Major Risk Factor For Atherosclerosis Research Articles

ABO Blood Group and Severity of Coronary Artery Disease Assessed by Syntax Score in Patients with Acute Myocardial

Introduction: As coronary artery disease (CAD) is a major cause of morbidity and mortality; timely diagnosis and appropriate therapy is of paramount importance to improve clinical outcomes. Though there are major risk factors for CAD but sometimes it does not correlate with ACS. So, search for new risk factor is necessary for better management of CAD specially STEMI. Aim: To see the association between ABO blood group and severity of CAD in patients with STEMI. Methods: This study was done during the period of January 2016 to June 2016 with STEMI at National Institute of Cardiovascular diseases, Dhaka, Bangladesh. 100 patients were grouped in I and II where group-I having 50 patients of non-O blood group and group-II having 50 patients of O blood group. After CAG all reports were analyzed by two experts and SYNTAX score were calculated and data were analyzed by SPSS. Results: Baseline characteristics (100 patients) were well matched between the groups. Low SYNTAX score (d”22) was 16% and 56%; intermediate score (23-32) was 40% and 36% and high score (>32) was 44% and 8% in group- I and group-II respectively. These indicate that patients of non-O blood group have high SYNTAX score that is more severe CAD. Univariate and multivariate regression analysis showed that non-O blood group is an independent risk factor for CAD. So easily available ABO blood grouping can be helpful to determine the severity of CAD in patients with STEMI. Bangladesh Heart Journal 2022; 37(2): 107-115

G0S2 ameliorates oxidized low-density lipoprotein-induced vascular endothelial cell injury by regulating mitochondrial apoptosis.

Oxidative low-density lipoprotein (ox-LDL)-induced endothelial cell damage is a major risk factor for atherosclerosis and its related cardiovascular diseases. The G0/G1 switch gene 2 (G0S2) is a multifunctional protein which has been poorly studied in atherosclerosis. In this study, ox-LDL was utilized to construct a human aortic endothelial cell (HAEC) injury model. It was found that ox-LDL impaired cell viability, augmented lactate dehydrogenase (LDH) release, and reduced G0S2 levels in HAECs in a dose-dependent manner. Further, G0S2 overexpression improved the viability and restrained apoptosis of HAECs treated by ox-LDL. Conversely, G0S2 depletion decreased the viability and aggravated apoptosis of HAECs treated by ox-LDL. At the molecular level, G0S2 overexpression significantly increased the secretion of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPH-Px), promoted intracellular reactive oxygen species (ROS) production and malondialdehyde (MDA) content in HAECs under either normal or ox-LDL conditions. Meanwhile, the ox-LDL-induced mitochondrial dysfunction, as demonstrated by decreased mitochondrial membrane potential, translocation of mitochondrial cytochrome c (Cyt-c) to the cytoplasm, and activation of caspase-3 and caspase-9, was significantly reversed by G0S2 overexpression. In addition, G0S2 overexpression promoted the activation of AMP-activated protein kinase (AMPK) and increased the expression of nuclear factor erythroid-2-related factor-2 (Nrf2), sirtuin 1 (SIRT1) and heme oxygenase 1 (HO-1) under normal and ox-LDL conditions. This study demonstrated that G0S2 protects against ox-LDL-induced vascular endothelial cell injury by regulating oxidative damage and mitochondrial homeostasis and may be a promising target for the treatment of atherosclerosis.

Abstract 13330: Cardiorespiratory Fitness is Associated With Decreased Platelet Reactivity

Introduction: Platelets are key mediators in atherosclerotic cardiovascular disease (CVD). Low cardiorespiratory fitness (CRF) is a major risk factor for atherosclerosis. However, little is known about the effects of CRF on platelet function. Methods: Platelet assays and cardiopulmonary exercise testing were conducted in the Framingham Heart Study (n= 3001). A linear mixed effects model was used to analyze associations between CRF (assessed by peak oxygen uptake [VO 2 ] in participants achieving a respiratory exchange ratio >= 1), and platelet reactivity traits from multiple platelet function assays: whole blood Multiplate impedance aggregometry (MP), Total-Thrombus Formation Analysis System (T-TAS), and light transmission aggregometry (LTA). Statistical models adjusted for relatedness, age, sex, and anti-platelet medications. Bonferroni correction for multiple statistical testing resulted in a significance threshold of p<7.35E-04. Results: Of 68 platelet traits analyzed, 31 traits passed the significance threshold, all with a direction of effect indicating higher CRF associated with decreased platelet reactivity. Significant traits spanned multiple platelet agonists. Our strongest associations were seen with MP after TRAP-6 (velocity, p=1.57E-26; AUC, p=2.33E-21; aggregation, p=5.30E-16) and ADP stimulation (velocity, p=1.63E-19; AUC, p=7.64E-17; aggregation, p=1.00E-11), and LTA after ristocetin stimulation (max aggregation, p=5.33E-11; AUC, p=1.11E-10). Conclusion: Our research adds to past work that shows CRF to be associated with reduced CVD by suggesting that decreased platelet reactivity may be involved mechanistically. We found significant associations with multiple platelet agonists, indicating higher CRF globally inhibits platelets; however, given the multiple strong associations after TRAP-6 and ADP stimulation, PAR-1 and purinergic signaling, respectively, may be most heavily involved. This is notable since each of these receptor pathways is directly or indirectly tied to anti-coagulant or anti-platelet therapies. Ultimately, our results suggest that CRF may be important for additional consideration in tailoring anti-platelet strategies.

The Mechanism and Role of N6-Methyladenosine (m6A) Modification in Atherosclerosis and Atherosclerotic Diseases.

N6-methyladenosine (m6A) modification is a newly discovered regulatory mechanism in eukaryotes. As one of the most common epigenetic mechanisms, m6A's role in the development of atherosclerosis (AS) and atherosclerotic diseases (AD) has also received increasing attention. Herein, we elucidate the effect of m6A on major risk factors for AS, including lipid metabolism disorders, hypertension, and hyperglycemia. We also describe how m6A methylation contributes to endothelial cell injury, macrophage response, inflammation, and smooth muscle cell response in AS and AD. Subsequently, we illustrate the m6A-mediated aberrant biological role in the pathogenesis of AS and AD, and analyze the levels of m6A methylation in peripheral blood or local tissues of AS and AD, which helps to further discuss the diagnostic and therapeutic potential of m6A regulation for AS and AD. In summary, studies on m6A methylation provide new insights into the pathophysiologic mechanisms of AS and AD, and m6A methylation could be a novel diagnostic biomarker and therapeutic target for AS and AD.

Prevalence and factors associated with dyslipidemia among adolescents in Saudi Arabia

Dyslipidemia is a major risk factor for atherosclerosis. Screening for dyslipidemia at an early age is essential to prevent and control its consequences. This study aimed to determine prevalence of dyslipidemia and its correlates among adolescents in Saudi Arabia. Data of 5854 adolescents aged 10–19 years from all 13 regions of Saudi Arabia were obtained from the Jeeluna study; a national cross-sectional, multistage stratified cluster sample survey. Dyslipidemia was defined based on the National Heart Lung and Blood Institute and National Cholesterol Education Program guidelines for adolescents. We found that a quarter of Saudi adolescents have dyslipidemia (males: 33.3%, females: 17.9%). Significant variation was observed by region (p < 0.001). Prevalence of abnormal Total Cholesterol was 6.7%, LDL-C 7.1%, HDL-C 12.8%, Non-HDL-C 8.3%, and Triglycerides 9.6%. Factors independently associated with dyslipidemia were male gender (OR = 2.19, 95% CI 1.78–2.70, p < 0.001), BMI (underweight OR = 0.80, 95% CI 0.69–0.94, overweight OR = 1.76, 95% CI 1.50–2.06, obese OR = 2.80, 95% CI 2.34–3.34, p < 0.001, vs. normal) and serum ferritin (high OR = 7.02, 95% CI 1.49–34.79, low OR = 0.82, 95% CI 0.67–1.01, p = 0.04 vs. normal) and ≥ 1 daily intake of carbonated beverage (OR = 1.10, 95% CI 1.00–1.20, p = 0.03 vs. no or not daily intake). Public health interventions for improving lipid profile of adolescents are urgently needed.

Reducing Proteoglycan Synthesis and NOX Activity by ROCK Inhibitors: Therapeutic Targets in Atherosclerosis.

Atherosclerosis is a chronic inflammatory disease of the arteries characterized by the accumulation of inflammatory cells in the arterial wall. Hypertension, dyslipidemia, and hyperglycemia are major risk factors of atherosclerosis. Rho-associated protein kinase (ROCK), a serine/threonine kinase, is a downstream effector of the small GTPase RhoA. ROCK is involved in different stages of atherosclerosis. Accumulating evidence has demonstrated that ROCK signaling plays vital roles in various cellular functions, such as contraction, migration, and proliferation of smooth muscle cells. Dysregulation of the ROCK pathway is associated with atherosclerosis and hypertension. Experimental studies have shown that ROCK inhibitors may have favorable effects in ameliorating atherosclerosis. ROCK signaling has a role in proteoglycan synthesis through transactivation of the TGF-β receptor Type I (TβRI) mediated by G-protein-coupled receptor (GPCR) agonists (endothelin-1, angiotensin II and …), and ROCK inhibitors could decrease proteoglycan synthesis and atherosclerotic plaque formation. Based on the hypothesis that targeting ROCK pathway may be effective in ameliorating atherosclerosis, we suggest that ROCK inhibitors may have a potential therapeutic role in inhibition or slowing atherogenesis. However, for this hypothesis more research is needed.

Combining body mass index with waist circumference to assess coronary microvascular function in patients with non-obstructive coronary artery disease

BackgroundCoronary microvascular dysfunction (CMD) may precede clinically overt coronary artery disease (CAD). Overall and central obesity (CO) are major risk factors for CAD. This study sought to investigate the subclinical significance of body adiposity patterns based on the CMD risk. MethodsA total of 128 patients with non-obstructive CAD were prospectively enrolled. Patients were categorized into 4 anthropometric groups: normal weight and non-CO (NWNCO, n = 41), normal weight and CO (NWCO, n = 20), excess weight and non-CO (EWNCO, n = 26), and excess weight and CO (EWCO, n = 41). Patients underwent rest/stress electrocardiography-gated 13N-ammonia positron emission tomography to measure absolute myocardial blood flow (MBF), myocardial flow reserve (MFR), hemodynamic parameters, and cardiac function. ResultsResting MBF did not differ between groups (P = .36). Compared with the NWNCO group, hyperemic MBF and MFR were significantly lower in the NWCO and EWCO groups. Notably, patients with NWCO presented the lowest hyperemic MBF and MFR and the highest incidence of CMD. Waist circumference was an independent risk factor for CMD (OR 1.05, 95% CI 1.01 to 1.10, P = .02). ConclusionIn patients with non-obstructive CAD, CO may be associated with an increased risk of CMD to better fit the study findings which did not assess management or monitoring of MBF and MFR.

Diets and cholesterol metabolism

<p indent="0mm">Cholesterol is an essential component of most biological membranes and is the precursor for synthesis of steroid hormones and bile acids. In addition, numerous proteins can be modified by cholesterol, which are essential for embryonic development and cell proliferation. However, high level of blood cholesterol is a major risk factor of atherosclerosis. Therefore, cholesterol metabolism is tightly regulated by mammalian cells. Humans acquire cholesterol through de novo biosynthesis and intestinal absorption from foods. Bao-Liang Song’s research team at Wuhan University has long been devoted to the research of cholesterol metabolism, and has made a series of important original discoveries. The team systematically elucidated the negative feedback regulatory pathway of cholesterol synthesis -- HMGCR degradation pathway, revealed the molecular pathway of dietary induction of cholesterol synthesis, and proposed a new lipid-lowering strategy. They also identified a series of important proteins in the intestinal cholesterol absorption pathway. They found a rare frameshift variant in the LIMA1 gene from a Chinese family of Kazakh ethnicity with inherited low LDL-C and reduced cholesterol absorption. They demonstrated LIMA1 as a key protein regulating intestinal cholesterol absorption. This article focuses on diets and cholesterol metabolism, and reviews the relevant mechanisms of cholesterol synthesis regulation and intestinal cholesterol absorption, as well as the important achievements made by the cholesterol research team of Wuhan University.

Phenotypic and Genetic Evidence for a More Prominent Role of Blood Glucose than Cholesterol in Atherosclerosis of Hyperlipidemic Mice.

Hyperlipidemia and type 2 diabetes (T2D) are major risk factors for atherosclerosis. Apoe-deficient (Apoe−/−) mice on certain genetic backgrounds develop hyperlipidemia, atherosclerosis, and T2D when fed a Western diet. Here, we sought to dissect phenotypic and genetic relationships of blood lipids and glucose with atherosclerotic plaque formation when the vasculature is exposed to high levels of cholesterol and glucose. Male F2 mice were generated from LP/J and BALB/cJ Apoe−/− mice and fed a Western diet for 12 weeks. Three significant QTL Ath51, Ath52 and Ath53 on chromosomes (Chr) 3 and 15 were mapped for atherosclerotic lesions. Ath52 on proximal Chr15 overlapped with QTL for plasma glucose, non-HDL cholesterol, and triglyceride. Atherosclerotic lesion sizes showed significant correlations with fasting, non-fasting glucose, non-fasting triglyceride, and body weight but no correlation with HDL, non-HDL cholesterol, and fasting triglyceride levels. Ath52 for atherosclerosis was down-graded from significant to suggestive level after adjustment for fasting, non-fasting glucose, and non-fasting triglyceride but minimally affected by HDL, non-HDL cholesterol, and fasting triglyceride. Adjustment for body weight suppressed Ath52 but elevated Ath53 on distal Chr15. These results demonstrate phenotypic and genetic connections of blood glucose and triglyceride with atherosclerosis, and suggest a more prominent role for blood glucose than cholesterol in atherosclerotic plaque formation of hyperlipidemic mice.

Association of lipid metabolism-related gene promoter methylation with risk of coronary artery disease.

Coronary artery disease (CAD) is a complex disease that is influenced by environmental and genetic factors. Lipid levels are regarded as a major risk factor for CAD, and epigenetic mechanisms might be involved in the regulation of CAD development. This study was designed to investigate the association between the DNA methylation status of 8 lipid metabolism-related genes and the risk of CAD in the Chinese Han population. A total of 260 individuals were sampled in this study, including 120 CAD cases and 140 normal healthy controls. DNA methylation status was tested via targeted bisulfite sequencing. The results indicated a significant association between hypomethylation of the APOC3, CETP and APOC1 gene promoters and the risk of CAD. Individuals with higher methylation levels of the APOA5 and LIPC gene promoters had increased risks for CAD. In addition, ANGPTL4 methylation level was significantly associated with CAD in males but not females. There were no significant differences in the methylation levels of the APOB and PCSK9 gene promoters between CAD patients and controls. The methylation status of the APOC3, APOA5, LIPC, CETP and APOC1 gene promoters may be associated with the development of CAD.

Nfe2l1 protects white adipocytes from cholesterol-induced inflammation

Background and Aims : Adipocytes are crucial regulators of cardiovascular health. During obesity, adipocytes become dysfunctional, which is associated with inflammation and insulin resistance, major risk factors for atherosclerosis. Here we determine the role of the proteostatic transcription factor Nfe2l1 in the regulation of cholesterol homeostasis, adipocyte inflammation and atherosclerosis.

Characteristics and risk factors of severe coronary artery disease in systemic lupus erythematosus: A multicenter, Chinese Rheumatism Date Center database study.

Systemic lupus erythematosus (SLE) with severe coronary artery disease (CAD) is associated with increased mortality. This study aimed to assess the characteristics and risk factors of severe CAD in SLE. This multicenter, cross-sectional study enrolled consecutive patients with SLE included in the Chinese Rheumatism Date Center registry. Patients with severe CAD including angiography-confirmed stenosis ≥50% in the left main, ≥70% in other major coronary arteries, or myocardial infarction were classified into the CAD group. Patients without CAD were classified into the control group. Subgroups were stratified according to age (set as above and below 45 and 50 for men and women, respectively) and gender. Binary logistic regression analysis was performed to determine independent risk factors of severe CAD in SLE. Forty-three patients had severe CAD from a total of 3744 patients with SLE, 30 of whom were female; 35 belonged to the older age group and 8 belonged to the younger age group. In older patients, independent risk factors included age, 5 major CAD risk factors, SLE Disease Activity Index 2000 (SLEDAI-2K), hyperuricemia, and corticosteroid exposure. In younger patients, the risk factors were 5 major CAD risk factors and positive antiphospholipid antibody (APL). Male risk factors were age and 5 major CAD risk factors, whereas female risk factors were age, 5 major CAD risk factors, SLEDAI-2K, and positive APL. Three-vessel disease was most prevalent in patients with severe CAD. We recommend screening for severe CAD in patients with SLE with age- and gender-stratified risk factors.

Baicalein inhibits macrophage lipid accumulation and inflammatory response by activating the PPARγ/LXRα pathway.

Lipid accumulation and inflammatory response are two major risk factors for atherosclerosis. Baicalein, a phenolic flavonoid widely used in East Asian countries, possesses a potential atheroprotective activity. However, the underlying mechanisms remain elusive. This study was performed to explore the impact of baicalein on lipid accumulation and inflammatory response in THP-1 macrophage-derived foam cells. Our results showed that baicalein up-regulated the expression of ATP binding cassette transporter A1 (ABCA1), ABCG1, liver X receptor α (LXRα), and peroxisome proliferator-activated receptor γ (PPARγ), promoted cholesterol efflux, and inhibited lipid accumulation. Administration of baicalein also reduced the expression and secretion of TNF-α, IL-1β, and IL-6. Knockdown of LXRα or PPARγ with siRNAs abrogated the effects of baicalein on ABCA1 and ABCG1 expression, cholesterol efflux, lipid accumulation as well as pro-inflammatory cytokine release. In summary, these findings suggest that baicalein exerts a beneficial effect on macrophage lipid accumulation and inflammatory response by activating the PPARγ/LXRα signaling pathway.

444-P: Associations of LDL-C with New-Onset Coronary Artery Disease (CAD) According to HDL-C Levels and Glucose Status

Whereas elevated LDL-C is a major risk factor for CAD, the inverse association between HDL-C levels and risk of CAD is well-known. Although insulin resistance and glucose intolerance are associated with low HDL-C levels, it is not clear whether the association of LDL-C with CAD differs depending on glucose status and HDL-C values. We examined associations of LDL-C with new-onset CAD according to HDL-C and glucose status using a nationwide claims database on 600,6individuals during 2008-20with no history of CAD. Cox proportional hazards model identified risks of CAD events among combinations of tertiles of HDL-C and sextiles of LDL-C according to glucose status. During a mean follow-up period of 5.6 years, 2,391 CAD events occurred. CAD risk increased from lower LDL-C levels accompanied by lower HDL-C levels regardless of glucose status (Table) . Compared with the highest tertile of HDL-C and lowest sextile of LDL-C, groups with the highest tertile of HDL-C and highest sextile of LDL-C and the lowest tertile of HDL-C and highest sextile of LDL-C had approximately 4-fold and 9-fold, respectively, increased risks of CAD regardless of glucose status. Despite the necessity of a lower LDL-C target for people with than without diabetes, our results demonstrated that the necessity of modulating the LDL-C target according to HDL-C levels is not affected by concomitant diabetes. Disclosure M.H.Yamada: None.

Altered Mitochondrial Opa1-Related Fusion in Mouse Promotes Endothelial Cell Dysfunction and Atherosclerosis.

Flow (shear stress)-mediated dilation (FMD) of resistance arteries is a rapid endothelial response involved in tissue perfusion. FMD is reduced early in cardiovascular diseases, generating a major risk factor for atherosclerosis. As alteration of mitochondrial fusion reduces endothelial cells’ (ECs) sprouting and angiogenesis, we investigated its role in ECs responses to flow. Opa1 silencing reduced ECs (HUVECs) migration and flow-mediated elongation. In isolated perfused resistance arteries, FMD was reduced in Opa1+/− mice, a model of the human disease due to Opa1 haplo-insufficiency, and in mice with an EC specific Opa1 knock-out (EC-Opa1). Reducing mitochondrial oxidative stress restored FMD in EC-Opa1 mice. In isolated perfused kidneys from EC-Opa1 mice, flow induced a greater pressure, less ATP, and more H2O2 production, compared to control mice. Opa1 expression and mitochondrial length were reduced in ECs submitted in vitro to disturbed flow and in vivo in the atheroprone zone of the mouse aortic cross. Aortic lipid deposition was greater in Ldlr−/--Opa1+/- and in Ldlr−/--EC-Opa1 mice than in control mice fed with a high-fat diet. In conclusion, we found that reduction in mitochondrial fusion in mouse ECs altered the dilator response to shear stress due to excessive superoxide production and induced greater atherosclerosis development.

Evaluation of serum adenosine deaminase activity with reference to dyslipidemia in ischemic heart disease

Ischemic health disease is a major health and a modern epidemic which is increasing in India. Dyslipidemia is a major risk factor for atherosclerosis. Serum adenosine deaminase activity is associated with coronary artery disease.The present work was done to understand the relation of serum adenosine deaminase activity with dyslipidemia in ischaemic heart disease.This cross-sectional study comprised 200 subjects; healthy and myocardial infarction. Serum ADA and lipids were estimated. Obtained data was statistically analysed.Increase in serum ADA activity correlating with dyslipidemia was found in Myocardial infarction subjects.Increased ADA has role in LDL oxidation, dyslipidemia, foam cell transformation etc. leading to atherosclerosis and ischemic heart disease. Adenosine deaminase has a crucial role in the evolution of ischemic heart disease through dyslipidemia and coronary artery disease.

Comparative study to evaluate lipid profile in smoking and non-smoking individual at tertiary care centre

Background: Cigarette smoking, which is considered a major risk factor for atherosclerosis and coronary heart disease, may lead to changes in normal plasma lipid profile. The aim of the study was to evaluate the effect of cigarette smoking on lipid parameters in smokers and non-smokers. Material and Methods: A cross sectional comparative study was carried out in 200 subjects. The subjects were divided into two groups. Group A consisted of 100 smokers and Group B consisted of 100 Non-smokers. After overnight fasting following laboratory investigations were done in all subjects, Serum total cholesterol, Serum high density lipoprotein (HDL), Serum low density lipoprotein (LDL), Serum very low-density lipoprotein (VLDL), Serum triglyceride (TGL), Fasting blood sugar (FBS), Serum Creatinine, Urine for albumin, sugar and microscopic examination and the results of these tests were compared between the two groups.Results: All the values of lipid profile, TC, HDL, LDL, VLDL, TGL, were found to be significantly higher among the smokers compared to the non-smokers. The mean value of HDL was higher in non-smokers when compared to that of smokers and were statistically significant.

Characterization of an Aging-Based Diagnostic Gene Signature and Molecular Subtypes With Diverse Immune Infiltrations in Atherosclerosis.

Objective: Advancing age is a major risk factor of atherosclerosis (AS). Nevertheless, the mechanism underlying this phenomenon remains indistinct. Herein, this study conducted a comprehensive analysis of the biological implications of aging-related genes in AS. Methods: Gene expression profiles of AS and non-AS samples were curated from the GEO project. Differential expression analysis was adopted for screening AS-specific aging-related genes. LASSO regression analysis was presented for constructing a diagnostic model, and the discriminatory capacity was evaluated with ROC curves. Through consensus clustering analysis, aging-based molecular subtypes were conducted. Immune levels were estimated based on the expression of HLAs, immune checkpoints, and immune cell infiltrations. Key genes were then identified via WGCNA. The effects of CEBPB knockdown on macrophage polarization were examined with western blotting and ELISA. Furthermore, macrophages were exposed to 100 mg/L ox-LDL for 48 h to induce macrophage foam cells. After silencing CEBPB, markers of cholesterol uptake, esterification and hydrolysis, and efflux were detected with western blotting. Results: This study identified 28 AS-specific aging-related genes. The aging-related gene signature was developed, which could accurately diagnose AS in both the GSE20129 (AUC = 0.898) and GSE43292 (AUC = 0.685) datasets. Based on the expression profiling of AS-specific aging-related genes, two molecular subtypes were clustered, and with diverse immune infiltration features. The molecular subtype–relevant genes were obtained with WGCNA, which were markedly associated with immune activation. Silencing CEBPB triggered anti-inflammatory M2-like polarization and suppressed foam cell formation. Conclusion: Our findings suggest the critical implications of aging-related genes in diagnosing AS and modulating immune infiltrations.

De Novo Sphingolipid Biosynthesis in Atherosclerosis.

Atherosclerosis is the formation of fibrofatty lesions in the arterial wall, and this inflammatory state of the artery is the main cause of advanced pathological processes, including myocardial infarction and stroke. Dyslipidemic conditions with excess cholesterol accumulate within the arterial vessel wall and initiate atherogenic processes. Following vascular reaction and lipid accumulation, the vascular wall gradually thickens. Together with the occurrence of local inflammation, early atherosclerotic lesions lead to advanced pathophysiological events, plaque rupture, and thrombosis. Ceramide and sphingomyelin have emerged as major risk factors for atherosclerosis and coronary artery disease. Currently, the clinical association between de novo sphingolipid biosynthesis and coronary artery disease has been established. Furthermore, therapeutic strategies to modulate this pathway, especially those involving serine palmitoyltransferase and sphingomyelin synthase, against atherosclerosis, cancer, type 2 diabetes, and non-alcoholic fatty liver disease are actively under development. In this chapter, we focus on the relationship between de novo sphingolipid biosynthesis and coronary artery disease.

Abstract 11104: Association of Cigarette Smoking and Coronary Artery and Extra-Coronary Calcification in Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Smoking is a major risk factor for atherosclerosis, but its impact is heterogeneous across different vascular beds (e.g., stronger association with peripheral artery disease than coronary disease). However, whether the association of cigarette smoking with vascular calcification is (dis)similar across vascular beds is uncertain. Methods: In 1,961 ARIC participants without a history of coronary heart disease at visit 7 (2018-19), we quantified the associations of pack-years of smoking and years since cessation with coronary artery calcium (CAC) and extra-coronary calcification (ECC) using multivariable logistic regression models. High CAC and ECC (aortic valve, aortic valve ring, mitral valve, ascending aorta, and descending aorta calcification) were defined as Agatston score &gt;75th percentile and were analyzed separately as dependent variables. Results: Pack-years of smoking demonstrated an independent and robust dose-response relationship with CAC, ascending and descending aorta calcification, and aortic valve ring calcification (Table). The association was particularly evident for descending aorta calcification (e.g., adjusted odds ratio [aOR] 3.57 [95%CI 2.46-5.19] for ≥40 pack-years). The results were similar for the duration since smoking cessation, with the most prolonged risk seen for the descending aorta (i.e., even ≥30 years of smoking cessation had OR of 1.34 [1.03-1.47]). Aortic valve and mitral valve calcification demonstrated modest associations with smoking. Conclusions: Cigarette smoking showed a robust association with coronary and extra-coronary calcification, and its association was particularly strong with descending aorta calcification. Our findings further emphasize the harm of smoking on broad ranges of vascular beds and simultaneously highlight unique pathophysiologic mechanisms across different vascular beds and cardiac valves.