Low Lipoprotein Research Articles

Overexpression of LOX-1 in hepatocytes protects vascular smooth muscle cells from phenotype transformation and wire injury induced carotid neoatherosclerosis through ALOX15

Neoatherosclerosis (NA), the main pathological basis of late stent failure, is the main limitation of interventional therapy. However, the specific pathogenesis and treatment remain unclear. In vivo, NA model was established by carotid wire injury and high-fat feeding in ApoE−/− mice. Oxidized low-density lipoprotein receptor-1/lectin-like oxidized low-density lipoprotein receptor-1 (OLR1/LOX-1), a specific receptor for oxidized low-density lipoprotein (ox-LDL), was specifically ectopically overexpressed in hepatocytes by portal vein injection of adeno-associated serotype 8 (AAV8)-thyroid binding globulin (TBG)-Olr1 and the protective effect against NA was examined. In vitro, LOX-1 was overexpressed on HHL5 using lentivirus (LV)-OLR1 and the vascular smooth muscle cells (VSMCs)-HHL5 indirect co-culture system was established to examine its protective effect on VSMCs and the molecular mechanism. Functionally, we found that specific ectopic overexpression of LOX-1 by hepatocytes competitively engulfed and metabolized ox-LDL, alleviating its resulting phenotypic transformation of VSMCs including migration, downregulation of contractile shape markers (smooth muscle α-actin (SMαA) and smooth muscle-22α (SM22α)), and upregulation of proliferative/migratory shape markers (osteopontin (OPN) and Vimentin) as well as foaminess and apoptosis, thereby alleviating NA, which independent of low-density lipoprotein (LDL) lowering treatment (evolocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9)). Mechanistically, we found that overexpression of LOX-1 in hepatocytes competitively engulfed and metabolized ox-LDL through upregulation of arachidonate-15-lipoxygenase (ALOX15), which further upregulated scavenger receptor class B type I (SRBI) and ATP-binding cassette transporter A1 (ABCA1). In conclusion, the overexpression of LOX-1 in liver protects VSMCs from phenotypic transformation and wire injury induced carotid neoatherosclerosis through ALOX15.

Risk modification role of opportunistic screening of lipoprotein(a) at first acute coronary syndrome admission in patients under 65 years old

Abstract Funding Acknowledgements Type of funding sources: None. Background/Introduction There is a strong association between lipoprotein(a) (Lp(a)) and atherosclerotic cardiovascular disease (ASCVD). Recent guidelines recommend its measure once in each adults’ lifetime, but the moment remains undefined. Moreover, little is known about Lp(a) in the acute setting. Purpose To describe Lp(a) levels in young patients (under 65) affected by its first acute coronary syndrome (ACS) as part of the standard evaluation during hospitalization and how it can affect lipid residual risk stratification. Methods We conducted a descriptive and retrospective study involving 51 patients under 65 years old admitted to hospital between July 2022 and October 2022, for ACS, irrespective of the onset of symptoms (unstable angina, myocardial infarction with or without ST-segment elevation (STEMI, NSTEMI). We tested Lp(a), apolipoprotein B (ApoB), low and high-density lipoprotein cholesterol (LDLc, HDLc), triglycerides (TG) and glycated haemoglobin (HbA1c), in those patients. Results We included 51 patients in our study. 76,5% were male. Mean age was 56,1 years (± 7,34). The distribution of risk factors was: smoking 68,6%, hypertension 52,9%, diabetes 31,4%, dyslipidaemia 43,1%. 30 patients had STEMI (58,8%), 17 NSTEMI (33,3%); 4 unstable angina. Immediate percutaneous coronary intervention was made in 33 patients (64,7%). Mean LVEF was 55,19% (± 9,4). Mean high-sensivity troponin I (hsTnI) peak was 47648,14 ng/L (± 71365). 13 patients had Lp(a) >50 mg/dL (25,5%), including 2 patients with Lp(a) levels above 180 mg/dL. The rest of the lipid profile is shown in Table 1. Conclusion In our sample of young ACS patients, one of each four patients has Lp(a) levels above 50 mg/dL, which confers a higher risk for ASCVD. We consider screening for Lp(a) in ACS as an opportunity to redefine cardiovascular risk and intensify lipid lowering therapies during follow-up.

Evaluation of the Causes of Door-to-Balloon Time Delays in Patients with ST-Elevation Myocardial Infarction at Tehran Heart Center.

Coronary artery disease (CAD) is the leading cause of cardiovascular death globally, and the most severe form of CAD, ST-elevation myocardial infarction (STEMI), needs immediate treatment. This study aimed to report patient characteristics and the causes of door-to-balloon time (D2BT) delays in STEMI patients admitted to Tehran Heart Center with a D2BT exceeding 90 minutes. This cross-sectional study was conducted at Tehran Heart Center, Iran, from March 20th, 2020, through March 20th, 2022. Variables consisted of age, sex, diabetes mellitus, hypertension, dyslipidemia, smoking, opium, family history of CAD, in-hospital mortality, primary percutaneous coronary intervention results, culprit vessels, causes of delays, the ejection fraction, triglycerides, and low and high-density lipoprotein levels. The study population was composed of 363 patients (272 males [74.9]) at a mean (SD) age of 60±11.47 years. The leading causes of D2BT delays were the catheterization lab used in 95 patients (26.2) and misdiagnosis in 90 (24.8). Other causes were ST-elevation less than 2 mm in electrocardiograms in 50 patients (13.8) and referral from other hospitals in 40 (11.0). The catheterization lab in use and misdiagnosis were the leading causes of D2BT delays. We recommend that high-volume centers allocate an additional catheterization lab with an on-call cardiologist. Improved resident training and supervision in hospitals with many residents are also necessary.

Identification and characterisation of a rare MTTP variant underlying hereditary non-alcoholic fatty liver disease

Background & AimsNon-alcoholic fatty liver disease (NAFLD) is a complex trait with an estimated prevalence of 25% globally. We aimed to identify the genetic variant underlying a four-generation family with progressive NAFLD leading to cirrhosis, decompensation, and development of hepatocellular carcinoma in the absence of common risk factors such as obesity and type 2 diabetes. MethodsExome sequencing and genome comparisons were used to identify the likely causal variant. We extensively characterised the clinical phenotype and post-prandial metabolic responses of family members with the identified novel variant in comparison with healthy non-carriers and wild-type patients with NAFLD. Variant-expressing hepatocyte-like cells (HLCs) were derived from human-induced pluripotent stem cells generated from homozygous donor skin fibroblasts and restored to wild-type using CRISPR-Cas9. The phenotype was assessed using imaging, targeted RNA analysis, and molecular expression arrays. ResultsWe identified a rare causal variant c.1691T>C p.I564T (rs745447480) in MTTP, encoding microsomal triglyceride transfer protein (MTP), associated with progressive NAFLD, unrelated to metabolic syndrome and without characteristic features of abetalipoproteinaemia. HLCs derived from a homozygote donor had significantly lower MTP activity and lower lipoprotein ApoB secretion than wild-type cells, while having similar levels of MTP mRNA and protein. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators, and production of reactive oxygen species. ConclusionsWe have identified and characterised a rare causal variant in MTTP, and homozygosity for MTTP p.I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinaemia. Our findings provide insights into mechanisms driving progressive NAFLD. Impact and ImplicationsA rare genetic variant in the gene MTTP has been identified as responsible for the development of severe non-alcoholic fatty liver disease in a four-generation family with no typical disease risk factors. A cell line culture created harbouring this variant gene was characterised to understand how this genetic variation leads to a defect in liver cells, which results in accumulation of fat and processes that promote disease. This is now a useful model for studying the disease pathways and to discover new ways to treat common types of fatty liver disease.

Potential Novel RNA-Targeting Agents for Effective Lipoprotein(a) Lowering: A Systematic Assessment of the Evidence From Completed and Ongoing Developmental Clinical Trials.

An increase in blood lipoprotein (a) [Lp(a)] levels, mostly genetically determined, has been identified as an independent risk factor of atherosclerotic cardiovascular disease. No drug has yet been approved that markedly lowers Lp(a) and thereby reduces residual cardiovascular risk. The aim of this article was to critically review the evidence from clinical development studies to date on the efficacy and safety of new RNA-based therapeutics for targeted lowering of Lp(a). PubMed/MEDLINE, Scopus, Web of Science, and ClinicalTrials.gov were searched without any language or date restriction up to November 5, 2022, and a total of 12 publications and 22 trial records were included. Several drugs were found that are currently in various stages of clinical development, such as the antisense oligonucleotide pelacarsen and the small interfering RNA molecule olpasiran and drugs coded as SLN360 and LY3819469. Among them, pelacarsen has progressed the most, currently reaching phase 3. All these drugs have so far shown satisfactory pharmacokinetic properties, consistently high and stable, dose-dependent efficacy in lowering Lp(a) even by more than 90%, with an acceptable safety profile in subjects with highly elevated Lp(a). In addition, reports of early clinical trials with pelacarsen imply a promising suppressive effect on key mechanisms of atherogenesis. Future research should focus on confirming these beneficial clinical effects in patients with lower average Lp(a) levels and clearly demonstrating the association between lowering Lp(a) and reducing adverse cardiovascular outcomes.

The Effect of using Nano-Selenium and Vitamin D3 on some Blood Parameters in Male Awassi Lambs

The research was carried out in the Animal Production Department of the College of Agriculture at Tikrit University in Iraq. The goal of this study was to examine the impact of administering nano-selenium and vitamin D3 to Awassi sheep on a variety of biochemical parameters of blood. Sixteen Awassi lambs were employed in the study; their ages ranged from (4-5) months, and their average weight was (19.56 0.17 kg). These lambs were randomly split into four groups (4 animals per group), and the investigation spanned two time periods (45 and 90 days). The first group (control) received 10 ml of distilled water (per animal), while the second group (treatment) was dosed with 0.5 mg of selenium nanoparticles/kg of feed and the third group (treatment) was dosed with 5.5 international units of vitamin D3/kg of body weight. Fourth, the results of this investigation showed that the levels of total cholesterol, triglycerides, and low lipoproteins all decreased significantly (P≤0.05) after a combination dose of the nano-element selenium and vitamin D3 (0.5 mg/kg feed + 5.5 international units/kg body weight). High-density lipoproteins were significantly increased (P≤0.05) in the second treatment compared to the control treatment, but low-density and very low-density lipoproteins were decreased. Serum creatinine levels were found to be significantly lower after the second and fourth treatments compared to the first (control) and third treatments (P≤0.05), whereas blood urea levels and AST and ALT enzyme levels were not statistically different between the treatments.

Correlation Between the Estimated and the Measured Serum Apolipoprotein –B100 in Kurd Subjects: A Trend to Establish a New Formula

Apolipoprotein B100 (ApoB100) provides a good assessment of atherogenic lipoproteins (very low, intermediate, and low-density lipoproteins (VLDL, IDL, and LDL)). There is evidence that polymorphism of ApoB100 was observed in many conditions and it links with obesity, diabetes mellitus hypertension, and chronic inflammation, which could be related to the broad field of the atherothrombotic process, and could be one of the leading causes of coronary artery disease (CAD). It can be computed using a formula that makes use of a measurement of non-high-density lipoprotein levels. This study aimed to derive an estimated equation of ApoB100 from the measured ApoB100 levels specific to the healthy subjects of Kurd race/ethnicity in the Kurdistan region of Iraq taking into consideration the gender-based effect and the status of fasting and postprandial effects. A total number of 45 healthy subjects (23 males and 22 females) were enrolled in the study. The following measurements were achieved: anthropometric indices, blood pressure, lipid profile, including ApoB100, and blood sugar. The biochemical measurements were carried out at fasting and postprandial states. Specific equations were derived for calculating the levels of ApoB100. Significant differences in the anthropometric indices, blood pressure, and lipid profile were observed between males and females. The calculated ApoB100 levels were significantly less than the measured ApoB100 levels in both genders and fasting and postprandial states. The estimated equations for ApoB100 for females have differed from that for males at fasting and postprandial states. The levels of ApoB100 can be determined instead of measuring it in the laboratory by using a specific equation for healthy Kurd people. These equations are gender and race/ethnicity based. The established equation of estimated ApoB100 levels in males differed from that in females which is attributed to the cardio-metabolic factors and higher levels of systolic and mean arterial blood pressures among males. Apo B level is a quantitative index of plasma atherogenic lipids in hypertensive patients who presented with dyslipidemia.

Protective Properties of Marine Alkyl Glycerol Ethers in Chronic Stress

In this paper we discuss the effect of alkyl glycerol ethers (AGs) from the squid Berryteuthis magister on a chronic stress model in rats. The study was performed on 32 male Wistar rats. Animals received AGs at a dose of 200 mg/kg through a gavage for six weeks (1.5 months), and were divided into four groups: group 1 (control), group 2 (animals received AGs), group 3 (stress control), group 4 (animals received AGs and were subjected to stress). Chronic immobilization stress was induced by placing each rat into an individual plexiglass cages for 2 h daily for 15 days. The serum lipid spectrum was evaluated by the content of total cholesterol, triglycerides, high-density lipoprotein cholesterol, low lipoprotein cholesterol and very low-density lipoprotein cholesterol. The atherogenic coefficient was calculated. The hematological parameters of peripheral blood were evaluated. The neutrophil-lymphocyte ratio was counted. The levels of cortisol and testosterone in blood plasma were determined. AGs at the selected dose did not have a significant effect on the body weight of rats in the preliminary period of the experiment. Under stress, the body weight gain, the concentrations of very low-density lipoprotein cholesterol and blood triglycerides decreased significantly. The neutrophil-lymphocyte ratio in animals treated with AGs shifted towards lymphocytes. A favorable increase in the percentage of lymphocytes was found in the stressed group of animals treated with AGs. So, for the first time, it was found that AGs prevent stress-induced suppression of the immune system. This confirms the benefit of AGs for the immune system under chronic stress. Our results prove the efficiency of the use of AGs for treating chronic stress, a serious social problem in modern society.

Effect of in-hospital evolocumab therapy on lipoprotein(a) in patients with acute myocardial infarction: a retrospective cohort study and a propensity score matching analysis.

This retrospective cohort analysis included a total of 467 AMI patients with LDL-C level >2.6 mmol/L upon admission, among whom 132 received in-hospital evolocumab (140 mg every 2 weeks) plus statin (20 mg atorvastatin or 10 mg rosuvastatin per day) and the remaining 335 received statin only. Lipid profiles at 1-month follow-up were compared between the two groups. A propensity score matching analysis was also conducted based on age, sex, and baseline lipoprotein(a) at a 1:1 ratio using a 0.02 caliper. At the 1-month follow-up, the lipoprotein(a) level decreased from 27.0 (17.5, 50.6) mg/dL to 20.9 (9.4, 52.5) mg/dL in evolocumab plus statin group, but increased from 24.5 (13.2, 41.1) mg/dL to 27.9 (14.8, 58.6) mg/dL in statin only group. The propensity score matching analysis included 262 patients (131 in each group). In subgroup analysis of the propensity score matching cohort stratified by the baseline lipoprotein(a) at cutoff values of 20 and 50 mg/dL, the absolute change in lipoprotein(a) was -4.9 (-8.5, -1.3), -5.0 (-13.9, 1.9), -0.2 (-9.9, 16.9) mg/dL in three subgroups in evolocumab plus statin group, and 0.9 (-1.7, 5.5), 10.7 (4.6, 21.9), 12.2 (2.9, 35.6) mg/dL in three subgroups in statin only group. In comparison to statin only group, evolocumab plus statin group had lower lipoprotein(a) level at 1 month in all subgroups (P < 0.05). In-hospital initiation of evolocumab on a background statin therapy reduced lipoprotein(a) level at 1-month follow-up in patients with AMI. Evolocumab plus statin therapy inhibited the increase in lipoprotein(a) in statin only therapy, regardless of the baseline lipoprotein(a) level.

RETINOL BINDING PROTEIN 4 (RBP 4) PADA OBESITAS SENTRAL

Obesity is currently a problem in the world. Lifestyles such as eating fast food, junk food, lack of activity and exercise which can cause obesity rates to increase every year. Obesity has a negative impact on health. Obesity may causing various diseases and may even causing death. Central obesity is a condition where the waist circumference is above 90 cm in men and above 80 cm in woman.Adipose tissue is also known as an endocrine organ that can release active mediators. One of the active mediators released is Retinol Binding Protein 4 (RBP4). RBP4 is a risk factor for diseases such as insulin resistance, affecting fat metabolisme such as increasing cholesterol, low swnsity lipoprotein (LDL), tryglicerides, apolipoprotein B (apo B), very low density lipoprotein (VLDL), diabetes mellitus type 2, heart disease and metabolic syndrome. RBP4 in subcutaneous adipose tissue is associated with several macrophages and inflammatory markers. RBP4 is known to increase TNFα which can stimulate lipolysis.

Adverse effects of low serum lipoprotein cholesterol on the immune microenvironment in gastric cancer: a case‒control study

BackgroundCholesterol is crucial for tumor immune microenvironment (TIME) remodeling. Serum lipoprotein cholesterol is closely associated with gastric cancer (GC) progression, but whether it affects TIME remodeling is unknown.MethodsGC patients with differential serum high-density lipoprotein (HDL) or low-density lipoprotein (LDL) cholesterol levels were collected. After balancing the baseline, immunohistochemical staining was performed on serial whole-tissue sections to detect B-cell and T-cell subsets, macrophages, and PD-L1. Features of tertiary lymphoid structures (TLSs) and the extra-TLS zone, including TLS distribution and maturation, immune cell density, and PD-L1 expression, were measured by annotating TLSs or regions of interest (ROIs) in the extra-TLS zone.ResultsA total of 9,192 TLSs and over 300 ROIs from 61 patients were measured. Compared to HDL-normal patients, HDL-low patients had a decreased secondary-TLS fraction or density but an elevated NK-cell density in the extra-TLS zone. Compared to LDL-normal patients, LDL-low patients had a higher ratio of PD-1 + T follicular helper cells to CD20 + B cells in TLSs, a higher ratio of PD-1 + T cells to CD8 + T cells and increased PD-1 + T-cell density in the extra-TLS zone. Different correlations were found in groups with differential HDL or LDL levels. Cell dynamics in the immune response were weaker in patients with low lipoprotein cholesterol. TLS parameters reached their peak earlier than those of the extra-TLS zone along with tumor progression.ConclusionLow serum lipoprotein cholesterol caused adverse effects on antitumor immunity in GC. Lipid management or immunometabolic drugs deserve more attention.

Association between non-high density lipoprotein-cholesterol fractions and presence of allostatic load among industrial workers

Objectives: Non-high density lipoprotein-cholesterol (non-HDL-C) fraction is the total cholesterol (TC) minus HDL-C. It is not a routinely reported component of lipid profile and is used in lipoprotein lowering therapy and prediction of coronary artery disease, target organ damage and atherosclerosis. Allostatic load (AL) is an imbalance between repetitive chronic exposure to stress and adaptive response. The present study investigates the association between non-HDL-C and its fractions (non-HDL-C/HDL-C, non-HDL-C/TC, non-HDL-C/ triglyceride [TG] and non-HDL-C/low-density lipoprotein-cholesterol [LDL-C]) and the presence of AL to determine, which fractions of non-HDL-C predict the diagnostic accuracy and optimal cut points. Materials and Methods: The study design is cross-sectional and data were collected from 169 male industrial workers. AL was measured using neuroendocrine (cortisol and dehydroepiandrosterone sulphate), cardiovascular (systolic blood pressure, diastolic blood pressure and heart rate), metabolic (TC, TG, HDL-C and LDL-C) and anthropometric (waist-hip ratio and body mass index) factors. The fractions of non-HDL-C/HDL-C, nonHDL-C/TC, non-HDL-C/TG and non-HDL-C/LDL-C were calculated using non-HDL-C, HDL-C, TC, TG and LDL-C values. Results: About 43.2% and 56.8% of workers had low and high AL, respectively. The non-HDL-C and its fractions such as non-HDL-C/HDL-C, non-HDL-C/TC and non-HDL-C/LDL-C were significantly increased in the high AL group. Stepwise regression analysis was used to examine the association between non-HDL-C fractions and AL. The fractions of non-HDL-C (b = 0.785, P = 0.001), non-HDL-C/TC (b = −0.336, P = 0.001) and nonHDL-C/LDL-C (b = 0.295, P = 0.001) influenced AL by 38.6%. The AUC with 95% CI in the high AL group was as follows: non-HDL-C 0.766 (0.696–0.837, P = 0.001); non-HDL-C/HDL-C 0.638 (0.555–0.721, P = 0.002); nonHDL-C/TC 0.635 (0.552–0.712, P = 0.003) and non-HDL-C/LDL-C 0.520 (0.433–0.607, P = 0.657). Non-HDL-C and its fractions were more precisely predicted in the high AL category of workers than in the low AL category. Non-HDL-C predicted the most precisely, followed by non-HDL-C/HDL-C, non-HDL-C/TC, non-HDL-C/ LDL-C and non-HDL-C/TG. Conclusion: According to the present study, non-HDL-C and its fractions such as non-HDL-C/HDL-C, nonHDL-C/TC and non-HDL-C/LDL-C should be considered regular lipid profiles and could be used as biomarkers to reduce the risk of AL.

Dyslipidemia and Inflammation as Hallmarks of Oxidative Stress in COVID-19: A Follow-Up Study.

Recent works have demonstrated a significant reduction in cholesterol levels and increased oxidative stress in patients with coronavirus disease 2019 (COVID-19). The cause of this alteration is not well known. This study aimed to comprehensively evaluate their possible association during the evolution of COVID-19. This is an observational prospective study. The primary endpoint was to analyze the association between lipid peroxidation, lipid, and inflammatory profiles in COVID-19 patients. A multivariate regression analysis was employed. The secondary endpoint included the long-term follow-up of lipid profiles. COVID-19 patients presented significantly lower values in their lipid profile (total, low, and high-density lipoprotein cholesterol) with greater oxidative stress and inflammatory response compared to the healthy controls. Lipid peroxidation was the unique oxidative parameter with a significant association with the total cholesterol (OR: 0.982; 95% CI: 0.969-0.996; p = 0.012), IL1-RA (OR: 0.999; 95% CI: 0.998-0.999; p = 0.021) IL-6 (OR: 1.062; 95% CI: 1.017-1.110; p = 0.007), IL-7 (OR: 0.653; 95% CI: 0.433-0.986; p = 0.042) and IL-17 (OR: 1.098; 95% CI: 1.010-1.193; p = 0.028). Lipid abnormalities recovered after the initial insult during long-term follow-up (IQR 514 days); however, those with high LPO levels at hospital admission had, during long-term follow-up, an atherogenic lipid profile. Our study suggests that oxidative stress in COVID-19 is associated with derangements of the lipid profile and inflammation. Survivors experienced a recovery in their lipid profiles during long-term follow-up, but those with stronger oxidative responses had an atherogenic lipid profile.

The development of lipoprotein apheresis in Saxony in the last years

Three hundred thirty-nine patients (230 men, 109 women) treated with lipoprotein apheresis in Saxony, Germany, in 2018 are described in terms of age, lipid pattern, risk factors, cardiovascular events, medication, and number of new admissions since 2014, and the data are compared with figures from 2010 to 2013. Patients were treated by 45.5 physicians in 16 lipoprotein apheresis centers. With about 10 patients per 100 000 inhabitants, the number of patients treated with lipoprotein apheresis in Saxony is twice as high as in Germany as a whole. The median treatment time was 3 years. Almost all patients had hypertension; type 2 diabetes mellitus was seen significantly more often in patients with low Lipoprotein(a). Cardiovascular events occurred in almost all patients before initiation of lipoprotein apheresis, under apheresis therapy the cardiovascular events rate was very low in this high-risk group. For some cardiovascular regions even no events could be observed. The importance of lipoprotein apheresis in Saxony had been increasing from 2010 to 2018.

Effects of SLCO1B1 Genetic Variant on Metabolite Profile in Participants on Simvastatin Treatment.

Organic-anion-transporting polypeptide 1B1 (OATP1B1), encoded by the solute carrier organic anion transporter family member 1B1 gene (SLCO1B1), is highly expressed in the liver and transports several endogenous metabolites into the liver, including statins. Previous studies have not investigated the association of SLCO1B1 rs4149056 variant with the risk of type 2 diabetes (T2D) or determined the metabolite signature of the C allele of SLCO1B1 rs4149056 (SLCO1B1 rs4149056-C allele) in a large randomly selected population. SLCO1B1 rs4149056-C inhibits OATP1B1 transporter and is associated with increased levels of blood simvastatin concentrations. Our study is to first to show that SLCO1B1 rs4149056 variant is not significantly associated with the risk of T2D, suggesting that simvastatin has a direct effect on the risk of T2D. Additionally, we investigated the effects of SLCO1B1 rs4149056-C on plasma metabolite concentrations in 1373 participants on simvastatin treatment and in 1368 age- and body-mass index (BMI)-matched participants without any statin treatment. We found 31 novel metabolites significantly associated with SLCO1B1 rs4149056-C in the participants on simvastatin treatment and in the participants without statin treatment. Simvastatin decreased concentrations of dicarboxylic acids, such as docosadioate and dodecanedioate, that may increase beta- and peroxisomal oxidation and increased the turnover of cholesterol into bile acids, resulting in a decrease in steroidogenesis due to limited availability of cholesterol for steroid synthesis. Our findings suggest that simvastatin exerts its effects on the lowering of low-density lipoprotein (LDL) cholesterol concentrations through several distinct pathways in the carriers of SLCO1B1 rs4149056-C, including dicarboxylic acids, bile acids, steroids, and glycerophospholipids.

CORRELATION OF SEVERITY OF CORONARY ARTERY DISEASE WITH LIPOPROTEIN A LEVEL IN YOUNG ADULTS

Objectives: To address the association between Lipoprotein (a) and coronary artery disease risk in young patients &amp; to evaluate whether high levels of lipoprotein (a) is a predictor of risk and is related to the severity of coronary artery disease.&#x0D; Methodology: This retrospective study was carried out at Cardiology Deptt of Hayatabad Medical Complex Peshawar between June and December 2021. Total 160 patients referred to the cardiac catheterization lab of either gender, aged 20-45 years who underwent coronary angiography for various clinical indications were enrolled in the study. Lipoprotein (a) level, lipid profile, fasting blood glucose, anthropometric and clinical parameters of the patients were analyzed.&#x0D; Results: Statistically significant differences were observed in the mean of serum lipoprotein (a) concentrations between group “A” (58.6 ± 3.20 mg/ dl) and group “B” (19.6+0.10 mg/ dl) P value &lt;0.001. Mean HDL was 32.6 ± 0.30 in group “A” and in group B it was 40.4 ± 0.39 (p value &gt;0.005), total cholesterol was 199 ± 2.00 in group “A” &amp; 152 ± 1.80 in group “B” (p value &lt;0.005), triglycerides (TGL) in group “A” (182.76 ± 43.86 mg/dl) &amp; in group “B” (124.14 ± 44.01 mg/dl) P value &lt;0.001, LDL in group “A” was (130±4.28 &amp; in group “B” (84.4±3.00) p value &lt;0.001, VLDL between group “A” (36.03 ± 9.19mg/dl) and group B (24.68 ± 8.89 mg/dl) P value &gt; 0.003. However total Cholesterol / HDL was significantly lower in group “B” 3.5 as compared to group “A” 5.8 P value &lt; 0.002.&#x0D; Conclusion: Irrespective of other traditional risk factors, increase in Lipoprotein (a) is an independent risk factor for coronary artery disease in young adults with positive family history. Thus elevated levels of Lipoprotein (a) may serve as an important criterion to identify the individuals who need to undergo lipoprotein (a) lowering treatment, thereby preventing them from myocardial infarction.

Low lipoprotein(a) concentration is associated with atrial fibrillation: a large retrospective cohort study

Background and aimsThe role of serum lipoprotein(a) [Lp(a)] levels in atrial fibrillation (AF) is still uncertain, especially in the Chinese population. Here, we aimed to elucidate the potential relationship between Lp(a) quantiles and AF.MethodsAll data were collected through inpatients with electronic health records from the Second Affiliated Hospital of Nanchang University, Jiangxi Province, China. The propensity score matching (PSM) method was used to match control and case groups. Interactions between AF, Lp(a) quantiles, and other clinical indices were analyzed by logistic regression and stratified analysis. Statistical analyses were performed with IBM SPSS statistical software and R software.ResultsFrom 2017 to 2021, 4,511 patients with AF and 9,022 patients without AF were 1:2 matched by the propensity score matching method. A total of 46.9% of the study group was women, and the baseline mean age was 65 years. The AF group exhibited lower median Lp(a) than the non-AF group (15.95 vs. 16.90 mg/dL; P < 0.001). Based on the Lp(a) quantiles, the study population was divided into four groups: Q1 (≤ 8.71 mg/dL), Q2 (8.71–16.54 mg/dL), Q3 (16.54–32.42 mg/dL) and Q4 (> 32.42 mg/dL). The AF prevalence of each group decreased from 34.2% (Q1) to 30.9% (Q4) (P < 0.001). Lp(a) quantiles 1–3 significantly increased AF to 1.162-fold (1.049–1.286), 1.198-fold (1.083–1.327), and 1.111-fold (1.003–1.231) in the unadjusted logistic regression model, respectively. In the adjusted model, Lp(a) < 32.42 mg/dL still showed a significant inverse association with AF. In the stratified analysis, Lp(a) levels in female patients exhibited a significant negative correlation with AF (OR of Q1: 1.394[1.194–1.626], P = 0.001). Age and hypertension did not affect the adverse correlation.ConclusionLow circulating Lp(a) levels were associated with AF, especially in the female Han population, suggesting that Lp(a) may be useful for risk stratification of AF in female individuals.

Reduction of cerebrovascular and peripheral events with PCSK9 inhibitors: Does it just depend on the lowering of the low-density lipoprotein?

Atherosclerotic cardiovascular disease is a systemic condition involving several vascular districts. The most involved vascular bed, beyond the coronary district, is represented by the peripheral arteries, whose involvement can give rise to cerebrovascular or peripheral events. PCSK9 inhibitors (PCSK9i) have established themselves as safe and effective drugs in reducing cholesterol linked to low-density lipoprotein (LDL-C), a causative factor of disease, with a consequent reduction in cardiovascular events. The two main studies on anti-PCSK9 antibodies, the FOURIER study for evolocumab and the ODYSSEY OUTCOMES study for alirocumab, highlighted the effectiveness in reducing LDL-C levels and its translation in a lower event rate of around 15%. Sub-analysis of these two trials showed how PCSK9i prevent cerebrovascular and/or peripheral events and how patients with already known cerebrovascular or peripheral disease benefit more from the action of these drugs than patients who do not have a widespread disease. Current evidence suggests that the preventive action of cerebrovascular and peripheral events is mainly expressed through reducing LDL-C levels. Although there are data regarding the association of PCSK9 levels and inflammatory status, propensity for thrombosis and platelet aggregation, these are currently less robust and do not justify a cardiovascular event reduction action that is independent of the action on LDL-C.

Role of lipoprotein(a) in plaque progression

Identified by Berg in 1963, lipoprotein(a) represents a key contemporary residual risk pathway in atherosclerotic cardiovascular disease (ASCVD) secondary prevention. Indeed, epidemiological and genetic studies have undoubtedly demonstrated that lipoprotein(a) is one of the strongest causal risk factors of ASCVD. Although a risk threshold has been set between 30 and 50 mg/dL, depending on the ethnicity, a linear risk gradient across the distribution has been demonstrated. In the context of the atherosclerotic process, hyperlipoproteinaemia(a) contributes to the atherosclerotic plaque formation by deposition of cholesterol in the same manner as low-density lipoprotein (LDL) cholesterol, due to the LDL particle component of lipoprotein(a). Lipoprotein(a) accumulates in human coronary and carotid atherosclerotic lesions. High concentrations of lipoprotein(a) are associated with accelerated progression of the necrotic core, but not with coronary calcium score (CAC), although in the latter case, the evaluation of lipoprotein(a) can overcome the potential limitation of CAC to capture the totality of ASCVD risk in asymptomatic individuals. Finally, in the absence of a pharmacological approach to lower lipoprotein(a) to the extent required to achieve a cardiovascular benefit, implementation strategies that increase awareness among the population, patients, and healthcare providers on the importance of lipoprotein(a) in the development of ASCVD are eagerly needed.

Abstract 15650: Relationship Between Lipoprotein (a) and Aortic Vulnerable Plaques Detected by Non-Obstructive General Angioscopy

Background: Although atherosclerotic disease including myocardial infarction had decreased with lipid-lowering therapy for LDL cholesterol, atherosclerotic risk factors as residual risks without low-density lipoprotein are pointed out. Especially, lipoprotein (a) had been reported as one of the cardiovascular risks. Non-obstructive general angioscopy (NOGA) can meticulously visualize directly aortic atherosclerosis. NOGA-derived aortic vulnerable plaques had been reported to be related to future cardiovascular events. However, the relationships between serum lipoprotein (a) value and NOGA-derived aortic plaques had not been fully investigated yet. Methods and Results: We investigated consecutive 165 cases with coronary artery disease evaluated for the aorta by NOGA. Atherosclerotic lesions of the aorta were screened using NOGA immediately after coronary arteriography. NOGA examination evaluated the presence of aortic ruptured plaques which were "puff-chandelier rupture" appearance as previously reported. The mean age was 68 years and the median lipoprotein (a) value was 16 [9-27]. The median number of plaque ruptures was 1 [0-3], and 60% of cases had at least one plaque rupture. In a logistic regression analysis for the presence of aortic plaque rupture, the serum lipoprotein (a) value was associated with NOGA-derived aortic plaque rupture (odds ratio, 1.01 [1.0-1.03], p &lt; 0.05). The study patients were divided into three groups according to the tertile of serum lipoprotein (a) value [1st tertile: 0-11 mg/dl, 2nd tertile: 12-24 mg/dl, 3rd tertile 25 mg/dl &lt;], the first tertile had the lowest prevalence of plaque rupture (the presence of plaque rupture: first tertile 50%, second tertile 71%, third tertile 72%, p = 0.03). Conclusion: Serum lipoprotein (a) value was related to the presence of the aortic plaque rupture. Further studies are needed to elucidate the effect of the low lipoprotein (a) on the prevention of aortic vulnerable plaques.