Progression Of Atherosclerotic Disease Research Articles

18F-Sodium fluoride positron emission tomography, aortic disease activity and ischaemic stroke risk

Abstract Background Arterial 18F-sodium fluoride (18F-NaF) activity on positron emission tomography (PET) is a marker of active microcalcification and atherosclerosis. Coronary 18F-NaF activity (CMA) predicts coronary artery disease progression and subsequent myocardial infarction. Objective To investigate whether aortic 18F-NaF activity (AMA) predicts thoracic aortic atherosclerotic disease progression and subsequent ischaemic stroke or myocardial infarction in patients with established cardiovascular disease. Methods In a post-hoc observational cohort study, we evaluated AMA and CMA in patients with stable coronary artery disease (n=239) or aortic stenosis (n=158) who had underwent thoracic 18F-NaF PET and computed tomography (CT). We assessed the associations between AMA or CMA and progression of calcified atherosclerotic plaque in both thoracic aortic and coronary territories on follow up CT, as well as subsequent ischaemic stroke or myocardial infarction. Results In 141 and 231 patients with repeat aortic and coronary CT imaging respectively at 12.7±2.7 months, AMA correlated with log progression of thoracic aortic calcium scores (r=0.21, p=0.011), volume (r=0.29, p<0.01) and mass (r=0.29, P<0.01) as well as log coronary calcium score progression (r=0.21, p=0.03). CMA correlated with log coronary (r=0.42, p<0.01), but not log aortic (p>0.80) calcium score progression. In 397 patients, 16 had an ischaemic stroke and 25 had a myocardial infarction after 4.7±1.6 years. After adjusting for clinical risk factors, CMA and calcium scoring, AMA was associated with stroke (hazard ratio, 1.71 [95% confidence interval 1.00–2.90], p=0.048]). AMA was superior to clinical risk and calcium scores in identifying patients with stroke (c-statistic 0.76 versus 0.58 versus 0.63 respectively, p<0.05). Survival analysis demonstrated that AMA was associated with ischaemic stroke (p<0.001) but not myocardial infarction (p=0.45), whereas CMA was associated with myocardial infarction (p<0.001) but not stroke (p=0.39). Conclusions In patients with established cardiovascular disease, AMA is associated with progression of aortic atherosclerosis and future ischaemic stroke. Arterial 18F-NaF identifies localised areas of atherosclerotic disease activity that relate to regional atherothrombotic events. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): British Heart Foundation AMA, disease progression and outcomesVariables associated with stroke

Piezo1 mediates endothelial atherogenic inflammatory responses via regulation of YAP/TAZ activation

The vascular endothelium plays a key role in the pathobiology of atherosclerotic cardiovascular disease. Endothelial cell Piezo1 mediates blood vessel formation, angiogenesis and regulation of blood pressure. However, changes of Piezo1 expression in atherosclerosis (AS) and the role of Piezo1 in the progression of atherosclerotic diseases remains obscure. Thus, the current study is to elucidate the role and mechanism of which Piezo1 mediates vascular inflammation in atherosclerotic mice and vascular endothelial inflammation induced by oxidized low density lipoprotein (ox-LDL) in vitro. Here, we have shown that the expression of Piezo1 was significantly increased in the stenotic carotid artery of ApoE-/- mice fed by high-fat diet (HFD). Pharmacological inhibition of Piezo1 (GsMTx-4) attenuated plaque formation, decreased the level of inflammation related factors (JNK, TNF-α, NF-κB, VCAM-1) of carotid plaque in atherosclerotic mice. Meanwhile, ox-LDL also upregulates Piezo1 and inflammation proteins (NF-κB, JNK and TNF-α) in endothelium cells (ECs). YAP/TAZ is activated accompanied by the enhanced Piezo1 activity in ECs induced by ox-LDL. Interference by siRNA of Piezo1 abolished the expression of YAP/TAZ and inflammation proteins (JNK, NF-κB and TNF-α). In addition, Ca2+ influx in ECs induced by ox-LDL was increased than control group, Piezo1 siRNA can reduce the calcium content. Piezo1 agonist Yoda1 increased Ca2+ influx and promote YAP nucleus translocation in ECs, genetic deletion of Piezo1 reversed it. Our results indicate that Piezo1 could mediate endothelial atherogenic inflammatory responses via regulation of YAP/TAZ activation and nuclear localization. Piezo1 may be a potential therapeutic target for atherosclerotic diseases in the future.

Inhibitors of the sodium-glucose transporter type 2 and new possibilities for managing vascular age in patients with type 2 diabetes mellitus

The article discusses the pathophysiological mechanisms of the development of vascular aging as a combination of the influence on the body of genetic, environmental, regulatory, metabolic and other factors causing biochemical, enzymatic and cellular changes in the arterial vascular bed. The concept of “early vascular aging” and “healthy vascular aging” is defined depending on the ratio of the biological and chronological age of the vessels. The role of diabetes mellitus in increasing vascular stiffness, early vascular aging, as well as the progression of atherosclerotic cardiovascular diseases and their complications is considered in detail. Approaches to multifactorial management of vascular age in patients with type 2 diabetes (lifestyle modification with strategy of aggressive treatment of modifiers of atherosclerosis, rejection of bad habits, adherence to dietary recommendations and the use of modern organo- and vasoprotective antidiabetic drugs) are revealed. The mechanism of realization of vasoprotective effects of inhibitors of sodium-glucose transporter-2 (iNGLT-2) is described in detail. The results of completed large random ized trials EMPA-REG Outcome and EMPA-REG BP of the most studied representative of the IGLT-2 group, empagliflozin, are presented. It has been shown that due to their glucose and natriuretic effects, the ability to reduce body weight and blood pressure, improve myocardial metabolism and bioenergetics, decrease the activity of the sympathetic nervous system, as well as positive effects on vascular stiffness, NGLT-2 inhibitors are the drugs of choice in patients with type 2 diabetes mellitus (T2DM) and cardiovascular diseases. This makes it possible to widely use this group of drugs for managing the vascular age of patients and represents a new opportunity in the prevention of vascular aging in T2DM.

Abstract MP25: Differential Expression Of Pparα In Peripheral Arterial Segments Of Patients With Advanced Atherosclerosis

Peripheral atherosclerosis manifests in both the extracranial carotid and lower extremity arteries and can lead to significant morbidity and mortality. However, atherosclerotic disease progression is often not homogenous and is accelerated by diabetes. We previously observed altered phospholipodomic profiles between minimally (MIN) and maximally (MAX) diseased peripheral arterial segments. Since Peroxisome Proliferator-Activated Receptor alpha ( pparα ) is a key regulator of lipid metabolism, we hypothesized that it may have variable content and signaling in MIN and MAX diseased arterial segments. To test our hypothesis, 12 patients who underwent carotid endarterectomy (CEA), and 19 patients who underwent major lower extremity amputation were recruited. MIN and MAX disease segments were obtained in real time from the operating room from CEA plaque and arterial segments from amputated lower extremities. mRNA was isolated from all specimens and relative content of pparα , Acyl-CoA Oxidase 1 ( acox1 ) , and Carnitine Palmitoyltransferase 1A ( cpt1a ) were evaluated. We observed significantly higher pparα expression in CEA segments in patients with diabetes (p < 0.01), as well as higher acox1 (p < 0.001) and cpt1a (p < 0.05) expression (A-C). Hemoglobin A1C had a significant correlation with ppara gene expression. There was no significant difference in gene expression between MAX and MIN diseased CEA plaque segments. Interestingly, we observed that in lower extremity arterial segments there was no difference in ppara , acox1 , and cpt1a in patients with and without diabetes, but downstream genes were significantly increased in MAX diseased arterial segments (D-F). This study demonstrates the variable expression pattern of pparα and its downstream genes in human peripheral arteries. Our findings suggest variable gene expression in different peripheral arterial beds, which may have an impact on mechanisms of disease progression and pharmacologic targeting.

DNA methylome profiling reveals epigenetic regulation of lipoprotein-associated phospholipase A2 in human vulnerable atherosclerotic plaque

BackgroundAtherosclerotic plaque vulnerability is a key feature of atheroprogression and precipitating acute cardiovascular events. Although the pivotal role of epigenetic regulation in atherosclerotic plaque destabilization is being recognized, the DNA methylation profile and its potential role in driving the progression and destabilization of atherosclerotic cardiovascular disease remains largely unknown. We conducted a genome-wide analysis to identify differentially methylated genes in vulnerable and non-vulnerable atherosclerotic lesions to understand more about pathogenesis.ResultsWe compared genome-wide DNA methylation profiling between carotid artery plaques of patients with clinically symptomatic (recent stroke or transient ischemic attack) and asymptomatic disease (no recent stroke) using Infinium Methylation BeadChip arrays, which revealed 90,368 differentially methylated sites (FDR < 0.05, |delta beta|> 0.03) corresponding to 14,657 annotated genes. Among these genomic sites, 30% were located at the promoter regions and 14% in the CpG islands, according to genomic loci and genomic proximity to the CpG islands, respectively. Moreover, 67% displayed hypomethylation in symptomatic plaques, and the differentially hypomethylated genes were found to be involved in various aspects of inflammation. Subsequently, we focus on CpG islands and revealed 14,596 differentially methylated sites (|delta beta|> 0.1) located at the promoter regions of 7048 genes. Integrated analysis of methylation and gene expression profiles identified that 107 genes were hypomethylated in symptomatic plaques and showed elevated expression levels in both advanced plaques and ruptured plaques. The imprinted gene PLA2G7, which encodes lipoprotein-associated phospholipase A2 (Lp-PLA2), was one of the top hypomethylated genes with an increased expression upon inflammation. Further, the hypomethylated CpG site at the promoter region of PLA2G7 was identified as cg11874627, demethylation of which led to increased binding of Sp3 and expression of Lp-PLA2 through bisulfate sequencing, chromatin immunoprecipitation assay and enzyme-linked immunosorbent assay. These effects were further enhanced by deacetylase.ConclusionExtensive DNA methylation modifications serve as a new and critical layer of biological regulation that contributes to atheroprogression and destabilization via inflammatory processes. Revelation of this hitherto unknown epigenetic regulatory mechanism could rejuvenate the prospects of Lp-PLA2 as a therapeutic target to stabilize the atherosclerotic plaque and reduce clinical sequelae.

Association of Statin Treatment With Progression of Coronary Atherosclerotic Plaque Composition

The density of atherosclerotic plaque forms the basis for categorizing calcified and noncalcified morphology of plaques. To assess whether alterations in plaque across a range of density measurements provide a more detailed understanding of atherosclerotic disease progression. This cohort study enrolled 857 patients who underwent serial coronary computed tomography angiography 2 or more years apart and had quantitative measurements of coronary plaques throughout the entire coronary artery tree. The study was conducted from 2013 to 2016 at 13 sites in 7 countries. The main outcome was progression of plaque composition of individual coronary plaques. Six plaque composition types were defined on a voxel-level basis according to the plaque attenuation (expressed in Hounsfield units [HU]): low attenuation (-30 to 75 HU), fibro-fatty (76-130 HU), fibrous (131-350 HU), low-density calcium (351-700 HU), high-density calcium (701-1000 HU), and 1K (>1000 HU). The progression rates of these 6 compositional plaque types were evaluated according to the interaction between statin use and baseline plaque volume, adjusted for risk factors and time interval between scans. Plaque progression was also examined based on baseline calcium density. Analysis was performed among lesions matched at baseline and follow-up. Data analyses were conducted from August 2019 through March 2020. In total, 2458 coronary lesions in 857 patients (mean [SD] age, 62.1 [8.7] years; 540 [63.0%] men; 548 [63.9%] received statin therapy) were included. Untreated coronary lesions increased in volume over time for all 6 compositional types. Statin therapy was associated with volume decreases in low-attenuation plaque (β, -0.02; 95% CI, -0.03 to -0.01; P = .001) and fibro-fatty plaque (β, -0.03; 95% CI, -0.04 to -0.02; P < .001) and greater progression of high-density calcium plaque (β, 0.02; 95% CI, 0.01-0.03; P < .001) and 1K plaque (β, 0.02; 95% CI, 0.01-0.03; P < .001). When analyses were restricted to lesions without low-attenuation plaque or fibro-fatty plaque at baseline, statin therapy was not associated with a change in overall calcified plaque volume (β, -0.03; 95% CI, -0.08 to 0.02; P = .24) but was associated with a transformation toward more dense calcium. Interaction analysis between baseline plaque volume and calcium density showed that more dense coronary calcium was associated with less plaque progression. The results suggest an association of statin use with greater rates of transformation of coronary atherosclerosis toward high-density calcium. A pattern of slower overall plaque progression was observed with increasing density. All findings support the concept of reduced atherosclerotic risk with increased densification of calcium.

Histone deacetylase 9 promotes endothelial-mesenchymal transition and an unfavorable atherosclerotic plaque phenotype.

Endothelial-mesenchymal transition (EndMT) is associated with various cardiovascular diseases and in particular with atherosclerosis and plaque instability. However, the molecular pathways that govern EndMT are poorly defined. Specifically, the role of epigenetic factors and histone deacetylases (HDACs) in controlling EndMT and the atherosclerotic plaque phenotype remains unclear. Here, we identified histone deacetylation, specifically that mediated by HDAC9 (a class IIa HDAC), as playing an important role in both EndMT and atherosclerosis. Using in vitro models, we found class IIa HDAC inhibition sustained the expression of endothelial proteins and mitigated the increase in mesenchymal proteins, effectively blocking EndMT. Similarly, ex vivo genetic knockout of Hdac9 in endothelial cells prevented EndMT and preserved a more endothelial-like phenotype. In vivo, atherosclerosis-prone mice with endothelial-specific Hdac9 knockout showed reduced EndMT and significantly reduced plaque area. Furthermore, these mice displayed a more favorable plaque phenotype, with reduced plaque lipid content and increased fibrous cap thickness. Together, these findings indicate that HDAC9 contributes to vascular pathology by promoting EndMT. Our study provides evidence for a pathological link among EndMT, HDAC9, and atherosclerosis and suggests that targeting of HDAC9 may be beneficial for plaque stabilization or slowing the progression of atherosclerotic disease.

PS5, A peptidomimetic of suppressor of cytokine signaling 1, as a novel antioxidant and anti-inflammatory agent to prevent atherosclerosis

Background and Aims: Dysregulated expression and/or activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway have been linked to several cardiovascular diseases including atherosclerosis. Suppressors of cytokine signaling (SOCS) negatively regulate the JAK/STAT pathway and have been considered an attractive target for therapeutic intervention. We hypothesize that SOCS1 protein could influence atheroma plaque development and composition by inhibiting JAK/STAT activity. Herein, we investigated the potentialities of a peptidomimetic of SOCS1, named PS5, to limit the progression of atherosclerotic disease.

Sodium fluoride in cardiovascular disorders: A systematic review

Background18-Fluorine sodium fluoride is a well-known radiotracer used for bone metastasis diagnosis. Its uptake correlation with cardiovascular (CV) risk was primarily suggested in oncological patients. Moreover, as a specific marker of microcalcification, it seems to correlate with CV disease progression and plaque instability. Methods and ResultsOur purpose was to systematically review clinical studies that characterized the use of this marker in CV conditions. In atherosclerosis, most studies report a positive correlation with the burden of CV risk factors and vascular calcification. A higher uptake was found in culprit plaques/rupture sites in coronary and carotid arteries and it was also linked to high-risk features in histology and intravascular imaging analysis of the plaques. In aortic stenosis, this tracer displayed an increasing uptake with disease severity. ConclusionsSodium fluoride positron emission tomography is a promising non-invasive technique to identify high-risk plaques, which sets ground to a potential use of this tracer in evaluating atherosclerotic disease progression and degenerative changes in aortic valve stenosis. Nevertheless, there is a need for further prospective evidence that demonstrates this technique’s value in predicting clinical events, adjusting treatment strategies, and improving patient outcomes.

The Importance of Lipoprotein Lipase Regulation in Atherosclerosis.

Lipoprotein lipase (LPL) plays a major role in the lipid homeostasis mainly by mediating the intravascular lipolysis of triglyceride rich lipoproteins. Impaired LPL activity leads to the accumulation of chylomicrons and very low-density lipoproteins (VLDL) in plasma, resulting in hypertriglyceridemia. While low-density lipoprotein cholesterol (LDL-C) is recognized as a primary risk factor for atherosclerosis, hypertriglyceridemia has been shown to be an independent risk factor for cardiovascular disease (CVD) and a residual risk factor in atherosclerosis development. In this review, we focus on the lipolysis machinery and discuss the potential role of triglycerides, remnant particles, and lipolysis mediators in the onset and progression of atherosclerotic cardiovascular disease (ASCVD). This review details a number of important factors involved in the maturation and transportation of LPL to the capillaries, where the triglycerides are hydrolyzed, generating remnant lipoproteins. Moreover, LPL and other factors involved in intravascular lipolysis are also reported to impact the clearance of remnant lipoproteins from plasma and promote lipoprotein retention in capillaries. Apolipoproteins (Apo) and angiopoietin-like proteins (ANGPTLs) play a crucial role in regulating LPL activity and recent insights into LPL regulation may elucidate new pharmacological means to address the challenge of hypertriglyceridemia in atherosclerosis development.

Metabolic Syndrome in an Aging Society - Role of Oxidant-Antioxidant Imbalance and Inflammation Markers in Disentangling Atherosclerosis.

IntroductionThe prevalence of metabolic syndrome among the elderly population is growing. The elements of metabolic syndrome in an aging society are currently being researched. Atherosclerosis is a slow process in which the first symptoms may be observed after many years. The mechanisms underlying the progression of atherosclerosis are oxidative stress and inflammation. Inflammation and oxidative stress are associated with the increased incidence of metabolic syndrome. Taking the above into consideration, metabolic syndrome is thought to be a clinical equivalent of atherosclerosis.AimThe aim of this paper is to review the impact of the interplay of oxidant-antioxidant and inflammation markers in metabolic syndrome in general as well as its components in the pathophysiology which underlies development of atherosclerosis in elderly individuals.MethodsA systematic scan of online resources designed for elderly (≥65 years) published from 2005 to the end of 2020 were reviewed. This was supplemented with grey literature and then all resources were narratively analyzed. The analysis included the following terms: “atherosclerosis or metabolic syndrome” and “oxidative stress or inflammation” and “elderly” to find reports of atherosclerotic disease from asymptomatic to life-threatening among the elderly population with metabolic syndrome .ResultsThe work summarizes articles that were applicable to this study, including systematic reviews, qualitative studies and opinion pieces. Current knowledge focuses on monitoring the inflammation and oxidant-antioxidant imbalance in disentangling atherosclerosis in patients diagnosed with metabolic syndrome. The population-based studies described inflammation, increased oxidative stress and weak antioxidant defense systems as the mechanisms underlying atherosclerosis development. Moreover, there are discussions that these targets could potentially be a point of intervention to reduce the development of atherosclerosis in the elderly, especially those with altered glucose and lipid metabolism. Specific markers may be used as an approach for the prevention and lifestyle modification of atherosclerotic disease in such population.ConclusionMetabolic syndrome and its components are important contributors in the progression of atherosclerotic disease in the elderly population but constant efforts should be made to broaden our knowledge of elderly groups who are the most susceptible for the development of atherosclerosis complications.

MO777HISTOLOGICAL AND IMMUNOPHENOTYPICAL VESSEL CHANGES IN CHRONIC KIDNEY DISEASE

Abstract Background and Aims Recent studies suggest thw possibility of activating immune mechanism in the onset and progression of atherosclerotic disease. The aim of the present study was to evaluate the role of immune mechanisms in the vessel of patients with Chronic Kidney Disease (CKD) and the association with clinical and laboratory indicators of atherosclerosis. Method Patients with CKD stage V, in whom a radiocephalic arteriovenous fistula (RC-AVF) was created, were included in the study. Patients were divided in two groups, group A was consisted of patients who were on stage V, pre-dialysis, and being prepared to start on hemodialysis (HD), and those who had already been on HD for at least 3 years, and were having a new RC-AVF formation, due to previous failure, group B. Inclusion criteria were: age 25-80 years, gradual deterioration of renal function up to stage V or under dialysis for more than 3 years. All patients should have been under close follow up for at least 3 years prior to enrolment, with adequate control of diabetes, hypertension, dyslipidemia, secondary hyperparathyroidism and anemia. The control group included healthy volunteers of similar age, sex and ethnicity, who agreed to have a radial artery biopsy during an orthopedic procedure because of a fracture. All patients were informed and signed the consent form. Patients’ history, primary disease and comorbid conditions, medication and clinical examination were recorded based on hospital outpatients’ files. Prior to the scheduled day of RC-AVF creation, all patients underwent laboratory examination, included hematological and serum biochemical analyses. The histological characteristics, inflammatory activation and immunophenotypic alterations of the radial artery wall were estimated and their association with the severity of calcification and atherosclerosis were studied. Presence and severity of atherosclerotic lesions in CKD patients was assessed based on the measurement of common carotid intima – media thickness (IMT) of the common and internal carotid on both sides. Results Significant correlation was fount between inflammatory infiltration [expression of CD3(+), CD20(+), CD68(+) cells], cellular activation [CD34(+), a-SMA(+) cells] and calcification regulators (MPG, RANKL, OPG) with the degree of vascular calcification, as this was estimated and classified based on Verhoff’s Elastic and von Kossa staining Forty five patients with chronic kidney disease (CKD), stage V, either pre-dialysis (p=25) (group A) or on hemodialysis (HD) (p=20) (group B) were included in the study. There were no significant differences in age, sex, race, and also in the frequency of hypertension, diabetes mellitus or smoking habits between patients and controls. Presence and severity of atherosclerotic lesions in CKD patients was assessed based on the measurement of common carotid intima – media thickness (IMT) of the common and internal carotid on both sides. Conclusion Atherosclerotic disease in Chronic KidnEy Disease and its clinical effects appear to be directly related to inflammatory ifiltration of blood vessels by T, B lymphocytes, macrophages and myofibrolasts, as well as factors that affect calcification.

Blood Flow Quantification in Peripheral Arterial Disease: Emerging Diagnostic Techniques in Vascular Surgery

The assessment of local blood flow patterns in patients with peripheral arterial disease is clinically relevant, since these patterns are related to atherosclerotic disease progression and loss of patency in stents placed in peripheral arteries, through mechanisms such as recirculating flow and low wall shear stress (WSS). However, imaging of vascular flow in these patients is technically challenging due to the often complex flow patterns that occur near atherosclerotic lesions. While several flow quantification techniques have been developed that could improve the outcomes of vascular interventions, accurate 2D or 3D blood flow quantification is not yet used in clinical practice. This article provides an overview of several important topics that concern the quantification of blood flow in patients with peripheral arterial disease. The hemodynamic mechanisms involved in the development of atherosclerosis and the current clinical practice in the diagnosis of this disease are discussed, showing the unmet need for improved and validated flow quantification techniques in daily clinical practice. This discussion is followed by a showcase of state-of-the-art blood flow quantification techniques and how these could be used before, during and after treatment of stenotic lesions to improve clinical outcomes. These techniques include novel ultrasound-based methods, Phase-Contrast Magnetic Resonance Imaging (PC-MRI) and Computational Fluid Dynamics (CFD). The last section discusses future perspectives, with advanced (hybrid) imaging techniques and artificial intelligence, including the implementation of these techniques in clinical practice.

PCSK9 Functions in Atherosclerosis Are Not Limited to Plasmatic LDL-Cholesterol Regulation.

The relevance of PCSK9 in atherosclerosis progression is demonstrated by the benefits observed in patients that have followed PCSK9-targeted therapies. The impact of these therapies is attributed to the plasma lipid-lowering effect induced when LDLR hepatic expression levels are recovered after the suppression of soluble PCSK9. Different studies show that PCSK9 is involved in other mechanisms that take place at different stages during atherosclerosis development. Indeed, PCSK9 regulates the expression of key receptors expressed in macrophages that contribute to lipid-loading, foam cell formation and atherosclerotic plaque formation. PCSK9 is also a regulator of vascular inflammation and its expression correlates with pro-inflammatory cytokines release, inflammatory cell recruitment and plaque destabilization. Furthermore, anti-PCSK9 approaches have demonstrated that by inhibiting PCSK9 activity, the progression of atherosclerotic disease is diminished. PCSK9 also modulates thrombosis by modifying platelets steady-state, leukocyte recruitment and clot formation. In this review we evaluate recent findings on PCSK9 functions in cardiovascular diseases beyond LDL-cholesterol plasma levels regulation.

Oxidative Stress Triggers Defective Autophagy in Endothelial Cells: Role in Atherothrombosis Development

Atherothrombosis, a multifactorial and multistep artery disorder, represents one of the main causes of morbidity and mortality worldwide. The development and progression of atherothrombosis is closely associated with age, gender and a complex relationship between unhealthy lifestyle habits and several genetic risk factors. The imbalance between oxidative stress and antioxidant defenses is the main biological event leading to the development of a pro-oxidant phenotype, triggering cellular and molecular mechanisms associated with the atherothrombotic process. The pathogenesis of atherosclerosis and its late thrombotic complications involve multiple cellular events such as inflammation, endothelial dysfunction, proliferation of vascular smooth muscle cells (SMCs), extracellular matrix (ECM) alterations, and platelet activation, contributing to chronic pathological remodeling of the vascular wall, atheromatous plague formation, vascular stenosis, and eventually, thrombus growth and propagation. Emerging studies suggest that clotting activation and endothelial cell (EC) dysfunction play key roles in the pathogenesis of atherothrombosis. Furthermore, a growing body of evidence indicates that defective autophagy is closely linked to the overproduction of reactive oxygen species (ROS) which, in turn, are involved in the development and progression of atherosclerotic disease. This topic represents a large field of study aimed at identifying new potential therapeutic targets. In this review, we focus on the major role played by the autophagic pathway induced by oxidative stress in the modulation of EC dysfunction as a background to understand its potential role in the development of atherothrombosis.

The Protective Role of Sestrin2 in Atherosclerotic and Cardiac Diseases.

Atherosclerotic disease, such as coronary artery disease (CAD), is known to be a chronic inflammatory disease, as well as an age-related disease. Excessive oxidative stress produced by reactive oxygen species (ROS) contributes to the pathogenesis of atherosclerosis. Sestrin2 is an anti-oxidant protein that is induced by various stresses such as hypoxia, DNA damage, and oxidative stress. Sestrin2 is also suggested to be associated with aging. Sestrin2 is expressed and secreted mainly by macrophages, endothelial cells, and cardiomyocytes. Sestrin2 plays an important role in suppressing the production and accumulation of ROS, thus protecting cells from oxidative damage. Since sestrin2 is reported to have anti-oxidant and anti-inflammatory properties, it may play a protective role against the progression of atherosclerosis and may be a potential therapeutic target for the amelioration of atherosclerosis. Regarding the association between blood sestrin2 levels and atherosclerotic disease, the blood sestrin2 levels in patients with CAD or carotid atherosclerosis were reported to be high. High blood sestrin2 levels in patients with such atherosclerotic disease may reflect a compensatory response to increased oxidative stress and may help protect against the progression of atherosclerosis. This review describes the protective role of sestrin2 against the progression of atherosclerotic and cardiac diseases.

Nutrition, atherosclerosis, arterial imaging, cardiovascular risk stratification, and manifestations in COVID-19 framework: a narrative review.

Background: Atherosclerosis is the primary cause of the cardiovascular disease (CVD). Several risk factors lead to atherosclerosis, and altered nutrition is one among those. Nutrition has been ignored quite often in the process of CVD risk assessment. Altered nutrition along with carotid ultrasound imaging-driven atherosclerotic plaque features can help in understanding and banishing the problems associated with the late diagnosis of CVD. Artificial intelligence (AI) is another promisingly adopted technology for CVD risk assessment and management. Therefore, we hypothesize that the risk of atherosclerotic CVD can be accurately monitored using carotid ultrasound imaging, predicted using AI-based algorithms, and reduced with the help of proper nutrition. Layout: The review presents a pathophysiological link between nutrition and atherosclerosis by gaining a deep insight into the processes involved at each stage of plaque development. After targeting the causes and finding out results by low-cost, user-friendly, ultrasound-based arterial imaging, it is important to (i) stratify the risks and (ii) monitor them by measuring plaque burden and computing risk score as part of the preventive framework. Artificial intelligence (AI)-based strategies are used to provide efficient CVD risk assessments. Finally, the review presents the role of AI for CVD risk assessment during COVID-19. Conclusions: By studying the mechanism of low-density lipoprotein formation, saturated and trans fat, and other dietary components that lead to plaque formation, we demonstrate the use of CVD risk assessment due to nutrition and atherosclerosis disease formation during normal and COVID times. Further, nutrition if included, as a part of the associated risk factors can benefit from atherosclerotic disease progression and its management using AI-based CVD risk assessment.

Transplant renal artery stenosis: urgent and judicious to avoid disaster; A narrative review

Transplant renal artery stenosis (TRAS) remains a dreaded complication of renal transplant surgery with potentially devastating sequelae. TRAS occurring early in the posttransplant period is mainly due to technical faults related to the graft implantation process. Late TRAS, in contrast, is more the result of either progressive atherosclerotic disease in the recipient vasculature or immunological, infective, and drug toxicity-related intimal injury. The clinical presentation may range from asymptomatic incidentally detected lesions to frank stenosis causing refractory hypertension or graft dysfunction. Accurate diagnosis with prompt intervention in the clinically significant lesions is the hallmark of successful management in TRAS, thereby averting the possible risk of renal artery thrombosis and graft loss.

DNA Methylome Profiling Reveals Epigenetic Regulation of Lipoprotein-Associated Phospholipase A &lt;sub&gt;2&lt;/sub&gt; in Human Vulnerable Atherosclerotic Plaque

Background: Atherosclerotic plaque vulnerability is a key feature of atheroprogression and precipitating acute cardiovascular events. The DNA methylation profile and its potential role in driving the progression and destabilization of atherosclerotic cardiovascular disease remains largely unknown. We conducted a genome-wide analysis to identify differentially methylated genes in vulnerable and non-vulnerable atherosclerotic lesions to understand more about pathogenesis. Methods: Carotid artery plaques were obtained from patients with clinically symptomatic disease (recent stroke or transient ischemic attack) and asymptomatic disease. Genome-wide DNA methylation was profiled using Infinium Methylation BeadChip arrays. Gene ontology analysis was performed to reveal pathophysiological functions of differentially methylated genes. The hypomethylated genes with increased expression in atherosclerotic plaques were identified by an integrated analysis of DNA methylome with transcriptomic data. The methylation status of the CpG sites at the promoter of the top hypomethylated genes was delineated by bisulfite sequencing. Findings: Genome-wide DNA methylation profiling of symptomatic and asymptomatic plaques identified 90,368 differentially methylated sites ( p <0.05) corresponding to 14,657 annotated genes. Among these genomic sites, 30% located at promoter regions and 14% located in CpG islands, according to genomic loci and genomic proximity to the CpG islands, respectively. Moreover, 67% displayed hypomethylation in symptomatic plaques, and the differentially hypomethylated genes were found to be involved in various aspects of inflammation. The imprinted gene PLA2G7, which encodes the lipoprotein-associated phospholipase A2 (Lp-PLA2), was one of the top hypomethylated genes with an increased expression upon inflammation. Further, the hypomethylated CpG site at the promoter region of PLA2G7 was identified as cg11874627, demethylation of which increased binding of Sp3 and expression of Lp-PLA2. Interpretation: Extensive DNA methylation modifications serve as a new and critical layer of biological regulation that contributes to atheroprogression and destabilization via inflammatory processes. Revelation of this hitherto unknown epigenetic regulatory mechanism could rejuvenate the prospects of Lp-PLA2 as a therapeutic target to stabilize the atherosclerotic plaque and reduce clinical sequelae. Funding: National Natural Science Foundation of China (81770359, 81270276, and 81500365); Beijing Health Technologies Promotion Program (BHTPP202004); Open Project Fund of State Key Laboratory of Molecular Developmental Biology of China (2021-MDB-KF-18 and 2020-MDB-KF-17); and Beijing Natural Science Foundation (7172040). Declaration of Interest: The authors declare no conflict of interest relevant to the present manuscript. Ethical Approval: All procedures involving humans were approved by the Institutional Ethics Review Board of China-Japan Friendship Hospital (No. 2019-85-K56) and conformed to the standards of the Declaration of Helsinki. All participants provided written informed consent before enrollment in this study.

“TAP” technique on bifurcation lesion of Y graft in a patient with NSTEMI complicated with cardiogenic shock

Introduction. Bifurcation lesions on venous Y grafts are rare. We present a case of a woman who developed non-ST segment elevation myocardial infarction complicated by cardiogenic shock due to a bifurcation lesion on the venous Y graft for left anterior descending artery (LAD) and ramus circumflex artery (RCX). Case outline. A 72-year-old woman was admitted to the coronary care unit as an emergency in September 2017 due to acute heart failure followed by the development of cardiogenic shock. Urgent coronarography revealed severe atherosclerotic disease of native coronary arteries with significant bifurcation lesion on venous Y graft for LAD and RCX (medina classification of 1,1,1) with thrombolysis in myocardial infarction (TIMI) grade 2 flow. According to the general condition of patient, a life-saving ad hoc percutaneous coronary intervention (PCI) was performed. Two stents were implanted in the Y graft with T and protrusion (TAP) technique achieving optimal result followed with patient stabilization. On one-year follow-up, the patient was without symptoms of angina, and computed tomography coronarography revealed patent both stents in the Y graft. To the best of our knowledge, this is the first described TAP technique used on the Y graft. Conclusion. The PCI on a vein graft is not uncommon either in elective cases or in cases with acute coronary syndrome due to the poorer persistence and more frequent progression of atherosclerotic disease in the venous grafts. The use of bifurcation techniques for the treatment of lesions on a vein graft and especially on the Y graft is rare, but it can be used the same way it is used in native vessels.