Progression Of Atherosclerotic Disease Research Articles

Mechanistic insights into the regression of atherosclerotic plaques.

Atherosclerosis is a major contributor to cardiovascular diseases and mortality globally. The progression of atherosclerotic disease results in the expansion of plaques and the development of necrotic cores. Subsequent plaque rupture can lead to thrombosis, occluding blood vessels, and end-organ ischemia with consequential ischemic injury. Atherosclerotic plaques are formed by the accumulation of lipid particles overloaded in the subendothelial layer of blood vessels. Abnormally elevated blood lipid levels and impaired endothelial function are the initial factors leading to atherosclerosis. The atherosclerosis research has never been interrupted, and the previous view was that the pathogenesis of atherosclerosis is an irreversible and chronic process. However, recent studies have found that the progression of atherosclerosis can be halted when patients' blood lipid levels are reversed to normal or lower. A large number of studies indicates that it can inhibit the progression of atherosclerosis lesions and promote the regression of atherosclerotic plaques and necrotic cores by lowering blood lipid levels, improving the repair ability of vascular endothelial cells, promoting the reverse cholesterol transport in plaque foam cells and enhancing the ability of macrophages to phagocytize and clear the necrotic core of plaque. This article reviews the progress of research on the mechanism of atherosclerotic plaque regression. Our goal is to provide guidance for developing better therapeutic approaches to atherosclerosis by reviewing and analyzing the latest scientific findings.

Racial and Socioeconomic Health Disparities in Peripheral Artery Disease.

Peripheral artery disease (PAD) is a progressive atherosclerotic disease that causes lower extremity arterial stenosis or occlusion. Patients with PAD are at increased risk of myocardial infarction, stroke, limitations in ambulation, and amputation. Despite the advances in medicine and technology, the outcomes from PAD, including critical limb-threatening ischemia, acute limb ischemia amputation, and mortality, remain increased among specific racial and ethnic groups that have been historically marginalized in America, including Black, Hispanic, and American Indian individuals in the United States when compared with White persons. The purpose of this review is to summarize PAD literature that incorporates racial and ethnic disparities in PAD. There are a rising number of studies focused on the interface of racial and ethnic disparities and PAD. The majority of these studies are specifically focused on Black race, whereas there are limited studies focused on other minoritized racial and ethnic groups in the United States. The application of race and ethnicity has also been shown to play a synergistic role with socioeconomic status on PAD outcomes. Effective strategies focused on implementing policies that support quality measures and focus on social determinants of health have been shown to promote health equity and reduce disparities. Current evidence suggests that biological differences are less likely to be the leading cause of disparities in PAD between racial and ethnic groups compared with White Americans and supports a renewed focus on social determinants of health to achieve health equity.

Intraplaque hemorrhage in carotid atherosclerotic plaques is associated with a local increase in inflammatory cytokines

Abstract Background One of the main features of vulnerability in atherosclerotic carotid plaques is intraplaque hemorrhage (IPH), which is related to a higher incidence of cerebrovascular events in patients with carotid artery disease. Additionally, inflammation plays a pivotal role in the progression of atherosclerotic disease. Purpose We aimed to determine plasma and tissue levels of inflammatory cytokines in patients with carotid artery disease hypothesizing that plaques with IPH are characterized by the presence of a more inflamed environment. Methods We retrospectively enrolled 104 consecutive patients undergoing carotid endarterectomy (CEA) with symptomatic (ischemic stroke, TIA, amaurosis fugax) or asymptomatic ipsilateral carotid artery disease. Plasma and carotid plaque specimens were collected at CEA. The tissue samples were stained with H&E to identify IPH and classified as specimens with and without IPH. Frozen homogenates of both plasma and tissue were analyzed using a customized 10-plex Luminex assay to determine the levels of inflammatory cytokines such as MCP-1/CCL2, IL-8/CXCL8, IFN-gamma, IL-10, IL-1beta/IL-1F2, IL-6, PDGF-AA, PDGF-AB/BB, TNF-alpha, and VEGF. Results IPH was identified in 53 patients (51.0 %). Cytokine levels in plasma and tissue from patients with and without IPH are reported in Table 1. In the univariate logistic regression MCP-1/CCL2, IL-8/CXCL8, IFN-gamma, IL-10, IL6, PDGF-AA, and PDGF-AB/BB were associated with IPH (Table 2). In the multivariate logistic regression, IL-6 was an independent predictor of IPH (HR 1.026 [95% CI 1.005-1.047]; p=0.014) after adjusting for cardiovascular risk factors such as age, BMI, sex, hypertension, diabetes mellitus, hyperlipidemia, ipsilateral carotid stenosis %. Conclusions Carotid plaques with IPH have an elevated inflammatory burden, potentially impacting adverse outcomes in this patient cohort. The local inflammatory cytokines in carotid plaques with IPH might serve as biomarkers and therapeutic targets in patients with carotid artery disease.

Factors influencing low-density-lipoprotein cholesterol after acute coronary syndrome and effectiveness of intensive teleconsultation monitoring, the teleobjectif cohort study

Abstract Context: Low-density lipoprotein cholesterol (LDL-c) plays a key role in the development and progression of atherosclerotic cardiovascular disease (ASCVD). Despite the availability of effective lipid-lowering treatments, patients who have experienced an acute coronary syndrome (ACS) continue to face a high risk of recurrent cardiovascular events and mortality. Achieving the recommended LDL-c target of <0.55 g/L in secondary cardiovascular prevention remains a significant challenge, with fewer than 30% of patients reaching this goal. Aim To investigate the factors influencing LDL-c control after ACS and the effectiveness of intensive teleconsultation monitoring to control LDL-c, even in sub-groups where control is poorest. Methods This bi-centric prospective cohort study conducted between december 2019 and december 2021 compared a group that received standard follow-up after an ACS with an interventional group that received regular follow-up by teleconsultation in addition of usual care to optimize lipid-lowering treatment. A subgroup analysis was carried out to examine the effect of teleconsultation in subpopulations known to be significantly associated with better or worse LDL-c control in the usual care group or described in the literature. Results 1602 patients met the inclusion criteria for our study (814 in the usual care group and 788 in the teleconsultation group). Baseline characteristics were similar between groups. In the usual care group, factors influencing lipid control included gender, diabetes, cardiology consultation, distance to the nearest cardiologist, social deprivation and initial LDL-C levels. Teleconsultation significantly improved LDL-C target attainment compared to usual care (74.7% vs. 26.6%, p<0.001 with multivariate analysis OR 5.06 [4.21 ; 6.07]), particularly benefiting geographically and socially disadvantaged patients. Conclusion Teleconsultation significantly improves lipid control in acute coronary syndrome patients compared to usual care. This universal intervention, particularly beneficial for geographically and socially disadvantaged patients, highlights the potential of telemedicine in enhancing cardiovascular management.analysis in usual care groupTeleconsultation effect in sub-groups

Intra-operative and post-operative management of conduits for coronary artery bypass grafting: a clinical consensus statement of the European Society of Cardiology Working Group on Cardiovascular Surgery and the European Association for Cardio-Thoracic Surgery Coronary Task Force.

The structural and functional integrity of conduits used for coronary artery bypass grafting is critical for graft patency. Disruption of endothelial integrity and endothelial dysfunction are incurred during conduit harvesting subsequent to mechanical or thermal injury and during conduit storage prior to grafting, leading to acute thrombosis and early graft failure. Late graft failure, in particular that of vein grafts, is precipitated by progressive atherogenesis. Intra-operative management includes appropriate selection of conduit-specific harvesting techniques and storage solutions. Arterial grafts are prone to vasospasm subsequent to surgical manipulation, and application of intra-operative vasodilatory protocols is critical. Post-operative management includes continuation of oral vasodilator therapy and selection of antithrombotic and lipid-lowering agents to attenuate atherosclerotic disease progression in conduits. In this review, the scientific evidence underlying the key aspects of intra- and post-operative management of conduits for coronary artery bypass grafting is examined. Clinical consensus statements for best clinical practice are provided, and areas requiring further research are highlighted.

The German Lipoprotein Apheresis Registry-Summary of the eleventh annual report

BackgroundIn 2012, the German Lipoprotein Apheresis Registry (GLAR) was launched. Real-world data on lipoprotein apheresis (LA) treatment are now available for a time period of 11 years. All patients received the maximally tolerated lipid-lowering therapy, which included statins, ezetimibe, bempedoic acid, and either proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies or antisense therapy. Methods and ResultsDuring the time period from 2012 to 2022, 92 German apheresis centers collected retrospective and prospective observational data of a total of 2,301 patients undergoing regular lipoprotein apheresis (LA) treatment of hypercholesterolemia or/and Lp(a)-hyperlipoproteinemia suffering from progressive atherosclerotic cardiovascular disease (ASCVD), with complete data sets of 1.125 patients, who were the subject of this analysis. More than 61,500 LA sessions are documented in the database. In 2022, all patients treated with LA demonstrated a significant immediate median reduction rate of LDL-C (68.8 %) and Lp(a) (72.9 %). Patient data were analyzed for the incidence rate of major coronary events (MACE) 1 and 2 years before the beginning of LA treatment (y-2 and y-1) and prospectively up to eleven years on LA treatment (y+1 to y+11). During the first two years of LA treatment (y+1 and y+2), a MACE reduction of 73 % was observed and continued to be low during y+3 to y+11, when all LA patients were analyzed. LA patients with only increased Lp(a) levels (Lp(a) ≥ 60 mg/dl (≥120 nmol/l) and an LDL-C < 100 mg/dl (<2.6 mmol/l)) had a higher MACE reduction (85 %; n = 443) in the first two years of LA treatment compared to LA patients with only increased LDL-C-levels (LDL-C ≥ 100 mg/dl (≥2.6 mmol/l); Lp(a) < 60 mg/dl (<120 nmol/l)) (53 %; n = 171). Adverse events of LA remained low (about 5 %) over the eleven years and mainly represented puncture problems (1.0 %). No side effects resulted in termination of LA therapy. ConclusionsThe current analysis of GLAR data indicates that regular LA leads to very low incidence rates of cardiovascular events in patients with high LDL-C and/or high Lp(a) levels, progressive ASCVD, and maximally tolerated lipid-lowering medication, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition. Additionally, LA was safe with a low rate of adverse effects over an 11-year period. The number of enrolled patients and the duration of observation establish GLAR as the largest LA registry worldwide.

Deciphering the extracellular effects of succinate in atherosclerotic disease progression: A translational approach

Deciphering the extracellular effects of succinate in atherosclerotic disease progression: A translational approach

Life cycle of macrophages in atherosclerotic inflammation progression and resolution: mediators and interventions (narrative review)

Abstract As one of the pathological causes of coronary heart disease, atherosclerosis poses a major threat to human health. Macrophages play an important role in regulating atherosclerotic disease progression. Specifically, atherosclerotic inflammation is initiated when low-density lipoproteins infiltrate the subcutaneous area and are phagocytosed by macrophages, leading to foam cell formation. The subsequent inflammation progression or resolution depends on the delicate balance between proinflammatory and anti-inflammatory mediators. In cases where proinflammatory factors dominate, macrophages tend to activate the pyroptosis and necrosis pathways, resulting in the release of intracellular damage-associated molecular patterns and promoting necrotic core formation and plaque progression. Conversely, when anti-inflammatory factors prevail, macrophages engage in autophagy-mediated intracellular lipid metabolism while inhibiting inflammation progression through the efferocytosis of apoptotic cells. The regulatory function of macrophages in atherosclerosis can also be understood from the perspective of their life cycles. Lipid retention within the arterial intima and its subsequent uptake by macrophages are the characteristic pathological hallmarks of atherosclerosis. As pivotal effector cells in this process, macrophages with their distinctive performances decisively determine the progression and resolution of atherosclerotic inflammation. The complete life cycle of macrophages in atherosclerotic plaques encompasses chemotaxis, infiltration, polarization, uptake of lipoproteins for metabolic efflux, foam cell formation, lipid overload, and various forms of programmed necrosis, including autophagy, pyroptosis, apoptosis, necrosis, and efferocytosis, to facilitate the removal of apoptotic macrophages and limit inflammation progression. The behavior of macrophages in atherosclerosis has rarely been comprehensively addressed in previous review articles. This article provides an extensive overview of the entire life cycle of macrophages following their response to atherosclerotic inflammation and the impact of regulatory factors on inflammation progression and resolution. Considering that macrophages play a pivotal role in the inflammatory response associated with atherosclerosis, targeting the regulation of their life cycle holds promise for therapeutic interventions against atherosclerosis-related cardiovascular diseases.

Progression of Coronary Artery Calcification and Risk of Clinical Events in CKD: The Chronic Renal Insufficiency Cohort Study

Coronary artery calcification (CAC) progresses rapidly in people with chronic kidney disease (CKD) compared with the general population. We studied the association between CAC progression and higher risks of atherosclerotic cardiovascular disease (CVD), congestive heart failure, and all-cause mortality among adults with CKD. Prospective cohort study. & Participants: 1,310 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study who had at least one CAC scan with no prior history of CVD and with observed or imputed data on changes in CAC over time. Observed or imputed CAC progression, categorized as incident CAC among participants with zero CAC on the baseline scan, or progressive CAC when the baseline scan demonstrated CAC and there was an increase in CAC ≥50 Agatston units per year. Atherosclerotic CVD (myocardial infarction or stroke), congestive heart failure, and all-cause mortality. Cause-specific Cox proportional hazards regression, stratified by presence of CAC at baseline. A total of 545 participants without and 765 with prevalent CAC at baseline were included. During a mean 3.3 years between CAC assessments, 177 (32.5%) participants without baseline CAC developed incident CAC while 270 participants (35.3%) with baseline CAC developed a ≥50 Agatston units per year increase in CAC. After multivariable adjustment, incident CAC was associated with 2.42-fold higher rate of atherosclerotic CVD (95% confidence interval [CI]: 1.23-4.79) and 1.82-fold higher rate of all-cause mortality (95% CI: 1.03-3.22). Progressive CAC (≥50 units per year) was not associated with atherosclerotic CVD (hazard ratio [HR]: 1.42; 95% CI: 0.85-2.35) but was associated with a 1.73-fold higher rate of all-cause mortality (95% CI: 1.31-2.28). Progressive CAC was not associated with incident heart failure. Residual confounding and limited statistical power for some outcomes. Among adults with CKD stages 2-4, CAC progression over a mean 3.3 years was associated with higher risk of atherosclerotic CVD and all-cause mortality. The associations were strongest among participants without CAC at baseline.

Establishment of precise prevention strategies for the occurrence and progression of coronary atherosclerotic heart disease using machine learning

BackgroundCoronary atherosclerotic heart disease (CHD) is highly prevalent in Northwest China; however, effective preventive measures are limited. This study aimed to develop metabolic risk models tailored for the primary and secondary prevention of CHD in Northwest China. MethodsThis hospital-based cross-sectional study included 744 patients who underwent coronary angiography. Data on demographic characteristics, comorbidities, and serum biochemical indices of the participants were collected. Three machine learning algorithms—recursive feature elimination, random forest, and least absolute shrinkage and selection operator—were employed to construct risk models. Model validation was performed using receiver operating characteristic and calibration curves, and the optimal cutoff values for significant risk factors were determined. ResultsThe predictive model for CHD onset included sex, overweight/obesity, and hemoglobin A1c (HbA1c) levels. For CHD progression to multiple coronary artery disease, the model included age, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and HbA1c levels. The model predicting an increased coronary Gensini score included sex, overweight/obesity, TC, LDL-C, high-density lipoprotein cholesterol, lipoprotein(a), and HbA1c levels. Notably, the optimal cutoff values for HbA1c and lipoprotein(a) for determining CHD progression were 6 % and 298 mg/L, respectively. ConclusionsRobust metabolic risk models were established, offering significant value for both the primary and secondary prevention of CHD in Northwest China. Weight loss, strict hyperglycemic control, and improvement in dyslipidemia may help prevent or delay the occurrence and progression of CHD in this region.

Coronary artery event-free or resilient familial hypercholesterolemia: what's in a name?

Familial hypercholesterolemia (FH) is an autosomal semi-dominant condition, characterized by excessive circulating low-density lipoprotein cholesterol (LDL-C) from birth that substantially accelerates the onset and progression of atherosclerotic cardiovascular disease (ASCVD), classically coronary artery disease (CAD). Elevated plasma LDL-C integrated over time is unequivocally the major determinant of ASCVD in heterozygous FH (HeFH); however, the wide variation in incidence and progression of ASCVD suggests a role for a wide spectrum of risk modifiers. We reviewed recent evidence describing the features of an ASCVD-free entity referred to as resilient FH among patients with HeFH. Compared with nonresilient FH patients, resilient patients are more likely to be female, and have a lower prevalence of ASCVD comorbidities, higher levels of HDL-C and larger HDL particles, as well as a lower level of lipoprotein(a). A lower SAFEHEART risk score is also an independent predictor of resilient FH. Gene expression studies also demonstrate that resilient FH patients are associated with a less atherogenic gene expression profile in relation to HDL metabolism and immune responses, as reflected by higher expression of ABCA1 and ABCG1, and lower expression of STAT2 and STAT3, respectively. A group of HeFH patients, referred as resilient FH, can survive to advance ages without experiencing any ASCVD events. Several key contributors to the event-fee CAD in HeFH patients have been identified. This could not only improve risk stratification and management for FH but also be of major importance for the general population in primary and secondary prevention. However, resilient FH remains an under-investigated area and requires further research.

Progression in the Relationship between Exosome Production and Atherosclerosis.

Atherosclerosis (AS) is the leading cause of cardiovascular disease, causing a major burden on patients as well as families and society. Exosomes generally refer to various lipid bilayer microvesicles originating from different cells that deliver various bioactive molecules to the recipient cells, exerting biological effects in cellular communication and thereby changing the internal environment of the body. The mechanisms of correlation between exosomes and the disease process of atherosclerosis have been recently clarified. Exosomes are rich in nucleic acid molecules and proteins. For example, the exosome miRNAs reportedly play important roles in the progression of atherosclerotic diseases. In this review, we focus on the composition of exosomes, the mechanism of their biogenesis and release, and the commonly used methods for exosome extraction. By summarizing the latest research progress on exosomes and atherosclerosis, we can explore the advances in the roles of exosomes in atherosclerosis to provide new ideas and targets for atherosclerosis prevention, diagnosis, and treatment.

Therapeutic Avenues to Modulate B-Cell Function in Patients With Cardiovascular Disease.

The adaptive immune system plays an important role in the development and progression of atherosclerotic cardiovascular disease. B cells can have both proatherogenic and atheroprotective roles, making treatments aimed at modulating B cells important therapeutic targets. The innate-like B-cell response is generally considered atheroprotective, while the adaptive response is associated with mixed consequences for atherosclerosis. Additionally, interactions of B cells with components of the adaptive and innate immune system, including T cells and complement, also represent key points for therapeutic regulation. In this review, we discuss therapeutic approaches based on B-cell depletion, modulation of B-cell survival, manipulation of both the antibody-dependent and antibody-independent B-cell response, and emerging immunization techniques.

A Systematic Review and Meta-Analysis on the Role of Bempedoic Acid in Cardiovascular Outcomes for Patients With Statin Intolerance.

Atherosclerosis, a multifaceted pathogenic process affecting the arteries and aorta, poses a significant threat because of its potential to impede or entirely obstruct blood flow by narrowing blood vessels. This intricate progression involves various factors such as dyslipidemia, immunological responses, inflammation, and endothelial dysfunction. The initial phase manifests as the formation of fatty streaks, considered a pivotal hallmark in the inception of atherosclerotic plaques, a process that can commence as early as childhood. Over time, this process evolves, characterized by the thickening of the arterial inner layer (intima) and accumulation of lipid-laden macrophages, commonly known as foam cells, along with the buildup of the extracellular matrix. Subsequent stages witness the proliferation and aggregation of smooth muscle cells, culminating in the formation of atheroma plaques. As these lesions progress, apoptosis can occur in the deeper layers, further recruiting macrophages, which may undergo calcification and transform into atherosclerotic plaques. Notably, mechanisms such as arterial remodeling and intraplaque hemorrhage also contribute significantly to the progression of atherosclerotic cardiovascular disease, although these facets fall beyond the scope of this article. This study aimed to systematically review and conduct a meta-analysis of randomized controlled trials investigating the efficacy and safety of bempedoic acid in statin-intolerant patients with hyperlipidemia and to provide conclusions and recommendations accordingly. A systematic search of databases, such as PubMed, Web of Science, and Embase, will be performed. Only randomized trials will be included comparing bempedoic acid with placebo in statin-intolerant patients. This study aimed to provide a comprehensive understanding of the role of bempedoic acid in managing hyperlipidemia in statin-intolerant patients. In primary prevention, for patients unable to tolerate recommended statins, bempedoic acid was associated with a significant reduction in major adverse cardiovascular events (MACE) as the primary endpoint.

Drug-interacting gene expression levels differ between atherosclerotic plaque subtypes

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The Dutch Heart foundation Recent transcriptomic-based clustering of human atherosclerotic plaques revealed that plaques have a diversity and complexity that cannot be accurately described by classical concepts. Previous plaque RNA sequencing that we performed in 654 lesions identified five major plaque types that reflect different mechanisms of progression of atherosclerotic disease. These include the following plaque subtypes: 0. Fibro-collagenous, 1. Intermediate, 2. Lipo-necrotic, 3. Fibro-inflammatory, and 4. Fibro-cellular. We hypothesize that these different plaque types may respond differentially upon drug treatment. Objective To assess differential expression levels of drug-responsive genes between the earlier described five plaque subtypes. For this in silico experiment, the differential expression of drug-responsive genes was examined after colchicine treatment in smooth muscle cells and endothelial cells. Methods To begin, a web-based search identified 46 published colchicine interacting genes. Then, colchicine was applied to cultured smooth muscle and endothelial cells to verify the publicly reported drug responsive genes. Next, we modelled the effect of colchicine on the five types of human atherosclerotic plaques for those genes that were considered drug responsive. This was achieved by projecting the in vitro derived expression changes onto the gene expression data from the carotid plaques of 654 patients who participated in the ATHERO-EXPRESS study. Besides colchicine, the same experimental approach was applied for atorvastatin and rofecoxib drug treatment. Finally, changes in drug responsive gene expression were validated with mice gene expression data. Results 34 out of the 46 publicly known colchicine interacting genes were differently expressed between plaque types (Figure 1). These genes included established determinants of cell motility and atherosclerosis development (SCD, ITGB1, Tubulins). Furthermore, in-silico colchicine treatment revealed colchicine's strong effect on the atherosclerotic plaques' transcriptome. We are currently assessing if these perturbations may lead to shifts in plaque subtypes and if these changes are reflected in mice transcriptomic data. Conclusion The pilot data demonstrated major differences in drug-interacting gene expression levels in advanced atherosclerotic lesions. Therefore, novel and standard drugs used to treat atherosclerosis may have varying effects depending on the atherosclerotic plaque subtype.

Association between atherosclerotic cardiovascular disease score and skin carotenoid levels estimated via refraction spectroscopy in the Japanese population: a cross-sectional study

Carotenoids play a role in preventing and impeding the progression of atherosclerotic cardiovascular diseases (ASCVDs) through their anti-oxidative effects. This study evaluated associations between ASCVD risk and skin carotenoid (SC) levels, reflecting dietary carotenoid intake. Participants’ ASCVD risk was assessed using the Hisayama ASCVD risk prediction model, and SC levels were measured through a reflection spectroscope (Veggie Meter). The associations between high ASCVD risk and SC levels were analyzed using logistic regression analysis and a restricted cubic spline (RCS) model. A total of 1130 men and women (mean age: 56 years) from participants who underwent a health examination in Seirei Center for Health Promotion and Prevention Medicine in 2019 and 2022 were analyzed. Of these, 4.6% had moderate or high ASCVD risk. Mean SC values were 236, 315, 376, 447, and 606 in quintile Q1 to Q5, respectively. The adjusted odds ratios (95% confidence intervals) of SC quintile for moderate- or high-risk ASCVD was 0.24 (0.12–0.51) in Q5 (495 ≤), 0.42 (0.23–0.77) in Q4, 0.50 (0.29–0.88) in Q3, and 0.68 (0.41–1.12) in Q2 compared to Q1 (< 281). High SC values continuously showed non-linear inverse association with moderate- or high-risk for ASCVD in Japanese adults. Non-invasive SC measurements may be a good indicator for recommending carotenoids to prevent cardiovascular disease.

Lipoprotein (a) concentration as a risk factor for ischaemic stroke and its subtypes.

To investigate the relationship between serum lipoprotein (a) [Lp(a)] concentration and the risk of ischaemic stroke (IS) and its subtypes. Lp(a) plays a role in atherogenic, pro-thrombotic, and antifibrinolytic processes. Elevated plasma Lp(a) is a strong independent risk factor for the development and progression of atherosclerotic disease. The association between lipoproteins and IS is more complex than that reported for cardiovascular diseases, with inconsistent and contradictory results from epidemiological studies. 231 patients with acute IS (defined as cases) and 163 age- and sex-matched control subjects were included in this prospective case-control study. Demographic and clinical variables (i.e. age, sex, smoking, presence of chronic diseases and concomitant medication) and laboratory data (i.e. concentrations of total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, triglycerides, Lp(a), apolipoprotein A1, apolipoprotein B) were recorded. The mean age and the percentage of men did not significantly differ between groups. Compared to controls, there was a significantly higher percentage of cases reported with concomitant diseases: diabetes mellitus, myocardial infarction, ischaemic heart disease, peripheral arterial disease, and atrial fibrillation. The study showed a significantly higher serum Lp(a) concentration in cases than in control subjects (81.81 nmol/L [c.32.7 mg/dL] vs. 59.75 nmol/L [c.23.9 mg/dL]; p = 0.036) and found an association between Lp(a) levels stratified by quartiles and the risk for ischaemic stroke (Q1 [Lp(a) < 13 nmol/L] vs. Q4 [Lp(a) > 117 nmol/L]: OR 2.23; 95% CI 1.23-4.03; p = 0.008). A subgroup analysis based on the TOAST classification of IS also showed a significant association between Lp(a) value of more than 75 nmol/L (30 mg/dL) and the risk of large-artery atherosclerosis stroke compared to the controls (OR 2.4; 95% CI 1.39-3.93; p = 0.001), as well as a statistically non-significant association with other subtypes of IS. The influence of Lp(a) remained significant even after adjusting for established risk factors for IS (OR 1.99; 95% CI 1.05-3.76; p = 0.04; respectively for the large-artery atherosclerotic subtype: OR 2.54; 95% CI 1.39-4.67; p = 0.003). We found that Lp(a) is an independent risk factor for ischaemic stroke, and for the large-artery atherosclerotic subtype of ischaemic stroke.

Abstract 2075: Vascular Smooth Muscle Cell Derived Pdgfd Promotes Vascular Remodeling And Plaque Progression In Atherosclerosis

We have recently identified rs2019090 and PDGFD as the functional variant and gene mediating CAD risk at the 11q22.3 locus, with our initial analysis using a global knockout (KO) model showing that this gene may promote phenotypic changes in smooth muscle cells (SMCs) in the plaque and contribute to neointimal vascular calcification. Nonetheless, the specific cell-type and phenotypic states through which PDGFD may confer disease risk remains unexplored.To delineate the impact of SMC-derived PDGFD signalling on cell state transitions and plaque progression in atherosclerosis, we have developed a novel SMC-specific lineage tracing and Pdgfd KO mouse ( Pdgfd ΔSMC/ΔSMC , Myh11 CreERT2 , ROSA tdT/+ , ApoE -/- ) allowing us to confidently define the impact of SMC-derived Pdgfd in the vascular SMC lineage as well as in neighbouring populations. Leveraging our lineage tracing KO mutants on a hypercholesterolemic diet, we have employed single cell RNA sequencing (scRNAseq) and histological analyses to characterize the cellular and molecular effect of Pdgfd in vascular disease. SMC-specific Pdgfd deletion resulted in alterations in the distribution of transitioning SMC populations, as well as previously unexplored gene expression differences within these cell types. This was accompanied by a significant reduction in atherosclerotic burden and plaque size across the aorta, including aortic root as well as descending abdominal aorta. Histological analysis revealed decreased monocyte recruitment, show by quantifying CD68+ cells within the plaque. To explore this further we interrogated the scRNAseq dataset to identify major pathways of cell-cell communication and the impact of altered Pdgfd signalling across different cell types. Overall, these data reveal that SMC-derived PDGFD substantially alters lesional SMC cell phenotype transitions, as well as inflammatory cell recruitment, implicating it as a major regulator of atherosclerotic disease progression.

Atherosclerosis evaluation and cardiovascular risk estimation using coronary computed tomography angiography.

Clinical risk scores based on traditional risk factors of atherosclerosis correlate imprecisely to an individual's complex pathophysiological predisposition to atherosclerosis and provide limited accuracy for predicting major adverse cardiovascular events (MACE). Over the past two decades, computed tomography scanners and techniques for coronary computed tomography angiography (CCTA) analysis have substantially improved, enabling more precise atherosclerotic plaque quantification and characterization. The accuracy of CCTA for quantifying stenosis and atherosclerosis has been validated in numerous multicentre studies and has shown consistent incremental prognostic value for MACE over the clinical risk spectrum in different populations. Serial CCTA studies have advanced our understanding of vascular biology and atherosclerotic disease progression. The direct disease visualization of CCTA has the potential to be used synergistically with indirect markers of risk to significantly improve prevention of MACE, pending large-scale randomized evaluation.

Relationship between Polyunsaturated Fatty Acid Metabolism and Atherosclerosis.

Multiple factors cause atherosclerosis, meaning its pathogenesis is complex, and has not been fully elucidated. Polyunsaturated fatty acids are a member of the fatty acid family, which are critical nutrients for mammalian growth and development. The types of polyunsaturated fatty acids ingested, their serum levels, and fatty acid desaturase can influence the atherosclerotic disease progression. The fatty acid desaturase gene cluster can regulate fatty acid desaturase activity and further affect atherosclerosis. This study reviewed the research progress on the effects of polyunsaturated fatty acids on atherosclerosis regulated by fatty acid desaturase and the relationship between genetic variants of the fatty acid desaturase gene cluster and atherosclerotic cardiovascular disease.