Stable Plaque Research Articles

Bioinformatics analysis of carotid vulnerable plaques associated with the SARS-CoV-2 pattern

The rupture of carotid artery vulnerable plaque plays a critical role in ischemic stroke, and the widely spread new coronavirus in recent years plays a certain role in the development of human carotid artery vulnerable plaque, we screened out 27 differential expression genes (DEGs) of stable plaque and vulnerable plaque associated with the new coronavirus. Through the construction of the protein–protein interaction (PPI) network, the Cathepsin B (CTSB) and Niemann-Pick Disease Type 2 (NPC2) were identified as crucial expression genes, and further, we confirmed the validity of core gene expression in two validation sets. Additionally, we discovered a significant connection between CTSB, NPC2 and 28 different kinds of immune cells in carotid plaque tissue. We screened out 65 target interacting drugs based on 10 differentially expressed genes through online tools and finally verified the high expression of 2 core genes in fragile plaques through clinical sample experiments. These findings imply that two core genes may be novel targets for molecular diagnostics and immunotherapy of vulnerable plaques.

Melatonin ameliorates atherosclerosis by suppressing S100a9-mediated vascular inflammation

Atherosclerosis (AS)-associated cardiovascular diseases are predominant causes of morbidity and mortality worldwide. Melatonin, a circadian hormone with anti-inflammatory activity, may be a novel therapeutic intervention for AS. However, the exact mechanism is unclear. This research intended to investigate the mechanism of melatonin in treating AS. Melatonin (20 mg/kg/d) was intraperitoneally administered in a high-fat diet (HFD)-induced AS model using apolipoprotein E-deficient (ApoE−/−) mice for 12 weeks. Immunohistochemical and immunofluorescence analyses, data-independent acquisition (DIA)-based protein profiling, ingenuity pathway analysis (IPA), and western blotting were employed to investigate the therapeutic effects of melatonin in treating HFD-induced AS. An adeno-associated virus (AAV) vector was further used to confirm the antiatherosclerotic mechanism of melatonin. Melatonin treatment markedly attenuated atherosclerotic lesions, induced stable phenotypic sclerotic plaques, inhibited macrophage infiltration, and suppressed the production of proinflammatory cytokines in ApoE−/− mice with HFD-induced AS. Notably, DIA-based quantitative proteomics together with IPA identified S100a9 as a pivotal mediator in the protective effects of melatonin. Moreover, melatonin significantly suppressed HFD-induced S100a9 expression at both the mRNA and protein levels. The overexpression of S100a9 significantly activated the NF-κB signaling pathway and markedly abolished the antagonistic effect of melatonin on HFD-induced vascular inflammation during atherogenesis. Melatonin exerts a significant antiatherogenic effect by inhibiting S100a9/NF-κB signaling pathway-mediated vascular inflammation. Our findings reveal a novel antiatherosclerotic mechanism of melatonin and underlie its potential clinical use in modulating AS with good availability and affordability.

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.

Low-intensity laser diode plus extracorporeal shock wave therapy: a new treatment strategy in the management of Peyronie's disease.

To assess the clinical effectiveness of extra corporeal shockwave therapy (ESWT) administration compared with ESWT plus a low-intensity laser diode therapy (LILDT) in the management of Peyronie's disease (PD) stable stage. In this study, 214 patients affected by PD in stable stage (≥ 12months), were divided into two groups. Group 1 (G1) counted 111 patients treated only with ESWT; Group 2 (G2) consisted of 103 patients that received ESWT with the same protocol of G1 plus LILDT for six weeks. The patients of both groups were assessed at baseline and follow-up for erectile function, painful erections, penile plaque size and penile curvature. The results were evaluated at baseline and 3, 6, 12months after the treatment. Three months after the treatment in G2 pain in an erection or during intercourse was resolved completely in 78.6% of the patients, whereas in 55.8% cases of G1 (p < 0.003). G2 patients had a reduction of curvature degree after the 3months treatment (p < 0.002). However, mean plaque size decreased in both groups without statistically differences with baseline values. Mean ± SD IIEF-5 score further improved significantly in the group treated with ESWT plus LILDT (p < 0.001). There were no permanent adverse sequelae after treatments. This study demonstrates an interesting therapeutic strategy when combined to the synergistic action of a shock wave therapy with low-intensity laser therapy on the stable plaques with significant benefits in terms of pain perception, penile curvature and sexual activity.

Assessment of stroke risk using MRI-VPD with automatic segmentation of carotid plaques and classification of plaque properties based on deep learning

PurposeThe primary goal of this study is to establish a technique for categorizing MRI scans into two distinct groups, namely, vulnerable and stable carotid plaques, for the purpose of evaluating risk of stroke levels based on imaging of carotid plaque. MethodThe study data was obtained from two hospitals and included cases of both stable and vulnerable conditions. The cohort comprised of 87 patients with established risk factors for atherosclerosis. A total of 3741 MRI scans were utilized, with each category evenly represented and randomly split into training and testing sets at a ratio of 70:30, respectively. Our methodology utilized the U-Net model for automatic extraction of the region of interest (ROI) from the MRI scans and subsequent plaque image segmentation, followed by the implementation of pre-trained ResNet-50 models for classification. ResultsOur proposed framework involved the integration of two deep learning models, namely U-net and ResNet-50, with hyperparameters fine-tuned and adjusted based on our classification problem. We attained the highest accuracy of 94.11% using our proposed framework, thus highlighting the efficacy of our approach. ConclusionOur study indicates that pre-trained deep learning models have the potential to classify MRI scans based on carotid plaque imaging with fine-tuning. The proposed framework can help reduce erroneous diagnoses caused by suboptimal image quality or individual expertise. Furthermore, our framework can assist radiologists in making better decisions for patient care. In conclusion, this study provides a useful tool for the assessment of stroke risk levels, which can ultimately improve patient outcomes.

Intraperitoneal Injection of Human Ferritin Heavy Chain Attenuates the Atherosclerotic Process in APOE-Knockout Mice.

Background: Iron overload can accelerate the accumulation of lipid oxides and contribute to the progression of atherosclerosis. Ferritin heavy chain (FT-H) exhibits oxidase activity, which inhibits the toxicity of ferrous ions and reduces oxidative damage. We investigated the effect of the intraperitoneal injection of FT-H on the progression of atherosclerosis in APOE-knockout mice (Apo-E(-/-) mice). Methods: All mice were fed on a high-fat diet. After 10 weeks, the mice were divided into an injection group (n = 4) and a control group (n = 4). The injection group was injected intraperitoneally with FT-H (50 mg/kg, once a week), and the control group was treated with PBS buffer (at an equal volume to the injection group, once a week). After 10 weeks of intervention, MRI of the aortas was performed. Then, the animals were sacrificed, and tissues were taken. Hematoxylin-eosin (HE) staining was used for histomorphometry, Masson staining was used to quantify the collagen content in the arteries, Prussian blue staining was used to visualize iron deposition in the arteries, and MRI was used to analyze the structure of the aorta in vivo. Immunohistochemistry was performed to detect the expression of MCP-1, MMP-2, MMP-9, FT-H, FT-L, TfR1, NRF-2 and GPX-4. Results: The serological results showed that the injection group had lower levels of glucose (Glu), triacylglycerol (TG), cholesterol (CHO), low-density lipoprotein-C (LDL-C) and malondialdehyde (MDA) (p = 0.0058, p = 0.0098, p = 0.0019, p = 0.0368 and p = 0.0025, respectively), and their serum ferritin (SF) and superoxide dismutase (SOD) levels were higher (p = 0.0004 and p < 0.0001). The Masson staining and MRI results showed that the injection group had less collagen deposition (p = 0.0226), a larger arterial lumen area and arterial volume (p = 0.0006 and p = 0.0005), thinner arterial wall thickness (p = 0.0013) and a more stable arterial plaque structure (p < 0.0001). The immunohistochemical results showed reduced expression of FT-H, FT-L, TfR1, MMP-2, MMP-9, MCP-1 and NRF-2 in the injection group (p = 0.0054, p = 0.0242, p = 0.0221, p = 0.0477, p = 0.0131, p = 0.0435 and p = 0.0179). Prussian blue staining showed that the area of iron-positive areas in the aortic plaques of the control group was larger than that of injected group. The expression of GPX-4 was lower in the control group than in the injection group (p = 0.016). Conclusions: The intraperitoneal administration of FT-H to Apo-E(-/-) mice resulted in lower blood glucose and lipid levels; reduced iron and iron metabolism protein deposition in the aorta; reduced indices of their ferroptosis, oxidation and inflammatory aggregation; and reduced collagen deposition in the aorta, which delayed the process of aortic atherosclerosis in mice.

Combining idebenone and rosuvastatin prevents atherosclerosis by suppressing oxidative stress and NLRP3 inflammasome activation

Atherosclerosis is a progressive inflammatory disease activated by excessive oxidized low-density lipoprotein (ox-LDL). Statins are the first-line choice to reduce the risk of cardiovascular disease. However, statin-associated side effects prompt dose reduction or discontinuation. Idebenone could protect against atherosclerosis by scavenging reactive oxygen species (ROS). Although both idebenone and statins have certain efficacy, neither of them can achieve a completely satisfactory effect. Here, we aim to investigate the anti-atherosclerotic effect of the combination of idebenone and statins. Apolipoprotein E knockout (ApoE−/−) mice were given idebenone (400 mg/kg/d), rosuvastatin (10 mg/kg/d) or a combination of idebenone and rosuvastatin. Histological and immunohistochemical staining were used to analyze the size and composition of the plaque. In vivo and in vitro experiments were conducted to explore the possible mechanism. Idebenone and rosuvastatin both reduced plaque burden and increased the stability of atherosclerotic plaques in the ApoE−/− mice. Mice receiving the combination therapy had even reduced and more stable atherosclerotic plaques than mice treated with idebenone or rosuvastatin alone. NLRP3 and IL-1β were further downregulated in mice receiving combination therapy compared with mice treated with monotherapy. The combination treatment also markedly reduced oxidative stress and cell apoptosis in vivo and in vitro. In conclusion, our data demonstrate that the combination of idebenone and rosuvastatin works synergistically to inhibit atherosclerosis, and that the use of both substances together is more effective than using either substance alone. From a therapeutic point, combining idebenone and rosuvastatin appears to be a promising strategy to further prevent atherosclerosis.

Development of a Model for Plaque Induction in Rat Carotid Arteries.

Objective Plaque induction through intimal injury using a balloon catheter in small animals and by artificial ligation of the carotid artery in large animals have been reported. However, these reports have not yet succeeded in inducing stable plaques nor creating a high degree of intimal thickening to be used as animal models. We have previously developed a plaque induction model in rats but have failed to obtain a plaque incidence frequency that can be used as a model. Thus, in the current study, we aimed to create a versatile disease model to examine the pharmacokinetics of drug administration, determine the efficacy of treatment, and examine the process of intimal thickening. We also attempted to create an improved model with shorter, more frequent, and more severe intimal thickening. Materials and Methods The common carotid artery of male Wistar rats was surgically exposed and completely ligated with a wire and 6-0 nylon thread. Then, the wire was removed to create a partial ligation. To create a high frequency and high degree of intimal thickening, 72 rats were divided into two groups: a single lesion group with a 0.25-mm wire and a single ligature point, and a tandem lesion group with a 0.3-mm wire and two ligature points. Each group was further divided into normal diet and high cholesterol diet groups. The presence and frequency of intimal thickening were examined for each group after 4, 8, and 16 weeks of growth. Results In the single lesion group, intimal thickening was observed in 42% of the 4-week group and 75% of the 8-week group. In the tandem lesion group, intimal thickening was observed in 75% of the 4-week group and 50% of the 8-week group. In addition, 50% of the individuals reared for 16 weeks developed intimal thickening. Conclusion We successfully induced intimal thickening in the carotid arteries of rats with high frequency in the single lesion and tandem lesion groups. The results also showed that the tandem lesion group tended to induce intimal thickening earlier than the single lesion group.

Relationship between carotid atherosclerotic plaque characteristics in magnetic resonance imaging and perioperative hemodynamic instability

Objective: To analyze the relationship between carotid atherosclerotic plaque characteristics in magnetic resonance imaging (MRI) and perioperative hemodynamic instability in patients with severe carotid artery stenosis undergoing carotid artery stenting (CAS). Methods: A total of 89 patients with carotid artery stenosis who underwent CAS treatment at Beijing Tsinghua Changgung Hospital affiliated to Tsinghua University from January 1, 2017, to December 31, 2021, were prospectively included. Among them, 74 were male and 15 were female, with an age range of 43 to 87 years (mean age: 67.8±8.2 years). Preoperative examinations included carotid artery MRI vessel wall imaging to analyze the existence of large lipid-rich necrotic core (LRNC), intraplaque hemorrhage (IPH), and fibrous cap rupture in carotid artery plaques. Plaques without the above-mentioned risk factors were defined as stable plaque group (34 cases), while those with such risk factors were defined as vulnerable plaque group (55 cases). The number of risk factors present in each plaque was also calculated. Intraoperative changes in blood pressure and heart rate were recorded, and the use of dopamine postoperatively was noted. Using the risk factors that the plaque has as independent variables and the clinical outcomes as dependent variables, the RR values were calculated, and the differences in clinical outcomes of patients with different risk factors were compared. Results: The incidence rates of hypotension and bradycardia were higher in patients with vulnerable plaques than those with stable plaques (60.0% (33/55) vs 14.7%(5/34) and 38.2%(21/55) vs 14.7%(5/34), respectively; both P<0.05). Based on MRI imaging features, the large LRNC was present in 45 cases, with RR values for hypotension and bradycardia of 3.15 (1.69-5.87) and 2.20 (1.07-4.53), respectively; IPH was present in 37 cases, with RR values for hypotension and bradycardia of 2.70 (1.61-4.55) and 2.25 (1.15-4.39), respectively; and fibrous cap rupture was present in 29 cases, with RR values for hypotension and bradycardia of 1.50 (0.94-2.40) and 1.29 (0.67-2.49), respectively. The higher the number of risk factors in vulnerable plaques, the higher the incidence of intraoperative blood pressure and heart rate decrease: when the number of risk factors ranged from 0 to 3, the incidence of blood pressure decrease was 14.7% (5/34), 9/18, 11/18, and 13/19, respectively (P<0.001), and the incidence of heart rate decrease was 14.7% (5/34), 6/18, 7/18, and 8/19, respectively (P=0.022). There was no significant difference in the number of cases of dopamine use between the two groups (P>0.05). Conclusion: Patients with a higher number of risk factors for vulnerable carotid plaques, as indicated by carotid artery MRI vessel wall imaging, are at a higher risk of experiencing blood pressure and heart rate decrease during CAS surgery.

The Association of Lipoprotein(a) and Neutrophil-to-Lymphocyte Ratio Combination with Atherosclerotic Cardiovascular Disease in Chinese Patients.

The association of lipoprotein(a) [Lp(a)] with atherosclerotic cardiovascular disease (ASCVD) risk can be modified by chronic systemic inflammation. The neutrophil-to-lymphocyte ratio (NLR) is a reliable and easily available marker of immune response to various infectious and non-infectious stimuli. The purpose of this study was to assess the combined effects of Lp(a) and NLR in predicting the ASCVD risk and coronary artery plaque traits. This study included 1618 patients who had coronary computed tomography angiography (CTA) with risk assessment of ASCVD. CTA was used to evaluate the traits of coronary atherosclerotic plaques, and the association of ASCVD with Lp(a) and NLR was assessed by multivariate logistic regression models. Plasma Lp(a) and NLR were significantly increased in patients having plaques. High Lp(a) was defined as the plasma Lp(a) level > 75 nmol/L and high NLR as NLR > 1.686. The patients were grouped into four categories according to normal or high NLR and plasma Lp(a) as nLp(a)/NLR-, hLp(a)/NLR-, nLp(a)/NLR+ and hLp(a)/NLR+. The patients in the latter three groups had higher risk of ASCVD compared to the reference group nLp(a)/NLR-, with the highest ASCVD risk in the hLp(a)/NLR+ group (OR = 2.39, 95% CI = 1.49-3.83, P = 0.000). The occurrence of unstable plaques was 29.94% in the hLp(a)/NLR+ group, which was significantly higher than groups nLp(a)/NLR+, hLp(a)/NLR- and nLp(a)/NLR- with 20.83%, 26.54% and 22.58%, respectively, and there was a significantly increased risk of unstable plaque in the hLp(a)/NLR+ group compared to the nLp(a)/NLR- group (OR = 1.67, 95% CI = 1.04-2.68, P = 0.035). The risk of stable plaque was not significantly increased in the hLp(a)/NLR+ group compared to the nLp(a)/NLR- group (OR = 1.73, 95% CI = 0.96-3.10, P = 0.066). The concomitant presence of elevated Lp(a) and higher NLR is associated with increased unstable coronary artery plaques in patients with ASCVD.

Spatially Resolved Metabolites in Stable and Unstable Human Atherosclerotic Plaques Identified by Mass Spectrometry Imaging.

Impairments in carbohydrate, lipid, and amino acid metabolism drive features of plaque instability. However, where these impairments occur within the atheroma remains largely unknown. Therefore, we sought to characterize the spatial distribution of metabolites within stable and unstable atherosclerosis in both the fibrous cap and necrotic core. Atherosclerotic tissue specimens from 9 unmatched individuals were scored based on the Stary classification scale and subdivided into stable and unstable atheromas. After performing mass spectrometry imaging on these samples, we identified over 850 metabolite-related peaks. Using MetaboScape, METASPACE, and Human Metabolome Database, we confidently annotated 170 of these metabolites and found over 60 of these were different between stable and unstable atheromas. We then integrated these results with an RNA-sequencing data set comparing stable and unstable human atherosclerosis. Upon integrating our mass spectrometry imaging results with the RNA-sequencing data set, we discovered that pathways related to lipid metabolism and long-chain fatty acids were enriched in stable plaques, whereas reactive oxygen species, aromatic amino acid, and tryptophan metabolism were increased in unstable plaques. In addition, acylcarnitines and acylglycines were increased in stable plaques whereas tryptophan metabolites were enriched in unstable plaques. Evaluating spatial differences in stable plaques revealed lactic acid in the necrotic core, whereas pyruvic acid was elevated in the fibrous cap. In unstable plaques, 5-hydroxyindoleacetic acid was enriched in the fibrous cap. Our work here represents the first step to defining an atlas of metabolic pathways involved in plaque destabilization in human atherosclerosis. We anticipate this will be a valuable resource and open new avenues of research in cardiovascular disease.

Near-Infrared Autofluorescence (NIRAF) in Atherosclerotic Plaque Dissociates from Intraplaque Hemorrhage and Bilirubin.

Near-infrared autofluorescence (NIRAF) in unstable atherosclerotic plaque has been suggested as a novel imaging technology for high-risk atherosclerosis. Intraplaque hemorrhage (IPH) and bilirubin, derived from the subsequent degradation of heme, have been proposed as the source of NIRAF, although their roles and the underlying mechanism responsible for NIRAF remain unclear. To test the proposed role of bilirubin as the source of NIRAF in high-risk atherosclerosis, Biliverdin reductase a gene and apolipoprotein E gene double-knockout (Bvra-/-Apoe-/-) mice were subjected to the Western diet and tandem stenosis (TS) surgery, as a model of both bilirubin deficiency and plaque instability. Human coronary arteries containing atherosclerotic plaques were obtained from heart transplant recipients. The NIRAF was determined by in vivo fluorescence emission computed tomography, and ex vivo infrared imaging. The cholesterol content was quantified by HPLC with UV detection. In Bvra+/+Apoe-/- TS mice, the NIRAF intensity was significantly higher in unstable plaque than in stable plaque, yet the NIRAF in unstable plaque was undistinguishable in Bvra+/+Apoe-/- and littermate Bvra-/-Apoe-/- TS mice. Moreover, the unstable plaque in TS mice exhibited a lower NIRAF compared with highly cellular plaque that lacked most of the features of unstable plaque. In human coronary arteries, the NIRAF associated with cholesterol-rich, calcified lesions, rather than just cholesterol-rich lesions. The NIRAF in atherosclerotic plaque can be dissociated from IPH and bilirubin, such that the compositional meaning of an elevated NIRAF remains obscure.

449-P: Truncations of Apolipoproteins C-I and C-II Are Associated with Coronary Artery Calcium Progression in Multiethnic Study of Atherosclerosis (MESA)

Higher truncated-to-native proteoform ratios of apolipoproteins (apo) C-I (C-I’/C-I) and C-II (C-II’/C-II) are associated with less atherogenic lipid profiles, including lower triglycerides (TG) and higher HDL levels. Here we examined the relationships of C-I’/C-II and C-II’/C-II, and total apoC-I and apoC-II concentrations with coronary artery calcium (CAC) progression. Apo C-I and C-II proteoforms were measured by mass spectrometry immunoassay in 5,791 baseline MESA plasma samples. Total apo C-I and C-II concentrations were assayed in 3,851 samples. CAC was measured 1 to 4 times (mean 2.5) over 10 years. Repeated measures regression models were adjusted for age, gender, race/ethnicity, and follow-up time (Model 1), then for BMI, diabetes, systolic BP, use of tobacco, statins and antihypertensive medications (Model 2), and then for plasma HDL and TG (Model 3). Among 5,069 participants with at least one follow-up CAC CT scan, 2,513 had CAC progression defined as events of CAC changing from 0 to &amp;gt; 0, or ≥ 10 units/yr from CAC &amp;gt; 0 but ≤ 100, or ≥ 10%/yr from CAC &amp;gt; 100. Progression was inversely associated with C-I’/C-I (Risk Ratio per 1 SD: 0.93 [95% CI 0.87, 0.97], Model 3). In those with baseline CAC = 0 (n = 2,581), risk of CAC &amp;gt; 0 (897 events) was inversely associated with C-I’/C-I in Model 1 only (0.85 [0.79, 0.93]). In those with baseline CAC &amp;gt; 0, C-II’/C-II was positively associated with follow-up change in density score (β-estimate per 1 SD 0.02 [95% CI: 0.001, 0.03] units) in Model 3, indicating a potentially more stable plaque. Baseline-adjusted follow-up density score was also positively related to total apoC-I in Model 2 (0.02 [0.004, 0.04]). None of the CAC measures were related to total apoC-II. In conclusion, increased truncation of apo C-I and C-II is associated with reduced CAC progression and/or improved stability of coronary atherosclerotic plaque that is not explained by total concentrations of both apolipoproteins. Disclosure J.Koska: None. J.Furtado: Employee; Biogen. Y.Hu: None. D.Billheimer: Advisory Panel; AstraZeneca. M.Allison: None. M.Budoff: Research Support; Novo Nordisk, Novartis, Boehringer Ingelheim Inc., Speaker's Bureau; Boehringer Ingelheim and Eli Lilly Alliance. D.Nedelkov: None. R.Mcclelland: None. P.Reaven: Research Support; Dexcom, Inc. Funding National Heart, Lung, and Blood Institute (R01HL138969, 75N92020D00001, HHSN268201500003I, N01HC95159, 75N92020D00005, N01HC95160, 75N92020D00002, N01HC95161, 75N92020D00003, N01HC95162, 75N92020D00006, N01HC95163, 75N92020D00004, N01HC95164, 75N92020D000

Increased risk of coronary plaque vulnerabilization following COVID-19 infection, identified by elevated FAI index of pericoronary inflammation at coronary CT

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This research has been funded by the research grant Intel-FAT, proposal registration code PN-III-P4-ID-PCE-2020-2861, contract number PCE 206/2021, Project funded by the European Union and the Government of Romania through the Ministry of European Funds, and the Doctoral School of the “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Romania. Background Inflammation plays an essential role in all stages of atherosclerosis, with stable plaques characterized by chronic inflammation and vulnerable or ruptured plaques exhibiting "active" inflammation. COVID infection may significantly increase systemic inflammation, but the role of SARS COV-2 infection on local plaque vulnerability is still not elucidated. Mapping the PCAT - FAI on routine CCTA can detect coronary artery inflammation non-invasively by measuring changes in the composition of pericoronary fat. Purpose The aim of this study was to assess the impact of COVID-19 infection on CAD in patients who underwent CCTA examinations for chest pain in the early stages after infection, using the new AI - powered CaRi-Heart® solution. Methods In our study, we included 158 patients (mean age was 61.63 ± 10.14 years) with chest pain and low to intermediate clinical likelihood of CAD, who underwent 128-slice CCTA for assessment of coronary anatomy, atherosclerosis, and determination of FAI – Score. The study population was divided into two main groups: Group 1 (n = 75) – patients who had a COVID-19 infection a few months prior to their CCTA examination, and Group 2 (n = 83) – patients adjusted for age and gender, who did not have a COVID-19 infection. Results The FAI - Score was consistently higher in the non COVID-19 group: LAD (11.61 ± 7.60 vs. 9.32 ± 6.00, p = 0.05), LCX (12.43 ± 6.65 vs. 10.48 ± 6.24, p = 0.05), RCA (15.40 ± 11.36 vs. 14.54 ± 12.17, p = ns), the average FAI - Score (12.81 ± 8.28 vs. 10.47 ± 7.19, p = 0.001). For the FAI-Score Centile, the overall pattern shifts significantly, as the values for all three coronary arteries are higher for the subjects in the COVID-19 positive group, as follows: LAD (0.66 ± 0.29 vs. 0.58 ± 0.28, p = 0.05), LCX (0.79 ± 0.16 vs. 0.68 ± 0.26, p = 0.03), RCA (0.83 ± 0.20 vs. 0.68 ± 0.29, p = 0.05). In both cases, the CaRi Heart® Risk (p &amp;lt; 0.0001) and the Duke Score (p &amp;lt; 0.0001) had significantly higher values for the patients in the COVID-negative group. Conclusion Lesions with higher pericoronary FAI - Score Centile values were more commonly found in patients who had previously been infected with COVID-19. The higher levels of inflammation in the pericoronary adipose tissue suggests that COVID-19 infection is linked to an increased risk of coronary plaque destabilization.

Smooth muscle differentiation of coronary intima in autopsy tissues after sirolimus-eluting stent implantation

BackgroundIn coronary atherosclerotic disease, the proliferation of intimal smooth muscle cells (SMCs) is regarded as beneficial with respect to stable and unstable plaques, but is thought detrimental in discussions on coronary stent restenosis. To resolve this discrepancy, we focused on the quality, not quantity, of intimal SMCs in coronary atherosclerotic disease. MethodsAutopsied coronary artery specimens from seven patients implanted with bare metal stents (BMS), three with paclitaxel-eluting stents (PES), and 10 with sirolimus (rapamycin)-eluting stents (SES) were immunostained for SMC markers. Cultured human coronary artery SMCs were also treated with sirolimus and paclitaxel. ResultsIntimal SMC differentiation, estimated by the ratio of h-caldesmon+ cells to α-smooth muscle actin+ (α-SMA+) cells, was significantly increased whereas dedifferentiation, estimated from the ratio of fibroblast activation protein alpha (FAPα)+ cells to α-SMA+ cells, was significantly decreased, in tissues of SES compared with BMS cases. No difference in the degree of differentiation was found between PES and BMS cases or between the three groups in nonstented arteries used as controls. Correlation analyses for each field of view revealed a significant positive correlation between h-caldesmon and calponin staining but significant negative correlations with FAPα staining in α-SMA+ cells. Cultured SMCs were shorter (dedifferentiated) and showed an increased FAPα/α-SMA protein when treated with paclitaxel, whereas they became elongated (differentiated) and showed increased calponin/α-SMA proteins with sirolimus. ConclusionsThe SMCs of the coronary intima may differentiate after SES implantation. SMC differentiation may explain both the plaque stabilization and reduced risk of reintervention associated with SES.

Comparative evaluation of efficacy and safety of calcipotriol versus calcitriol ointment, both in combination with narrow-band ultraviolet B phototherapy in the treatment of stable plaque psoriasis.

Vitamin D analogues and NBUVB are both well-recognised modes of therapy in the treatment of chronic stable plaque psoriasis. The objective of this open label intraindividual, left right study was to compare two different vitamin D analogues, calcipotriol and calcitriol, in combination with NBUVB phototherapy in psoriasis. Thirty patients with stable plaque psoriasis were enrolled for a 12-week clinical trial. The target lesion on the left side was treated topically with calcitriol ointment, while that on the right side was treated with calcipotriol ointment once daily. The whole body was irradiated with narrow-band ultraviolet B phototherapy (NBUVB) three times per week. Efficacy was assessed by target plaque scoring. Both therapies resulted in a statistically significant reduction in erythema, scaling, thickness, and target plaque score, seen as early as 2 weeks into therapy. However, the calcipotriol combination led to an earlier clearance of plaques and a lesser relapse rate than the calcitriol combination. The number of treatment sessions and cumulative NBUVB doses were significantly lower in the calcipotriol-treated group. Both vitamin D analogues appear to be safe, effective, and cosmetically acceptable, with calcipotriol being more efficacious, well tolerated, with a rapid onset of action and a better maintenance of response.

CYP metabolic pathway related gene polymorphism increases the risk of embolic and atherothrombotic stroke and vulnerable carotid plaque in southeast China

ObjectiveTo investigate the association of CYP metabolic pathway-related genetic polymorphisms with the susceptibility to ischemic stroke and stability of carotid plaque in southeast China. MethodsWe consecutively enrolled 294 acute ischemic stroke patients with carotid plaque and 282 controls from Wenling First People's Hospital. The patients were divided into the carotid vulnerable plaque group and stable plaque group according to the results of carotid B-mode ultrasonography. Polymorphisms of CYP3A5 (G6986A, rs776746), CYP2C9*2 (C430T, rs1799853), CYP2C9*3 (A1075C, rs1057910), and EPHX2 (G860A, rs751141) were determined using polymerase chain reaction and mass spectrometry analysis. ResultsEPHX2 GG may reduce the susceptibility to ischemic stroke (OR = 0.520, 95% CI: 0.288 ∼ 0.940, P = 0.030) and AA+AG may increase the risk for ischemic stroke (OR = 1.748, 95% CI: 1.001 ∼ 3.052, P = 0.050). The distribution of CYP3A5 genotypes showed significant differences between the vulnerable plaque and stable plaque groups (P = 0.026). Multivariate logistic regression analysis found that CYP3A5 GG could reduce the risk of vulnerable plaques (OR = 0.405, 95% CI: 0.178 ∼ 0.920, P = 0.031). ConclusionEPHX2 G860A polymorphism may reduce the stroke susceptibility, while other SNPs of CYP genes are not associated with ischemic stroke in southeast China. Furthermore CYP3A5 polymorphism was related with carotid plaque instability.

The role of endothelial shear stress, shear stress gradient, and plaque topography in plaque erosion

Background and aimsPlaque erosion is a common underlying cause of acute coronary syndromes. The role of endothelial shear stress (ESS) and endothelial shear stress gradient (ESSG) in plaque erosion remains unknown.We aimed to determine the role of ESS metrics and maximum plaque slope steepness in plaques with erosion versus stable plaques. MethodsThis analysis included 46 patients/plaques from TOTAL and COMPLETE trials and Brigham and Women's Hospital's database who underwent angiography and OCT. Plaques were divided into those with erosion (n = 24) and matched stable coronary plaques (n = 22). Angiographic views were used to generate a 3-D arterial reconstruction, with centerlines merged from angiography and OCT pullback. Local ESS metrics were assessed by computational fluid dynamics. Among plaque erosions, the up- and down-slope (Δ lumen area/frame) was calculated for each culprit plaque. ResultsCompared with stable plaque controls, plaques with an erosion were associated with higher max ESS (8.3 ± 4.8 vs. 5.0 ± 1.9 Pa, p = 0.02) and max ESSG any direction (9.2 ± 7.5 vs. 4.3 ± 3.11 Pa/mm, p = 0.005). Proximal erosion was associated with a steeper plaque upslope while distal erosion with a steeper plaque downslope. Max ESS and Max ESSG any direction were independent factors in the development of plaque erosion (OR 1.32, 95%CI 1.06–1.65, p = 0.014; OR 1.22, 95% CI 1.03–1.45, p = 0.009, respectively). ConclusionsIn plaques with similar luminal stenosis, plaque erosion was strongly associated with higher ESS, ESS gradients, and plaque slope as compared with stable plaques. These data support that ESS and slope metrics play a key role in the development of plaque erosion and may help prognosticate individual plaques at risk for future erosion.

Adipokine-Cytokine Profile in Patients with Unstable Atherosclerotic Plaques and Abdominal Obesity.

The study included 145 men aged 38-79 with atherosclerosis of the coronary arteries (CA) and stable angina pectoris II-III FC who were hospitalized for coronary bypass surgery (2011-2022). The final analysis included 116 patients. Notably, 70 men had stable plaques in the CA (of which 44.3% had AO), and 46 men had unstable plaques in the CA (of which 43.5% had AO). Adipocytokine levels were determined using multiplex analysis (Human Metabolic Hormone V3 panel). In the subgroup of patients with unstable plaques, patients with AO had a GLP-1 level that was 1.5 times higher and a lipocalin-2 level that was 2.1 times lower, respectively. GLP-1 is direct, and lipocalin-2 is inversely associated with AO in patients with unstable plaques. Among patients with AO, the level of lipocalin-2 in patients with unstable plaques was 2.2 times lower than in patients with stable plaques in the CA. The level of lipocalin-2 was inversely associated with the presence of unstable atherosclerotic plaques in the CA. GLP-1 is directly associated with AO in patients with unstable atherosclerotic plaques. Lipocalin-2 is inversely associated with unstable atherosclerotic plaques in patients with AO.

Shear Wave Elastography for the Assessment of Carotid Plaque Vulnerability: A Systematic Review

Evidence for the management of asymptomatic carotid stenosis and possibly symptomatic nonstenosing carotid artery disease is limited. In contrary to calcified plaques, soft plaques are considered vulnerable and prone to rupture. Shear wave elastography (SWE), a novel ultrasound technique which uses acoustic wave force to propagate shear wave in tissues, can quantify tissue stiffness through the estimation of Young’s modulus (YM) in kPa or shear wave velocity in meter/second. This systematic review is aimed at evaluating the feasibility of SWE in carotid plaque risk stratification in relation to ischemic stroke (PROSPERO registration: CRD42022309709). 18 studies, obtained via search on PubMed, Cochrane, and Embase from inception until November 1, 2022, assessed SWE’s feasibility in carotid plaque risk stratification in humans (13 studies) and phantom models (5 studies). Human studies showed heterogeneity with respect to SWE devices, acquisition settings, and methodology, which consequently reflected in the between-study variability of YM values used for distinguishing vulnerable/symptomatic (27–52 kPa) and stable/asymptomatic (28–115 kPa) carotid plaques. However, within-study assessment of all human studies indicated SWE’s feasibility in carotid plaque risk stratification. Furthermore, four out of five carotid plaque phantom studies showed the potential of SWE to discriminate tissues of different stiffness comparable to the carotid vessel wall, soft and hard plaques, and with good reproducibility. SWE may potentially offer a bedside risk stratification tool for identifying patients with vulnerable carotid plaques, who may benefit from carotid surgery, stenting, or prolonged dual antiplatelet therapy. Patients with stable carotid plaques could be spared the risks of potentially harmful treatments and complications. However, available data are not enough to facilitate the immediate clinical application of SWE, and therefore, larger prospective clinical are warranted.