Plaque Formation In Arteries Research Articles

A study on serum potassium and serum magnesium levels in acute myocardial infarction with special emphasis on rhythm disturbance

Background and objectives. Myocardial infarction (MI) is a severe cardiac event associated with plaque formation in arteries, leading to reduced blood flow to the heart. Arrhythmias, such as bradyarrhythmia or tachyarrhythmia, commonly accompany MI, contributing to its morbidity and mortality. Electrolyte disturbances, particularly potassium and magnesium imbalances, can exacerbate arrhythmic risks in MI patients. This study aimed to assess the incidence of alterations in serum potassium and magnesium levels during acute MI and their correlation with rhythm disturbances. Material and methods. A prospective analytical study was conducted with 150 patients diagnosed with acute MI based on ECG changes and elevated cardiac markers. Serum potassium and magnesium levels were measured, and rhythm disturbances were assessed using continuous cardiac monitoring and standard ECG. Spearman correlation analysis was performed to evaluate the association between serum potassium, serum magnesium, and rhythm changes. Results. The study investigated the demographic and clinical characteristics of participants and the potential relationship between serum electrolyte levels and arrhythmic changes. The mean age of the participants was 54.3 years, with a male predominance (76% male, 24% female). Among the participants, 50.67% had diabetes, 52% had hypertension, and 28% had both conditions. Serum electrolyte analysis showed elevated magnesium levels in 6.66% and elevated potassium levels in 12.66% of patients. Notably, arrhythmic changes in ECG were present in 62% of patients, with sinus tachycardia being the most prevalent (17%). However, statistical analysis revealed no significant correlation between serum magnesium, serum potassium, and rhythm changes (p >0.05). These findings suggest that while arrhythmic changes are common, they are not directly associated with elevated levels of these electrolytes, indicating the need for further investigation into other potential factors influencing arrhythmias in this population. Conclusion. Despite the prevalence of electrolyte disturbances in acute MI patients, this study found no significant association between serum magnesium, serum potassium levels, and rhythm disturbances. Further research is warranted to elucidate the complex interplay between electrolyte imbalances and arrhythmias in MI.

Vascular medicine in the 21st century: Embracing comprehensive vasculature evaluation and multidisciplinary treatment.

The field of vascular medicine has undergone a profound transformation in the 21st century, transforming our approach to assessment and treatment. Atherosclerosis, a complex inflammatory disease that affects medium and large arteries, presents a major challenge for researchers and healthcare professionals. This condition, characterized by arterial plaque formation and narrowing, poses substantial challenges to vascular health at individual, national, and global scales. Its repercussions are far-reaching, with clinical outcomes including ischemic heart disease, ischemic stroke, and peripheral arterial disease-conditions with escalating global prevalence. Early detection of vascular changes caused by atherosclerosis is crucial in preventing these conditions, reducing morbidity, and averting mortality. This article underscored the imperative of adopting a holistic approach to grappling with the intricacies, trajectories, and ramifications of atherosclerosis. It stresses the need for a thorough evaluation of the vasculature and the implementation of a multidisciplinary treatment approach. By considering the entire vascular system, healthcare providers can explore avenues for prevention, early detection, and effective management of this condition, ultimately leading to improved patient outcomes. We discussed current practices and proposed new directions made possible by emerging diagnostic modalities and treatment strategies. Additionally, we considered healthcare expenditure, resource allocation, and the transformative potential of new innovative treatments and technologies.

A Molecular Communication Perspective on Detecting Arterial Plaque Formation

A Molecular Communication Perspective on Detecting Arterial Plaque Formation

ASSOCIATION BETWEEN TOTAL BILIRUBIN LEVELS WITH INCIDENCE OF ATHEROSCLEROSIS: SYSTEMATIC REVIEW AND META-ANALYSIS

Background. Bilirubin is a byproduct of the breakdown of erythrocytes. Bilirubin levels can potentially serve as a biomarker for cardiovascular risk assessment. In this study, we would be investigating most recent manuscripts, published in the last 5 years, that studied association of serum bilirubin level to atherosclerosis progression to elicit how strongly low level of total bilirubin can prognose the disease progression. Methods. Using Pubmed search engine, all articles that included keywords “bilirubin” and “atherosclerosis” were retrieved. In total 67 search results emerged for the 2019-2023 timeline, the last 5 years.6 population-based studies that studied association between total bilirubin concentration and atherosclerosis development were used for the meta-analysis. Results. Increasing blood total bilirubin level seems to decrease the odds of developing atherosclerosis, meaning that there is an inverse correlation between total bilirubin level and arterial plaque formation or stenosis. Pooled odds ratio was found to be 0.86 (95% CI 0.83-0.9), suggesting that there is 14% decreased chance of developing atherosclerosis for each mmol/L increase in bilirubin levels. Overall, higher total serum bilirubin levels were associated with a significantly decreased risk of progression to atherosclerosis. Conclusion. The meta-analysis indicates a significant inverse association between low total bilirubin levels and the risk of developing atherosclerosis, suggesting that higher bilirubin levels may be protective against the progression of this disease.

Abstract 3019: Piezo-1 Expression Decreases Under Disturbed Flow Model Of Femoral Atherosclerosis.

Background: Peripheral arterial disease (PAD) is often manifest by focal atherosclerotic plaque formation in the infra-inguinal arteries. However, murine models of atherosclerosis in the infra-inguinal arteries are lacking. It is well known that low and oscillatory wall shear stress, which occurs around blockages in PAD, promotes focal atherosclerotic plaque, but this has not been tested in vivo. Piezo1 is a mechanosensitive ion channel associated with hemodynamic changes in the arterial wall, but its role in flow-mediated atherosclerotic plaque deposition is not known. Objective: To develop a flow-mediated murine model of focal atherosclerotic plaque in the femoral arteries. Methods: 8 male and female S129 mice underwent partial femoral artery ligation (Figure A/B). Wall shear stress was calculated from duplex ultrasound imaging (Figure C/D). Atherogenic conditions were imposed with PCSK9 infection and high fat diet; this was initiated 1 week prior to partial femoral ligation. Histologic comparison of the left (partial femoral ligation) and right (normal stable flow) was performed. Results: Low wall shear stress was induced in this model (Figure C/D). Piezo1 expression was decreased in both male and female arteries under these conditions in this model (Figure E). Atherosclerotic plaque was induced by the partial femoral artery ligation but not on the normal stable flow side (Figure F). Conclusions: We have successfully developed a flow-mediated model of focal atherosclerotic plaque in murine femoral arteries. This is associated with downregulation of Piezo1 gene expression. Ongoing work is examining the causative role of Piezo1 on endothelial response to disturbed flow.

Enhancing Coronary Heart Disease Risk Prediction with Machine Learning and Deep Learning

Enhancing Coronary Heart Disease Risk Prediction with Machine Learning and Deep Learning

Molecular Imaging of Fibroblast Activation in Rabbit Atherosclerotic Plaques: a Preclinical PET/CT Study.

Atherosclerosis remains the pathological basis of myocardial infarction and ischemic stroke. Early and accurate identification of plauqes is crucial to improve clinical outcomes of atherosclerosis patients. Our study aims to evaluate the potential value of fibroblast activation protein inhibitor (FAPI)-04 PET/CT in identifying plaques via a preclinical rabbit model of atherosclerosis. New Zealand white rabbits were fed high-fat diet (HFD), and randomly divided into the model group injured by the balloon, and the sham group only with incisions. Ultrasound was performed to detect plaques, and FAPI-avid was determined through Al18F-NOTA-FAPI-04 PET/CT. Mean standardized uptake values (SUVmean) in lesions were compared, and biodistribution of Al18F-NOTA-FAPI-04 and target-to-background ratios (TBRs) were calculated. Histological staining was performed to display arterial plaques, and autoradiography (ARG) was employed to measure the in vitro intensity of Al18F-NOTA-FAPI-04. At last, the correlation among FAP levels, plaque area, SUVmean values and fibrous cap thickness was assessed. The rabbit carotid and abdominal atherosclerosis model was established. Al18F-NOTA-FAPI-04 showed a higher uptake in carotid plaques (SUVmean 1.32 ± 0.11) and abdominal plaques (SUVmean 0.73 ± 0.13) compared to corresponding controls (SUVmean 1.07 ± 0.06; 0.46 ± 0.03) (P < 0.05). Biodistribution analysis of Al18F-NOTA-FAPI-04 revealed that the bigger plaques were delineated with higher TBRs. Pathological staining showed the formation of arterial plaques, and ARG staining exhibited a higher intensity of Al18F-NOTA-FAPI-04 in the bigger plaques. Lastly, plaque area was found to be positively correlated to FAP expression and SUVmean, while FAP expression was negatively correlated to fibrous cap thickness of plaques. We successfully achieve molecular imaging of fibroblast activation in atherosclerotic lesions of rabbits, suggesting Al18F-NOTA-FAPI-04 PET/CT may be a potentially valuable tool to identify plaques.

Geniposide ameliorates atherosclerosis by restoring lipophagy via suppressing PARP1/PI3K/AKT signaling pathway

BackgroundAtherosclerosis (AS) is the leading cause of global death, which manifests as arterial lipid stack and plaque formation. Geniposide is an iridoid glycoside extract from Gardenia jasminoides J.Ellis that ameliorates AS by mediating autophagy. However, how Geniposide regulates autophagy and treats AS remains unclear. PurposeTo evaluate the efficacy and mechanism of Geniposide in treating AS.Study design and methods: Geniposide was administered to high-fat diet-fed ApoE−/− mice and oxidized low-density lipoprotein-incubated primary vascular smooth muscle cells (VSMCs). AS was evaluated with arterial lipid stack, plaque progression, and collagen loss in the artery. Foam cell formation was detected by lipid accumulation, inflammation, apoptosis, and the expression of foam cell markers. The mechanism of Geniposide in treating AS was assessed using network pharmacology. Lipophagy was measured by lysosomal activity, expression of lipophagy markers, and the co-localization of lipids and lipophagy markers. The effects of lipophagy were blocked using Chloroquine. The role of PARP1 was assessed by Olaparib (a PARP1 inhibitor) intervention and PARP1 overexpression. ResultsIn vivo, Geniposide reversed high-fat diet-induced hyperlipidemia, plaque progression, and inflammation. In vitro, Geniposide inhibited VSMC-derived foam cell formation by suppressing lipid stack, apoptosis, and the expressions of foam cell markers. Network pharmacological analysis and in vitro validation suggested that Geniposide treated AS by enhancing lipophagy via suppressing the PI3K/AKT signaling pathway. The benefits of Geniposide in alleviating AS were offset by Chloroquine in vivo and in vitro. Inhibiting PARP1 using Olaparib promoted lipophagy and alleviated AS progression, while PARP1 overexpression exacerbated foam cell formation and lipophagy blockage. The above effects of PARP1 were weakened by PI3K inhibitor LY294002. PARP1 also inhibited the combination of the ABCG1 and PLIN1. ConclusionGeniposide alleviated AS by restoring PARP1/PI3K/AKT signaling pathway-suppressed lipophagy. This study is the first to present the lipophagy-inducing effect of Geniposide and the binding of ABCG1 and PLIN1 inhibited by PARP1.

Investigating the relationship between intracranial atherosclerotic plaque remodelling and diabetes using high-resolution vessel wall imaging.

Intracranial atherosclerosis, a leading cause of stroke, involves arterial plaque formation. This study explores the link between plaque remodelling patterns and diabetes using high-resolution vessel wall imaging (HR-VWI). To investigate the factors of intracranial atherosclerotic remodelling patterns and the relationship between intracranial atherosclerotic remodelling and diabetes mellitus using HR-VWI. Ninety-four patients diagnosed with middle cerebral artery or basilar artery atherosclerosis were enrolled. Their basic clinical data were collected, and HR-VWI was performed. The vascular area at the plaque (VAMLN) and normal reference vessel (VAreference) were delineated and measured using image postprocessing software, and the Remodelling index (RI) was calculated. According to the value of the RI, the patients were divided into a positive remodelling (PR) group, intermediate remodelling (IR) group, negative remodelling (NR) group, PR group and non-PR (N-PR) group. The PR group exhibited a higher prevalence of diabetes and serum cholesterol levels than the IR and NR groups [45.2%, 4.54 (4.16, 5.93) vs 25%, 4.80 ± 1.22 and 16.4%, 4.14 (3.53, 4.75), respectively, P < 0.05]. The diabetes incidence was also significantly greater in the PR group than in the N-PR group (45.2% vs 17.5%, P < 0.05). Furthermore, the PR group displayed elevated serum triglyceride and cholesterol levels compared to the N-PR group [1.64 (1.23, 2.33) and 4.54 (4.16, 5.93) vs 4.54 (4.16, 5.93) and 4.24 (3.53, 4.89), P < 0.05]. Logistic regression analysis revealed diabetes mellitus as an independent influencing factor in plaque-PR [odds ratio (95% confidence interval): 3.718 (1.207-11.454), P < 0.05]. HR-VWI can clearly show the morphology and signal characteristics of intracranial vascular walls and plaques. Intracranial atherosclerotic plaques in diabetic patients are more likely to show PR, suggesting poor plaque stability and a greater risk of stroke.

Racial and ethnic influences on carotid atherosclerosis: Epidemiology and risk factors.

Carotid atherosclerosis-related stenosis, marked by atherosclerotic plaque formation in the carotid artery, significantly increases ischemic stroke risk. Its prevalence varies across ethnic groups, reflecting racial disparities. Epidemiological studies have highlighted different susceptibilities to carotid stenosis among racial groups. Native Americans and Whites show greater vulnerability, indicating genetic and environmental influences. The impact of carotid stenosis is more severe in Hispanic and Black populations, with a higher incidence of related brain injuries, underscoring the need for targeted interventions. Comparative imaging studies between Chinese and White individuals reveal unique patterns of carotid stenosis, enhancing understanding of its pathophysiology and management across ethnicities. This review also categorizes risk factors, distinguishing those with racial disparity (such as genetic loci, sleep apnea, and emotional factors, socioeconomic status) from those without. In summary, racial disparities affect carotid stenosis, leading to varying susceptibilities and outcomes among ethnic groups. Recognizing these differences is essential for developing effective prevention, diagnosis, and management strategies. Addressing these disparities is critical to reducing ischemic stroke's burden across populations. Continued research and targeted interventions are crucial to improve outcomes for individuals at risk of carotid stenosis and its complications.

The value of Lp(a) and TG/HDLC in peripheral blood to assess the stability of carotid plaque in patients with ischemic stroke.

The objective of this study was to investigate the relationship between lipoprotein (a) (Lp(a)), triglyceride/high-density lipoprotein cholesterol (TG/HDL-C), and the stability of carotid atherosclerotic plaque in patients with acute ischemic stroke. A total of 142 patients with acute ischemic stroke were selected and divided into group A (59 cases of stable plaque formation) and group B (83 cases of unstable plaque formation) according to the characteristics of carotid artery plaque formation detected by carotid color Doppler ultrasound. The serum Lp(a), lipid metabolism indexes, peripheral blood routine indexes, and related serum inflammatory factors indexes were compared between the two groups. Receiver operating characteristic curve and multivariate logistic regression model were used to analyze the relationship between each index and the formation of carotid unstable plaque. There were no significant differences in serum total cholesterol (TC), HDL-C, and low-density lipoprotein cholesterol (LDL-C) between groups A and B (p > .05). The values of Lp(a), TG, and TG/HDL-C in group B were higher than those in group A, and the differences were statistically significant (p < .05). There were no significant differences in serum TC, HDL-C, and LDL-C between groups A and B (p > .05). The values of Lp(a), TG, and TG/HDL-C in group B were higher than those in group A, and the differences were statistically significant (p < .05). The values of HBA1C, Lp-PLA2, CRP, CysC, Hcy, TNF-α, neutrophils, and NLR in group B were higher than those in group A, and the differences were statistically significant (p < .05). There was no significant difference in FPG, systolic blood pressure, diastolic blood pressure, Hb, white blood cells, platelets, and lymphocytes between groups A and B (p > .05). The results of logistic regression model showed that the increase of Lp(a), TG/HDL-C, HBA1C, Lp-PLA2, CRP, CysC, Hcy, and NLR could increase the risk of carotid artery unstable plaque in patients with ischemic stroke (p < .05). Lp(a) and TG/HDL-C have certain value in evaluating the stability of carotid atherosclerotic plaque in patients with acute ischemic stroke, and the increased levels of LP (a) and TG/HDL-C will significantly increase the risk of carotid unstable plaque in patients.

The effects of IGF-1 and IGFBP-2 treatments on the atherosclerosis in the aorta and the coronary arteries of the high cholesterol diet-fed rabbits

Several studies have demonstrated suppression of aortic atherosclerosis by insulin like growth factor-1 (IGF-1) in hypercholesterolemic rabbits. Though a recent study has reported that IGF-1 exerts anti-atherogenic effects in coronary arteries, the mechanisms of IGF-1 in coronary arteries need to be further verified. Studies about insulin like growth factor binding protein-2 (IGFBP-2) in atherosclerosis are rarely. The objective of this study is to examine the effects of IGF-1 and IGFBP-2 on the atherosclerosis development in the aorta and coronary arteries of the high-cholesterol diet (HCD)-fed rabbits. New Zealand white rabbits were fed either normal chow (n = 5) or a diet containing 1.0 % cholesterol (n = 18) for 12 weeks. Cholesterol-fed rabbits were given IGF-1 or IGFBP-2 or saline intravenously (each n = 6) for 10 weeks. The results revealed that IGF-1 decreased total cholesterol (TC) and low-density lipoprotein (LDL) levels (p < 0.05), whereas IGFBP-2 did not. IGF-1 significantly attenuated atherosclerotic lesions and reduced accumulated macrophages within the coronary artery plaques, whereas IGFBP-2 deteriorated these changes. Moreover, IGF-1 reduced serum platelet-activating factor acetylhydrolase levels, C reactive protein (CRP), and inhibited the protein expression levels of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). IGFBP-2 elevated serum 8-hydroxy-2′-deoxyguanosine levels, CRP, and promoted the protein expression levels of TNF-α and IL-6. In conclusion, IGF-1 can substantially suppress plaque formation in coronary arteries with a marked inhibition of macrophage accumulation likely via its anti-inflammatory properties, whereas IGFBP-2 plays an opposite effect on atherosclerosis. The present study highlighted a theoretical basis for pharmacological treatment of atherosclerosis.

Lower extremity arterial plaque in patients with type 2 diabetes mellitus: A cross-sectional study of 25-(OH)D3 and other risk factors

ObjectiveThe occurrence of chronic vascular complications in individuals with type 2 diabetes mellitus(T2DM) is influenced by multiple factors. This study aims to analyze the correlation between serum 25-(OH)D3 levels and other risk factors with the formation and severity of arterial plaques in the lower extremities, and explore its role in clinical diagnosis and treatment. MethodsA total of 628 Chinese patients with T2DM were included in this study. Based on the intima-media thickness (IMT) and plaque echogenicity measured by lower extremity vascular ultrasound, the patients were divided into the no plaque group(NP), low-risk plague group(LP), moderate-risk plague group(MP), and severe-risk plague group(SP). Based on 25-(OH)D3 levels, patients were categorized as vitamin D deficient group (VDD，25-(OH)D3 ≤ 20 ng/mL), vitamin D insufficient group (VDI，25-(OH)D3 between>20 ng/mL and < 30 ng/mL), and vitamin D sufficient group (VDS，25-(OH)D3 ≥ 30 ng/mL). The correlation between the severity of lower extremity arterial plaques and serum 25-(OH)D3 levels was analyzed, as well as the risk factors for lower extremity arterial plaque formation in patients with T2DM. ResultsThe levels of 25-(OH)D3 in patients with arterial plaques were significantly lower than those in the NP (p = 0.002). Additionally, with the increasing severity of lower extremity arterial plaques, 25-(OH)D3 levels also decreased significantly (p = 0.01). The proportion of patients with sufficient 25-(OH)D3 levels was highest in NP, while the proportion of deficient and insufficient groups was higher in LP (p<0.001). Multivariate logistic regression analysis showed that low levels of 25-(OH)D3 were an independent risk factor for lower extremity arterial plaques in T2DM patients. Compared to patients with 25-(OH)D3>20 ng/mL, the odds ratios for the formation of moderate-risk plaques were 2.525 (95 % CI: 1.45–4.39) in patients with 25-(OH)D3 ≤ 20 ng/mL, and 2.893 (95 % CI: 1.59–5.26) for the formation of high-risk plaques. ConclusionSerum 25-(OH)D3 levels may be correlated with the occurrence and severity of lower extremity arterial plaques in patients with T2DM. Low serum 25-(OH)D3 concentration is a risk factor for lower extremity vascular lesions.

Nanogels with covalently bound and releasable trehalose for autophagy stimulation in atherosclerosis

Atherosclerosis, cholesterol-driven plaque formation in arteries, is a complex multicellular disease which is a leading cause of vascular diseases. During the progression of atherosclerosis, the autophagic function is impaired, resulting in lipid accumulation-mediated foam cell formation. The stimulation of autophagy is crucial for the recovery of cellular recycling process. One of the potential autophagy inducers is trehalose, a naturally occurring non-reducing disaccharide. However, trehalose has poor bioavailability due to its hydrophilic nature which results in poor penetration through cell membranes. To enhance its bioavailability, we developed trehalose-releasing nanogels (TNG) for the treatment of atherosclerosis. The nanogels were fabricated through copolymerization of 6-O-acryloyl-trehalose with the selected acrylamide-type monomers affording a high trehalose conjugation (~ 58%, w/w). TNG showed a relatively small hydrodynamic diameter (dH, 67 nm) and a uniform spherical shape and were characterized by negative ζ potential (-18 mV). Thanks to the trehalose-rich content, TNG demonstrated excellent colloidal stability in biological media containing serum and were non-hemolytic to red blood cells. In vitro study confirmed that TNG could stimulate autophagy in foam cells and enhance lipid efflux and in vivo study in ApoE−/− mice indicated a significant reduction in atherosclerotic plaques, while increasing autophagic markers. In conclusion, TNG hold great promise as a trehalose delivery system to restore impaired autophagy-mediated lipid efflux in atherosclerosis and subsequently reduce atherosclerotic plaques.Graphical abstract

Colchicine delivered by a novel nanoparticle platform alleviates atherosclerosis by targeted inhibition of NF-κB/NLRP3 pathways in inflammatory endothelial cells

Atherosclerosis, a chronic inflammatory disease characterized by arterial plaque formation, is one of the most prominent causes of cardiovascular diseases. However, the current treatments often do not adequately compromise the chronic inflammation-mediated plaque accumulation and the disease progression. Therefore, a new and effective strategy that blocks atherosclerosis-associated inflammation is urgently needed to further reduce the risk. Colchicine, a potent anti-inflammatory medication, has shown great potential in the treatment of atherosclerosis, but its adverse effects have hampered its clinical application. Herein, we developed a novel delivery nanosystem encapsulated with colchicine (VHPK-PLGA@COL), which exhibited improved biosafety and sustained drug release along with the gradual degradation of PLGA and PEG as confirmed both in vitro and in vivo. Surface modification of the nanoparticles with the VHPK peptide ensured its capability to specifically target inflammatory endothelial cells and alleviate atherosclerotic plaque accumulation. In the ApoE − / − atherosclerotic mouse model, both colchicine and VHPK-PLGA@COL treatment significantly decreased the plaque area and enhanced plaque stability by blocking the NF-κB/NLRP3 pathways, while VHPK-PLGA@COL exhibited enhanced therapeutic effects due to its unique ability to target inflammatory endothelial cells without obvious long-term safety concerns. In summary, VHPK-PLGA@COL has the potential to overcome the key translational barriers of colchicine and open new avenues to repurpose this drug for anti-atherosclerotic therapy.

The role of EZH2 and H3K27me3 epigenetic signature in modulating T-cell polarization in atherosclerosis

Abstract Background Atherosclerosis is a chronic inflammatory disease, characterized by the formation of luminal plaques in arteries. Atheroprogression is accompanied by strong immune activation, during which T cells play a pivotal role. Genes driving T-cell activation are regulated by the polycomb repressive complex 2(PRC2), whose major component is the Enhancer of Zeste Homolog 2(EZH2), responsible for the methylation of Histone 3 Lysine 27(H3K27me3) epigenetic mark. Purpose We hypothesize that EZH2 mediates T-cell activation and modulates T-helper (Th) cell polarization, thus atherogenesis. Methods To study the effect of EZH2 in atherosclerosis, we backcrossed mice with Ezh2 flanked by loxP-sites sensitive to Cre-mediated inactivation in T cells to apolipoprotein E (Apoe-/-)mice and fed a high cholesterol diet to have hyperlipidemic Ezh2fl/flCd4CreApoe-/-mice and controls. Atherosclerotic plaque progression and immune cell phenotyping were assessed by histology, flow cytometry (FC), gene and protein expression analysis and single cell (sc)RNA-sequencing (Seq) as well as by functional in vitro assays. Results T cell-specific EZH2 deficiency resulted in a significant reduction in H3K27me3 in T-cells. Female Ezh2fl/flCd4Cre mice developed 34% less atherosclerotic plaques in the aortic root compared to wildtype (WT) littermates. FC analysis of spleen and lymph nodes of Ezh2fl/flCd4Cre mice revealed a shift from naive to effector CD4+ T cells, and the majority were Th2 cells (p&amp;lt;0.0001). Accordingly, plasma levels of lL4 and aortic IL4 transcripts were increased in Ezh2fl/flCd4Cre mice(p=0.05 and p=0.0079, respectively). Functional analysis revealed that splenic CD4+ T cells from Ezh2fl/flCd4Cre mice showed decreased migratory capacity towards the chemokines CXCL10, CCL17, CCL22, CCL19. To unravel mechanisms driving the type 2 immune response, bulk RNA-Seq of CD4+ T cells and scRNA-Seq of splenic CD3+ T cells from Ezh2fl/flCd4Cre and WT mice revealed that CD4+ T cell EZH2 deficiency caused upregulation of promyelocytic leukemia zinc finger (Plzf), a transcription factor of NKT cells of the NKT2 subtype, characterized by high IL4 production. Via FC we confirmed the increase in splenic NKT cells in Ezh2fl/flCd4Cre mice. Likewise, Plzf aortic mRNA levels were also significantly increased(p=0.002). To exploit the translational potential of T cell-specific EZH2 targeting, we treated Jurkat T cells with EZH2 inhibitors, the FDA-approved drug Tazemetostat and GSK126. Corroborating our in vivo data, EZH2 inhibitor-treated cells showed decreased H3K27me3 and 70% reduced migration towards the chemokine CXCL12. Conclusions Our study demonstrates that CD4+ T-cell specific EZH2 deficiency impairs T cell-migration and skews the immune response towards a type 2 response, resulting in protection against atherosclerosis. We aim at investigating whether the epigenetic mark H3K27me3 in T cells may be a promising therapeutic target for future cardiovascular immunotherapies.

The role of coronary artery disease in lung transplantation

Abstract Background Coronary artery disease (CAD) is a common comorbidity in patients suffering from terminal lung disease and a recurrent problem in pre-transplant evaluation. While historically, CAD has been treated as a contraindication for lung transplantation, data from multiple small studies suggests that CAD in well selected patients might not be associated with a worse outcome. In its 2020 consensus document for the selection of lung transplant candidates, the International Society for Heart and Lung Transplantation states that CAD should not be considered an absolute contraindication but a potential marker for an unfavourable phenotype. However, data backing up this decision is limited and in parts inconclusive. Purpose This study aims to provide solid data on the relevance of pre-existing CAD in the setting of lung transplantation. Furthermore, defining cardiovascular risk factors and their effect in this unique population is required to support evidence-based risk stratification. Methods 1003 patients receiving lung transplantation between January 2000 and August 2021 were included in this study. The median follow up was 3.24 years [1.30, 4.82]. Plaque formation in the coronary arteries was identified by coronary angiography in 230 patients. A relevant CAD defined by stenosis &amp;gt;50% or previous percutaneous coronary intervention/coronary artery bypass graft was present in 104 patients. Results Baseline characteristics of the CAD group differed significantly from the non-CAD group in terms of Age at Transplantation [y] (60.28 [56.71, 63.24] vs. 53.96 [44.45, 59.85], p&amp;lt;0.001), Sex [male] (74.0% vs. 52.3%, p&amp;lt;0.001) and BMI [kg/m2] (24.13 [21.25, 27.41] vs 22.22 [19.37, 25.62], p&amp;lt;0.001) as well as the abundance of cardiovascular risk factors including hypertension (67.3% vs 32.1%, p&amp;lt;0.001) and smoking (67.3% vs 40.9%, p&amp;lt;0.001). Therefore 1:1 propensity score matching was performed, resulting in 98 matched pairs. Matching variables, including demographics, cardiovascular risk factors, results from the right heart catheter and lung testing, were well balanced without significant differences between the groups. The primary endpoint overall survival was similar in the matched groups: HR=0.94, 95% CI 0.64-1.39, p=0.77. Graph 1 pictures the corresponding Kaplan – Meier curves. In addition, no significant differences in intrahospital mortality between patients with and without CAD (8.2% vs 5.1%, p=0.566) could be detected. Furthermore, there was no significant difference in the occurrence of myocardial infarction (6.1% vs 4.1%, p=0.745) or stroke (2.0% vs 5.1%, p=0.441) post transplantation. Conclusion The finding of this study provides further evidence indicating that CAD itself may not be associated with worse short – or long-term survival following lung transplantation. Careful evaluation and patient selection can allow patients suffering from CAD to successfully undergo lung transplantation without inferior survival.Survival Analysis

In silico based analysis to explore genetic linkage between atherosclerosis and its potential risk factors

Atherosclerosis (ATH) is a chronic cardiovascular disease characterized by plaque formation in arteries, and it is a major cause of illness and death. Although therapeutic advances have significantly improved the prognosis of ATH, missing therapeutic targets pose a significant residual threat. This research used a systems biology approach to identify the molecular biomarkers involved in the onset and progression of ATH, analysing microarray gene expression datasets from ATH and tissues impacted by risk factors such as high cholesterol, adipose tissue, smoking, obesity, sedentary lifestyle, stress, alcohol consumption, hypertension, hyperlipidaemia, high fat, diabetes to find the differentially expressed genes (DEGs). Bioinformatic analyses of Protein-Protein Interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) were conducted on differentially expressed genes, revealing metabolic and signaling pathways (the chemokine signaling pathway, cytokine-cytokine receptor interaction, the cytosolic DNA-sensing pathway, the peroxisome proliferator-activated receptors signaling pathway, and the nuclear factor-kappa B signaling pathway), ten hubs proteins (CCL5, CCR1, TLR1, CCR2, FCGR2A, IL1B, CD163, AIF1, CXCL-1 and TNF), five transcription factors (YY1, FOXL1, FOXC1, SRF, and GATA2), and five miRNAs (mir-27a-3p, mir-124–3p, mir-16–5p, mir-129-2-3p, mir-1-3p). These findings identify potential biomarkers that may increase knowledge of the mechanisms underlying ATH and their connection to risk factors, aiding in the development of new therapies.

Abstract 15340: Octacosanol Exerts Anti-Inflammatory Effects on Primary Human Aorta Endothelial Cells (HAEC) Induced With Lipopolysaccharides (LPS)

Atherosclerosis is a complex process characterized by chronic systemic inflammation, endothelial dysfunction, retention of lipoproteins, plaque formation in large and medium-sized arteries, and has become one of the most common causes of death in the elderly nowadays. Octacosanol, a very long chain (C28) aliphatic alcohol, is believed to be the main active ingredient in the Policosanol, which is extracted from plants, such as sugar cane and wheat germ. Policosanol has been used as a potential diet supplementary to improve fatigue, obesity and lipid metabolism. Previous animal studies have shown that both Policosanol and Octacosanol can significantly ameliorate formation of atherosclerotic lesion. To further explore the possible mechanism of Octacosanol on the formation of atherosclerosis, we examined the anti-inflammatory effects of Octacosanol on HAEC treated with LPS at 100ng/ml FBS-free cell culture medium. LPS treatment significantly enhanced human monocyte (THP1) adherence to HAEC cells in time-dependent and dose-dependent style, but Octacosanol at 1.25 or 2.5 μM markedly blocked the adhesion of THP1 to HAEC. ELISA showed that LPS can significantly increase the expression of inflammatory cytokines and adhesion molecules by HAEC at 100ng/ml within 4 hours. LPS stimulated more than 3-fold of release of IL-6, IL-8, MCP-1 at 4 hours. By flow cytometry and ELISA, LPS dramatically increase the expression of PE-Selectin and VCAM-1. When HAEC were pretreated with Octacosanol (1.25μM or 2.5μM), it significantly reduced the release of inflammatory cytokines, MCP-1(p&lt;0.01), IL-6 (p&lt;0.001) and IL-8(P&lt;0.001), and inhibited the expression of PE-selectin(p&lt;0.001) and VCAM-1(P&lt;0.001). Confocal imaging analysis of HAEC cells showed Octacosanol considerably reduced the expression of PE-Selectin and VCAM-1 and VE-Cadherin, leading to the maintenance of cell membrane integrity and underlying ECM and the prevention of THP1 cell adherence. By RNAseq analysis, Octacosanol inhibits LPS-induced inflammatory pathways related to NFKB 2 and RAS-related signaling. In summary, the beneficial effects of octacosanol on atherosclerosis appears to be related, at least partially to, is potent anti-inflammatory effects in cytokine-induced cell adherence.

Unraveling the Molecular Mechanisms of Activated Protein C (APC) in Mitigating Reperfusion Injury and Cardiac Ischemia: a Promising Avenue for Novel Therapeutic Interventions.

Ischemic heart disease, which results from plaque formation in the coronary arteries, hinders the flow of oxygenated blood to the heart, leading to ischemia. Reperfusion injury remains a significant challenge for researchers, and the mechanisms underlying myocardial ischemia-reperfusion injury (MIRI) are not entirely understood. The review directs future research into potential targets in clinical treatment based on our present understanding of the pathophysiological mechanisms of MIRI. The study provides insights into the mechanisms underlying MIRI and offers direction for future research in this area. The use of targeted therapies may hold promise in improving cardiac function in the elderly and minimizing the adverse effects of revascularization therapies. The purpose of this review is to analyze the role of activated protein C (APC) in the pathogenesis of ischemic heart disease, heart failure, and myocardial ischemia-reperfusion injury, and discuss the potential of APC-based therapeutics.