Atherosclerotic Plaque Instability Research Articles

PURPL and NEAT1 Long Non-Coding RNAs Are Modulated in Vascular Smooth Muscle Cell Replicative Senescence.

Cellular senescence is characterized by proliferation and migration exhaustion, senescence-associated secretory phenotype (SASP), and oxidative stress. Senescent vascular smooth muscle cells (VSMCs) contribute to cardiovascular diseases and atherosclerotic plaque instability. Since there are no unanimously agreed senescence markers in human VSMCs, to improve our knowledge, we looked for new possible senescence markers. To this end, we first established and characterized a model of replicative senescence (RS) in human aortic VSMCs. Old cells displayed several established senescence-associated markers. They stained positive for the senescence-associated β-galactosidase, showed a deranged proliferation rate, a dramatically reduced expression of PCNA, an altered migratory activity, increased levels of TP53 and cell-cycle inhibitors p21/p16, and accumulated in the G1 phase. Old cells showed an altered cellular and nuclear morphology, downregulation of the expression of LMNB1 and HMGB1, and increased expression of SASP molecules (IL1β, IL6, IL8, and MMP3). In these senescent VSMCs, among a set of 12 manually selected long non-coding RNAs (lncRNAs), we detected significant upregulation of PURPL and NEAT1. We observed also, for the first time, increased levels of RRAD mRNA. The detection of modulated levels of RRAD, PURPL, and NEAT1 during VSMC senescence could be helpful for future studies on potential anti-aging factors.

Associations Between Resolvin D1 and Culprit Plaque Morphologies: An Optical Coherence Tomography Study in Patients with ST-Segment Elevation Myocardial Infarction.

As a specialized pro-resolving lipid mediator, resolvin D1 (RvD1) inhibits atherosclerosis progression in vivo by reducing regional oxidative stress and chronic inflammation. However, it is unclear how RvD1 is involved in human coronary artery disease. This study aims to investigate the association between plasma levels of RvD1 and culprit-plaque characteristics in patients with ST-segment elevation myocardial infarction (STEMI). A total of 240 STEMI patients undergoing optical coherence tomography (OCT) examination were analyzed. RvD1 levels were measured in patient plasma samples using an enzyme-linked immunosorbent assay. Logistic regression was performed to assess the association between RvD1 levels and various culprit plaque morphologies, and the receiver operating curve was used to search for an optimal cutoff threshold to predict certain pathological features. The median RvD1 level was 129.7 (56.6-297.8) pg/mL. According to multivariable logistic regression, high RvD1 was associated with plaque rupture (≥111.5 pg/mL, odds ratio [OR]: 2.09, 95% confidence interval [CI]: 1.20-3.66, P = 0.010), healed plaques (≥246.4 pg/mL, OR: 2.17, 95% CI: 1.11-4.24, P = 0.023), and calcification (≥293.38 pg/mL, OR: 2.10, 95% CI: 1.21-3.66, P = 0.008) at culprit lesions. Increased levels of RvD1 were associated with higher instability of coronary atherosclerotic plaques in STEMI patients.

Endothelial dysfunction as predictor of atherosclerosis during a translatitudinal sea voyage in the Arctic: prospective study

INTRODUCTION. Human labor activity in the Arctic takes place in severe climatic conditions associated with cooling, atmospheric pressure drops, high humidity, photoperiodicity, low oxygen content in the air. Endothelial dysfunction is an early pathophysiological sign and an independent predictor of poor prognosis in most cardiovascular diseases.
 OBJECTIVE.Тo analyze the dynamics of the level of metalloproteinase-9 and thrombin activity as predictors of the development of atherosclerosis in sailors during a translatitudinal sea voyage in the Arctic.
 MATERIALS AND METHODS. A prospective clinical and laboratory study of crew members was performed during the integrated marine research expedition “Transarctic-2019”. A clinical and laboratory study of the level of metalloprotease-9 (enzyme-linked immunosorbent assay), coagulation analysis of the parameters of the thrombin generation test, as well as ultrasonic dopplerography of the thickness of the intima-media complex were carried out. Statistical data processing was carried out using the methods of descriptive and analytical statistics in the StataCorp Stata 14.2 program. The study protocol was approved by the local ethical committee of the SSMU (protocol No. 03/5 dated May 27, 2015) and supported by the state task reg. No. NIOKTR 121030300111-7.
 RESULTS. A statistically significant increase in the level of MMP-9 in sailors after the expedition was noted, the relationship between the level of MMP-9, indicators of the thrombin generation test (lag time, min (p=0.0190), tPeak (p=0.0177), Peak (p= 0.0217) and KIM thickening.
 DISCUSSION. MMP-9 levels may be a predictor of early atherosclerosis and atherosclerotic plaque instability, as well as a risk factor for future adverse cardiovascular events. The relationship of MMP-9 with the kinetics of thrombin (one of the regulators of the antithrombotic state of the endothelium) during a translatitudinal voyage in sailors indicates the formation of readiness for prothrombotic events.
 CONCLUSION. Thus, in Arctic conditions, under conditions of chronic oxidative stress, which contribute to the progression of the development of endothelial dysfunction in the presence of external risk factors, the likelihood of progression of atherosclerotic vascular lesions increases, and, as a result, the development of vascular events.

Dapagliflozin decreases atherosclerotic plaque instability via regulating macrophage pyroptosis

Abstract Background Vulnerable plaques are characterized by infiltration of inflammatory cells, playing a key role in the progression of acute coronary events. It’s important to clarify the inflammatory mechanism of unstable plaque formation. Several clinical trials have demonstrated that dapagliflozin could reduce major adverse cardiac events in whether diabetic or non-diabetic patients. However, the underlying cardioprotective mechanism of dapagliflozin remains unclear. This study was aimed to investigate the role of dapagliflozin in regulating macrophage pyroptosis and vulnerable plaque formation. Methods 20 ApoE-/- mice (control) were fed with high fat diet while another 20 ApoE-/- mice were challenged with high fat diet plus dapagliflozin for 12 weeks. The extent and instability of atherosclerotic plaque was determined by oil-red staining, HE staining, immunofluorescence staining and electron microscopy. Changes in subsets of immune cells were evaluated by flow cytometry. Plasma cytokines were assessed by ELISA. Microarray analysis was applied to detect gene expressions while Western blot and real-time PCR was used to assess gene expression levels. Results Morphology studies revealed that dapagliflozin could inhibit plaque formation and reduce instability in ApoE-/- mice. FACS data showed that dapagliflozin could decrease CD11b+Ly6Chigh M1 macrophages differentiation and inhibit foam cells formation in ApoE-/- mice. Microarray analysis and in vitro studies exhibited that dapagliflozin could induce the down regulation of NLRP3, caspase-1, IL-1β, IL-18 and MMP-7/10/12/14 to retard macrophage pyroptosis and foam cell formation. Conclusions We have characterized a novel role for dapagliflozin in modulating atherosclerotic lesion development and progression. We envision that this study may provide several potential therapeutic targets for treatment of acute coronary syndromes.

Abstract 11734: Allopurinol & Plaque Stabilization in Patients With Acute Coronary Syndrome: A Randomized Clinical Trial

Background: Allopurinol, a xanthine inhibitor that lowers uric acid (UA) concentration, has been proven to reduce inflammation and oxidative stress in patients with cardiovascular disease. However, it is unknown whether these beneficial effects translate into favorable plaque modification in acute coronary syndromes (ACS). Aims: This study aimed to investigate whether allopurinol therapy could improve plaque stabilization in ACS patients using coronary computed tomography angiography (CCTA). Methods: This was a prospective, single-center, randomized, double-blind clinical trial began in March 2019 (clinical trial.gov identifier NCT03745729). A total of 162 acute coronary syndromes (ACS) patients aged 18-80 years with a blood level of high-sensitivity C-reactive protein (hsCRP) > 2 mg/L were included. The subjects were randomly assigned in a 1:1 ratio to receive either allopurinol sustained-release capsules (at a dose of 0.25 g once daily) or placebo for 12 months. The primary efficacy endpoint was the change in low-attenuation plaque volume (LAPV) from baseline to the 12-month follow-up. Results: Among 162 patients, 54 in allopurinol group and 51 in placebo group completed the study. There were no significant differences between the allopurinol and placebo groups in terms of baseline data for age (58.5±10.2 years vs. 56.8±10.0 years, P=0.392) and sex (male/female, 40/14 vs. 40/11, P=0.600). The median follow-up duration was 14 months in both groups. Compared with placebo, allopurinol therapy did not significantly alter LAPV (-13.4±3.7% vs. -17.8±3.6%, P=0.390), intermediate attenuation plaque volume (-16.1±3.0% vs. -16.2±2.9%, P=0.992), dense calcified plaque volume (12.2±13.7% vs. 9.7±13.0%, P=0.894), total atheroma volume (-15.2±3.2% vs. -16.4±3.1%, P=0.785), remodeling index (2.0±3.9% vs. 5.4±3.8%, P=0.536) or hsCRP levels (-73.6 [17.9-91.6] % vs. -81.2 [47.7-95.4] %, P=0.286). Conclusions: Our findings suggest, for the first time, that allopurinol therapy does not improve atherosclerotic plaque instability or inflammation in ACS.

The potential role of radiochemical analysis of CT images of epicardial adipose tissue in the prognosis of acute myocardial infarction

Introduction. Multispiral computed tomography (MSCT) coronary angiography (CAG) is a highly informative method of visualizing atherosclerotic plaques in the coronary arteries and assessing their structure. At the same time, this method has a few significant drawbacks associated with the intravenous administration of iodine-containing radiopaque agents as well as high radiation exposure. The radiomic analysis of contrast-free MSCT images allows calculating many additional quantitative parameters, which can potentially be associated with atherosclerotic plaque instability and the degree of coronary artery stenosis. At the same time, the prognostic and diagnostic value of radiomic characteristics has not been investigated.Aim: To assess whether there is an association between radiomic indexes of EAT on non-contrast MSCT cardiac images with the degree of atherosclerotic coronary artery stenosis in patients with stable CAD, as well as the incidence of acute coronary syndrome (ACS) within 5 years in this category of patients.Material and Methods. We retrospectively reviewed 100 MSCT-CAG studies performed to diagnose coronary heart disease in patients. 39 patients with signs of coronary stenosis up to 50% and registered in Tomsk medical information systems (MIS) for at least 5 years were selected, as well as 15 people without signs of coronary arteries (CA) atherosclerosis as a control group. Epicardial adipose tissue (EAT) volume was assessed and 837 radiomic characteristics were calculated on non-contrasted MSCT cardiac images of all patients (54 people). The presence or absence of ACS within 5 years after MSCT-CAG in each patient was monitored according to Tomsk MIS data. Statistical analysis and comparison of indices were performed in control group (group 2) and study group (group 1), as well as in subgroups of patients who had suffered AMI (group 1a) and those who had not (group 1b).Results. When comparing group 1 with the control group, significant differences (p < 0.05) were found for all radiomic parameters, density, and volume of EAT. Correlation analysis did not reveal any relationship between the radiomic characteristics of EAT and the degree of coronary artery stenosis, as well as the calcium index. According to the results of the MIS of Tomsk analysis, group 1 was divided into 2 subgroups: without ACS (group 1a; n = 27 (50%)) and with ACS (group 1b; n = 12 (22%)). When comparing subgroups 1a and 1b, there were no significant differences in the volume and density of EAT (p > 0.05), however, 8 out of 837 radiomic parameters differed significantly. Multiple regression analysis has shown that the Size Zone Nonuniformity gray level zone matrix (SZN-GLSZM) and Gray Level Variance (GLCM) gray co-occurrence matrix are independent predictors of the development of ACS within 5 years. According to the results of the ROC analysis, the logistic model with the inclusion of radiomic data showed high sensitivity and specificity in predicting the development of ACS (cut-off point <8025.7; specificity 96%, sensitivity 75%, AUC = 0.806, p < 0.001 for SZN; cut-off point <4.08; specificity 93%, sensitivity 83%, AUC = 0.861 for GLV; p < 0.001).Conclusion. SZN GLSZM and GLV GLCM radiomic features on non-contrast MSCT images of EAT are associated with the incidence of ASC in patients with coronary artery atherosclerosis. Radiomic analysis of EAT could potentially be used for personalized assessment of the ACS risk.

Role of neutrophil extracellular trap and immune infiltration in atherosclerotic plaque instability: Novel insight from bioinformatics analysis and machine learning.

The instability of atherosclerotic plaques increases the risk of acute coronary syndrome. Neutrophil extracellular traps (NETs), mesh-like complexes consisting of extracellular DNA adorned with various protein substances, have been recently discovered to play an essential role in atherosclerotic plaque formation and development. This study aimed to investigate novel diagnostic biomarkers that can identify unstable plaques for early distinction and prevention of plaque erosion or disruption. Differential expression analysis was used to identify the differentially expressed NET-related genes, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed. We filtered the characteristic genes using machine learning and estimated diagnostic efficacy using receiver operating characteristic curves. Immune infiltration was detected using single-sample gene set enrichment analysis and the biological signaling pathways involved in characteristic genes utilizing gene set enrichment analysis were explored. Finally, miRNAs- and transcription factors-target genes networks were established. We identified 8 differentially expressed NET-related genes primarily involved in immune-related pathways. Four were identified as capable of distinguishing unstable plaques. More immune cells infiltrated unstable plaques than stable plaques, and these cells were predominantly positively related to characteristic genes. These 4 diagnostic genes are involved in immune responses and the modulation of smooth muscle contractility. Several miRNAs and transcription factors were predicted as upstream regulatory factors, providing further information on the identification and prevention of atherosclerotic plaques rupture. We identified several promising NET-related genes (AQP9, C5AR1, FPR3, and SIGLEC9) and immune cell subsets that may identify unstable atherosclerotic plaques at an early stage and prevent various complications of plaque disruption.

High Uric Acid Promotes Atherosclerotic Plaque Instability by Apoptosis Targeted Autophagy.

Acute rupture or erosion of unstable atherosclerotic plaques is a major cause of adverse consequences of atherosclerotic cardiovascular disease, often leading to myocardial infarction or stroke. High uric acid (HUA) is associated with the increasing risk of cardiovascular events and death. However, the mechanism by which HUA promotes atherosclerosis and whether HUA affects plaque stability are still unclear. We constructed an atherosclerotic Apoe-/- mouse model with HUA. The progression of atherosclerosis and plaques was determined by Oil Red O staining, hematoxylin and eosin (H&E) staining, and Masson staining. TdT-mediated dUTP nick-end labeling assay and immunohistochemistry were used to observe the changes of apoptosis and autophagy in plaques, respectively. Then, we validated the in vivo results with RAW 264.7 cell line. HUA promoted atherosclerosis and exacerbated plaque vulnerability, including significantly increased macrophage infiltration, lipid accumulation, enlarged necrotic cores, and decreased collagen fibers. HUA increased cell apoptosis and inhibited autophagy in plaques. In vitro results showed that HUA decreased cell viability and increased cell apoptosis in foam cells macrophages treated with oxidized low-density lipoprotein. An activator of autophagy, rapamycin, can partially reverse the increasing apoptosis. HUA promoted atherosclerosis and exacerbated plaque vulnerability, and HUA facilitates foam cell apoptosis by inhibiting autophagy.

Influenza Vaccination Decreases The Risk Of Cardiovascular Disease In End Stage Renal Disease Patients.

Madam, Influenza is a viral respiratory tract infection that causes symptoms such as fever, sore throat, cough and runny nose with a mostly self-limiting prognosis. However, it can cause an increased risk of hospitalization and mortality in high-risk groups such as those suffering from end-stage renal disease (ESRD) [1]. CVD is present in >50% of cases of ESRD and is associated with a 20 times greater relative risk of death than in the general population, particularly with patients infected with influenza [2] [3]. This is due to the dysfunctional immunity in those affected by chronic kidney disease. The pathophysiology behind the influenza infection leading to CVD in ESRD patients is due to the rise of acute phase reactants in response to viral infection markers triggering a systemic inflammatory reaction. This reaction comprises damage to the endothelial cell lining of vessels, impaired vasodilation, dysfunctional platelet activation, and elevated pro-coagulation. In addition, the increased metabolic demand and altered coronary vascular tone can bring about disruption and instability of atherosclerotic plaques in coronary arteries, thus inducing an acute coronary syndrome. [1] Using influenza vaccine can significantly lower the risk of CVD in ESRD patients. Currently, available influenza vaccines include inactivated, recombinant, and live-attenuated (LAIVs).[4] Inactivated vaccines contain either surface glycoproteins such as hemagglutinin (HA) and neuraminidase (NA) or whole viral protein without the lipid envelope or chemically inactivated virus, whereas recombinant vaccines are composed of genetically synthesized HA subunits and LAIVs have the whole virus with weakened pathogenicity. These vaccines are produced as either trivalent (with both, influenza A subtypes H1N1 andH3N2 and dominant influenza B of either Yamagata or Victoria lineage) or quadrivalent (having both influenza B lineages) vaccines.[4] According to a population-based case-cohort study, annual influenza vaccinations have been seen to greatly reduce the hospitalisation rates for CVD in elderly patients with chronic kidney disease regardless of gender and influenza seasonality [5]. Moreover, it reduces the risk of CVD in patients with a hazard ratio of 0.74 for hospitalisation due to CVD among the vaccinated group compared to the non-vaccinated group, indicating a 26% lower risk and 35% reduction in overall mortality. [3] Therefore, the protective mechanism of influenza vaccination may be beneficial in reducing the risk of hospitalisations and morbidity in ESRD patients by reducing the likelihood of cardiovascular-associated complications. Thus, it should be incorporated as an integral part of the management of ESRD.

The Effect of PCSK9 Inhibition on the Stabilization of Atherosclerotic Plaque Determined by Biochemical and Diagnostic Imaging Methods.

Atherosclerosis is a multifactorial, progressive, chronic inflammatory disease. Ultrasound and magnetic resonance imaging are the most accurate predictors of atherosclerotic plaque instability (MRI). Cytokines such as osteopontin, osteoprotegerin, and metalloproteinase 9 could be used as the most recent markers to identify and track the efficacy of anti-atherosclerotic therapy. Patients with USG and MRI-verified unstable atherosclerotic plaque were included in the study. Biomarker concentrations were measured and compared before and after PCSK9 inhibitor therapy. Additionally, concentrations prior to treatment were correlated with MRI images of the carotid artery. After treatment with alirocumab, the concentrations of MMP-9 (p < 0.01) and OPN, OPG (p < 0.05) decreased significantly. Furthermore, the results of OPN, OPG, and MMP 9 varied significantly depending on the type of atherosclerotic plaque in the MRI assay. In stable atherosclerotic plaques, the concentrations of OPN and OPG were greater (p < 0.01), whereas the concentration of MMP9 correlated with the instability of the plaque (p < 0.05). We demonstrated, probably for the first time, that alirocumab therapy significantly decreased the serum concentration of atherosclerotic plaque markers. In addition, we demonstrated the relationship between the type of atherosclerotic plaque as determined by carotid MRI and the concentration of these markers.

Role of the CXCL12/CXCR4 axis in atherosclerotic plaque instability

Role of the CXCL12/CXCR4 axis in atherosclerotic plaque instability

Increased Piezo1 expression in myofibroblasts in patients with symptomatic carotid atherosclerotic plaques undergoing carotid endarterectomy: A pilot study.

We aimed to investigate Piezo1 expression in myofibroblasts in symptomatic and asymptomatic patients undergoing carotid endarterectomy and its relationship with atherosclerotic plaque formation. This cross-sectional study analyzed carotid plaques of 17 randomly selected patients who underwent carotid endarterectomy from May 2015 to August 2017. In total, 51 sections (the most stenotic lesion, and the sections 5-mm proximal and distal) stained with hematoxylin-eosin and elastica-Masson were examined. Immunohistochemistry was performed using antibodies to Piezo1. The Piezo1 score of a section was calculated semiquantitatively, averaged across 30 randomly selected myofibroblasts in the fibrous cap of the plaque. Of 17 patients (mean age: 74.2 ± 7.1 years), 15 were men, 9 had diabetes mellitus, and 13 had hypertension. Symptomatic patients had higher mean Piezo1 score than asymptomatic patients (1.78 ± 0.23 vs 1.34 ± 0.17, p < .001). Univariate linear regression analyses suggested an association between plaque rupture, thin-cap fibroatheroma and microcalcifications and the Piezo1 score (p = .001, .008, and 0.003, respectively). Increased Piezo1 expression of myofibroblasts may be associated with atherosclerotic carotid plaque instability. Further study is warranted to support this finding.

MARKERS OF ENDOTHELIAL DYSFUNCTION IN CORONARY HEART DISEASE PATIENTS DEPENDING ON ARTERIAL HYPERTENSION PRESENCE

Objective: To evaluate the role of arterial hypertension (AH) on endothelial functional state in the coronary heart disease (CHD) patients. Design and method: 173 CHD patients were examined (the average age was 57.24±5.12 years): 92 patients with stable angina (45 with II functional class (FC) (23 without and 22 with AH) and 47 with III FC (26 without and 21 with AH) and 81 patients with acute coronary syndromes (ACS)(43–with unstable angina (UA) (22 without and 21 with AH) and 38–with acute myocardial infarction (MI) (20 without and 18 with AH)). Endothelial dysfunction was assessed by the levels of vasoconstrictor endothelin-1 (ET-1) and the concentration of soluble vascular adhesion molecule (sVCAM), which were determined by ELISA. Results: Both markers of endothelial dysfunction increased with an increase in disease severity. The most severe changes were in patients with ACS, although differences between patients with UA and MI were not significant (p&gt;0.05). Levels of ET-1 were significantly higher (p&lt;0.05) in all clinical variants of CHD in patients with AH regarding patients without it. The same tendance (difference with p&lt;0.01 ) was observed with sVCAM levels, but only in stable CHD patients. sVCAM levels raised significantly in ACS patients not only according to the control group, but also patients with stable CHD (p&lt;0.05), but without difference depending on AH presence in both groups with UA and MI (p&gt;0.05). There were no significant associations between levels of endothelial dysfunction markers and troponin I and T (p&gt;0.05). The significant relationships between levels of sVCAM and ET-1 on one hand and C-reactive protein on other were noted in both groups with stable CHD and with ACS, regardless of the presence of hypertension. Conclusions: Elevated levels of ET-1 and sVCAM in blood of CHD patients are the indicator of atherosclerotic plaque instability and the possibility of ACS development, especially with AH comorbidity.

Biliverdin Reductase B Is a Plasma Biomarker for Intraplaque Hemorrhage and a Predictor of Ischemic Stroke in Patients with Symptomatic Carotid Atherosclerosis

Background: Intraplaque hemorrhage (IPH) is a hallmark of atherosclerotic plaque instability. Biliverdin reductase B (BLVRB) is enriched in plasma and plaques from patients with symptomatic carotid atherosclerosis and functionally associated with IPH. Objective: We explored the biomarker potential of plasma BLVRB through (1) its correlation with IPH in carotid plaques assessed by magnetic resonance imaging (MRI), and with recurrent ischemic stroke, and (2) its use for monitoring pharmacotherapy targeting IPH in a preclinical setting. Methods: Plasma BLVRB levels were measured in patients with symptomatic carotid atherosclerosis from the PARISK study (n = 177, 5 year follow-up) with and without IPH as indicated by MRI. Plasma BLVRB levels were also measured in a mouse vein graft model of IPH at baseline and following antiangiogenic therapy targeting vascular endothelial growth factor receptor 2 (VEGFR-2). Results: Plasma BLVRB levels were significantly higher in patients with IPH (737.32 ± 693.21 vs. 520.94 ± 499.43 mean fluorescent intensity (MFI), p = 0.033), but had no association with baseline clinical and biological parameters. Plasma BLVRB levels were also significantly higher in patients who developed recurrent ischemic stroke (1099.34 ± 928.49 vs. 582.07 ± 545.34 MFI, HR = 1.600, CI [1.092–2.344]; p = 0.016). Plasma BLVRB levels were significantly reduced following prevention of IPH by anti-VEGFR-2 therapy in mouse vein grafts (1189 ± 258.73 vs. 1752 ± 366.84 MFI; p = 0.004). Conclusions: Plasma BLVRB was associated with IPH and increased risk of recurrent ischemic stroke in patients with symptomatic low- to moderate-grade carotid stenosis, indicating the capacity to monitor the efficacy of IPH-preventive pharmacotherapy in an animal model. Together, these results suggest the utility of plasma BLVRB as a biomarker for atherosclerotic plaque instability.

C83 BEHIND MYOCARDITIS DIAGNOSIS

Abstract Background Myocarditis is an inflammatory disease of myocardium, with a wide range of clinical presentation. Myocarditis may mimic acute coronary syndrome (ACS), but it is also possible an overlap between these two different syndromes, as we considered the close relationship between wide inflammatory systemic condition and coronary atherosclerotic plaque instability Case report: We report the case of 29 years old man admitted to emergency department for burning chest pain changed with breathing and in different positions of the body, associated to dyspnea on mild–moderate exertion. Symptoms had begun to arise a week earlier, with flu–like symptoms, and got worse in the last 48 hours. In his clinical history the patient reports: previous myocarditis, dyslipidemia, hyperhomocysteinemia, overweight, family history of cardiovascular disease and a previous COVID infection. Blood tests found a rise of Troponin I HS. Electrocardiogram showed diphasic T wave in antero–lateral leads. An echocardiogram showed left ventricle with normal cavitary dimensions and preserved global systolic function, apical segment of interventricular septum and inferior wall hypokinetic; minimal pericardial detachment with leaflet hyperecogenicity. The patient was admitted to Cardiology ward, and he was given a medical therapy with colchicina 0.5 mg 1 cp x 2/die and AcetylSalicilic Acid 1000 mg x 3 /die. Cardiac Magnetic Resonance showed epi–mesocardial LGE in inferior and lateral distal segments, compatible with myocarditis. CT coronary angiography exhibited a calcified plaque determining partial caliber reduction in anterior descending coronary proximal segment, the coronary in its apical portion appeared ectatic, hypodense and poorly dulled likely for steno–occlusion. Therefore, it was performed a coronary angiography that revealed an anterior descending coronary artery occluded at the apical tract, the OCT showed plaque erosion with thrombotic apposition at the mid–proximal tract of the vessel. Finally, considered results of instrumental exams, a second antiplatelet agent, a hypolipidemic drug were added Discussion According to the cardiac MRI findings and the coronary angiography, it was hypothesized a picture of acute coronary syndrome triggered by erosion of the unstable coronary plaque, induced by the massive myocardial inflammation related to the myocarditis. The relationship between acute infections and myocardial infarction has been already established in COVID–19 patients

Impact of glucose intolerance on the risk of carotid plaque instability assessed by MRI

Atherosclerotic disease is a complex multifactorial and systemic condition that affects arteries, including carotid arteries. Atherosclerotic plaque instability can predict plaque rupture, the major cause of ischemic strokes. Intraplaque hemorrhage (IPH) is an important contributor of plaque instability caused by the pro-inflammatory and hypoxic environment of the atherosclerotic plaque promoting the development of intraplaque neo-vessels. Metabolic disturbances are known to promote atherosclerotic plaque formation. Ischemic stroke prevalence is increase in patients with obesity and/or type-2 diabetes. The objective of the present study is to evaluate whether glucose intolerance can increase IPH in patients with carotid atherosclerosis. This study involves 57 patients with carotid atherosclerotic plaque with more than 50% stenosis, asymptomatic for more than 6 months, with no surgical indication for endarterectomy and no recent inflammatory disease. IPH was evaluated by magnetic resonance imaging (MRI). A score was defined for IPH (from 0: non hemorrhage to 3: large hemorrhage). Fasting blood glucose level was measured and patients were allocated in glucose tolerant (< 5,6 mM) or glucose intolerant (> 5,6 mM) groups. We showed that the score of IPH quantified by MRI was increased in the glucose intolerant subgroup of patients (0.39 vs. 0.84, P = 0.04). This result was confirmed by a higher prevalence of hemorrhagic plaque in the glucose intolerant group (73 vs. 41%, P < 0.05). Interestingly, the fasting blood glucose level is higher in patients with a hemorrhagic plaque than non-hemorrhagic plaque (5.6 vs. 6.9 mM, P = 0.04). Moreover, neither other known pro-atherogenic markers (LDL, cholesterol, TG) nor obesity seem to increase the degree of IPH. In conclusion, we demonstrated a strong impact of blood glucose level on the risk of plaque instability reflected by IPH. Further experiments are needed to strengthen the relation between type-2 diabetes, blood glucose level and IPH to understand the underlying mechanisms.

Acute ischemic stroke: how to investigate the association between disease etiology and gene expression profiles

Background: Acute ischemic stroke (AIS) represents one of the principal causes of neurological morbidity and mortality worldwide. For a prompt and efficient cerebral blood restoration, intravenous treatment with rt-PA is often combined with mechanical thrombectomy (MT) which provides cerebral thrombi (CT) as study material, allowing the investigation of its cellular composition, morphological and histopathological features. Indeed, the determination of stroke etiology, typically defined by the TOAST classification, is paramount for prognostic factors, outcome, and management of the event. Aim of the study is therefore to highlight and analyze gene expression profiles in thrombotic tissue and peripheral blood (PB) in the comparison between strokes of cardioembolic (CE) and atherosclerotic (LAA) origin. Methods: We performed gene expression profiles of 92 patients. CT were stored in RNA later and RNA was extracted by PAX gene blood miRNA kit. The global gene expression profile was assessed by Affymetrix technology using GeneChip Human Transcriptome Array 2.0 combined with Affymetrix Transcriptome Analysis Console (TAC) Software. Results: Currently, we focused our attention on CT data analysis. The analysis revealed a significant difference (p-value&lt;0.05 and FoldChange=2 as threshold) in gene expression when comparing LAA and CE stroke. In particular, from CT of atherosclerotic origin emerges an overexpression of 1766 genes. Prominent among them are genes such as MMP-9, TGFB, TGFBR and CXCL1, primarily involved in neutrophil-mediated immunity, Blood-Brain Barrier (BBB) disruption processes, and associated with atherosclerotic plaque instability and related to poor neurological outcome, suggesting a deleterious role in human brain injury. As concerns CE patients, 57 genes mainly involved in transcriptional regulatory processes turn out to be significantly overexpressed. Conclusions: Transcriptome profiling is a powerful weapon for revealing expression patterns associated with complex disorders. The variation of gene expression profiles confirmed and extended several known pathophysiological mechanisms and may be one way of delineating different stroke etiology.

Five-Year Changes in Inflammatory, Metabolic, and Oxidative Biomarkers and 10-Year Cardiovascular Disease Incidence: The REGICOR Cohort Study.

Ischemic cardiovascular diseases (CVD) originate from an imbalance between atherosclerotic plaque formation, instability, and endothelial healing dynamics. Our aim was to examine the relationship between 5-year changes in inflammatory, metabolic, and oxidative biomarkers and 10-year CVD incidence in a population without previous CVD. This was a prospective cohort study of individuals aged 35-74 years (n = 419) randomly selected from 5263 REGICOR participants without CVD recruited in 2005. Biomarkers were measured at baseline and in 2010. Participants were followed up until 2020 for a composite CVD endpoint including coronary artery disease, stroke, and peripheral artery disease. We used Cox regression to analyze the effect of biomarker levels on the occurrence of the composite endpoint, adjusted for traditional CVD risk factors and baseline levels of each biomarker. Individuals with elevated IL-6 or insulin after 5 years had a higher independent risk of CVD at 10 years, compared to those with lower levels. Each rise of 1 pg/mL of IL-6 or 10 pg/mL of insulin increased the 10-year risk of a CVD event by 32% and 2%, respectively. Compared to a model with traditional CVD risk factors only, the inclusion of IL-6 and insulin improved continuous reclassification by 51%. Elevated serum levels of IL-6 and insulin were associated with a higher risk of CVD at 10 years, independently of traditional CVD risk factors.

Anti-Atherogenic Protection by Oligomeric Proanthocyanidins via Regulating Collagen Crosslinking Against CC Diet-Induced Atherosclerosis in Rats.

The synthesis of collagen and its turnover remained as critical determinants for the progression of atherosclerosis. During this condition, proteases secreted by SMCs and foam cells in the necrotic core degrade collagen. Growing evidences demonstrated that consumption of antioxidant rich diet is highly associated with a reduced risk of atherosclerosis. Oligomeric proanthocyanidins (OPC) have been proved to possess promising antioxidant, anti-inflammatory and cardioprotective activity, based on our previous studies. The present study aims to investigate the efficacy of OPC isolated from Crataegus oxyacantha berries as a natural collagen crosslinker and anti-atherogenic agent. Spectral studies like FTIR, ultraviolet and circular dichroism analysis confirmed the in vitro crosslinking ability of OPC with rat tail collagen when compared to the standard epigallocatechin gallate. The administration of cholesterol:cholic acid (CC) diet induces proteases-mediated collagen degradation that could result in plaque instability. Further, the CC diet fed rats showed significantly increased levels of total cholesterol and triacylglycerols which, in turn, increases the activities of collagen degrading proteases-MMPs (MMP 1, 2 and 9) and Cathepsin S and D. Upon OPC treatment, marked reduction in the lipid content, activation of proteases with concomitant increase in the mRNA levels of collagen Type I and Type III as similar to atorvastatin treatment were observed .Thus, OPC supplementation may contribute to the prevention of atherosclerotic plaque instability by acting as a natural crosslinker of collagen.

Patient with non-cardioembolic ischemic stroke or high-risk transient ischemic attack. Part 1. Diagnosis

Non-cardioembolic stroke and transient ischemic attack (TIA) are heterogeneous conditions, some variants of which are associated with a high short-term and long-term risk of cardiovascular events. The article presents clinical portraits of patients in high and very high risk groups: 1) patients with extracranial atherosclerosis and severe stenosis/subocclusion/occlusion or CT signs of atherosclerotic plaque instability; 2) all patients with intracranial atherosclerosis, especially those with symptoms of hemodynamic compromise or multiple infarcts; 3) all patients with mobile/ulcerative atheroma of the aortic arch. For the timely identification of these subtypes, it is necessary to use clinical and radiological clues with necessary diagnostic search. In addition, the following patients with TIA may be at high or very high risk: those with an ABCD2 score of ≥4 points or an ABCD3-I score of ≥8 points; with TIA in the vertebrobasilar basin, "crescendo" or "limb shaking" type, orthostatic TIA, as well as patients with warning capsular and bridge syndromes. Assigning a patient to one of the considered categories requires the immediate administration of enhanced secondary prevention, which will be discussed in the second part of this article.