Risk Factors For Atherosclerosis Research Articles

Noninvasive assessment of human microvascular function in health and disease using incident dark-field microscopy.

Reduced peripheral microvascular reactivity is associated with an increased risk for major adverse cardiac events (MACEs). Tools for noninvasive assessment of peripheral microvascular function are limited, and existing technology is poorly validated in both healthy populations and patients with cardiovascular disease (CVD). Here, we used a handheld incident dark-field imaging tool (CytoCam) to test the hypothesis that, compared with healthy individuals (no risk factors for CVD), subjects formally diagnosed with coronary artery disease (CAD) or those with ≥2 risk factors for CAD (at risk) would exhibit impaired peripheral microvascular reactivity. A total of 17 participants (11 healthy, 6 at risk) were included in this pilot study. CytoCam was used to measure sublingual microvascular total vessel density (TVD), perfused vessel density (PVD), and microvascular flow index (MFI) in response to the topical application of acetylcholine (ACh) and sublingual administration of nitroglycerin (NTG). Baseline MFI and PVD were significantly reduced in the at-risk cohort compared with healthy individuals. Surprisingly, following the application of acetylcholine and nitroglycerin, both groups showed a significant improvement in all three microvascular perfusion parameters. These results suggest that, despite baseline reductions in both microvascular density and perfusion, human in vivo peripheral microvascular reactivity to both endothelial-dependent and -independent vasoactive agents remains intact in individuals with CAD or multiple risk factors for disease.NEW & NOTEWORTHY To our knowledge, this is the first study to comprehensively characterize in vivo sublingual microvascular structure and function (endothelium-dependent and -independent) in healthy patients and those with CVD. Importantly, we used an easy-to-use handheld device that can be easily translated to clinical settings. Our results indicate that baseline microvascular impairments in structure and function can be detected using the CytoCam technology, although reactivity to acetylcholine may be maintained even during disease in the peripheral microcirculation.

Comparative Prevalence of Cerebrovascular Disease in Vietnamese Communities in South-Western Sydney.

Culturally and linguistically diverse (CALD) communities are growing globally. Understanding patterns of cerebrovascular disease in these communities may improve health outcomes. We aimed to compare the rates of transient ischaemic attack (TIA), ischaemic stroke (IS), intracerebral haemorrhage (ICH), intracranial atherosclerosis (ICAD), and stroke risk factors in Vietnamese-born residents of South-Western Sydney (SWS) with those of an Australian-born cohort. A 10-year retrospective analysis (2011-2020) was performed using data extracted from the Health Information Exchange database characterising stroke presentations and risk factor profiles. The rates of hypertension (83.7% vs. 70.3%, p < 0.001) and dyslipidaemia (81.0% vs. 68.2%, p < 0.001) were significantly higher in Vietnamese patients, while the rates of ischaemic heart disease (10.4% vs. 20.3%, p < 0.001), smoking (24.4% vs. 40.8%, p < 0.001), and alcohol abuse (>1 drink/day) (9.6% vs. 15.9%, p < 0.001) were lower. The rates of ICAD and ICH were higher in Vietnamese patients (30.9% vs. 6.9%, p < 0.001 and 24.7% vs. 14.4%, p = 0.002). Regression analysis revealed that diabetes (OR: 1.86; 95% CI: 1.14-3.04, p = 0.014) and glycosylated haemoglobin (OR: 1.51; 95% CI: 1.15-1.98, p = 0.003) were predictors of ICAD in Vietnamese patients. Vietnamese patients had higher rates of symptomatic ICAD and ICH, with unique risk factor profiles. Culturally specific interventions arising from these findings may more effectively reduce the community burden of disease.

Correlation and risk factors of peripheral and cervicocephalic arterial atherosclerosis in patients with ischemic cerebrovascular disease

Patients with ischemic cerebrovascular disease (ICVD) frequently develop concomitant peripheral artery disease (PAD) or renal artery stenosis (RAS), and multiterritorial atherosclerotic patients usually have a worse prognosis. We aimed to evaluate the status of peripheral atherosclerosis (AS) and cervicocephalic AS (CAS) in ICVD patients with AS, their correlation, and related risk factors contributing to coexisting cervicocephalic-peripheral AS (CPAS). Based on the severity and extent of AS evaluated by computed tomography angiography and ultrasound, the degree of AS was triple categorized to assess the correlation between CAS and PAD/RAS. CAS and PAD/RAS were defined as the most severe stenosis being ≥ 50% luminal diameter in cervicocephalic or lower limb arteries, and a peak systolic velocity at the turbulent site being ≥ 180 cm/s in the renal artery. Among 403 patients with symptom onset within 30 days, CAS, PAD, and RAS occurrence rates were 68.7%, 25.3%, and 9.9%, respectively. PAD was independently associated with the degree of extracranial and intracranial CAS (p = 0.042, OR = 1.428, 95% CI 1.014–2.012; p = 0.002, OR = 1.680, 95% CI 1.206–2.339), while RAS was independently associated with the degree of extracranial CAS (p = 0.001, OR = 2.880, 95% CI 1.556–5.329). Independent CPAS risk factors included an ischemic stroke history (p = 0.033), increased age (p < 0.01), as well as elevated fibrinogen (p = 0.021) and D-dimer levels (p = 0.019). In conclusion, the occurrence rates of RAS and PAD in ICVD patients with AS is relatively high, and with the severity of RAS or PAD increase, the severity of CAS also increase. Strengthening the evaluation of peripheral AS and controlling elevated fibrinogen might be crucial for preventing and delaying the progression of multiterritorial AS in ICVD patients with AS, thereby improving risk stratification and promoting more effective prevention and treatment strategies.

#2009 FGF23 in patients with diabetic kidney disease and atherosclerosis

Abstract Background and Aims Diabetes mellitus (DM) and chronic kidney disease (CKD) are risk factors for vascular atherosclerosis, a pathological process with an important inflammatory component. The coexistence of these conditions in patients with diabetic kidney disease (DKD) has additive effects with worst cardiovascular mortality and morbidity rates when compared to non-diabetic CKD patient on cardiovascular outcomes. Accumulating research has shown that increased levels of bone-derived fibroblast growth factor 23 (FGF23), the major phosphate-regulating hormone, constitute a novel predictor of cardiovascular and all-cause mortality in CKD patients, with potential effects on disorders of glucose metabolism as well. The objective of this comparative study is to determine the differences in FGF23 levels in two groups of patients with CKD, with and without DM, matched by age, sex and renal function, all of them with clinical atherosclerotic disease. We also evaluated the relationships of FGF23 with several inflammatory markers and parameters of glucose metabolism. Method Sixty-six patients with CKD stages 3-4 (33 of them with DM) and diagnosed with peripheral vascular disease were included in the study. Whole blood and serum samples were obtained from all participants. CRP values, neutrophil/lymphocyte (N/L) ratio, HbA1c (%), fasting glucose, and Triglycerides and glucose (TyG) index, among other parameters, were obtained using standardized routine methods. Circulating levels of the intact form of FGF23, tumor necrosis factor (TNF) α, interleukin (IL) 6, and IL10 were determined by ELISA immunoassays in both groups. We also performed gene expression analysis for these three cytokines in peripheral blood cells (PBCs) using qPCR. Results The mean values of eGFR, ACR and phosphate were 37.6 ± 11.2 ml/min/1.73 m2; 294.1 ± 271.2 mg/g; 3.8 ± 0.82 mg/dL; respectively without differences between patients with and without DM The median circulating FGF23 values were higher in the DM group (51.59 [37.73-89.68] vs. 38.1 [33-54.14] pg/mL; p&amp;lt;0.001). Likewise, patients with DM presented higher levels of TNFα both in serum concentration (1.78 [0.72-2.47] vs. 1.28 [1.01-1.88] pg/mL; p&amp;lt;0.01) as in the expression of mRNA in PBCs (2.1 ± 1.26 vs. 1.87 ± 1.16 a.u.; p&amp;lt;0.05). No differences were observed for IL6 and IL10 levels, nor for CRP concentration or N/L ratio. As expected, fasting glucose, HbA1c and TyG index were higher in the group of subjects with DM. FGF23 was inversely correlated with eGFR (r=−0.435, p&amp;lt;0.0001), while it showed a positive association with ACR (r=0.416, p&amp;lt;0.001) and, interestingly, with proinflammatory cytokines including circulating TNFα (r=0.44, p&amp;lt;0.001), circulating IL6 (r=0.27, p=0.04), and TNF mRNA expression in PBCs (r=0.245, p=0.047). Furthermore, circulating FGF23 was also direct and significantly correlated with HbA1c (r=0.34, p&amp;lt;0.01). Conclusion These results suggest that FGF23 levels are higher in DKD than in non-DM CKD patients with similar renal function. DKD patients also had higher levels of the proinflammatory cytokine TNFα. Our results also show positive correlations of FGF23 with the inflammatory cytokines TNFα and IL6, as well as with HbA1c. Previous studies, shown that elevated TNFα and glucose promote FGF23 production, which may help to explain the higher levels of FGF23 in patients with DM Future studies should clarify whether FGF23 is simply a marker of atherosclerosis disease severity or a contributing factor to this complication in CKD.

The impact of smoking on third-degree atrioventricular block outcomes: A propensity-matched analysis

BackgroundThird-degree atrioventricular (AV) blocks are rare but cause significant symptoms and require immediate intervention. Coronary artery disease (CAD) is felt to be the most common etiology. Although smoking is a prominent risk factor for CAD, there is a paucity of data assessing the direct effect of smoking on third-degree AV block. MethodsWe performed a retrospective cohort study on adult-weighted admissions in 2019–2020 with a primary diagnosis of third-degree AV block and a history of smoking using the National Inpatient Sample (NIS) database. In-hospital mortality, rates of pacemaker insertion, cardiogenic shock, cardiac arrest, acute kidney injury (AKI), stroke, tracheal intubation, mechanical ventilation, mechanical circulatory support, vasopressor use, length of stay (LOS), and total hospitalization costs were analyzed using regression analysis. We performed a secondary analysis using propensity score matching to confirm the results. ResultsA total of 77,650 admissions met inclusion criteria (33,625 females [43.3 %], 58,315. Caucasians [75 %], 7030 African American [9 %], 6155 Hispanic [7.9 %]; mean [SD] age 75.4.[10.2] years) before propensity matching. A total of 29,380 (37.8 %) patients with AV block were smokers.A total of 5560 patients with and without a history of smoking were matched for the analysis. Smokers had.decreased odds of mortality (aOR, 0.59; CI, 0.44–0.78; p < 0.001), cardiogenic shock, cardiac arrest, tracheal intubation, mechanical ventilation, shorter LOS, and lower total hospital costs in both the multivariable regression and propensity-matched analyses. ConclusionThird-degree AV block had lower in-hospital mortality, cardiogenic shock, cardiac arrest, LOS, and total hospitalization cost in patients with smoking history.

Study on risk factors of carotid atherosclerosis in type 2 diabetes mellitus and development of prediction model

Study on risk factors of carotid atherosclerosis in type 2 diabetes mellitus and development of prediction model

Elevated remnant cholesterol is a risk factor for acute ischemic stroke

ObjectivesRemnant cholesterol (RC) is thought to be an important pathogenic risk factor for atherosclerosis, however, the relationship between RC and acute ischemic stroke (AIS) is still unclear. This study aimed to determine whether fasting blood RC level is an independent risk factor for AIS. Materials and methodsA retrospective analysis was performed on 650 patients with AIS and 598 healthy controls during the same time period. The association between RC and AIS was investigated using binary logistic regression, and the relationship between RC and AIS risk was demonstrated using Restricted Cubic Splines (RCS). ResultsRC was significantly higher in the AIS group compared with control group, and was an independent risk factor for AIS when the covariates were not adjusted;After adjusting some covariates, RC was still an independent risk factor for AIS. The RCS analysis found the risk was non-linear: when RC concentration was less than 0.69 mol/L, the risk of AIS increased with the elevation of RC, and when RC concentration was more than or equal to 0.69 mol/L, the risk of AIS was insignificant with the elevation of RC. Correlation analysis revealed that RC was associated with diabetes and fasting glucose. Further analysis revealed that the incidence of AIS in diabetic patients increased significantly with the increase of RC, and RCS analysis revealed that the risk of AIS in diabetic patients increased with the increase of RC when RC was more than 1.15 mol/L. ConclusionsThis study confirms RC as an independent risk factor for AIS, which highlights a distinct non-linear association between RC levels and AIS risk. These findings suggest the need for targeted AIS risk assessment strategies, especially in diabetic patients, and underscore the relevance of RC as a biomarker in AIS risk stratification.

Is Common Trunk Anomaly Frequent in Hemifacial Spasm? Comparison with Normal Subjects Using Magnetic Resonance Imaging

PurposeHemifacial spasm (HFS) results from vascular compression at the root exit of the facial nerve. Although the underlying etiology has yet to be identified, it has been suggested that congenital vascular anomalies are involved. We have hypothesized common trunk anomaly of the anterior inferior cerebellar artery (AICA) and posterior inferior cerebellar artery (PICA), may play a role in HFS. However, no previous studies have directly compared the incidence of this anomaly between HFS patients and normal subjects. The present study was designed to address this gap in the literature. MethodsThis case-control study compared magnetic resonance angiography data from 65 HFS patients and 65 normal subjects. Dominant AICA/PICA is defined as the absence of PICA/AICA, with the remaining AICA/PICA supplying both vascular territories. The term "common trunk" encompasses both dominant AICA and dominant PICA. The frequency of common trunk and dominant AICA/PICA was compared between the two groups. ResultsThere were no significant differences in the incidence of a common trunk (68.5% and 64.6%), dominant AICA (30.8% and 32.3%) and dominant PICA (37.7% and 32.3%) between the two groups. Additionally, no differences were found in the frequency of atherosclerosis risk factors. ConclusionsThere was no apparent association between common trunk anomaly and HFS. It is suspected that some vascular anomalies other than a common trunk are involved in HFS.

Histological Changes in the Popliteal Artery Wall in Patients with Critical Limb Ischemia.

This prospective study aims to illustrate the histopathological arterial changes in the popliteal artery in peripheral arterial disease of the lower limbs. A total of 60 popliteal artery segments taken from patients who had undergone lower limb amputation were examined between April and June 2023. The degree of arterial stenosis, medial calcinosis, and the vasa vasorum changes in the arterial adventitia were quantified. The presence of risk factors for atherosclerosis was also observed. Atherosclerotic plaque was found in all of the examined segments. Medial calcinosis was observed in 40 (66.6%) of the arterial segments. A positive association between the degree of arterial stenosis and the vasa vasorum changes in the arterial adventitia was also found (p = 0.025). The level of blood sugar and cholesterol were predictive factors for the severity of atherosclerosis. Atherosclerosis and medial calcinosis are significant in patients who underwent lower limb amputation. Medial calcinosis causes damage to the arterial wall and leads to a reduction in responsiveness to dilator stimuli.

Causal role of circulating inflammatory cytokines in cardiac diseases, structure and function

BackgroundInflammation is implicated in cardiovascular disease (CVD) pathogenesis, but causal roles of specific circulating inflammatory cytokines remain unclear. Mendelian randomization (MR) studies are well-poised to provide etiological insights beyond constraints of conventional research. MethodsWe conducted a large-scale MR study to investigate potential causal relationships of 91 inflammatory proteins with CVD outcomes and cardiac remodeling using summary-level genetic data. Outcomes included coronary artery disease, myocardial infarction, stroke, atrial fibrillation, heart failure, abdominal aortic aneurysm, deep vein thrombosis of lower extremities, pulmonary embolism, cardiac structure and functional parameters. Inverse-variance weighted analysis was undertaken as the primary analysis, with several sensitivity analyses applied. ResultsHepatocyte growth factor (HGF) demonstrated a causal relationship with increased susceptibility to both any stroke (OR 1.111; 95 % CI 1.044 - 1.183; P = 9.50e-04) and ischemic stroke (OR 1.121; 95 % CI 1.047 - 1.200; P = 1.04e-03). Programmed cell death 1 ligand 1 (PD-L1) was negatively associated with atrial fibrillation risk (OR 0.936, 95 % CI 0.901 - 0.973; P = 7.69e-04). CCL20, CDCP1, Flt3L and IL-10RA were identified as causal coronary artery disease risk factors, while LIF and ST1A1 had protective effects. IL-4 and LIF-R demonstrated causal links with right heart functional changes. ConclusionsOur MR study nominates specific circulating inflammatory cytokines as potential targets for CVD treatment and prevention. Further research into mechanisms and clinical translation are warranted.

Autoimmune thyroid disease as a risk factor of atherosclerosis

Autoimmune thyroid disease as a risk factor of atherosclerosis

Insulin sensitivity estimates and their longitudinal association with coronary artery disease in type 1 diabetes. Does it matter?

BackgroundInsulin resistance and chronic kidney disease are both associated with increased coronary artery disease risk. Many formulae estimating glucose disposal rate in type 1 diabetes infer insulin sensitivity from clinical data. We compare associations and performance relative to traditional risk factors and kidney disease severity between three formulae estimating the glucose disposal rate and coronary artery disease in people with type 1 diabetes.MethodsThe baseline glucose disposal rate was estimated by three (Williams, Duca, and Januszewski) formulae in FinnDiane Study participants and related to subsequent incidence of coronary artery disease, by baseline kidney status.ResultsIn 3517 adults with type 1 diabetes, during median (IQR) 19.3 (14.6, 21.4) years, 539 (15.3%) experienced a coronary artery disease event, with higher rates with worsening baseline kidney status. Correlations between the three formulae estimating the glucose disposal rate were weak, but the lowest quartile of each formula was associated with higher incidence of coronary artery disease. Importantly, only the glucose disposal rate estimation by Williams showed a linear association with coronary artery disease risk in all analyses. Of the three formulae, Williams was the strongest predictor of coronary artery disease. Only age and diabetes duration were stronger predictors. The strength of associations between estimated glucose disposal rate and CAD incidence varied by formula and kidney status.ConclusionsIn type 1 diabetes, estimated glucose disposal rates are associated with subsequent coronary artery disease, modulated by kidney disease severity. Future research is merited regarding the clinical usefulness of estimating the glucose disposal rate as a coronary artery disease risk factor and potential therapeutic target.

Association of Blood Copper With the Subclinical Carotid Atherosclerosis: An Observational Study.

Copper exposure is reported to be associated with increased risk of stroke. However, the association of copper exposure with subclinical carotid atherosclerosis remains unclear. This observational study included consecutive participants from Xinqiao Hospital between May 2020 and August 2021. Blood metals were measured using inductively coupled plasma mass spectrometry and carotid atherosclerosis was assessed using ultrasound. Modified Poisson regression was performed to evaluate the associations of copper and other metals with subclinical carotid plaque presence. Blood metals were analyzed as categorical according to the quartiles. Multivariable models were adjusted for age, sex, body mass index, education, smoking, drinking, hypertension, diabetes, dyslipidemia, estimated glomerular filtration rate, and coronary artery disease history. Bayesian Kernel Machine Regression was conducted to evaluate the overall association of metal mixture with subclinical carotid plaque presence. One thousand five hundred eighty-five participants were finally enrolled in our study, and carotid plaque was found in 1091 subjects. After adjusting for potential confounders, metal-progressively-adjusted models showed that blood copper was positively associated with subclinical carotid plaque (relative risk according to comparing quartile 4 to quartile 1 was 1.124 [1.021-1.238], relative risk according to per interquartile increment was 1.039 [1.008-1.071]). Blood cadmium and lead were also significantly associated with subclinical carotid plaque. Bayesian Kernel Machine Regression analyses suggested a synergistic effect of copper-cadmium-lead mixture on subclinical carotid plaque presence. Our findings identify copper as a novel risk factor of subclinical carotid atherosclerosis and show the potential synergistic proatherogenic effect of copper, cadmium, and lead mixture.

Role of C1q/TNF-Related Protein 6 for the Evaluation of Coronary Heart Disease Associated with Type 2 Diabetes.

Coronary artery disease (CAD) and type 2 diabetes (T2DM) are closely associated with increased rate of death. C1q/TNF-related protein 6 (CTRP6) is a novel adipocytokine which plays an important role in glucose and lipid metabolism. Little is known about the function of CTRP6 in CAD and T2DM patients. Herein, we aimed to study the association of CTRP6 level with CAD and T2DM. This study included 51 CAD, 44 CAD+T2DM and 65 non-CAD+T2DM patients from Affiliated Aoyang Hospital of Jiangsu University. Serum CTRP6 concentrations were detected by ELISA. Multiple logistic regression was used to analyze the association of serum CTRP6 with CAD and T2DM. Serum CTRP6 concentrations were significantly lower in CAD patients than controls. However, there is no significant statistical difference between CAD+T2DM patients and non-CAD+T2DM patients. Serum CTRP6 was negatively correlated with low-density lipoprotein cholesterol (LDL-C) (ρ=-0.2769, p=0.028) in controls. Serum CTRP6 was positively correlated with age (ρ=0.4121, p=0.0027), systolic blood pressure (SBP) (ρ=0.4012, p=0.0035), Creatinine (ρ=0.3295, p=0.0194), uric acid (UA) (ρ=0.3386, p=0.0162), and left ventricular end diastolic diameter (LVD) (ρ=0.4277, p=0.0042) and negatively correlated with ejection fraction (EF) (ρ=-0.3237, p=0.0342) in CAD patients. Serum CTRP6 was negatively correlated with high-density lipoprotein cholesterol (HDL-C) (ρ=-0.3164, p=0.0387) in CAD+T2DM patients. Multiple logistic regression showed that the decrease of CTRP6 was significantly related to the increased prevalence of CAD. What is more, CTRP6 increased prevalence of T2DM in CAD patients. Lower serum CTRP6 could be a risk factor of CAD. However, higher circulating CTRP6 associated with the increased prevalence of T2DM in CAD patients.

Abstract 132: Immunosenescence-related Biomarkers And Potential Therapeutic Targets For Coronary Artery Disease Identified Via Plasma Proteome And Immune Cell Traits

There is a pressing need to identify novel biomarkers and therapeutic targets to address the epidemiological burden of coronary artery disease (CAD). Mendelian Randomization analysis (MR) leverages Genome-Wide Association Study (GWAS) data to infer the causal mechanism underlying the phenotype of interest. The proteome is the central mediator of the etiology and pathophysiology of multifactorial diseases such as CAD. Here, we screened for potential biomarkers and therapeutic targets for CAD through MR by using genetically predicted levels of plasma proteome followed by immune cell traits and transcriptomic analysis. The main workflow of our study is outlined in Figure 1. Briefly, MR analysis was performed with protein quantitative trait loci (pQTL) and meta-analysis of four independent GWASs. Sensitivity analysis was performed to ensure the robustness of identified proteins. Pathway Enrichment analysis on whole-blood transcriptome was performed with GSEA. Secondary MR explored the causal effect of 731 immune cell traits on CAD risk. In total, 11 overlapping candidate proteins (P&lt;0.05, OR&gt;1.0) were identified from the plasma proteome meta-analysis, including LPA, PLA2G7, and PCSK9, substantiating the validity of our MR analysis. Functional annotation of candidate proteins identified LCAT and CA11 as promising therapeutic targets and biomarkers. LCAT suppression is protective against atherosclerosis in mice models, while the functional significance of CA11 remains to be elucidated. Transcriptomic analysis shows enrichment in IL-2 signaling pathways reflective of the exhaustion of CD28 on cytotoxic T cells identified via secondary MR using immune-cell traits. Together, these results are indicative of immunosenescence as a risk factor for CAD. Overall, our results revealed that an altered immune landscape increased the risk for CAD and unraveled an encouraging avenue for early diagnosis and treatment of CAD.

Advanced Glycation End Products-Induced Alzheimer's Disease and Its Novel Therapeutic Approaches: A Comprehensive Review.

Advanced glycation end products (AGEs) accumulate in the brain, leading to neurodegenerative conditions such as Alzheimer's disease (AD). The pathophysiology of AD is influenced by receptors for AGEs and toll-like receptor 4 (TLR4). Protein glycation results in irreversible AGEs through a complicated series of reactions involving the formation of Schiff's base, the Amadori reaction, followed by the Maillard reaction, which causes abnormal brain glucose metabolism, oxidative stress, malfunctioning mitochondria, plaque deposition, and neuronal death. Amyloid plaque and other stimuli activate macrophages, which are crucial immune cells in AD development, triggering the production of inflammatory molecules and contributing to the disease's pathogenesis. The risk of AD is doubled by risk factors for atherosclerosis, dementia, advanced age, and type 2 diabetic mellitus (DM). As individuals age, the prevalence of neurological illnesses such as AD increases due to a decrease in glyoxalase levels and an increase in AGE accumulation. Insulin's role in proteostasis influences hallmarks of AD-like tau phosphorylation and amyloid β peptide clearance, affecting lipid metabolism, inflammation, vasoreactivity, and vascular function. The high-mobility group box 1 (HMGB1) protein, a key initiator and activator of a neuroinflammatory response, has been linked to the development of neurodegenerative diseases such as AD. The TLR4 inhibitor was found to improve memory and learning impairment and decrease Aβ build-up. Therapeutic research into anti-glycation agents, receptor for advanced glycation end products (RAGE) inhibitors, and AGE breakers offers hope for intervention strategies. Dietary and lifestyle modifications can also slow AD progression. Newer therapeutic approaches targeting AGE-related pathways are needed.

EFFECTIVENESS &amp; TOLERABILITY OF METOPROLOL ER, TELMISARTAN &amp; CHLORTHALIDONE IN ESSENTIAL HYPERTENSION PATIENTS WITH STABLE CAD: INDIAN REAL-WORLD STUDY STRATIFIED BY COMORBIDITIES

Objective: We conducted a real-world study to assess effectiveness (on blood pressure [BP; mmHg]) and tolerability of fixed dose combination (FDC) of 25/50 mg Metoprolol + 40 mg Telmisartan + 12.5 mg Chlorthalidone in treating hypertension and stable coronary artery disease (CAD). Considering comorbidities as risk factors for hypertension and CAD, this subgroup analysis was conducted in patients with common comorbidities. Design and method: A retrospective, multicenter study retrieved data over 15 months from electronic medical records of 1,810 adult patients with essential hypertension [systolic BP (SBP) greater than or equal to 140 and/or diastolic BP (DBP) greater than or equal to 90] and stable CAD. Of 1,784 patients who received this FDC for 24 ± 2 weeks; 1,224 had comorbidities (obesity: 1,062; diabetes mellitus: 494; dyslipidaemia: 270; hypothyroidism: 121). Results: Mean change in SBP / DBP (obese: -31.1 / -12.2; diabetes mellitus: -29.8 / -11.4; dyslipidaemia: -28.6 / -10.7; hypothyroidism: -26.4 / -8.5) from baseline to 24 ± 2 weeks was significant (p&lt;0.001, Fig 1). Proportions of patients achieving target BP (SBP &lt; 140 and DBP &lt; 90) was &gt;90% in diabetes mellitus and hypothyroidism and &gt;82% in obese and dyslipidaemia patients. Of 14 patients with adverse events (hypotension being most common), 10 had comorbidities. Conclusions: This real-world study demonstrated that the FDC of Metoprolol + Telmisartan + Chlorthalidone was effective in reducing blood pressure and well tolerated in treating patients with hypertension and CAD who had common comorbidities.

Abstract 116: Apolipoprotein E Registry In Discoidal Lipoproteins Influences Uptake

Introduction: Apolipoprotein E (apoE) is of great interest due to its role as a risk factor for Alzheimer's disease and atherosclerosis. ApoE is secreted by astrocytes in the central nervous system as HDL-like lipoparticles. Currently there is no high-resolution structural model of lipidated apoE, resulting in a limited mechanistic understanding of how apoE functions in health and disease. Research Questions: The goal of this research was to utilize cryoEM to characterize the structure of apoE in discoidal lipoproteins. Methods: Astrocyte secreted apoE was immunopurified from culture media and characterized by TEM and cryoEM. Recombinant apoE (rapoE) was lipidated with DMPC to model astrocyte secreted lipoproteins. Results: TEM and cryoEM imaging of astrocyte apoE and rapoE found that apoE forms a dimer on discoidal lipoproteins. These results provide support for the “double belt” model of two apoE in an anti-parallel conformation. This conformation was independent of apoE isoform, suggesting it is a general feature of apoE in discoidal lipoproteins. ApoE isoforms differ by the addition or loss of a Cys residue. ApoE2 has 2 Cys residues (Cys112, Cys158), apoE3 has 1 Cys residue (Cys112), and apoE4 has no Cys residues. Accordingly, apoE4 cannot form disulfide bonds, apoE3 can form intermolecular disulfide bonds, and apoE2 can form both intramolecular and intermolecular disulfide bonds. Due to the presence of two apoE on discoidal lipoproteins, apoE3 can form a disulfide bridge between the two apoE protein. Disulfide bridge formation and experimental reduction of these disulfide bridges revealed that disulfide-linked apoE3 was uptaken significantly more by Neuro2a cells (P ≤ 0.0001) than nondisulfide-linked apoE3. Conclusion: All isoforms of apoE adopt an antiparallel dimer in discoidal lipoprotein. Different registries, regulated through the formation of disulfide bonds between the anti-parallel apoE polypeptides, leads to differential uptake of apoE by Neuro2a cells. Since the different isoforms of apoE have inherently different capacity to generate disulfide bridges, we conclude that this property affecting receptor uptake may strongly impact differential biological properties of the different isoforms.

Abstract 2077: The Epigenetic Regulator PRDM16 Controls Smooth Muscle Phenotypic Modulation And Atherosclerosis Risk

Despite decades of progress, coronary artery disease (CAD) remains the top cause of death worldwide. Additionally, trends in outcomes have worsened recently, highlighting the critical need for additional treatments. Human genetics has identified over 300 loci associated with CAD, but understanding the molecular mechanisms leading to disease remains a huge barrier to developing new therapies. These CAD-associated loci are enriched in smooth muscle cells (SMC) of the vascular wall, but no current therapies target these cells. Since insulin resistance is an important risk factor for CAD, understanding the molecular functions of genes associated with both insulin resistance and CAD will prioritize therapeutic candidates, especially if expressed in SMCs. One promising candidate is the gene PRDM16 (PR domain containing 16), which is highly expressed in vascular tissue. PRDM16 regulates cell fate decisions and insulin resistance in adipose tissue, but its role in atherosclerosis and SMC function is unknown. Recent advances in lineage tracing and conditional SMC knockout mouse models in conjunction with single cell technologies have demonstrated the cellular trajectories of SMC into several cellular states, including fibromyocytes (FMC) and chondromyocytes (CMC). Here, we employ this innovative approach to understand the role of Prdm16 on SMC phenotypic modulation in vivo and its role in the development of FMC and CMC. We also demonstrate the impact of Prdm16 in atherosclerosis and other important lesion characteristics relating to disease risk. We validate these effects in vitro and employ epigenetic analysis to identify the gene regulatory mechanisms whereby PRDM16 mediates its effects on SMC phenotypic modulation. Collectively these data demonstrate that PRDM16 is a causal factor that promotes risk of CAD.

Prevalence and risk factors associated with coronary artery disease in Iranian patients with peripheral artery disease

IntroductionIt is well known that peripheral artery disease (PAD) and coronary artery disease (CAD) coexist and therefore, patients diagnosed with PAD have an increased chance of developing concomitant CAD. CAD-related complications could be a leading cause of postoperative mortality in individuals with PAD undergoing vascular surgery. We present a case series of 48 patients who underwent coronary angiography before vascular surgery and an updated review of previous reports to determine the prevalence of concomitant CAD in a convenience sample of Iranian patients. MethodsThis cross-sectional study was performed on 48 patients with confirmed PAD admitted to Imam Ali Hospital, affiliated with the Kermanshah University of Medical Sciences (KUMS), Kermanshah Province, Iran. A vascular surgeon diagnosed PAD based on the patient's symptoms, Doppler ultrasound, and CT angiography (CTA). All patients underwent coronary angiography to determine if they also had CAD. We defined significant CAD as a ≥70% luminal diameter narrowing of a major epicardial artery or a ≥50% narrowing of the left main coronary artery. ResultsOf 48 patients, 35 (72.9%) were male, 13 (27.1%) were female, and the mean age was 64.18±12.11 years (range, 30 to 100 years). The incidence of CAD in patients with PVD was 85.42% (41/48). The patients with CAD were more likely to be hypertensive than those without CAD (80.5 vs. 14.3, p-value<0.001). Of 41 patients with CAD, 9 (22.0%) had one-vessel disease, 10 (24.3%) had two-vessel disease, and 22 (53.7%) had three-vessel disease. ConclusionHypertension was a significant risk factor for CAD. Patients with hypertension and multiple major coronary risk factors scheduled for PVD surgery should be carefully evaluated for concomitant CAD.