Lower LDL-C Levels Research Articles

Abstract 2048: Pla2g12b Is Critical For Intestinal Lipid Absorption In Mice

We previously showed that Pla2g12bhlb218/hlb218 (Pla2g12bmt/mt) mice injected with viruses expressing mutant PCSK9, fed a western diet had significantly lower plasma lipids and fewer atherosclerotic plaques. Here, we aimed to explain mechanisms for resistance to hyperlipidemia and atherosclerosis in these mice. We performed studies in 3-month-old male and female chow fed Pla2g12bmt/mt and control mice. Dual x-ray absorptiometry did not reveal any significant differences in body weight, fat weight and fat percentage in Pla2g12bmt/mt mice compared to controls. Moreover, there were no significant differences in energy expenditure and food intake between mutant and control mice. However, these mice had significantly lower levels of plasma glucose, insulin, triglyceride, cholesterol, HDL-c, LDL-c, apoB48, and apoB100. In oral fat tolerance test Pla2g12bmt/mt mice showed significant defects in triglyceride absorption. Furthermore, these mice excreted more fecal triglyceride, but not cholesterol. Oil Red O, H & E staining, transmission electron microscopy, and quantifications of lipids in the duodenum indicated accumulation of large lipid droplets and dilated endoplasmic reticulum. These studies suggest that Pla2g12bmt/mt mice have significant defect in intestinal fat absorption. These defects were not due to reductions in apoB and MTP expression. RNA-Seq analysis of duodenal samples revealed upregulation of glycerolipid metabolism, arachidonic acid metabolism, oxidative phosphorylation, and thermogenesis. These pathways were likely upregulated to increase cellular catabolism and oxidation of accumulated lipids. Down upregulated pathways were related to pancreatic secretion, protein digestion and absorption. Despite severe defects in fat absorption, these mice maintain normal growth and physiology. These mice may serve as model to understand metabolism in hypolipidemia disorders associated with significant defects in lipid absorption such as abetalipoproteinemia and hypobetalipoproteinemia.

CHARACTERISTICS OF DIFFERENT HYPERTENSION STAGES IN CHINA —RESULTS FROM A NATIONAL CROSS-SECTIONAL UPPDATE STUDY

Objective: We sought to investigate the prevalence and characteristics of patients with hypertension stage 1, 2, and 3 according to 2023 ESH guidelines for the management of hypertension. Design and method: A cross-sectional study was carried out in 90 centers from 15 cities in China from 2017-2018. Patients aged over 18 years with essential hypertension were investigated. Hypertension stage 1 was defined as uncomplicated hypertension without hypertension-mediated organ damage (HMOD), diabetes, cardiovascular disease (CVD) and without chronic kidney disease (CKD) >=stage 3. Hypertension stage 2 was defined as presence of HMOD, diabetes, or CKD stage 3. Hypertension stage 3 was defined as presence of CVD or CKD stage 4 or 5. Results: A total of 4286 patients were included, 56% of whom were male. Hypertension stage 1, 2, and 3 account for 28%, 50%, and 22% respectively. Ninety-three % of the total patients were having antihypertensive therapy. The average BP was 133±12/85±11 mmHg, 146±17/83±12 mmHg, and 143±19/84±13 mmHg in hypertension stage 1, 2, and 3 respectively. Lipid lowering therapy accounted for 40%, 49%, and 71% respectively, which was relatively low. The average LDL-C level was 3.0±1.0mmol/L, 2.9±1.0mmol/L, and 2.6±1.4mmol/L respectively, which was far from the goal of LDL-C management. Homocysteine was 11.2±9.6 μmol/L, 13.6±9.1 μmol/L, and 19.0±11.2 μmol/L, which increased from stage 1 to stage3. Conclusions: Hypertension stage 2 accounted for half of the patients with hypertension in China. The average blood pressure was much higher in stage 2 and stage 3. Only 71% of hypertension stage 3 were having lipid lowering therapy and LDL-C levels were far from the recommended goal. Homocysteine was positively associated with hypertension stage.

Advancements In Pharmacotherapy for Hyperlipidemia: A Comprehensive Review of Recent Drug Innovations and Clinical Outcomes

Hyperlipidemia, characterized by elevated blood lipid levels, significantly contributes to cardiovascular diseases (CVDs), the leading cause of global mortality per the World Health Organization (WHO). Studies reveal a 20-30% increase in coronary heart disease risk for every 1 mmol/L rise in LDL-C levels. While statins are widely used, novel pharmacotherapeutic approaches are necessary for effective hyperlipidemia management and CVD risk reduction. Recent clinical trials demonstrate the efficacy of innovative drugs like proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in lowering LDL-C levels and reducing adverse cardiovascular events. These findings highlight the potential of new therapies to enhance existing treatments for hyperlipidemia. Additionally, safety evaluations of emerging lipid-lowering agents address concerns about adverse effects and long-term risks. Despite progress, challenges persist in refining treatment strategies and ensuring equitable access to advanced therapies, especially for marginalized populations. Incorporating innovative pharmacotherapies into current approaches offers personalized and efficient hyperlipidemia management. Continued research and interdisciplinary collaborations are vital for advancing our understanding of lipid metabolism and translating scientific discoveries into improved patient outcomes and cardiovascular health. Ongoing innovation and investment in tailored hyperlipidemia therapies are crucial for better outcomes in individuals at risk of CVDs.
 Keywords: hyperlipidemia, pcsk9 inhibitors, bempedoic acid, evinacumab, inclisiran mipomersen, volanesorsen

Drug Target Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Atrial Fibrillation

Introduction: Atrial fibrillation (AF) is a prevalent cardiac arrhythmia with significant clinical implications. The potential influence of lipid-lowering therapies, specifically PCSK9 inhibitors (PCSK9i) and HMG-CoA reductase inhibitors (statins), on AF risk remains a topic of interest. This mendelian randomization (MR) study aimed to elucidate the causal relationship between genetically predicted inhibition of PCSK9 and HMG-CoA reductase and the risk of AF. Methods: Utilizing publicly available, summary-level genome-wide association study data, we employed single-nucleotide polymorphisms associated with lower LDL-C levels as instruments for gene-simulated inhibition of PCSK9 and HMG-CoA reductase. Multiple MR techniques were applied to estimate the causal effects, and sensitivity analyses were conducted to validate the results. Results: Genetically predicted inhibition of PCSK9 demonstrated a reduced risk of AF, with an odds ratio (OR) of 0.92 (95% CI: 0.85–0.99, p = 0.01) using the inverse variance-weighted (IVW) method. In contrast, the inhibition of HMG-CoA reductase did not exhibit a statistically significant association with AF risk (IVW: OR = 1.11, 95% CI: 1.00–1.22, p = 0.05). Conclusion: Our MR study suggests that genetically predicted inhibition of PCSK9, but not HMG-CoA reductase, is associated with a lower risk of AF. These findings provide evidence for a causal protective effect of PCSK9i on AF and support the use of PCSK9i for AF prevention in patients with dyslipidemia. Further studies are needed to elucidate the mechanisms underlying the differential effects of PCSK9i and statins on AF and to confirm the clinical implications of our findings.

Associations of Dietary Intake with Cardiovascular Risk in Long-Term "Plant-Based Eaters": A Secondary Analysis of a Cross-Sectional Study.

A plant-based diet rich in whole foods and fiber is beneficial for cardiovascular (CV) health. This impact is often linked to specific food groups and their preparation methods, reflecting the overall dietary pattern. However, research on the long-term effects of a carefully designed plant-based diet on adults transitioning from a typical Western lifestyle is limited. Notably, studies on people managing CV risk factors effectively are scarce. As part of a cross-sectional study, we examined 151 individuals committed to a long-term, well-designed plant-based diet and active lifestyle. We investigated how specific food groups and macronutrient intake are related to various CV health markers. In this secondary analysis, our comprehensive approach encompassed several methods: 3-day weighted dietary records, fasting blood lipid and blood pressure measurements, body composition assessments, and evaluations of lifestyle status. We adjusted our analysis for multiple variables, such as age, sex, current body mass index, smoking status, physical activity, and time (years) following the plant-based diet. Our findings revealed several associations between macronutrient intake (per 50 g) and CV risk markers, although these associations were generally weak. Individuals who consumed more whole grains and fruits had lower levels of total, low-density lipoprotein (LDL-C), and high-density lipoprotein (HDL-C) cholesterol. We also found associations between the intake of legumes and nuts/seeds and reduced HDL-C levels. These findings suggested that these food groups might influence the lipid profile, contributing to CV health in a plant-based diet. A greater intake of spices/herbs was associated with lower uric acid levels, while diets rich in plant-based fast food and pasta (made from white flour) were associated with higher uric acid levels. A greater intake of various macronutrients, such as fiber, carbohydrates (from whole-food sources), proteins, and different types of fats (saturated fatty acids [SFAs], monounsaturated fatty acids [MUFAs], and polyunsaturated fatty acids [PUFAs]), was associated with lower levels of total cholesterol, LDL-C (only for carbohydrates), and HDL-C. We found a unique negative correlation between PUFA intake and LDL-C, suggesting that PUFAs might significantly affect LDL-C levels. In contrast, increased fiber, protein and SFA consumption were associated with increased uric acid levels. These findings support the impact of dietary patterns on CV risk factors, highlighting that even small amounts of unhealthy food groups can significantly influence specific CV risk markers, regardless of the overall diet.

Elucidating the mechanisms of formononetin in modulating atherosclerotic plaque formation in ApoE-/- mice

BackgroundAtherosclerosis(AS) poses a pressing challenge in contemporary medicine. Formononetin (FMN) plays a crucial role in its prevention and treatment. However, the detailed impact of FMN on the stability of atherosclerotic plaques and its underlying mechanisms remain to be elucidated.MethodsAn intervention consisting of FMN was given along with a high-fat food regimen in the ApoE-/- mouse model. The investigation included the evaluation of the degree of atherosclerotic lesion, the main components of the plaque, lipid profiles, particular markers indicating M1/M2 macrophage phenotypes, the quantities of factors related to inflammation, the infiltration of macrophages, and the identification of markers linked to the α7nAChR/JAK2/STAT3 axis effect molecules.ResultsThe evaluation of aortic morphology in ApoE-/-mice revealed that FMN significantly improved the plaque area, fibrous cap protrusion, lipid deposition, and structural alterations on the aortic surface, among other markers of atherosclerosis,and there is concentration dependence. Furthermore, the lipid content of mouse serum was assessed, and the results showed that the low-, medium-, and high-dosage FMN groups had significantly lower levels of LDL-C, ox-LDL, TC, and TG. The results of immunohistochemical staining indicated that the low-, medium-, and high-dose FMN therapy groups had enhanced CD206 expression and decreased expression of CD68 and iNOS. According to RT-qPCR data, FMN intervention has the potential to suppress the expression of iNOS, COX-2, miR-155-5p, IL-6, and IL-1β mRNA, while promoting the expression of IL-10, SHIP1, and Arg-1 mRNA levels. However, the degree of inhibition varied among dosage groups. Western blot investigation of JAK/STAT signaling pathway proteins and cholinergic α7nAChR protein showed that p-JAK2 and p-STAT3 protein expression was suppressed at all dosages, whereas α7nAChR protein expression was enhanced.ConclusionsAccording to the aforementioned findings, FMN can reduce inflammation and atherosclerosis by influencing macrophage polarization, blocking the JAK/STAT signaling pathway, and increasing α7nAChR expression.

Role of Proprotein Convertase Subtilisin Kexin Type 9 Inhibitor Therapy in treatment of Patients with Polycystic Ovary Syndrome: A systemic Review of Metabolic and Cardiovascular Outcomes

Polycystic Ovary Syndrome (PCOS) is a common endocrine condition that affects both obese and nonobese women of reproductive age group. Its clinical presentation is dysmenorrhea, hirsutism, acne, metabolic complications, infertility, and polycystic ovaries. The study is aimed to assess the efficacy of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors to lower dyslipidemia in women with PCOS to prevent long term cardio-metabolic complications. PCSK 9 Inhibitors ( Alirocumab, Evolocumab, and Inclisiran) bind to LDL receptors in liver and lower LDLC levels, preventing long term adverse side effects. This review aims at showing that these drugs can be effective when prescribed to women with PCOS earlyon to prevent some serious cardiovascular and metabolic complications in the long run. In terms of medical therapy, most physicians prescribe Metformin and Statins as first line agents to control risk factors. But much of the research supported the use of PCSK 9 Inhibitors early in the disease process or as an add-on to statins for controlling the lipid profile. When compared to Statins, the control rates of PCSK 9 Inhibitors were equal or superior and they showed additive effect when given along with other lipid lowering agents. Studies showed these drugs have only minor side effects and have good tolerability profile. They do not have severe side effects as compared to statins or fibrates.

Effectiveness of Pumpkin Juice and Butylated Hydroxyanisole Supplemented to Yogurt on Lipid Profile for Hypercholesterolemia Rats

Experimental animals with hypercholesterol will be fed yogurt fortified with concentrated pumpkin juice and the industrial antioxidant butylated hydroxyanisole (BHA), and their health will be monitored. Rats were fed either a standard diet (T1), a high-fat diet (T2), or a high-fat diet (T3) supplemented with 2 ml of yogurt per day. Rats were also fed either a high-fat diet (T4) supplemented with 2 ml of yogurt per day fortified with concentrated pumpkin juice (T4), or a diet high in fat (T5) supplemented with 2 ml of yogurt per day fortified with the synthetic antioxidant Hypercholesterolemia in male rats as measured by plasma total cholesterol, triglycerides, high density lipoprotein cholesterol, low density lipoprotein cholesterol, and liver enzymes. Adult rats were fed by tube feeding and weighed, then randomized into five groups. One of the most notable findings was that hypercholesterolemia in animals resulted in a statistically significant increase (p0.05) in cholesterol, triglyceride, and LDL-C concentrations compared to the control group, and a statistically significant decrease (p0.05) in HDL-C concentration. The experimental results showed that the groups given yogurt supplemented with pumpkin juice had significantly higher HDL concentrations and lower levels of cholesterol, triglycerides, LDL-C, AST, and ALT compared to the control group.

Successful ESC recommended LDL-C reduction after percutaneous coronary intervention: real-world data from the contemporary ZON-HR registry

Abstract Background Low density lipoprotein-cholesterol (LDL-C) reduction in patients who underwent percutaneous coronary intervention (PCI) is recommended by ESC guidelines to prevent secondary events. Lipid lowering treatment is indicated to reach a LDL-C of less than 1.4mmol/l in these very high risk patients. The ‘’Zuid-Oost Nederland Heart Registry’’ (ZON-HR) is a multicentre prospective registry designed to improve secondary prevention after PCI by a patient-tailored approach. Purpose Cholesterol management in patients after percutaneous coronary intervention (PCI) from the ZON-HR was evaluated. Methods Since November 2020 real-world data from 4628 patients who underwent PCI were collected in four hospitals. Patient characteristics, LDL-C values at baseline and after 30 days and medication at discharge were collected. The association between predefined variables and a LDL-C <1.4 mmol/l was assessed in multivariable logistic regression. Results LDL-C at baseline and one-month follow-up was complete in 306 patients. This number is limited, because LDL-C was not routinely tested in every patient at baseline and during 30 day follow-up. Patients with a chronic coronary syndrome (CCS) undergoing PCI were significantly older compared to patients with ACS (66.8 vs 63.9 years)(table 1). After one month, the LDL-C value decreased significantly both in ACS as well as CCS patients. No significant differences in cholesterol lowering medication at discharge between CCS and ACS patients were observed. Statins (87.8%) were most frequent prescribed, with low numbers of new therapies (8.2% ezetimibe, 2.6% PCSK-9 inhibitor). The goal LDL <1.4 mmol/l was reached in 33% of patients. Lower LDL-C levels at baseline, ACS indication for PCI, and a combination of lipid lowering treatment were independent predictors for achieving the goal LDL-C <1.4 (table 2). Conclusion Our contemporary registry reveals the following important observations: 1) LDL-C assessment at one month follow-up is performed in a minority of patients. 2) The LDL-C goal of 1.4 mmol/l is reached in a minority of patients. 3) Predictors for reaching the ESC recommended target include an ACS indication and combination lipid lowering treatment, emphasizing the importance of secondary prevention.Baseline characteristicsPredictors reaching LDL-C target value

Identification of potent small-molecule PCSK9 inhibitors based on quantitative structure-activity relationship, pharmacophore modeling, and molecular docking procedure

Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) attaches to the domain of LDL receptor (LDLR), diminishing LDL-C influx and LDLR cell surface presentation in hepatocytes, resulting in higher circulating LDL-C levels. PCSK9 dysfunction has been linked to lower levels of plasma LDLC and a decreased CHD risk. Purpose To identify a potent small-molecule PCSK9 inhibitor in compounds that are currently being studied in clinical trials. Methods We first performed chemical absorption, distribution, metabolism, excretion, and toxicity filtering of 9800 clinical trial compounds obtained from the ZINC 15 database using Lipinski's rule of five and achieved 3853 compounds. Two-dimensional (2D) Quantitative Structure-Activity Relationship (QSAR) was initiated by computing molecular descriptors and selecting important descriptors of 23 PCSK9 inhibitors. Multivariate calibration was performed with the partial least square regression (PLS) method with 18 compounds for training to design the QSAR model and five compounds for the test set to assess the model. The best latent variables (LV) (LV=6) with the lowest value of Root-Mean-Square Error of Cross-Validation (RMSECV) of 0.48 and leave-one-out cross-validation correlation coefficient (R2CV)=0.83 were obtained for the QSAR model. The low RMSEC (0.21) with high R²cal (0.966) indicates the probability of fit between the experimental data and the calibration model. Results Using QSAR analysis of 3853 compounds, 2635 had a pIC50<1 and were considered for pharmacophore screening. The PHASE module designed the pharmacophore hypothesis through multiple ligands. The top 14 compounds (pIC50>1) were defined as active, whereas nine (pIC50<1) were considered as an inactive set. Three five-point pharmacophore hypotheses achieved the highest score: DHHRR1, DHHRR2, and DHRRR1. The highest and best model with survival scores (5.365) was DHHRR1, comprising one hydrogen donor (D), two hydrophobic groups (H), and two rings of aromatic (R) features. We selected the molecules with a higher 1.5 fitness score (257 compounds) in pharmacophore screening (DHHRR1) for molecular docking screening.Molecular docking indicates that ZINC000051951669, with a binding affinity: of -13.2 kcal/mol and two H-bonds, has the highest binding to the PCSK9 protein. ZINC000011726230 with energy binding: -11.4 kcal/mol and three H-bonds, ZINC000068248147 with binding affinity: -10.7 kcal/mol and one H-bond, ZINC000029134440 with a binding affinity: -10.6 kcal/mol and four H-bonds were ranked next, respectively. Conclusion The archived molecules identified as inhibitory PCSK9 candidates, and especially ZINC000051951669 may therefore significantly inhibit PCSK9 and should be considered in the newly designed trials.Figure 1.The six-top docking compound against PCSK9 with lowest binding affinity. A) ZINC000051951669, B) ZINC000011726230, C) ZINC000068248147, D) ZINC000029134440, E) ZINC000000602086, F) ZINC000034630885.

Abstract 16462: Phenotypic Features of Lipidic Plaque in Patients With Polyvascular Disease: Findings From the Reassure Near-Infrared Spectroscopy Imaging Multi-Center Registry

Introduction: Polyvascular disease (PolyVD) is a high-risk atherosclerotic phenotype presenting worse cardiovascular outcomes. However, its atherosclerotic features remain to be fully elucidated yet. Near-infrared spectroscopy (NIRS) imaging quantifies lipidic plaque associated with clinical outcome. Hypothesis: Given a clustering of atherogenic risks in PolyVD, PolyVD may exhibit a distinct plaque phenotype, which accounts for their outcome. Methods: 224 culprit lesions in 203 CAD patients receiving PCI were evaluated by NIRS imaging. PolyVD was defined as those with additional ASCVD (stroke and/or LEAD). NIRS-derived lipidic plaque feature (maxLCBI 4mm ) and clinical outcome (all-cause death+non-fatal MI+stroke) were compared in PolyVD and non-PolyVD subjects. Results: 28.6% of study subjects exhibited PolyVD. They were older (77 v. 71 years, p=0.02) with a greater frequency of CKD (61 v. 45%, p=0.03). Under the use of statin (81 v. 71%, p=0.15) and ezetimibe (32 v. 21%, p=0.09), PolyVD patients had a lower LDL-C level (73 v. 84 mg/dL, p=0.01). Despite their LDL-C control, maxLCBI 4mm did not differ in two groups (median: 458 v. 576, p=0.19). Moreover, 64% of PolyVD patients still showed maxLCBI 4mm ≧400 (69% in non-PolyVD, p=0.44). On multivariate analysis, ACS independently predicted maxLCBI 4mm ≧400 (Figure) in PolyVD patients. Of note, PolyVD presenting ACS had a higher maxLCBI 4mm (790 v. 411, p=0.001) compared to those without ACS, whereas this relationship did not exist in non-PolyVD (622 v. 561, p=0.19, Figure). During the 3-year observational period, PolyVD was associated with an elevated risk of MACE (p=0.002). Conclusions: Despite lowering LDL-C levels, PolyVD harbored a large amount of lipidic materials, accompanied by worse cardiovascular outcomes. Given the relationship of ACS with maxLCBI 4mm in PolyVD, additional therapies which modulates ACS-related inflammatory activity may be warranted to alter their disease substrate and outcomes.

Abstract 14714: Long-Term Neurocognitive Safety of LDL-C Lowering With Evolocumab: Open-Label Extension Data From FOURIER

Background: Concerns have been raised about low LDL-C levels and possible adverse effects on cognition. PCSK9 inhibitors markedly lower LDL-C, yet EBBINGHAUS, a prespecified substudy within the FOURIER trial, did not show adverse cognitive changes with evolocumab over 19 months median follow-up. Purpose: To investigate the long-term effects of evolocumab on cognitive function. Methods: EBBINGHAUS was a substudy of cognitive function using the Cambridge Neuropsychological Test Automated Battery (CANTAB) within the FOURIER randomized trial of evolocumab vs placebo in patients with established ASCVD. Patients in North America and Europe who completed EBBINGHAUS on study drug were eligible for an open-label extension (OLE) study with evolocumab. The primary endpoint was change in spatial working memory strategy index of executive function score (SWMI) from baseline over time. Secondary endpoints were measures of working memory, episodic memory, and psychomotor speed. A paired t-test was used to compare baseline vs post-baseline scores during OLE. Results: Of 1204 patients from EBBINGHAUS, 306 entered the OLE and were treated with evolocumab for a median of 5.1 years. Median achieved LDL-C was 34 mg/dL (IQR 21-50). No significant change in SWMI occurred during the OLE period overall [mean (±SD) change -0.1±2.7, p=0.73] or when stratified by original randomized allocation ( Figure 1A ). For secondary outcomes, one showed no change during the OLE period, two showed small changes (10-15% of SD), but these were directionally inconsistent (one higher, one lower). In 152 patients originally randomized to evolocumab, there was no significant change in SWMI from randomization through long-term follow-up over a median of 6.7 and a maximum of 7.2 years (mean change 0.1±2.6, p=0.66) ( Figure 1B ). Conclusion: Evolocumab did not lead to any apparent long-term decline in cognitive function through follow-up extending up to 7.2 years.

Performance of the enhanced Sampson-NIH equation for VLDL-C and LDL-C in a population with familial combined hyperlipidemia

IntroductionLow-density cholesterol (LDL-C) has long been estimated by the Friedewald formula (F-LDL-C); however, this method underestimates LDL-C in patients with hypertriglyceridemia (HTG) or low LDL-C levels. The Martin (M-LDL-C) and Sampson (S-LDL-C) formulas partially resolve these limitations. Recently, Sampson et al. developed a new equation (eS-VLDL-C) that includes ApoB. This new equation could be particularly useful in FCHL, which is characterized by the predominance of triglyceride-rich VLDL and a discordance between LDL-C and ApoB. MethodsVery low-density lipoproteins (VLDL-C) was measured in 336 patients with FCHL by sequential ultracentrifugation. LDL-C was estimated by subtracting VLDL-C, estimated by the different equations, from non-HDL cholesterol. Spearman correlations, R2, mean squared error (RMSE), and bias were used to compare the accuracy of the different equations. Concordance of the estimated LDL-C values with LDL-C thresholds and ApoB was also assessed by their kappa coefficients and ROC analysis. ResultsOverall population had a mean age of 47 years, and 61.5% were women. 19.5% had type 2 diabetes, hypertension was present in 20.8%, and only 12.2% were on statin treatment. Both S-LDL-C and eS-LDL-C performed similarly, and better than M-LDL-C and F-LDL-C. In Bland-Altman analysis, eS-LDL-C showed the lowest bias, better performance in HTG, and better concordance with LDL-C treatment goals compared to other formulas (e.g. ρ: 0.87, 95% CI 0.84–0.89). ConclusionsLDL-S and LDL-eS equations estimate the concentration of LDL-C with greater accuracy than other formulas. The LDL-eS has best performance in estimating LDL-C with lower RMSE than other formulas.

Observational multicentre prospective study to assess changes in cognitive function in patients treated with PCSK9i. Study protocol

ObjectivePCSK9 inhibitors have been shown to reduce LDLc by up to about 60% and 85% when used with high doses of statins and ezetimibe (2019 ESC/EAS Guidelines). These therapies may lead to very low levels of LDLc and have been associated with possible cognitive deterioration. No significant differences were found in the only specific study (EBBINGHAUS).The objective is to prospectively evaluate cognitive deterioration and its repercussion on quality of life and changes in LDLc in patients starting treatment with PCKS9 inhibitors. MethodIt is a postauthorization, multicentre, non-randomized, prospective study. Patients starting treatment for the first time with PCSK9 inhibitors will be recruited in 11 Galician Hospitals over a period of 12 months and with 24 months of follow-up. The primary outcome will be to evaluate changes in cognitive function using the Montreal Cognitive Assessment (MOCA) questionnaire. The secondary outcome will be to evaluate changes in quality of life using the EuroQol-5D. Changes in LDLc will be assessed. The sample size will be 275 patients, taking into account a loss to follow-up of no more than 10%.The primary outcome will be studied through the dichotomous variable cognitive deterioration (0/1). Cognitive changes over the follow-up period will be analysed using the McNemar test. In addition, an analytical approach using logistic regression will be followed to identify patients at risk of cognitive deterioration. As a result, this analysis will obtain a frequency measurement: the odds ratio (OR). The specific objectives will be studied using bivariate analysis. Continuous contrast variables will be studied using the f-test or ANOVA and categorical variables will be studied using the chi-square test. ConclusionsThe MEMOGAL study will provide information on safety in terms of cognitive deterioration in patients starting treatment with PCSK9 inhibitors.

FRI086 Statin Use After Lobar Intracerebral Hemorrhage- Is It Safe?

Abstract Disclosure: D. Vedamurthy: None. M. Ambrosino: None. K. Suri: None. D. Soffer: None. D. Jacoby: None. Background: Observational studies and randomized clinical trials have yielded conflicting data on the role of statins in causing intracerebral hemorrhage. It is unclear whether it is safe to continue statins in patients who have atherosclerotic cardiovascular disease (ASCVD) when they sustain an intracerebral hemorrhage (ICH). It is also not clear whether this risk of ICH (if present) relates to statin use or “too low” levels of LDL-C. Case: 75-year-old female with history of hypertension, hyperlipidemia, and a coronary artery calcium score of 450, presented to the hospital with severe headache and was diagnosed to acute right ICH. She did not smoke, use street drugs or drink excess alcohol. She did not have a family history of premature ASCVD. Her other medication included amlodipine, rosuvastatin and aspirin. Her lipid panel at hospitalization was TC 130 mg/dl, HDL 38 mg/dl, TG 137 mg/dl and LDL-C 70 mg/dl. Imaging studies were negative for cortical venous thrombosis, reversible cerebrovascular constriction, vasculitis, aneurysm, or AV fistula as etiologies. TEE was negative for cardioembolic source. Her hypertension medications were optimized, and she was discharged without any statin therapy. She fortunately recovered with mild deficits. She enrolled in an open-label randomized study- SATURN- which aims to assess safety of statin use in recurrent ICH. Her lipid panel while off statins showed a TC 274 mg/dl, TG 159 mg/dl, markedly elevated LDL-C of 197 mg/dl, and HDL-C 47 mg/dl. She presents to the lipid clinic for risk reduction. Early studies suggested increased ICH related to very low LDL-C levels, especially in the East Asian population. Concerns about statin use and ICH sparked after post-hoc analyses of SPARCL. Data from mendelian randomization studies and meta-analysis have failed to show convincing associations between statin use and ICH. Certain genetic variants, especially related to Apo E, have been shown to enhance this risk for ICH. There is a diversity in management of patients who have sustained an ICH (especially the lobar type as opposed to deep). An open label randomized trial (SATURN) is currently recruiting patients to answer this unresolved question. The dilemma is compounded in patients who have comorbid ASCVD. There are signals that PCSK9 inhibitors may be safer in terms of less propensity to cause intracerebral hemorrhage, but more data is needed. Moreover, the very low LDL-C levels achieved with use of PCSK-9 inhibitors may be concerning. Conclusion: There are no clear major society guidelines to advice clinicians on the best way to manage patients who have sustained a lobar intracerebral hemorrhage and have a compelling reason to be on statins for lipid lowering therapy to treat ASCVD. There are no clear guidelines on how low is “too low” as far as LDL-C targets are concerned. We present this case study as a call for more robust and expedient research in this field. Presentation: Friday, June 16, 2023

THU308 Metabolic And Neuroendocrine Adaptability Following One Night Of Partial Sleep Restriction In Dutch Males

Abstract Disclosure: I. Pelsma: None. R. van den Berg: None. S. Kooijman: None. M. Snel: None. G. Zhu: None. A. Moore: Employee; Self; Unilever. J. Pople: Employee; Self; Unilever. S. Lavrijsen: None. M. Birch-Machin: None. R. Bhogal: Employee; Self; Unilever. A. El Ghalbzouri: None. B. Martinez-Tellez: None. T. Giesbrecht: Employee; Self; Unilever. S. Kersten: None. M. van Weeghel: None. O.C. Meijer: None. A.M. Pereira Arias: None. D. Gunn: Employee; Self; Unilever. P. Rensen: None. N. Biermasz: None. Introduction: Chronic and acute short sleep associate with many adverse effects. Metabolic and neuroendocrine effects during the day following short sleep, however, are unknown. Methods: Randomized cross-over study using short sleep (4h) vs normal sleep (8h) in 31 males (31 years (IQR 23-47, BMI 26.0±4.2 kg/m2 (range 20.1-35.0). Glucose, lipid, incretin, ACTH, and cortisol levels, as well as respiratory exchange ratio (RER; indirect calorimetry) were assessed following standardized mixed meals. RNAseq of morning skeletal muscle biopsies and pathway analysis on differentially expressed genes was performed. Results: Short sleep increased fasting free fatty acids (0.34 mmol/L (IQR 0.26 - 0.38) vs 0.47 mmol/L (IQR 0.38 - 0.70), P<0.0001). Cortisol levels peaked upon early wake-up, which eliminated a peak at normal wake-up. Morning postprandial glucose peaked later (time P<0.001, levels P=0.106, pattern P=0.031), whilst insulin was unaffected. Afternoon postprandial insulin was lowered (time P<0.001, levels P=0.044, pattern P=0.419), whilst glucose was unaffected. Morning and afternoon postprandial TC, and LDL-c were lowered (morning: TC, time P<0.0001, levels P=0.009, pattern P=0.289; LDL-c, time P<0.001, levels P=0.038, pattern P=0.797; afternoon: TC, time P<0.001, levels P=0.007, pattern P=0.92; LDL-c, time P<0.001, levels P=0.055, pattern P=0.991). Pathway analysis of muscle revealed increased fatty acid oxidation (FAO), reflected by increased Oxidative Phosphorylation and Mitochondrial Dysfunction pathways, accompanied by lowered fasting RER (0.87 (IQR 0.86 - 0.92) vs 0.86 (IQR 0.84 - 0.87), P=0.0033). Conclusions: Acute partial sleep restriction subtly and temporarily changed glucose dynamics (morning), and insulin levels (afternoon), and lowered TC and LDL-c levels in the morning and afternoon, with concurrent increased FAO and mitochondrial dysfunction pathways in skeletal muscle, and calorimetric shifting from glucose towards lipid oxidation (fasted and postprandial), potentially highlighting increased delipidation of chylomicrons following sleep restriction. Presentation: Thursday, June 15, 2023

Serological Investigation of Persistent Villous Atrophy in Celiac Disease.

Persistent villous atrophy (VA) is not uncommon in celiac disease (CeD) while patients take a gluten-free diet (GFD). We conducted a retrospective study with 122 serum samples collected from controls and patients with CeD either at the initial diagnosis or at the follow-up during endoscopy. These samples were assigned to 3 groups: nonceliac control, non-VA CeD (Marsh score 0-2), and VA CeD (Marsh score 3a-3c). We established an in-house multiplex assay to identify potential serological biomarkers for VA. We assessed autoantibodies reported to affect the small intestine, including IgA and IgG antibodies against tissue transglutaminase (tTG), interferons, villin, actin, autoimmune enteropathy-related 75 kDa antigen (AIE-75), and tryptophan hydroxylase (TPH)-1, as well as 27 cytokines. The apolipoproteins quantified included apo A1, apo B-100, and apo A4, which were produced predominantly by the intestinal epithelium or expressed specifically in villi. Autoantibody levels were high only for tTG antibodies, which performed well in initial CeD diagnosis, but suboptimally for VA prediction during follow-up, because 14.6% of the follow-up patients with VA had low tTG-IgA. Increasing dilution improved tTG-IgA quantification, particularly when the antibody levels were extremely high but did not significantly improve VA detection. Among those with low tTG-IgA and persistent VA, high proinflammatory cytokines were observed in 2 patients. Median low-density lipoprotein cholesterol levels were significantly lower in the VA CeD group ( P = 0.03). Apolipoprotein levels were similar in patients with and without VA but diverged between those on a GFD or not. tTG-IgA as a biomarker is suboptimal for VA prediction while on a GFD. Persistent VA is associated with low low-density lipoprotein cholesterol levels and partially related to persistent high proinflammatory cytokines.

Dyslipidemia in adults with congenital heart disease: A systematic review and meta-analysis

AimsSeveral particular characteristics of patients with congenital heart disease could affect lipid levels. The objectives of this study were: a) to analyze the prevalence of dyslipidemia in congenital heart disease patients; 2) to compare lipid levels between congenital heart disease patients and a control group. Data synthesisThis systematic review and meta-analysis was performed according to PRISMA guidelines (PROSPERO CRD42023432041). A literature search was performed to detect studies that have reported lipid levels or the prevalence of dyslipidemia in congenital heart disease patients. We performed a qualitative analysis (studies that reported dyslipidemia prevalence) and quantitative analysis (studies that compared lipid values between congenital heart disease patients and controls). In total, 29 observational studies involving 22,914 patients with congenital heart disease and 641,086 controls were eligible for this review. The reported presence of “hyperlipidemia” or “dyslipidemia” ranged from 14.3% to 69.9%. When studies analyzed lipid variables dichotomously between congenital heart disease patients and controls, the results were conflicting. The quantitative analysis showed that patients with congenital heart disease have lower levels of total cholesterol (MD: −18.9 [95% CI: −22.2 to −15.7]; I2 = 93%), LDL-C (MD: −10.7 [95% CI: −13.1 to −8.3]; I2 = 90%) and HDL-C (MD: −6.3 [95% CI: −7.7 to −4.9]; I2 = 95%) compared to controls. ConclusionsThe qualitative analysis showed some concerns, but the quantitative analysis indicates that congenital heart disease patients showed lower levels of total cholesterol, LDL-C, and HDL-C compared to controls. New research should be developed to clarify this relevant topic.

Long-term safety and effectiveness of alirocumab and evolocumab in familial hypercholesterolemia (FH) in Belgium

Background: In 2019, the European Atherosclerosis Society (EAS) published updated guidelines, recommending even lower blood cholesterol targets than previously. In patients with familial hypercholesterolaemia (FH), who have very elevated blood cholesterol levels and are at (‘Very’) ‘High risk’ of atherosclerotic cardiovascular disease (ASCVD), this represents a real challenge. Anti-Proprotein convertase subtilisin/kexin type 9 monoclonal antibody (anti-PCSK9 mAb) has been commercially available for FH in Belgium since 2015. Our study aims to investigate the real-life efficacy of anti-PCSK9 mAb in FH patients. Method: We sourced patients from the EAS FH Studies Collaboration database (an international database on FH in which Belgium participates). We only retained patients using anti-PCSK9 mAb and followed at our Lipid Clinic. Results: Of the 239 subjects included in this study (mean age: 56 years), 85% were considered at ‘Very High Risk’ (56% with a history of ASCVD), the remaining 15% were at ‘High Risk’. The PCSK9 mAb treatment reduced LDL-C levels by 54% within the first year. This reduction was maintained over the follow-up (FU) period (3.0 ± 1.8 years). The EAS targets were reached in 50% of the subjects, 93% of whom were also treated with statins. The treatment was very well tolerated. At the end of the observation period, 96% patients continued receiving PCSK9 mAb. Conclusions: Anti-PCSK9 mAb are a safe and effective therapeutic option for lowering LDL-C levels in FH patients. It allowed a significant portion of our FH patients to reach their lipid targets, mainly in those with combined therapy with statin and/or ezetimibe.

Association of low HDL-c levels with severe symptoms and poor clinical prognosis in patients with severe fever and thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is an acute infectious disease caused by a novel bunyavirus, characterized by high fever, thrombocytopenia, and multiple organ damage. Disturbances in lipid metabolism often occur during viral infections, but the changes and clinical significance of lipid profiles in SFTS patients remain unclear. This study aimed to investigate the alterations in lipid profiles and their clinical significance in SFTS patients. A total of 157 SFTS patients and 157 healthy controls were enrolled in this study. Serum lipid levels were collected and analyzed among different groups and prognosis categories. Receiver operating characteristic (ROC) curve analysis was performed to assess the ability of lipid levels in distinguishing between severe and mild cases, as well as surviving and non-surviving patients. Pearson correlation analysis was used to examine the associations between lipid levels and clinical laboratory parameters. SFTS patients exhibited significantly lower levels of HDL-c, LDL-c, cholesterol, APoAI, and ApoB compared to healthy controls, while triglyceride levels were significantly higher. Serum HDL-c and ApoAI demonstrated good performance as indicators for distinguishing between survivors and non-survivors (AUC of 0.87 and 0.85, respectively). Multivariate regression analysis indicated that HDL-c independently acts as a protective factor in patients with SFTS. HDL-c levels showed decline in non-survivors but recovered in survivors. Moreover, HDL-c exhibited significant correlations with various clinical laboratory parameters (IL-6, CRP, AST, TT, APTT, PLT, ALB, and CD4). This study identified abnormalities in serum lipid metabolism among SFTS patients. HDL-c and ApoAI levels hold potential as biomarkers for distinguishing survivors from non-survivors. Additionally, HDL-c and ApoAI may serve as therapeutic targets for the management of SFTS patients.