Particle Cholesterol Research Articles

NMR-Based Lipid Metabolite Profiles to Predict Outcomes in Patients Undergoing Interventional Therapy for a Hepatocellular Carcinoma (HCC): A Substudy of the SORAMIC Trial.

Simple SummaryA hepatocellular carcinoma (HCC) is the most common cause of death in patients suffering from chronic liver diseases. In order to improve the prediction of outcomes in HCC patients, there is a need for new biomarkers. This pilot study aimed at identifying serum metabolites for the prediction of outcomes of HCC patients using nuclear magnetic resonance (NMR) spectroscopy. This analysis revealed that high serum concentrations of myo-inositol or dimethylamine were associated with an improved overall survival. In contrast, high concentrations of total cholesterol, LDL-cholesterol and LDL particles (LDL-P) were associated with a decreased overall survival. The identification of novel biomarkers using this NMR-based technology holds promise for opening new directions in the conduction of interventional trials in HCCs.Background: This exploratory study aimed to evaluate lipidomic and metabolomic profiles in patients with early and advanced HCCs and to investigate whether certain metabolic parameters may predict the overall survival in these patients. Methods: A total of 60 patients from the prospective, randomized-controlled, multicenter phase II SORAMIC trial were included in this substudy; among them were 30 patients with an early HCC who underwent radiofrequency ablation combined with sorafenib or a placebo and 30 patients with an advanced HCC who were treated with a selective internal radiation therapy (SIRT) plus sorafenib vs. sorafenib alone. The blood serum of these patients was analyzed using a standardized nuclear magnetic resonance (NMR) platform. All tested metabolites were correlated with the overall survival. Results: The overall survival (OS) was significantly higher in patients with an early HCC (median OS: 34.0 months) compared with patients with an advanced HCC (median OS: 12.0 months) (p < 0.0001). Patients with high serum concentrations of myo-inositol (MI) had a higher overall survival compared with patients with low concentrations (21.6 vs. 13.8 months) with a Pearson correlation coefficient of 0.331 (p = 0.011). Patients with high serum concentrations of dimethylamine had a higher overall survival compared with patients with low concentrations (25.1 vs. 19.7 months) with a Pearson correlation coefficient of 0.279 (p = 0.034). High concentrations of total cholesterol, LDL-cholesterol and LDL particles (LDL-P) were associated with a decreased overall survival. Conclusions: NMR-based lipidomic and metabolomic profiling has the potential to identify individual metabolite biomarkers that predict the outcome of patients with an HCC exposed to non-invasive therapeutic management.

A Study of Creatinine Level among Patients with Dyslipidemia and Type 2 Diabetes Mellitus using Multilayer Perceptron and Multiple Linear Regression.

Background and Objective:Dyslipidemia is one of the most important risk factors for coronary heart disease with diabetes mellitus. Diabetic dyslipidemia is correlated with reduced concentrations of high-density lipoprotein cholesterol, elevated concentrations of plasma triglycerides, and increased concentrations of dense small particles of low-density lipoprotein cholesterol. Furthermore, dyslipidemia is one of the factors that accelerate renal failure in patients with nephropathy that is observed to be higher in these patients. This paper aims to propose the variable selection using the multilayer perceptron (MLP) neural network methodology before performing the multiple linear regression (MLR) modeling. Dataset consists of patient with Dyslipidemia, and Type 2 Diabetes Mellitus was selected to illustrate the design-build methodology. According to clinical expert's opinion and based on their assessment, these variables were chosen, which comprises the level of creatinine, urea, total cholesterol, uric acid, sodium, and HbA1c.Materials and Methods:At the first stage, all the selected variables will be a screen for their clinical important point of view, and it was found that creatinine has a significant relationship to the level of urea reading, a total of cholesterol reading, and the level of uric acid reading. By considering the level of significance, α = 0.05, these three variables are being selected and used for the input of the MLP model. Then, the MLR is being applied according to the best variable obtained through MLP process.Results:Through the testing/out-sample mean squared error (MSE), the performance of MLP was assessed. MSE is an indication of the distance from the actual findings from our estimates. The smallest MSE of the MLP shows the best variable selection combination in the model.Conclusion:In this research paper, we also provide the R syntax for MLP better illustration. The key factors associated with creatinine were urea, total cholesterol, and uric acid in patients with dyslipidemia and type 2 diabetes mellitus.

72-OR: HDL Particle Concentration Predicts Incident Coronary Artery Disease (CAD) in Type 1 Diabetes (T1D)

We have shown that elevated HDL cholesterol (HDL-C) levels (≥80 mg/dL) associate with increased CAD risk in women with T1D. Furthermore, HDL-C levels are not necessarily cardioprotective in nondiabetic individuals, suggesting that the cholesterol content of HDL does not accurately assess CAD risk. We thus determined whether two other HDL metrics, HDL particle concentration (HDL-P) and cholesterol efflux capacity (CEC), predicted incident CAD in a large cohort of childhood onset T1D (n=550). At baseline, mean age was 27.8 yrs, T1D duration was 19.6 yrs and 49% were women. HDL-P was assessed by calibrated ion mobility analysis and CEC was quantified with validated assays in cAMP stimulated J774 cells and in ABCA1-expressing BHK cells. CAD was defined as CAD death, myocardial infarction and/or revascularization. During a median follow-up of 26 yrs, we observed 203 incident CAD cases (36.9%). At baseline, incident cases were older, more likely to have smoked, have hypertension, longer duration of T1D, higher non-HDL-C and markers of kidney disease and inflammation. Cases were also more likely to have lower HDL-P concentrations but similar CEC to non-cases. Cox models with backward elimination were constructed for each HDL metric, allowing for potential confounding variables, including HDL-C. In separate multivariable models, higher concentrations of total HDL-P (T-HDL-P, HR=0.88, 95% CI: 0.83-0.92) and 3 major HDL subpopulations - small (S-HDL-P, HR=0.78, 0.67-0.92), medium (M-HDL-P, HR=0.79, 0.71-0.88) and large-sized (L-HDL-P, HR=0.74, 0.61-0.89) particles - associated with a lower CAD incidence whereas HDL-C did not. Higher total CEC in J774 cells also predicted lower CAD risk (HR=0.74, 0.55-0.996) after similar adjustments, but became non-significant after further adjusting for HDL-P. ABCA1-specific CEC did not predict CAD. Our results suggest that increased HDL-P levels are cardioprotective in T1D, in contrast to HDL-C and CEC which did not independently predict CAD. Disclosure T. Costacou: None. T. Vaisar: Consultant; Self; AstraZeneca. K. Bornfeldt: None. T. J. Orchard: None. J. Heinecke: None. Funding National Institutes of Health (HL130153, DK34818)

OP0221 TARGETED METABOLOMIC PROFILING AND PREDICTION OF CARDIOVASCULAR EVENTS: A PROSPECTIVE STUDY OF PATIENTS WITH PSORIATIC ARTHRITIS AND PSORIASIS

Background:Psoriatic arthritis and psoriasis, collectively termed psoriatic disease (PsD), are associated with increased cardiovascular (CV) risk. Metabolites comprise biomarkers that may add predictive value over traditional CV risk factors.Objectives:We aimed to identify metabolites associated with CV events (CVEs) and to determine whether they could improve CV risk prediction beyond traditional CV risk factors.Methods:Patients from a longitudinal PsD cohort without a prior history of CVEs were included. In the first available serum sample, a targeted nuclear magnetic resonance (NMR) metabolomics platform was used to quantify 64 metabolite measures comprised of lipoprotein subclasses, fatty acids, glycolysis precursors, ketone bodies and amino acids. The study outcome included any of the following CVEs occurring within the first 10 years of biomarker assessment: angina, myocardial infarction, congestive heart failure, transient ischemic attack, cerebrovascular accident, revascularization procedures and CV death. The association of each metabolite with incident CVEs were analyzed separately using Cox proportional hazards regression models first adjusted for age and sex, and subsequently for traditional CV risk factors. Variable selection was performed using penalization with boosting after adjusting for age and sex. The added predictive value of the selected metabolites to improve risk prediction beyond traditional CV risk factors was assessed using the area under the receiver operator characteristic curve (AUC).Results:A total of 977 patients with PsD, followed between 2002 and 2019, were analyzed (mean age 49.1 ± 12.6 years, 45.1% female). During a mean follow-up of 7.1 years, 70 (7.2%) patients developed incident CVEs. In Cox regression models adjusted for CV risk factors, alanine, tyrosine, total high-density lipoprotein (HDL) cholesterol, medium and large HDL particles, and the degree of unsaturation of fatty acids were significantly associated with decreased CV risk. Glycoprotein acetyls, apolipoprotein B, remnant cholesterol, very low-density lipoprotein (VLDL) cholesterol, and very small VLDL particles were associated with an increased CV risk. In proportional sub-distribution hazards regression models adjusted for age and sex, 13 metabolites were selected (Table 1). The age- and sex-adjusted expanded model (base model + 13 metabolites) significantly improved prediction of CVEs beyond the base model (only age and sex) with an AUC of 79.9 vs. 72.6, respectively (p=0.019) (Figure 1).Table 1.Regression coefficients of the selected metabolites in a model adjusted for age and sex.CategoryMetaboliteModel adjusted for Age and SexAmino AcidsAlanine-0.1179Glycine-0.0339Tyrosine-0.1010Fatty acid ratios, relative to total fatty acidsDocosahexaenoic acid-0.0862Unsaturation degree, double bonds per fatty acid-0.1265Fluid BalanceAlbumin+0.0685GlyceridesTriglycerides in IDL cholesterol+0.1546Glycolysis precursorsGlucose+0.1391InflammationGlycoprotein acetyls+0.1478Ketone bodiesAcetoacetate+0.0464Lipoprotein subclassesHDL3 Cholesterol-0.0211Medium HDL-0.0296Large HDL-0.0309Figure 1.Predictive performance of a model with age and sex alone is compared to a model with age and sex plus selected metabolites.Conclusion:Using NMR metabolomics profiling, we identified a variety of metabolites associated with a lower and higher risk of developing CVEs in patients with PsD. Further study of their underlying association with CVEs is needed to clarify the clinical utility of these biomarkers to guide CV risk assessment in this population.

Analysis of the Mechanism of Cholesterol Particle Formation by Liquid Antisolvent Crystallization

Analysis of the Mechanism of Cholesterol Particle Formation by Liquid Antisolvent Crystallization

The influence of ultra-processed food consumption in anthropometric and atherogenic indices of adolescents

ABSTRACT Objective To investigate the influence of ultra-processed food consumption on anthropometric and atherogenic indices. Methods A cross-sectional study was conducted with 327 adolescents aged 14 to 19 years. Sociodemographic, anthropometric, biochemical, and food consumption data were evaluated. The ratios of atherogenic indices were calculated using the Castelli I (Total Cholesterol/High Density Lipoprotein Cholesterol), Castelli II (Low Density Lipoprotein Cholesterol/High Density Lipoprotein Cholesterol), and estimated Low Density Lipoprotein Cholesterol particle size (Atherogenic Index of Plasma=Triglycerides/High-Density Lipoprotein Cholesterol) indices. Logistic regression was used for the unadjusted and adjusted analysis between ultra-processed foods consumption, anthropometric, and atherogenic indices. The level of significance was 5%. Results Most participants were female (59.3%). Girls had a higher consumption of ultra-processed foods (26.6% vs. 20.5%). Of the total number of adolescents, 16.5% were overweight and 65.7% were from public schools. Adolescents with altered values for the Castelli I and II Index, and for the Atherogenic Index of Plasma had significantly higher weights, Waist Circumference, Waist Circumference/ Height and Body Mass Index/ Age values. The adjusted analysis identified a significant association (Odds ratio=2.29; 95% Confidence interval: 1.23-4.28) between the high consumption of ultra-processed foods and the Castelli II index. Conclusion The associations between atherogenic indices and anthropometric indices and the consumption of ultra-processed foods highlight the negative influence of these foods on adolescents’ cardiovascular health.

Thromboembolic and atherosclerotic cardiovascular events in inflammatory bowel disease: epidemiology, pathogenesis and clinical management.

Inflammatory bowel disease (IBD) is associated with an increased risk of cardiovascular disease (CVD). The increased risk of CVD concerns an increased risk of venous thromboembolism (VTE), atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF), at corresponding relative risks of 2.5, 1.2 and 2.0, respectively, as compared with the general population. Especially young patients under the age of 40 years run a relatively high risk of these complications when compared with the general population. Chronic systemic inflammation causes a hypercoagulable state leading to the prothrombotic tendency characteristic of VTE, and accelerates all stages involved during atherogenesis in ASCVD. Increased awareness of VTE risk is warranted in patients with extensive colonic disease in both ulcerative colitis and Crohn’s disease, as well as during hospitalization, especially when patients are scheduled for surgery. Similarly, critical periods for ASCVD events are the 3 months prior to and 3 months after an IBD-related hospital admission. The increased ASCVD risk is not fully explained by an increased prevalence of traditional risk factors and includes pro-atherogenc lipid profiles with high levels of small dense low-density lipoprotein cholesterol particles and dysfunctional high-density lipoprotein cholesterol. Risk factors associated with HF are location and extent of inflammation, female sex, and age exceeding 40 years. A dose-dependent increase of overall CVD risk has been reported for corticosteroids. Immunomodulating maintenance therapy might reduce CVD risk in IBD, not only by a direct reduction of chronic systemic inflammation but possibly also by a direct effect of IBD medication on platelet aggregation, endothelial function and lipid and glucose metabolism. More data are needed to define these effects accurately. Despite accumulating evidence on the increased CVD risk in IBD, congruent recommendations to develop preventive strategies are lacking. This literature review provides an overview of current knowledge and identifies gaps in evidence regarding CVD risk in IBD, by discussing epidemiology, pathogenesis, and clinical management.

Heterogeneity of T Cells in Atherosclerosis Defined by Single-Cell RNA-Sequencing and Cytometry by Time of Flight.

The infiltration and accumulation of pro- and anti-inflammatory leukocytes within the intimal layer of the arterial wall is a hallmark of developing and progressing atherosclerosis. While traditionally perceived as macrophage- and foam cell-dominated disease, it is now established that atherosclerosis is a partial autoimmune disease that involves the recognition of peptides from ApoB (apolipoprotein B), the core protein of LDL (low-density lipoprotein) cholesterol particles, by CD4+ T-helper cells and autoantibodies against LDL and ApoB. Autoimmunity in the atherosclerotic plaque has long been understood as a pathogenic T-helper type-1 driven response with proinflammatory cytokine secretion. Recent developments in high-parametric cell immunophenotyping by mass cytometry, single-cell RNA-sequencing, and in tools exploring antigen-specificity have established the existence of several unforeseen layers of T-cell diversity with mixed TH1 and T regulatory cells transcriptional programs and unpredicted fates. These findings suggest that pathogenic ApoB-reactive T cells evolve from atheroprotective and immunosuppressive CD4+ T regulatory cells that lose their protective properties over time. Here, we discuss T-cell heterogeneity in atherosclerosis with a focus on plasticity, antigen-specificity, exhaustion, maturation, tissue residency, and its potential use in clinical prediction.

Autologous adipose mesenchymal stem cell administration in arteriosclerosis and potential for anti-aging application: a retrospective cohort study

ObjectiveArteriosclerosis is an age-related disease and a leading cause of cardiovascular disease. In animal experiments, mesenchymal stem cells and its culture-conditioned medium have been shown to be promising tools for prevention or treatment of arteriosclerosis. On the basis of these evidences, we aimed to assess whether administration of autologous adipose-derived mesenchymal stem cells (Ad-MSC) is safe and effective for treatment of arteriosclerosis.MethodsWe retrospectively reviewed clinical records of patients with arteriosclerosis who had received autologous Ad-MSC administration at our clinic. Patients’ characteristics were recorded and data on lipid profile, intimal-media thickness (IMT), cardio-ankle vascular index (CAVI), and ankle-brachial index (ABI) before and after Ad-MSC administration were collected and compared.ResultsTreatment with Ad-MSC significantly improved HDL, LDL, and remnant-like particle (RLP) cholesterol levels. No adverse effect or toxicity was observed in relation to the treatment. Of the patients with abnormal HDL values before treatment, the vast majority showed improvement in the values. Overall, the measurements after treatment were significantly increased compared with those before treatment (p < 0.01). In addition, decreases in LDL cholesterol and RLP levels were observed after treatment in patients who had abnormal LDL cholesterol or RLP levels before treatment. The majority of patients with pre-treatment abnormal CAVI values had improved values after treatment. In patients with available IMT values, a significant decrease in the IMT values was found after therapy (p < 0.01). All patients with borderline arteriosclerosis disease had improved laboratory findings after treatment. In general, post-treatment values were significantly decreased as compared with pre-treatment values. Of the patients with normal ABI values before treatment at the same time as CAVI, the vast majority remained normal after treatment.ConclusionsThese findings suggest that Ad-MSC administration is safe and effective in patients developing arteriosclerosis, thereby providing an attractive tool for anti-aging application.

Association between size of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol particles and cardiovascular events in type 2 diabetes subjects

Association between size of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol particles and cardiovascular events in type 2 diabetes subjects

Importance of the triglyceride level in identifying patients with a Type III Hyperlipoproteinemia phenotype using the ApoB algorithm

Hyperlipoproteinemia Type III (HLP3), also known as dysbetalipoproteinemia, is defined by cholesterol and triglyceride (TG) enriched remnant lipoprotein particles (RLP). The gold standard for diagnosis requires demonstration of high remnant lipoprotein particle cholesterol (RLP-C) by serum ultracentrifugation (UC), which is not readily available in daily practice. The apoB algorithm can identify HLP3 using total cholesterol (TC), plasma triglyceride (TG), and apoB. However, the optimal TG cutoff is unknown. We analyzed apoB algorithm defined HLP3 at different TG levels to optimize the TG cutoff for the algorithm. 128,485 UC lipid profiles in the Very Large Database of Lipids (VLDbL) were analyzed. RLP-C was assessed at TG≥133mg/dL, ≥175mg/dL, ≥200mg/dL, and ≥ 250mg/dL. Sensitivity (Sn), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), and prevalence adjusted and bias-adjusted kappa (PABAK) were calculated against UC Criterion (VLDL-C/TG≥0.25) for HLP3. The median age (IQR) was 57years (46-68). 45% were men, 20.1% had diabetes, and 25.5% had hypertension. The median RLP-C level for the TG cutoffs (mg/dL) of ≥ 133, ≥ 175, ≥ 200, and ≥ 250 were 34, 43, 50, and 62 mg/dL, respectively, compared to 67 mg/dL in UC defined HLP3. TG≥133mg/dL yielded optimal results (Sn 29.5%, Sp 98.5%, PABAK 0.96, PPV 13.6%, NPV 99.4%). TG≥133mg/dL allows for high sensitivity in screening for HLP3. Higher TG cutoffs may identify more severe HLP3 phenotypes, but with a large loss in sensitivity for HLP3.

Maternal High-Sucrose Diet Affects Phenotype Outcome in Adult Male Offspring: Role of Zbtb16.

Overnutrition in pregnancy and lactation affects fetal and early postnatal development, which can result in metabolic disorders in adulthood. We tested a hypothesis that variation of the Zbtb16 gene, a significant energy metabolism regulator, modulates the effect of maternal high-sucrose diet (HSD) on metabolic and transcriptomic profiles of the offspring. We used the spontaneously hypertensive rat (SHR) strain and a minimal congenic rat strain SHR-Zbtb16, carrying the Zbtb16 gene allele originating from the PD/Cub rat, a metabolic syndrome model. Sixteen-week-old SHR and SHR-Zbtb16 rat dams were fed either standard diet (control groups) or a high-sucrose diet (HSD, 70% calories as sucrose) during pregnancy and 4 weeks of lactation. In dams of both strains, we observed an HSD-induced increase of cholesterol and triacylglycerol concentrations in VLDL particles and a decrease of cholesterol and triacylglycerols content in medium to very small LDL particles. In male offspring, exposure to maternal HSD substantially increased brown fat weight in both strains, decreased triglycerides in LDL particles, and impaired glucose tolerance exclusively in SHR. The transcriptome assessment revealed networks of transcripts reflecting the shifts induced by maternal HSD with major nodes including mir-126, Hsd11b1 in the brown adipose tissue, Pcsk9, Nr0b2 in the liver and Hsd11b1, Slc2a4 in white adipose tissue. In summary, maternal HSD feeding during pregnancy and lactation affected brown fat deposition and lipid metabolism in adult male offspring and induced major transcriptome shifts in liver, white, and brown adipose tissues. The Zbtb16 variation present in the SHR-Zbtb16 led to several strain-specific effects of the maternal HSD, particularly the transcriptomic profile shifts of the adult male offspring.

Lipoprotein characterization in Quaker parrots (Myiopsitta monachus) using gel‐permeation high‐performance liquid chromatography

Lipid accumulation disorders, such as atherosclerosis and hepatic lipidosis, are common in psittacine birds and associated with various dyslipidemias. Gel-permeation high-performance liquid chromatography (GP-HPLC) is a reference method for advanced lipoprotein profiling based on particle size separation, followed by an analysis of lipid contents. The objectives were to (a) characterize Quaker parrot lipoproteins using a commercial GP-HPLC method (Liposearch panel), and (b) obtain preliminary information on the reliability of the Friedewald formula for low-density lipoprotein-cholesterol (LDL-C) measurements. Plasma samples were collected from 12 fasted healthy Quaker parrots. Cholesterol concentrations, triglyceride concentrations, particle sizes, and particle numbers were determined by GP-HPLC for four classes and 20 sub-fractions of lipoproteins. The LDL-C concentrations obtained using the Friedewald formula and direct measurements were compared with Bland-Altman plots. Alternate formulas were determined using multiple linear regression. High-density lipoprotein (HDL) was the predominant lipoprotein in Quaker parrots, and most particles were of medium-to-small sizes belonging to two sub-fractions (average size, 10.6nm). LDL was the second most common lipoprotein and included large-to-small particles belonging to three sub-fractions (average size, 24.9nm). Very-low-density lipoproteins (VLDL) and portomicrons were present in low concentrations. The Friedewald formula underestimated LDL-C concentrations with a significant bias of 0.44mmol/L. An alternate formula was proposed: LDL-C=0.75*Non-HDL-C. GP-HPLC allowed unprecedented characterization of plasma lipoproteins in Quaker parrots. Characterizing psittacine lipoprotein is useful for validation and interpretation of routine clinical tests as well as for use in epidemiologic and experimental research on psittacine lipid accumulation disorders.

HDL Cholesterol Efflux Capacity is Impaired in Severe Short-Term Hypothyroidism Despite Increased HDL Cholesterol.

Severe hypothyroidism has profound effects on lipoprotein metabolism including high-density lipoprotein (HDL) cholesterol elevations but effects on HDL function metrics are unknown. To determine the impact of severe short-term hypothyroidism on HDL particle characteristics, HDL cholesterol efflux capacity (CEC), and HDL antioxidative capacity. Observational study with variables measured during severe short-term hypothyroidism (median TSH 81 mU/L) and after 20 weeks of thyroid hormone supplementation (median TSH 0.03 mU/L) (Netherlands Trial Registry ID 7228). University hospital setting in The Netherlands. Seventeen patients who had undergone a total thyroidectomy for differentiated thyroid carcinoma. HDL particle characteristics (nuclear magnetic resonance spectrometry), CEC (human THP-1-derived macrophage foam cells and apolipoprotein B-depleted plasma), and HDL anti-oxidative capacity (inhibition of low-density lipoprotein oxidation). During hypothyroidism plasma total cholesterol, HDL cholesterol and apolipoprotein A-I were increased (P ≤ 0.001). HDL particle concentration was unchanged, but there was a shift in HDL subclasses toward larger HDL particles (P < 0.001). CEC was decreased (P = 0.035), also when corrected for HDL cholesterol (P < 0.001) or HDL particle concentration (P = 0.011). HDL antioxidative capacity did not change. During severe short-term hypothyroidism CEC, an important antiatherogenic metric of HDL function, is impaired. HDL cholesterol and larger HDL particles are increased but HDL particle concentration is unchanged. Combined, these findings suggest that HDL quality and quantity are not improved, reflecting dysfunctional HDL in hypothyroidism.

A Randomized Placebo-Controlled Trial of Secukinumab on Aortic Vascular Inflammation in Moderate-to-Severe Plaque Psoriasis (VIP-S)

Psoriasis, a chronic immune-mediated disease, is associated with an increased risk of cardiovascular events and mortality. Secukinumab selectively neutralizes IL-17A and has reported high efficacy with a favorable safety profile in various psoriatic disease manifestations. Subsequent to the 12-week randomized, placebo-controlled, double-blind treatment period, patients with moderate-to-severe psoriasis received secukinumab for 40 weeks. Vascular inflammation using 18F-2-fluorodeoxyglucose-positron emission tomography/computed tomography imaging and blood-based cardiometabolic was assessed at week 0, 12, and 52. The difference in change in aortic inflammation from baseline to week 12 for secukinumab (n = 46) versus placebo (n = 45) was -0.053 (95% confidence interval= -0.169 to 0.064; P= 0.37). Small increases in total cholesterol, low-density lipoprotein, and low-density lipoprotein particles, but no changes in markers of inflammation, adiposity, insulin resistance, or predictors of diabetes, were observed with secukinumab treatment compared with placebo. At week 52, reductions in TNF-α (P= 0.0063) and ferritin (P= 0.0354), and an increase in fetuin-A (P= 0.0024), were observed with secukinumab treatment compared with baseline. No significant changes in aortic inflammation or markers of advanced lipoprotein characterization, adiposity, or insulin resistance were observed with secukinumab treatment compared with baseline. Secukinumab exhibited a neutral impact on aortic vascular inflammation and biomarkers of cardiometabolic disease after 52 weeks of treatment.

Comparison of nonfasting and fasting lipoprotein subfractions and size in 15,397 apparently healthy individuals: An analysis from the VITamin D and OmegA-3 TriaL

Elevated postprandial triglycerides reflect a proatherogenic milieu, but underlying mechanisms are unclear. We examined differences between fasting and nonfasting profiles of directly measured lipoprotein size and subfractions to assess if postprandial triglycerides reflected increases in very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and remnants, or small dense lipid depleted LDL (sdLDL) particles. We conducted a cross-sectional analysis of 15,397 participants (10,135 fasting; 5262 nonfasting [<8hours since last meal]) from the VITamin D and OmegA-3 TriaL. Baseline cholesterol subfractions were measured by the vertical auto profile method and particle subfractions by ion mobility. We performed multivariable linear regression adjusting for cardiovascular and lipoprotein-modifying risk factors. Mean age (SD) was 68.0years (±7.0), with 50.9% women. Adjusted mean triglyceride concentrations were higher nonfasting by 17.8±1.3%, with higher nonfasting levels of directly measured VLDL cholesterol (by 3.5±0.6%) and total VLDL particles (by 2.0±0.7%), specifically large VLDL (by 12.3±1.3%) and medium VLDL particles (by 5.3±0.8%), all P<.001. By contrast, lower concentrations of low density lipoprotein (LDL) and IDL cholesterol and particles were noted for nonfasting participants. sdLDL cholesterol levels and particle concentrations showed no statistically significant difference by fasting status (-1.3±2.1% and 0.07±0.6%, respectively, P>.05). Directly measured particle and cholesterol concentrations of VLDL, not sdLDL, were higher nonfasting and may partly contribute to the proatherogenicity of postprandial hypertriglyceridemia. These differences, although statistically significant, were small and may not fully explain the increased risk of postprandial hypertriglyceridemia.

Participation of white adipose tissue dysfunction on circulating HDL cholesterol and HDL particle size in apparently healthy humans.

To use the combined presence of the elevated insulin resistance index in adipose tissue (Adipo-IR) and low values of adiponectin as a marker of dysfunctional adipose tissue, and to analyze its possible association with low values of high-density lipoprotein cholesterol (HDL-C) and small size of HDL particles. The analysis included 253 subjects with functional adipose tissue and 253 with dysfunctional adipose tissue, considering similar gender, age, and body mass index (BMI). Adipo-IR was considered when index values (free fatty acids × insulin concentrations) were ≥75th percentile. Low levels of adiponectin were considered when concentration in serum was <25th percentile (determined by ELISA). HDL size was estimated by a quantitative validated equation. Small HDL size was considered when values were <25th percentile. When comparing subjects with functional adipose tissue with those of dysfunctional adipose tissue, the latter had a higher prevalence of low HDL-C (51.4% vs. 64.0%; p = 0.004) and small HDL (56.9% vs. 67.6%; p = 0.009). Multivariate analysis indicated that independently from other metabolic risk factors, dysfunction of adipose tissue is significantly associated with low HDL-C (OR: 1.624 [CI 95%: 1.100-2.397]) and small HDL (OR: 1.462 [CI 95%: 1.000-2.139]). Adding BMI, waist circumference, and subcutaneous or visceral adipose tissue did not modify the association. Dysfunction of adipose tissue is associated with a 65 and 50% higher probability of having low HDL-C and small HDL. Identification of dysfunctional adipose tissue could be a useful tool in the clinical setting to prevent the cardiometabolic risk independently from adiposity.

Lowering Targeted Atherogenic Lipoprotein Cholesterol Goals for Patients at "Extreme" ASCVD Risk.

To review randomized interventional clinical and imaging trials that support lower targeted atherogenic lipoprotein cholesterol goals in "extreme" and "very high" atherosclerotic cardiovascular disease (ASCVD) risk settings. Major atherosclerotic cardiovascular event (MACE) prevention among the highest risk patients with ASCVD requires aggressive management of global risks, including lowering of the fundamental atherogenic apolipoprotein B-associated lipoprotein cholesterol particles [i.e., triglyceride-rich lipoprotein remnant cholesterol, low-density lipoprotein cholesterol (LDL-C), and lipoprotein(a)]. LDL-C has been the long-time focus of imaging studies and randomized clinical trials (RCTs). The 2004 adult treatment panel (ATP-III) update recognized that the long-standing targeted LDL-C goal of < 100mg/dL potentially fostered substantial undertreatment of the very highest coronary heart disease (CHD) risk individuals and was lowered to < 70mg/dL as an "optional" goal for "very high" 10-year CHD [CHD death + myocardial infarction (MI)] risk exceeding 20%. This evidence-based guideline change was supported by the observed benefits demonstrated in the high-risk primary and secondary prevention populations in the Heart Protection Study (HPS), the acute coronary syndrome (ACS) population in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 trial (PROVE-IT), and the secondary prevention population in the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) intravascular ultrasound (IVUS) study. Subsequent national and international guidelines maintained a targeted LDL-C goal < 70mg/dL, or a threshold for management of > 70mg/dL for patients with CHD, CHD risk equivalency, or ASCVD. Subgroup or meta-analyses of several RCTs, IVUS imaging studies, and the ACS population in IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) supported the evidence-based 2017 American Association Clinical Endocrinologist (AACE) guideline change establishing a targeted LDL-C goal < 55mg/dL, non-HDL-C < 80mg/dl, and apolipoprotein B (apo B) < 70mg/dL for patients at "Extreme" ASCVD risk, i.e., 10-year 3-point-MACE-composite (CV death, non-fatal MI, or ischemic stroke) risk exceeding 30%. Moreover, with no recognized lower-limit-associated intolerance or safety issues, even more intensive lowering of atherogenic cholesterol levels is supported by the following evidence base: (1) analysis of eight high-intensity statin-based prospective secondary prevention IVUS atheroma volume regression trials; (2) a distribution analysis of on-treatment, ezetimibe and background-statin, of the very low LDL-C levels reached and CVD event risk in the IMPROVE-IT ACS population; (3) the secondary prevention Global Assessment of Pl\aque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) on background-statin; and (4) the secondary prevention population of Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER). By example, in FOURIER, the population on background-statin at a baseline median 92mg/dL achieved median LDL-C level of 30mg/dL and non-HDL-C to < 65mg/dl, and apo B to < 50mg/dL, and subgroup and post hoc analyses all demonstrated additional ASCVD event reduction benefits as LDL-C was further reduced. The level of ASCVD risk determines the degree, urgency, and persistence in global risk management, including fundamental atherogenic lipoprotein cholesterol particle lowering. "Extreme" risk patients may require extremely low targeted LDL-C, non-HDL-C and apo B goals; such efforts, implied by more recent interventional trials and analyses, are aimed at maximal atheroma plaque regression, stabilization, and MACE event reduction with the aspiration of improved quality lifespan.

Syndecan-1: A Review on Its Role in Heart Failure and Chronic Liver Disease Patients' Assessment.

The close connection and interaction between the cardiac and the liver functions are well-known, as cirrhotic cardiomyopathy is an important clinical entity which best describes the mutual pathogenical influence between these two organs. Due to the fact that cardiac dysfunction in patients with chronic hepatic disorders is oligosymptomatic or even asymptomatic, an early diagnosis represents a challenge for every physician. Syndecan-1—a transmembrane proteoglycan that exerts its functions mainly via its heparane sulfate chains—is a very promising biomarker, correlated not only with the degree of cardiac fibrosis but also with the severity of liver fibrosis. Many studies highlighted its role in the development of cardiac fibrosis or atherogenesis, being significantly correlated with the activity of angiotensin II. Multiple evidence revealed that syndecan-1 is also associated with tissue injury and may regulate inflammatory and regenerative responses, being considered a protective molecule that limits the inflammation and reduces cardiac remodelling and dysfunction after a myocardial infarction. Syndecan-1 may also be used as a reliable biomarker for the noninvasive assessment of liver fibrosis. Under various fibrogenetic conditions, shedding of syndecan's extracellular domain took place, becoming a soluble form that binds different growth factors and inhibits further fibrosis. This complex molecule is also involved in the lipid metabolism, by altering the clearance of cholesterol particles, and in chronic hepatitis, by enhancing the viral invasion of hepatocytes. Due to the growing interest in this biomarker, multiple studies aimed at revealing syndecan-1's potential benefits in the diagnosis and prognosis assessment in patients with heart failure or chronic liver disorders. In this review, we review the mechanisms by which syndecan-1 exerts its effects and the possible perspectives opened by its use as a dual cardio-hepatic biomarker.

Alirocumab therapy in individuals with type 2 diabetes mellitus and atherosclerotic cardiovascular disease: analysis of the ODYSSEY DM-DYSLIPIDEMIA and DM-INSULIN studies

BackgroundIndividuals with diabetes often have high levels of atherogenic lipoproteins and cholesterol reflected by elevated low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and LDL particle number (LDL-PN). The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events. We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778).MethodsIn DM-DYSLIPIDEMIA, individuals with T2DM and mixed dyslipidemia (non-HDL-C ≥ 100 mg/dL; n = 413) were randomized to open-label alirocumab 75 mg every 2 weeks (Q2W) or usual care (UC) for 24 weeks, with UC options selected before stratified randomization. In DM-INSULIN, insulin-treated individuals with T2DM (LDL-C ≥ 70 mg/dL; n = 441) were randomized in a double-blind fashion to alirocumab 75 mg Q2W or placebo for 24 weeks. Study participants also had a glycated hemoglobin < 9% (DM-DYSLIPIDEMIA) or < 10% (DM-INSULIN). Alirocumab dose was increased to 150 mg Q2W at week 12 if week 8 LDL-C was ≥ 70 mg/dL (DM-INSULIN) or non-HDL-C was ≥ 100 mg/dL (DM-DYSLIPIDEMIA). Lipid reductions and safety were assessed in patients with ASCVD from these studies.ResultsThis analysis included 142 DM-DYSLIPIDEMIA and 177 DM-INSULIN participants with ASCVD, including 95.1% and 86.4% with coronary heart disease, and 32.4% and 49.7% with microvascular diabetes complications, respectively. At week 24, alirocumab significantly reduced LDL-C, non-HDL-C, ApoB, and LDL-PN from baseline versus control. This translated into a greater proportion of individuals achieving non-HDL-C < 100 mg/dL (64.6% alirocumab/23.8% UC [DM-DYSLIPIDEMIA]; 65.4% alirocumab/14.9% placebo [DM-INSULIN]) and ApoB < 80 mg/dL (75.1% alirocumab/35.4% UC and 76.8% alirocumab/24.8% placebo, respectively) versus control at week 24 (all P < 0.0001). In pooling these studies, 66.4% (alirocumab) and 67.0% (control) of individuals reported treatment-emergent adverse events. The adverse event pattern was similar with alirocumab versus controls.ConclusionsAmong individuals with T2DM and ASCVD who had high non-HDL-C/LDL-C levels despite maximally tolerated statin, alirocumab significantly reduced atherogenic cholesterol and LDL-PN versus control. Alirocumab was generally well tolerated.Trial registration Clinicaltrials.gov. NCT02642159. Registered 30 December 2015 and Clinicaltrials.gov. NCT02585778. Registered 23 October 2015