxamates) were in the nanomolar range for MMP2/9. The analogue with highest inhibitory potency and selectivity was radiolabelled with [123I], resulting in moderate radiochemical yield, and high radiochemical purity. Biodistribution studies in mice, revealed stabilization in blood 1 hour after intravenous bolus injection. Intravenous infusion of the radioligand and subsequent autoradiography of excised aortas showed tracer uptake in atheroprone mice. Distribution of the radioligand showed co-localization with MMP2/9 immunohistochemical staining. In conclusion, we have developed a novel selective radiolabeled MMP2/9 inhibitor, suitable for single photon emission computed tomography (SPECT) imaging that effectively targets atherosclerotic lesions in mice.

The potential inhibitory effects of miR‑19b on vulnerable plaque formation via the suppression of STAT3 transcriptional activity.

Atherosclerotic plaque growth requires angiogenesis, and acute coronary syndrome (ACS) is usually triggered by the rupture of unstable atherosclerotic plaques. Previous studies have identified typically circulating microRNA (miRNA/miR) profiles in patients with ACS. miRNAs serve important roles in the pathophysiology of atherosclerotic plaque progression. The present study aimed to investigate the potential role and mechanism of miR-19b in plaque stability. miRNA array data indicated that 28 miRNAs were differentially expressed in the plasma of patients with unstable angina (UA; n=12) compared with in control individuals (n=12), and miR-19b exhibited the most marked upregulation. Circulating miR-19b levels were further validated in another independent cohort, which consisted of 34 patients with UA and 24 controls, by quantitative polymerase chain reaction. Gene Ontology annotations of the predicted target genes of miR-19b suggested that miR-19b may be involved in endothelial cell (EC) proliferation, migration and angiogenesis, which was confirmed by Cell Counting kit-8, wound healing and tube formation assays in the present study. Finally, the present study indicated that miR-19b may suppress signal transducer and activator of transcription 3 (STAT3) tyrosine phosphorylation and transcriptional activity in ECs, as determined by western blot analysis and luciferase reporter assay. In conclusion, the present study revealed that increased miR-19b expression may delay unstable plaque progression in patients with UA by inhibiting EC proliferation, migration and angiogenesis via the suppression of STAT3 transcriptional activity.

Lipoprotein apheresis downregulates IL-1α, IL-6 and TNF-α mRNA expression in severe dyslipidaemia

Background and aimsDyslipidaemias are associated with cardiovascular mortality and morbidity, driven by unstable atherosclerotic plaques with inflammatory infiltrates. Levels of messenger RNA (mRNA) for pro-inflammatory cytokines have been positively correlated with atherosclerotic disease progression. Therapeutic lipoprotein apheresis (LA) reduces plasma lipid levels and reduces inflammation. We evaluated the effects of LA on expression of mRNA coding for key pro-inflammatory cytokines in patients with dyslipidaemia, homo-/hetero-zygous familial hypercholesterolaemia (HoFH, HeFH) or hyperlipoprotein(a)aemia [hyperLp(a)] and associated coronary artery disease (CAD). ApproachTen patients (five males and five females, mean age 47 ± 9.2 years) were enrolled, all with HyperLp(a) or confirmed genetic diagnoses of dyslipidaemia, HoFH, or HeFH; all had associated CAD. mRNA determinations were via reverse transcriptase polymer chain reaction (RT-qPCR). ResultsLA was associated with downregulation of mRNA expression for IL-1α, IL-6 and TNF-α, starting after the first LA session. The observed reduction was progressively enhanced during the interval between the first and second LA sessions to achieve a maximum decrease by the end of the second session (IL-1α: −49%, p < 0.001; IL-6: −35%, p < 0.001; TNF-α: −56%, p < 0.001). ConclusionsLA suppresses the expression of IL-1α, IL-6 and TNF-α mRNA in patients with dyslipidaemias. This may contribute to the arterial anti-inflammatory effect of LA.

MMP1 and MMP3 gene polymorphisms in patients with acute coronary syndromes.

Matrix metalloproteinases (MMPs) are the group of proteolytic enzymes that break down the components of the connective tissue matrix leading to unstable atherosclerotic plaques. The aim of this study was to examine the association between MMP1-1607dupG (rs1799750) and MMP3-1171dupA (rs3025058) gene polymorphisms and acute coronary syndromes (ACS) in the form of unstable angina. This study included 197 patients with ACS in the form of unstable angina confirmed by coronary angiography (defined by >70% stenosis in at least one major coronary artery) and 144 healthy controls. There was no statistically significant difference in the distribution of the MMP1-1607dupG (rs1799750) polymorphism between patients with unstable angina and the control group. With regard to the MMP3-1171dupA (rs3025058) polymorphism, a significant increase in the frequency of the 6A/6A genotype among patients with unstable angina was detected. This association was confirmed in multivariate logistic regression analysis, where male sex and rs3025058 6A/6A genotype were significantly associated with an increased risk of ACS. © 2017 IUBMB Life, 69(11):850-855, 2017.

Endothelial-to-Mesenchymal Transition: A Potential Mechanism for Atherosclerosis Plaque Progression and Destabilization.

Endothelial-to-mesenchymal transition (EndMT) is a cellular reprogramming mechanism by which endothelial cells acquire a mesenchymal phenotype. EndMT is associated with fibroproliferative diseases, such as cancer progression and metastasis and cardiac and kidney fibrosis, and this condition has been extensively investigated over the past decade. Recently, studies showed that EndMT contributes to the initiation and progression of atherosclerotic lesion and plaque destabilization. Unstable atherosclerotic plaque rupture and subsequent thrombosis are the main pathological causes of acute cardiovascular events. EndMT is plastic and reversible. Therefore, our enhanced understanding on the mechanisms controlling EndMT and its roles in the atherosclerosis plaque progression and instability may provide a basis for the development of novel therapeutic strategies to stabilize and reverse atherosclerotic plaques.

Decreased cathepsin K levels in human atherosclerotic plaques are associated with plaque instability.

Investigating the determinants and dynamics of atherosclerotic plaque instability is a key area of current cardiovascular research. Extracellular matrix degradation from excessive proteolysis induced by enzymes such as cathepsin K (Cat K) is implicated in the pathogenesis of unstable plaques. The current study assessed the expression of Cat K in human unstable atherosclerotic plaques. Specimens of popliteal arteries with atherosclerotic plaques were classified as stable (<40% lipid core plaque area; n=6) or unstable (≥40% lipid core plaque area; n=14) based on histopathological examinations of hematoxylin and eosin stained sections. The expression of Cat K and cystatin C (Cys C) were assessed by immunohistochemical examination and levels of Cat K mRNA were detected by semi-quantitative reverse transcriptase polymerase chain reaction. Morphological changes including a larger lipid core, endothelial proliferation with foam cells and destruction of internal elastic lamina were observed in unstable atherosclerotic plaques. In unstable plaques, the expression of Cat K protein and mRNA was upregulated, whereas Cys C protein expression was downregulated. The interplay between Cat K and Cys C may underlie the progression of plaques from stable to unstable and the current study indicated that Cat K and Cys C are potential targets for preventing and treating vulnerable atherosclerotic plaque ruptures.

Defective autophagy in vascular smooth muscle cells promotes an unstable atherosclerotic plaque phenotype and increased expression of mitophagy markers in Apo E-/- mice

Defective autophagy in vascular smooth muscle cells promotes an unstable atherosclerotic plaque phenotype and increased expression of mitophagy markers in Apo E-/- mice

P677Defective autophagy in vascular smooth muscle cells promotes an unstable atherosclerotic plaque phenotype and increased expression of mitophagy markers in Apo E−/− mice

P677Defective autophagy in vascular smooth muscle cells promotes an unstable atherosclerotic plaque phenotype and increased expression of mitophagy markers in Apo E−/− mice

Age-Specific Sex Differences in Magnetic Resonance Imaging-Depicted Carotid Intraplaque Hemorrhage.

Stroke rates are higher in men compared with women in the fourth through seventh decades of life, and higher rates may result from differences in carotid intraplaque hemorrhage (IPH), an unstable atherosclerotic plaque component. We report age-specific sex differences in the presence of magnetic resonance imaging-depicted carotid IPH. Patients (n=1115) underwent magnetic resonance imaging for carotid IPH between 2005 and 2014. Low-grade carotid stenosis patients (n=906) without prior endarterectomy were eligible for this cross-sectional study. Of the 906 patients included (mean age±SD in years, 66.98±15.15), 63 (6.95%) had carotid IPH. In men and women, carotid IPH was present in 11.43% (48 of 420) and 3.09% (15 of 486), respectively (P<0.0001). Multivariable logistic regression analysis confirmed greater odds of carotid IPH in men for all ages: 45 to 54 (odds ratio=45.45; 95% confidence interval, 3.43-500), 55 to 64 years (odds ratio=21.74; 95% confidence interval, 3.21-142.86), 65 to 74 years (odds ratio=10.42; 95% confidence interval, 2.91-37.04), and ≥75 years (odds ratio=5.00; 95% confidence interval, 2.31-10.75). Male sex modified the effect of age on the presence of carotid IPH (β=0.074; SE=0.036; P=0.0411). Men have greater age-specific odds of magnetic resonance imaging-depicted carotid IPH compared with women. With increasing age post-menopause, the odds of carotid IPH in women becomes closer to that of men. Delayed onset of carotid IPH in women, an unstable plaque component, may partly explain differential stroke rates between sexes, and further studies are warranted.

Vnetje – skupni patogenetski dejavnik arterijske aterosklerotične in venske trombembolične bolezni

Inflammation is among the basic mechanisms of arterial atherosclerotc diseases and is most likely also involved in the onset of venous thromboembolic disease. Various risk factors for atherosclerosis cause damage to the vascular wall and trigger inflammatory changes, which may lead to the development of atherosclerosis. Therefore, people with advanced atherosclerosis, and particularly those with unstable atherosclerotic plaques as a result of intense inflammatory changes, are found to have elevated levels of inflammatory markers in the blood. The most frequent findings include elevated levels of highly specific C-reactive protein (hs-CRP), which is a non-specific systemic indicator of inflammation, and certain interleukins (interleukin–6, interleukin–8) that are considered to be more specific markers of vascular wall inflammation. Therefore, studies are underway to improve the prognostic value for cardiovascular events by the determination of inflammatory markers in the blood. However, due to the unspecifcity of individual inflammatory markers, different methods of their determination and close relation between marker levels and the established risk factors, these have failed to contribute significantly to the evaluation of the role of inflammation in the occurrence of cardiovascular events. Currently, the determination of hs-CRP as one of the most prominent risk factors is recommended only in persons at high risk for cardiovascular events, in those that do not have classical risk factors and are at risk due to other causes, such as e.g. familial predisposition.Recently, it has also been found that inflammation is implicated in the pathogenesis of venous thrombosis. In the case of a damaged venous wall inflammation occurs as a response to injury, while in idiopathic venous thrombosis without the presence of risk factors the vascular wall inflammation is probably a primary event that is followed by coagulation activation. Namely, there is a close association between inflammation and coagulation. Inflammation stimulates procoagulant activity and inhibits endogenous fibrinolysis, and therefore patients with the history of venous thrombosis present with elevated levels of systemic inflammatory markers, particularly of hs-CRP and interleukin. However, it has not been fully explained yet whether the elevated systemic inflammatory markers are a cause of a consequence of venous thrombosis. Te results of our study show that they are most probably a cause for prothrombotic characteristics of the blood and stimulate the occurrence of venous thrombosis, as patients with a history of venous thrombosis even in their stable period (3–5 years) present with elevated inflammatory markers.The increased systemic inflammatory response in arterial atherosclerotic and venous thromboembolic disease is indicative of a close association between both diseases, which are similar as to their pathogenesis but have different clinical features.The recognition of inflammatory basis of arterial and venous diseases is also important from the therapeutic point of view since until recently, in comparison with anticoagulants, medicines with anti-inflammatory activity were rather neglected. Not only has aspirin long been known for its antithrombocytic and also anti-inflammatory activity, it also appears to be effective in long-term prevention of recurrences and progressions of venous thromboses.

Inflammation - a common pathogenic factor of arterial atherosclerotic and venous thromboembolic disease.

Inflammation is among the basic mechanisms of arterial atherosclerotc diseases and is most likely also involved in the onset of venous thromboembolic disease. Various risk factors for atherosclerosis cause damage to the vascular wall and trigger inflammatory changes, which may lead to the development of atherosclerosis. Therefore, people with advanced atherosclerosis, and particularly those with unstable atherosclerotic plaques as a result of intense inflammatory changes, are found to have elevated levels of inflammatory markers in the blood. The most frequent findings include elevated levels of highly specific C-reactive protein (hs-CRP), which is a non-specific systemic indicator of inflammation, and certain interleukins (interleukin–6, interleukin–8) that are considered to be more specific markers of vascular wall inflammation. Therefore, studies are underway to improve the prognostic value for cardiovascular events by the determination of inflammatory markers in the blood. However, due to the unspecifcity of individual inflammatory markers, different methods of their determination and close relation between marker levels and the established risk factors, these have failed to contribute significantly to the evaluation of the role of inflammation in the occurrence of cardiovascular events. Currently, the determination of hs-CRP as one of the most prominent risk factors is recommended only in persons at high risk for cardiovascular events, in those that do not have classical risk factors and are at risk due to other causes, such as e.g. familial predisposition. Recently, it has also been found that inflammation is implicated in the pathogenesis of venous thrombosis. In the case of a damaged venous wall inflammation occurs as a response to injury, while in idiopathic venous thrombosis without the presence of risk factors the vascular wall inflammation is probably a primary event that is followed by coagulation activation. Namely, there is a close association between inflammation and coagulation. Inflammation stimulates procoagulant activity and inhibits endogenous fibrinolysis, and therefore patients with the history of venous thrombosis present with elevated levels of systemic inflammatory markers, particularly of hs-CRP and interleukin. However, it has not been fully explained yet whether the elevated systemic inflammatory markers are a cause of a consequence of venous thrombosis. Te results of our study show that they are most probably a cause for prothrombotic characteristics of the blood and stimulate the occurrence of venous thrombosis, as patients with a history of venous thrombosis even in their stable period (3–5 years) present with elevated inflammatory markers. The increased systemic inflammatory response in arterial atherosclerotic and venous thromboembolic disease is indicative of a close association between both diseases, which are similar as to their pathogenesis but have different clinical features. The recognition of inflammatory basis of arterial and venous diseases is also important from the therapeutic point of view since until recently, in comparison with anticoagulants, medicines with anti-inflammatory activity were rather neglected. Not only has aspirin long been known for its antithrombocytic and also anti-inflammatory activity, it also appears to be effective in long-term prevention of recurrences and progressions of venous thromboses.

MORPHOLOGICAL CHARACTERISTICS OF CORONARY AND CAROTID ATHEROSCLEROTIC PLAQUES IN PATIENTS WITH MYOCARDIAL INFARCTION

Aim - to study the correlation between the thickness of the fibrous cap and collagen in the coronary and carotid plaques in patients with myocardial infarction. Materials and methods. The objects of the study were 81 coronary and carotid atherosclerotic plaques obtained during autopsy study of 15 patients who died from complications of myocardial infarction. Histological and morphometric study and immunohistochemistry were performed. Immunohistochemical examination was carried out using monoclonal antibodies against collagen types II, III, IV, VI, VII. Results. There is a combination of complicated, unstable and stable coronary and carotid atherosclerotic plaques in patients with myocardial infarction. Unstable atherosclerotic plaque is characterized by thinning of the fibrous cap mainly in the peripheral areas and the growth of destructive changes in the collagen types III, IV and VI. Conclusion. There is a critical thinning in the caps of unstable carotid and coronary plaques in myocardial infarction with signs of disorganization of collagen, leading to decreased resistance to mechanical stress of this type of plaques.

Molecular Imaging of Atherothrombotic Diseases: Seeing Is Believing.

Molecular imaging, with major advances in the development of both innovative targeted contrast agents/particles and radiotracers, as well as various imaging technologies, is a fascinating, rapidly growing field with many preclinical and clinical applications, particularly for personalized medicine. Thrombosis in either the venous or the arterial system, the latter typically caused by rupture of unstable atherosclerotic plaques, is a major determinant of mortality and morbidity in patients. However, imaging of the various thrombotic complications and the identification of plaques that are prone to rupture are at best indirect, mostly unreliable, or not available at all. The development of molecular imaging toward diagnosis and prevention of thrombotic disease holds promise for major advance in this clinically important field. Here, we review the medical need and clinical importance of direct molecular imaging of thrombi and unstable atherosclerotic plaques that are prone to rupture, thereby causing thrombotic complications such as myocardial infarction and ischemic stroke. We systematically compare the advantages/disadvantages of the various molecular imaging modalities, including X-ray computed tomography, magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography, fluorescence imaging, and ultrasound. We further systematically discuss molecular targets specific for thrombi and those characterizing unstable, potentially thrombogenic atherosclerotic plaques. Finally, we provide examples for first theranostic approaches in thrombosis, combining diagnosis, targeted therapy, and monitoring of therapeutic success or failure. Overall, molecular imaging is a rapidly advancing field that holds promise of major benefits to many patients with atherothrombotic diseases.

Relationship between CHOP/GADD153 and unstable human carotid atherosclerotic plaque

Background and aims: The signaling protein C/EBP homologous protein (CHOP) and corresponding growth-arrest-and-DNA-damage-inducible gene 153 (GADD153) is associated with endoplasmic reticulum stress (ERS), which can lead to apoptosis. Our study aims to elucidate the role of CHOP/GADD153 in unstable atherosclerotic (AS) plaque formation isolated from confounding factors such as diabetes mellitus, primary hyperlipidemia, autoimmune deficiencies/abnormalities, essential hypertension, chronic heart failure, chronic kidney disease, and smoking.Material and methods: We collected carotid artery tissue samples from patients aged 50–80 years-old who received carotid endarterectomies (CEA) at our institution. We obtained fresh AS plaque samples during CEA and preserved the specimens immediately in the operating room with liquid nitrogen. Samples were categorized as stable or unstable AS plaques according to a six-stage histologic classification. CHOP/GADD153 expression was then examined with immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR).Results: A total of 32 patients met our inclusion and exclusion criteria, with 24 (75.0%) classified as unstable lesions. The mean optical density ratio normalized to GAPDH for CHOP/GADD153 in stable and unstable groups was 0.357 ± 0.025 and 0.490 ± 0.027, respectively (p < .05). Positive immunostaining of CHOP/GADD153 was found in macrophages and smooth muscle cells of unstable AS plaques with a mean integrated optical density of 0.63 ± 0.03, compared to 0.17 ± 0.05 in the stable group (p < .05).Conclusions: In conclusion, we were able to show significant elevation of CHOP/GADD153 in unstable plaques independent of other confounding factors that induce ERS.

Cytokine status’ pattern in acute period of ischemic stroke subtypes

Purpose The aim of this study was to assess a different pattern of inflammatory mediators in relation of ischemic stroke subtypes in acute period. Materials and Methods. The study involved 482 patients with different ischemic stroke (IS) subtypes. We studied the content of inflammatory interleukins (IL-1β, IL-2, IL-6, IL-8, CRP, TNF-α) and anti-inflammatory interleukin IL-10 in blood serum. Results The study revealed increasing content of pro-inflammatory cytokines in acute period of IS subtypes, especially at Large Artery AtheroSclerosis (LAAS) and CardioEmbolic Infarct (CEI). In patients with LAAS the level of IL-2, IL-6 and CRP was significantly higher compared to other IS subtypes. The content of IL-10 was significantly lower compared to patients with Undetermined Etiology (UDE) stroke and LACunar (LAC) stroke. We established the relationship between the concentration of IL-1β and IL-6 with the severity of LAAS, CEI and UDE on the 1 st day of stroke. On the 7 th day the concentration of IL-1β and IL-8 was significantly decreased at LAC, IL-2 – at LAC and LAAS, IL-6 and TNF-α at LAC and UDE. At LAAS the content of inflammatory mediators depended on the degree of arteries stenosis, the presence of unstable atherosclerotic plaques, the intima-media thickness. We found a direct relationship between the severity of LAAS and CEI on the 14 th day with the CRP concentration on the 1 st day (at LAAS – (r = 0.73, p = 0.003), at CEI – (r = 0.71, p = 0.002), indicating predictive value of CRP-content on the course of acute period of IS subtypes. We established the dependence between cardiac morphometric parameters with the level of pro-inflammatory interleukins in acute period of UDE. We found the relation between the content of IL-1β, IL-6 with left ventricular myocardial mass index at UDE. Conclusions The content of inflammatory mediators in acute period of ischemic stroke depends on the pathogenic subtype of stroke.

Expression of Circulating miR-17-92 Cluster and HDAC9 Gene in Atherosclerotic Patients with Unstable and Stable Carotid Plaques.

The miR-17-92 cluster and the HDAC9 gene are involved in inflammatory, apoptotic, and angiogenic processes that are activated in the vulnerable carotid plaque. The aim of this research was to determine whether expression of one or more of the miRs of the miR-17-92 cluster and/or HDAC9 expression could represent biomarkers for patients with unstable atherosclerotic carotid plaques. Plasma levels of miRs and HDAC9 expression in peripheral blood were analyzed by real-time PCR in patients with histologically classified stable or unstable plaques. No differences were observed between the two groups. Levels of the miR-17-92 cluster in plasma and HDAC9 gene expression in peripheral blood cannot be considered appropriate biomarkers to identify patients with unstable plaques at risk of rupture.