Possible Heterozygous Hypercholesterolemia Among Adults in Basrah, Southern Iraq.

Background Familial hypercholesterolemia (FH) is an autosomal dominant disease and is one of the most prevalent genetic disorders. We aimed to determine the prevalence of patients with elevated levels of low-density lipoprotein cholesterol (LDL-C), presumptively indicating possible heterozygous familial hypercholesterolemia (HeFH). Methods Retrospective data analysis was conducted for adult patients aged 18 and above with fasting LDL-C ≥ 190 mg/dL registered in Faiha Specialized Diabetes, Endocrine and Metabolism Center (FDEMC) in Basrah for the period from August 2008 to December 2023. The total number of enrolled individuals was 59,026. Results From the data records of the 59,026 individuals enrolled in the study, it was found that 4,093 (6.9 %) had LDL-C levels ≥190 mg/dL and 361 (0.6 %) had very high total cholesterol according to the Make Early Diagnosis to Prevent Early Death (MEDPED) Criteria. Around 30,527 (51.7 %) were aged 40-59 years, representing the peak age group. Women comprised 34,688 (58.8 %), and 42,310 (71.7 %) had diabetes mellitus. Individuals with obesity comprise 27,375 (48.8 %). Out of the 4,093 patients with LDL-C ≥190 mg/dL, 2,422 (59.2 %) were in the 40-59 years age group, and 2,847 (69.6 %) were women. Diabetes was found in 3,442 (84.1 %) patients and obesity in 1,954 (49.9 %) patients. The average blood pressure was higher in the individuals with LDL-C ≥190 (137/83 versus 134/82 respectively, p < 0.001). Conclusions Being one of the largest studies of its kind in the country, the percentage of individuals who might meet the criteria for having possible HeFH in Basrah (Southern Iraq) should raise awareness about the size of the problem in the country, both to encourage family screening programs and to broaden the need for lipid-lowering therapies. Future studies are needed to have further clarifications about the differences in the prevalence between sexes and age groups. These findings need further confirmation by genetic studies including LDL-receptor mutations.

Role of low-density cholesterol and Interleukin-17 interaction in breast cancer pathogenesis and treatment.

Breast cancer (BC) has become the most prevalent cancer worldwide, and further research is being conducted to deepen our understanding of its pathogenesis and treatment. Lipid metabolism disorder is a significant alteration in cancer cells, and the investigation into the role of Interleukin-17 (IL-17) in malignant tumors has emerged as a research focus in recent years. Thus, exploring changes in lipid metabolism and inflammatory factors in BC cells is crucial in identifying potential therapeutic targets. This article summarizes the progress made in the research on the main low-density cholesterol (LDL) transporter and IL-17 in lipid metabolism, and their potential involvement in the development of BC. The article aims to establish a theoretical foundation for the development of BC-related therapies.

Lipid-Lowering Treatment Gaps in Patients after Acute Myocardial Infarction: Using Global Database TriNetX.

Background and Objectives: Patients with previous acute myocardial infarction are at significantly higher risk of recurrent events. Early and intensive lipid-lowering therapy targeting low-density lipoprotein cholesterol is a key strategy for reducing cardiovascular risk in post-acute myocardial infarction patients worldwide. This study aimed to assess patients' real-life lipid-lowering treatment gaps after acute myocardial infarction using a global network, TriNetX, of anonymous, real-time patient data. The uniqueness of the study was the use of the novel, evolving, and constantly improving TriNetX platform and the evaluation of its feasibility for clinical research. Materials and Methods: A retrospective study was conducted on global repository patients in 2020, diagnosed with acute myocardial infarction, with a three-year follow-up. Results: After acute myocardial infarction, the prescribing rate of lipid-lowering medication (statins, ezetimibe and PCSK9I) was insufficient to reach target LDL-C values. The mean LDL-C level decreased from 2.7 mmol/L (103 mg/dL) as measured on the day of AMI to 1.97 mmol/L (76 mg/dL) between 31D and 3M. During the second and third years, the mean LDL-C value was stable (around 2.0 mmol/L (78 mg/dL)). LDL-C goals were not sufficiently reached, as only 7-12% of patients were reported to have LDL-C values < 55 mg/dL (1.4 mmol/L) and 13-20% of patients were reported to have LDL-C values < 70 mg/dL (1.8 mmol/L) during the follow-up periods. This means that a substantial number of patients remain at a very high risk for CV complications and mortality. Most cardiovascular complications happen within three months after acute myocardial infarction. Conclusions: Gaps remain between the recommendations for managing LDL-C in guidelines and what occurs in real life. The TriNetX platform is an innovative platform with significant potential and should be further developed for clinical research, as it enables the use of valuable interinstitutional data.

Polypills in the Management of Cardiovascular Risk-A Perspective.

Cardiovascular disease and cardiovascular risk factors are global healthcare problems, given their high prevalence and the recognized low rates of adequate control despite the abundant body of evidence on different therapeutic options. The World Heart Federation has scrutinized the reasons for poor control of cardiovascular risk factors. Among these reasons, patients' poor adherence to treatment regimens as well as limited rates of evidence-based therapy prescription from healthcare providers play a substantial role in the challenge of cardiovascular risk management. Polypills are fixed-dose combinations including two or more active drugs, from different pharmacological classes, combined in a single dosage form. Polypills were designed to simplify the clinical management of pharmacotherapy and increase adherence to treatment. From this perspective, we discuss the current literature on the use of polypills in the primary and secondary prevention of cardiovascular disease as well as future challenges and the potentials of this treatment strategy.

Exploring the Interplay: Obesity, Lipid Metabolism, and Clinical Manifestations in Atopic Dermatitis.

BACKGROUND: The interest toward the association between atopic dermatitis (AD) and obesity is increasing, yet the possibility of abnormal lipid metabolism has never been investigated before. OBJECTIVE: To identify the characteristics of patients with AD who are obese and analyze the serum lipid profiles of these patients. METHODS: This observational study included 167 patients diagnosed with AD and underwent evaluations for serum lipid panels between July 2017 and October 2017. The patients' body mass index was used to determine obesity and the serum lipid panels were analyzed between patients who are obese and non-obese. Also, the disease severity and subjective symptoms were evaluated and serum total immunoglobulin E (IgE) and specific IgE levels were assessed. RESULTS: Of the 167 patients with AD, there were 36 obese and 131 non-obese subjects. Obese patients were found to have a significantly higher disease severity, as well as higher serum triglyceride and low-density lipoprotein-cholesterol levels and lower high-density lipoprotein-cholesterol levels, which was most pronounced in adult males. Obesity AD patients also had a significantly higher serum total IgE, itch intensity score, and number of allergens sensitized. CONCLUSION: Patients with AD who are obese should be monitored for possible abnormalities in lipid metabolism. Obesity may be a factor that contributes to a higher disease severity of AD.

An 8-SNP LDL Cholesterol Polygenic Score: Associations with Cardiovascular Risk Traits, Familial Hypercholesterolemia Phenotype, and Premature Coronary Heart Disease in Central Romania.

Familial hypercholesterolemia (FH) is the most significant inherited risk factor for coronary heart disease (CHD). Current guidelines focus on monogenic FH, but the polygenic form is more common and less understood. This study aimed to assess the clinical utility of an 8-SNP LDLC polygenic score in a central Romanian cohort. The cohort included 97 healthy controls and 125 patients with premature (P)CHD. The weighted LDLC polygenic risk score (wPRS) was analyzed for associations with relevant phenotypic traits, PCHD risk, and clinical FH diagnosis. The wPRS positively correlated with LDLC and DLCN scores, and LDLC concentrations could be predicted by wPRS. A trend of increasing LDLC and DLCN scores with wPRS deciles was observed. A +1 SD increase in wPRS was associated with a 36% higher likelihood of having LDLC > 190 mg/dL and increases in LDLC (+0.20 SD), DLCN score (+0.16 SD), and BMI (+0.15 SD), as well as a decrease in HDLC (-0.14 SD). Although wPRS did not predict PCHD across the entire spectrum of values, individuals above the 90th percentile were three times more likely to have PCHD compared to those within the 10th or 20th percentiles. Additionally, wPRS > 45th percentile identified "definite" clinical FH (DLCN score > 8) with 100% sensitivity and 45% specificity. The LDLC polygenic score correlates with key phenotypic traits, and individuals with high scores are more likely to have PCHD. Implementing this genetic tool may enhance risk prediction and patient stratification. These findings, the first of their kind in Romania, are consistent with the existing literature.

Assessing Cardiovascular Target Attainment in Type 2 Diabetes Mellitus Patients in Tertiary Diabetes Center in Romania.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) share a bidirectional link, and the innovative antidiabetic molecules GLP-1 Ras and SGLT-2is have proven cardiac and renal benefits, respectively. This study aimed to evaluate CV risk categories, along with lipid-lowering and antidiabetic treatments, in patients with T2DM from a real-life setting in Romania. MATERIAL AND METHODS: A cross-sectional evaluation was conducted on 405 consecutively admitted patients with T2DM in an ambulatory setting, assessing them according to the 2019 ESC/EAS guidelines for moderate, high, and very high CV risk categories. RESULTS: The average age of the group was 58 ± 9.96 years, with 38.5% being female. The mean HbA1C level was 7.2 ± 1.7%. Comorbidities included HBP in 88.1% of patients, with a mean SBP and DBP of 133.2 ± 13.7 mm Hg and 79.9 ± 9 mm Hg, respectively, and obesity in 66.41%, with a mean BMI of 33 ± 6.33 kg/m2. The mean LDL-C levels varied by CV risk category: 90.1 ± 34.22 mg/dL in very high risk, 98.63 ± 33.26 mg/dL in high risk, and 105 ± 37.1 mg/dL in moderate risk. Prescribed treatments included metformin (100%), statins (77.5%), GLP-1 Ras (29.4%), and SGLT-2is (29.4%). CONCLUSIONS: In Romania, patients with T2DM often achieve glycemic control targets but fail to meet composite targets that include glycemic, BP, and lipid control. Additionally, few patients benefit from innovative glucose-lowering therapies with proven cardio-renal benefits or from statins.

The impact of steatotic liver disease on coronary artery disease through changes in the plasma lipidome.

Steatotic liver disease has been shown to associate with cardiovascular disease independently of other risk factors. Lipoproteins have been shown to mediate some of this relationship but there remains unexplained variance. Here we investigate the plasma lipidomic changes associated with liver steatosis and the mediating effect of these lipids on coronary artery disease (CAD). In a population of 2579 Swedish participants of ages 50 to 65 years, lipids were measured by mass spectrometry, liver fat was measured using computed tomography (CT), and CAD status was defined as the presence of coronary artery calcification (CAC score > 0). Lipids associated with liver steatosis and CAD were identified and their mediating effects between the two conditions were investigated. Out of 458 lipids, 284 were found to associate with liver steatosis and 19 of them were found to also associate with CAD. Two fatty acids, docosatrienoate (22:3n6) and 2-hydroxyarachidate, presented the highest mediating effect between steatotic liver disease and CAD. Other mediators were also identified among sphingolipids and glycerophospholipids, although their mediating effects were attenuated when adjusting for circulating lipoproteins. Further research should investigate the role of docosatrienoate (22:3n6) and 2-hydroxyarachidate as mediators between steatotic liver disease and CAD alongside known risk factors.

Dengue NS1 interaction with lipids alters its pathogenic effects on monocyte derived macrophages.

BACKGROUND: While dengue NS1 antigen has been shown to be associated with disease pathogenesis in some studies, it has not been linked in other studies, with the reasons remaining unclear. NS1 antigen levels in acute dengue are often associated with increased disease severity, but there has been a wide variation in results based on past dengue infection and infecting dengue virus (DENV) serotype. As NS1 engages with many host lipids, we hypothesize that the type of NS1-lipid interactions alters its pathogenicity. METHODS: Primary human monocyte derived macrophages (MDMs) were co-cultured with NS1 alone or with HDL, LDL, LPS and/or platelet activating factor (PAF) from individuals with a history of past dengue fever (DF = 8) or dengue haemorrhagic fever (DHF = 8). IL-1ß levels were measured in culture supernatants, and gene expression analysis carried out in MDMs. Monocyte subpopulations were assessed by flow cytometry. Hierarchical cluster analysis with Euclidean distance calculations were used to differentiate clusters. Differentially expressed variables were extracted and a classifier model was developed to differentiate between past DF and DHF. RESULTS: Significantly higher levels of IL-1ß were seen in culture supernatants when NS1 was co-cultured with LDL (p = 0.01, median = 45.69 pg/ml), but lower levels when NS1 was co-cultured with HDL (p = 0.05, median = 4.617 pg/ml). MDMs of those with past DHF produced higher levels of IL-1ß when NS1 was co-cultured with PAF (p = 0.02). MDMs of individuals with past DHF, were significantly more likely to down-regulate RPLP2 gene expression when macrophages were co-cultured with either PAF alone, or NS1 combined with PAF, or NS1 combined with LDL. When NS1 was co-cultured with PAF, HDL or LDL two clusters were detected based on IL10 expression, but these did not differentiate those with past DF or DHF. CONCLUSIONS: As RPLP2 is important in DENV replication, regulating cellular stress responses and immune responses and IL-10 is associated with severe disease, it would be important to further explore how differential expression of RPLP2 and IL-10 could lead to disease pathogenesis based on NS1 and lipid interactions.

Early statin use is associated with improved survival and cardiovascular outcomes in patients with atrial fibrillation and recent ischaemic stroke: A propensity-matched analysis of a global federated health database.

INTRODUCTION: Statins reduce recurrent stroke and cardiovascular events in patients with non-cardioembolic stroke. The benefits of statins in patients with AF and recent IS remain unclear. We aimed to investigate the benefits of statins in patients with AF and recent IS. PATIENTS AND METHODS: This retrospective, cohort study was conducted using deidentified electronic medical records within TriNetX platform. Patients with AF and recent IS, who received statins within 28 days of their index stroke were propensity score-matched with those who did not. Patients were followed up for up to 2 years. Primary outcomes were the 2-year risk of recurrent IS, all-cause mortality and the composite outcome of all-cause mortality, recurrent IS, transient ischaemic attack (TIA), and acute myocardial infarction (MI). Secondary outcomes were the 2-year risk of TIA, intracranial haemorrhage (ICH), acute MI, and hospital readmission. Cox regression analyses were used to calculate hazard ratios (HRs) with 95% confidence intervals (95%CI). RESULTS: Of 20,902 patients with AF and recent IS, 7500 (35.9%) received statins within 28 days of their stroke and 13,402 (64.1%) did not. 11,182 patients (mean age 73.7 ± 11.5; 5277 (47.2%) female) remained after propensity score matching. Patients who received early statins had significantly lower risk of recurrent IS (HR: 0.45, 95%CI: 0.41-0.48, p < 0.001), mortality (HR: 0.75, 95%CI: 0.66-0.84, p < 0.001), the composite outcome (HR: 0.48, 95%CI: 0.45-0.52, p < 0.001), TIA (HR: 0.37, 95%CI: 0.30-0.44, p < 0.001), ICH (HR: 0.59, 95%CI: 0.47-0.72, p < 0.001 ), acute MI (HR: 0.35, 95%CI: 0.30-0.42, p < 0.001) and hospital readmission (HR: 0.46, 95%CI: 0.42-0.50, <0.001). Beneficial effects of early statins were evident in the elderly, different ethnic groups, statin dose intensity, and AF subtypes, large vessel occlusion and embolic strokes and within the context of statin lipophilicity, optimal LDL-cholesterol levels, various cardiovascular comorbidities, treatment with intravenous thrombolysis or endovascular thrombectomy, and NIHSS 0-5 and NIHSS > 5 subgroups. DISCUSSION AND CONCLUSION: Patients with AF and recent IS, who received early statins, had a lower risk of recurrent stroke, death, and other cardiovascular outcomes including ICH, compared to those who did not.

Excess Triglycerides in Very Low-Density Lipoprotein (VLDL) Estimated from VLDL-Cholesterol could be a Useful Biomarker of Metabolic Dysfunction Associated Steatotic Liver Disease in Patients with Type 2 Diabetes.

AIMS: We report that small dense low-density lipoprotein cholesterol (sdLDL-C) levels are sensitive biomarkers of metabolic dysfunction-associated steatotic liver disease (MASLD). Since triglyceride (TG)-rich very low-density lipoprotein (VLDL) is a precursor of sdLDL and is overproduced by MASLD, the composition of VLDL may be more directly associated with MAFLD than sdLDL-C or plasma TG. To identify TG-rich VLDL, this author proposed "Excess TG" and examined its association with MASLD. METHODS: Patients with type 2 diabetes (n=1295), excluding fasting hypertriglyceridemia (TG ≥ 400 mg/dL) and heavy drinkers were examined. Liver steatosis and visceral fat area (VFA) were evaluated using CT. VLDL-C was calculated as the total C minus direct LDL-C minus HDL-C. The average VLDL-TG level can be estimated using VLDL-C×5, according to the principle of the Friedewald equation for LDL-C. Thus, VLDL-TG was estimated as VLDL-C×5, and Excess TG was calculated as plasma TG minus VLDL-C×5. RESULTS: Patients with MASLD were younger, more likely to be men and drinkers, and had higher VFA, TG, sdLDL-C, and excess TG, while VLDL-C was comparable. Excess TG was found to be the most sensitive lipid parameter for identifying MASLD, independent of sdLDL-C, TG, TG/VLDL-C, and VFA. The odds ratios for MASLD were 2.4-, 3.7-, and 3.9-fold higher for Excess TG ranges of 0-24, 25-49, and ≥ 50 mg/dL, respectively, relative to ＜0 mg, and a close relationship remained significant after adjustment for lipid- and adiposity-related parameters. CONCLUSIONS: Excess TG in VLDL was strongly associated with MASLD beyond TG and sdLDL-C levels, which may reflect the presence of TG-rich VLDL.

Development and validation of cardiometabolic risk predictive models based on LDL oxidation and candidate geromarkers from the MARK-AGE data.

The predictive value of the susceptibility to oxidation of LDL particles (LDLox) in cardiometabolic risk assessment is incompletely understood. The main objective of the current study was to assess its relationship with other relevant biomarkers and cardiometabolic risk factors from MARK-AGE data. A cross-sectional observational study was carried out on 1089 subjects (528 men and 561 women), aged 40-75 years old, randomly recruited age- and sex-stratified individuals from the general population. A correlation analysis exploring the relationships between LDLox and relevant biomarkers was undertaken, as well as the development and validation of several machine learning algorithms, for estimating the risk of the combined status of high blood pressure and obesity for the MARK-AGE subjects. The machine learning models yielded Area Under the Receiver Operating Characteristic Curve Score ranging 0.783-0.839 for the internal validation, while the external validation resulted in an Under the Receiver Operating Characteristic Curve Score between 0.648 and 0.787, with the variables based on LDLox reaching significant importance within the obtained predictions. The current study offers novel insights regarding the combined effects of LDL oxidation and other ageing markers on cardiometabolic risk. Future studies might be extended on larger patient cohorts, in order to obtain reproducible clinical assessment models.

Validation of physical examinations of tendon xanthomas and changes in the cutoff values of Achilles tendon thickness on radiography in the clinical criteria of heterozygous familial hypercholesterolemia in Japan.

BACKGROUND: The 2022 Japan Atherosclerosis Society familial hypercholesterolemia (FH) clinical criteria were modified. In particular, the cutoff value of Achilles tendon thickness (ATT) on radiography was changed from ≥9 mm in both sexes to ≥8.0 mm in men and ≥7.5 mm in women. METHODS: A total of 872 patients with FH were retrospectively reviewed. Patients were categorized by an ATT of <7.5/8.0 mm (group 1), ≥7.5/8.0 and <9.0 mm (group 2, new group with FH by ATT), and ≥9 mm (group 3). RESULTS: In total, 492 patients fell into in group 1, 102 in group 2, and 263 in group 3, and 14.0%, 55.9%, and 79.8% of patients in groups 1, 2, and 3, respectively, were positive for a FH mutation. Further, among patients with an LDL cholesterol >180 mg/dL, 37.3%, 77.3%, and 86.5% of patients had a FH mutation in groups 1, 2, and 3, respectively. The proportion of patients with protein-truncating mutation (3.8%, 16.7%, and 53.2%, respectively) differed significantly across groups 1 through 3, respectively. Interestingly, only a very small proportion of the patients in groups 2 and 3 had palpable xanthomas (3.0% and 14.4% respectively). CONCLUSIONS: This study validates the new radiographic ATT criteria, since the vast majority of patients in the intermediate ATT category had true FH, as shown by positive genetic testing, whereas the old ATT criteria left them with just a deferred diagnosis of FH. In addition, use of physical examination alone for the presence of tendon xanthoma may lead to underdiagnosis of FH.

Rapid achievement of low-density lipoprotein cholesterol goals within 1 month after acute coronary syndrome during combination therapy with rosuvastatin, ezetimibe and bempedoic acid: Initial experience from the LAI-REACT study.

Rapid reduction of low-density lipoprotein cholesterol (LDL-C) to target levels immediately following acute coronary syndrome (ACS) event is critical to prevent future events. High-dose statins alone often fail to achieve LDL-C goals. Proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i) combined with high-dose statins improves LDL-C goal attainment, but is unaffordable for many patients in India and worldwide. In a real-world open-label study, we demonstrated in a cohort of 122 patients with ACS, concurrent triple therapy with rosuvastatin 40 mg/d, ezetimibe 10 mg/d, and bempedoic acid 180 mg/d (REB) started at the time of hospital admission was associated with 57.7%, 61.7%, 61.9% and 60.6% reductions in LDL-C from 115.6 mg/dL at baseline to 48.9 mg/dL at week 1, 44.3 mg/dL at week 2, 44.1 mg/dL at week 4, and 45.6 mg/dL at week 6, respectively (each p < 0.001 compared to baseline; p < 0.001 across repeated measures). REB provided significant reductions in LDL-C within as early as one week and enabled 76.3% and 92.2% of patients to achieve the Lipid Association of India and American College of Cardiology recommended LDL-C targets of <50 mg/dl and <70 mg/dl within 2-weeks, respectively, which were sustained at 4-6 weeks. REB was generally well tolerated. Our study demonstrates the capacity to rapidly achieve LDL-C goals after ACS with triple REB therapy, an affordable regimen in India.

Investigating the Role of Cannabinoid Type 1 Receptors in Vascular Function and Remodeling in a Hypercholesterolemic Mouse Model with Low-Density Lipoprotein-Cannabinoid Type 1 Receptor Double Knockout Animals.

Hypercholesterolemia forms the background of several cardiovascular pathologies. LDL receptor-knockout (LDLR-KO) mice kept on a high-fat diet (HFD) develop high cholesterol levels and atherosclerosis (AS). Cannabinoid type 1 receptors (CB1Rs) induce vasodilation, although their role in cardiovascular pathologies is still controversial. We aimed to reveal the effects of CB1Rs on vascular function and remodeling in hypercholesterolemic AS-prone LDLR-KO mice. Experiments were performed on a newly established LDLR and CB1R double-knockout (KO) mouse model, in which KO and wild-type (WT) mice were kept on an HFD or a control diet (CD) for 5 months. The vascular functions of abdominal aorta rings were tested with wire myography. The vasorelaxation effects of acetylcholine (Ach, 1 nM-1 µM) were obtained after phenylephrine precontraction, which was repeated with inhibitors of nitric oxide synthase (NOS) and cyclooxygenase (COX), Nω-nitro-L-arginine (LNA), and indomethacin (INDO), respectively. Blood pressure was measured with the tail-cuff method. Immunostaining of endothelial NOS (eNOS) was carried out. An HFD significantly elevated the cholesterol levels in the LDLR-KO mice more than in the corresponding WT mice (mean values: 1039 ± 162 mg/dL vs. 91 ± 18 mg/dL), and they were not influenced by the presence of the CB1R gene. However, with the defect of the CB1R gene, damage to the Ach relaxation ability was moderated. The blood pressure was higher in the LDLR-KO mice compared to their WT counterparts (systolic/diastolic values: 110/84 ± 5.8/6.8 vs. 102/80 ± 3.3/2.5 mmHg), which was significantly elevated with an HFD (118/96 ± 1.9/2 vs. 100/77 ± 3.4/3.1 mmHg, p < 0.05) but attenuated in the CB1R-KO HFD mice. The expression of eNOS was depressed in the HFD WT mice compared to those on the CD, but it was augmented if CB1R was knocked out. This newly established double-knockout mouse model provides a tool for studying the involvement of CB1Rs in the development of hypercholesterolemia and atherosclerosis. Our results indicate that knocking out the CB1R gene significantly attenuates vascular damage in hypercholesterolemic mice.

Angiopoietin-like Proteins and Lipoprotein Lipase: The Waltz Partners That Govern Triglyceride-Rich Lipoprotein Metabolism? Impact on Atherogenesis, Dietary Interventions, and Emerging Therapies.

Over 50% of patients who take statins are still at risk of developing atherosclerotic cardiovascular disease (ASCVD) and do not achieve their goal LDL-C levels. This residual risk is largely dependent on triglyceride-rich lipoproteins (TRL) and their remnants. In essence, remnant cholesterol-rich chylomicron (CM) and very-low-density lipoprotein (VLDL) particles play a role in atherogenesis. These remnants increase when lipoprotein lipase (LPL) activity is inhibited. ApoCIII has been thoroughly studied as a chief inhibitor and therapeutic options to curb its effect are available. On top of apoCIII regulation of LPL activity, there is a more precise control of LPL in various tissues, which makes it easier to physiologically divide the TRL burden according to the body's requirements. In general, oxidative tissues such as skeletal and cardiac muscle preferentially take up lipids during fasting. Conversely, LPL activity in adipocytes increases significantly after feeding, while its activity in oxidative tissues decreases concurrently. This perspective addresses the recent improvements in our understanding of circadian LPL regulations and their therapeutic implications. Three major tissue-specific lipolysis regulators have been identified: ANGPTL3, ANGPTL4, and ANGPTL8. Briefly, during the postprandial phase, liver ANGPTL8 acts on ANGPTL3 (which is released continuously from the liver) to inhibit LPL in the heart and muscle through an endocrine mechanism. On the other hand, when fasting, ANGPTL4, which is released by adipocytes, inhibits lipoprotein lipase in adipose tissue in a paracrine manner. ANGPTL3 inhibitors may play a therapeutic role in the treatment of hypertriglyceridemia. Several approaches are under development. We look forward to future studies to clarify (a) the nature of hormonal and nutritional factors that determine ANGPTL3, 4, and 8 activities, along with what long-term impacts may be expected if their regulation is impaired pharmacologically; (b) the understanding of the quantitative hierarchy and interaction of the regulatory actions of apoCIII, apoAV, and ANGPTL on LPL activity; (c) strategies for the safe and proper treatment of postprandial lipemia; and (d) the effect of fructose restriction on ANGPTL3, ANGPTL4, and ANGPTL8.

Concordance between LDL-C estimated by various formulas and directly measured LDL-C.

BACKGROUND: Although direct measurement of LDL cholesterol (LDL-C) in blood is possible, there are several formulas for its estimation. The performance and concordance of these formulas have not been evaluated in Colombia. OBJECTIVE: To determine the concordance between LDL-C directly measured using the enzymatic technique and existing methods to calculate it. METHODS: Study of diagnostic tests, and concordance. We analyzed complete lipid profile samples, which included direct measurement of LDL-C, from 2014 to 2022 at Hospital Universitario San Ignacio (Bogotá, Colombia). The direct LDL-C measurements were compared with estimations using the DeLong, Sampson, Friedewald, extended Martin/Hopkins, Anandaraja, and Cordova methods. Lin's concordance correlation coefficient (CCC) and Bland-Altman plots were employed, conducting subgroup analyses based on triglycerides (TG), and LDL-C levels. Kappa coefficients assessed agreement in LDL-C risk categories according to dyslipidemia guidelines. RESULTS: A total of 2144 samples were evaluated. The formulas with the best CCC were DeLong (0.971) and Sampson (0.969), with no relevant differences. The extended Martin/Hopkins formula (0.964) and the Friedewald formula (0.964) also performed well. The Anandaraja (0.921) and Cordova (0.881) equations exhibited inferior performance. For all formulas, a decrease in concordance was observed when triglycerides were ≥400 mg/dL or when LDL-C was <100 mg/dL. Most formulas demonstrated optimal agreement when assessed using risk categories according to dyslipidemia guidelines, except for Anandaraja and Cordova. CONCLUSIONS: The DeLong, Sampson, extended Martin/Hopkins, and Friedewald formulas show the best concordance with directly measured LDL-C, so in most cases the results can be considered interchangeable. However, the Anandaraja and Cordova formulas are not recommended.

Quantifying Triglyceride-Rich Lipoprotein Atherogenicity, Associations With Inflammation, and Implications for Risk Assessment Using Non-HDL Cholesterol.

BACKGROUND: Triglyceride-rich lipoproteins and remnants (TRL/remnants) have a causal, but not yet quantified, relationship with coronary heart disease (CHD): myocardial infarction plus revascularization. OBJECTIVES: The authors sought to estimate TRL/remnant per-particle atherogenicity, investigate causal relationships with inflammation, and determine whether differences in the atherogenicity of TRL/remnants and low-density lipoprotein (LDL) impact the causal association of non-high-density lipoprotein cholesterol (non-HDL-C) with CHD. METHODS: Single nucleotide polymorphisms (SNPs) (N = 1,357) identified by genome-wide association in the UK Biobank were ranked into 10 clusters according to the effect on TRL/remnant-C vs LDL-C. Mendelian randomization analysis was used to estimate for each SNP cluster CHD ORs per 10 mg/dL apolipoprotein B (apoB) and per 0.33 mmol/L non-HDL-cholesterol, and to evaluate association of TRL/remnants with biomarkers of systemic inflammation. RESULTS: SNPs in cluster 1 predominantly affected LDL-C, whereas SNPs in cluster 10 predominantly affected TRL/remnant-C. CHD risk per genetically predicted increase in apoB and in non-HDL-C rose across clusters. ORs per 10 mg/dL higher apoB was 1.15 (95% CI: 1.11-1.19) in cluster 1 vs 1.70 (95% CI: 1.52-1.90) in cluster 10. Comparing ORs between these TRL/remnant-predominant and LDL-predominant clusters, we estimated that TRL/remnants were at least 3.9 (95% CI: 2.8-5.4) times more atherogenic than LDL on a per-particle basis. For non-HDL-C, CHD ORs per 0.33 mmol/L rose from 1.15 (95% CI: 1.11-1.19) for cluster 1 to 1.40 (95% CI: 1.30-1.50) for cluster 10. TRL/remnants exhibited causal relationships with inflammation, but this did not explain their greater atherogenicity. CONCLUSIONS: TRL/remnants are about 4 times more atherogenic than LDL. Variation in the causal association of non-HDL-C with CHD indicates that adjustment for percentage TRL/remnant-C may be needed for accurate risk prediction.

Elevated remnant cholesterol as a potential predictor for cardiovascular events in rheumatoid arthritis patients.

Objective: The risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) remains inadequately defined. Consequently, this study aims to evaluate the predictive value of remnant cholesterol (RC) for assessing CVD risk in RA patients. Methods: Plasma RC levels were measured in 114 RA patients and 41 healthy controls, calculated as total cholesterol minus HDL-C and LDL-C. These levels were further analyzed using 1H-NMR lipid/metabolomics. Meanwhile, the 28-joint Disease Activity Score (DAS28) assessed RA activity. Results: RC levels were significantly elevated in RA patients (19.0 mg/dl, p < 0.001) compared to healthy controls (14.5 mg/dl). Furthermore, RC levels were significantly elevated at 37.4 mg/dl in patients who experienced cardiovascular event (CVE) compared to 17.4 mg/dl in those without CVE (p < 0.001). To enhance the precision and reliability of RC measurements, RC concentrations were further validated using 1H-NMR spectroscopy. Additionally, a positive correlation was observed between RC levels and DAS28. Multivariate analysis identified RC as a significant predictor of CVE (odds ratio = 1.82, p = 0.013). ROC curve analysis revealed superior predictive capability of RC for CVE (AUC = 0.919, p < 0.001) compared to LDL-C (AUC = 0.669, p = 0.018), with a high sensitivity of 94.7% and a specificity of 82.1%. Conclusion: Elevated RC levels demonstrate greater accuracy in predicting CVE occurrence in RA patients compared to traditional measures such as LDL-C. These findings suggest that elevated RC levels may serve as a novel predictor for occurrence of CVE in RA patients, facilitating early intervention strategies based on the risk stratification.