Small Low-density Lipoprotein Research Articles

5123 Remission of Antibodies Blocking the Insulin Receptor Reduces Atherogenicity of LDL Particles but Increases HDL Particle Atherogenicity

Abstract Disclosure: M. Hwang: None. R. Shamburek: None. M. Lightbourne: None. M. Sampson: None. A. Remaley: None. B. Abel: None. R.J. Brown: None. Background: Type B insulin resistance syndrome (TBIR) is a rare autoimmune disorder defined by the presence of autoantibodies against the insulin receptor, usually in the context of systemic autoimmune diseases such as lupus. In TBIR, insulin signaling is disrupted at the receptor-level, resulting in failure of insulin to both suppress hepatic glucose production and to stimulate de novo lipogenesis. This leads to a phenotype of extreme insulin resistance (IR) and hyperglycemia without dyslipidemia. IR and hyperglycemia resolve when remission of the autoantibody is induced by immunosuppression. Given the known association between IR and cardiovascular disease (CVD), we sought to compare biomarkers of CVD risk using lipoprotein particles measured by Nuclear Magnetic Resonance (NMR) in patients with TBIR during their active disease state vs remission. Methods: Patients with TBIR (N=14) had fasting labs including NMR lipoprotein profiles (analyzed using LP4 deconvolution algorithm) during active disease (positive antibodies to the insulin receptor and severe IR) and remission (defined by discontinuation of insulin or amelioration of hyperglycemia). Particle size (nm) and concentration of subclasses by size were measured for low-density lipoprotein (LDL) particles (nmol/L) and high-density lipoprotein (HDL) particles (umol/L). Results: Upon remission from TBIR, there were large decreases in hemoglobin A1c (from 10.9±3.0% to 6.1±1.1%, p<0.001) and insulin (from 1000.0 (715.9, 1000.0) mcU/mL to 16.8 (8.1, 39.2) mcU/mL, normal 2.6-24.9 mcU/mL, p<0.001), and increases in BMI (from 21.8±3.5 to 28.6±7.4 kg/m2, p<0.01), C3 (from 76±27 to 114±20 mg/dL, normal 82-185 mg/dL, p<0.01), and C4 (from 16±8 to 25±9 mg/dL, normal 15-53 mg/dL, p<0.01). After remission of TBIR, LDL profiles became less atherogenic: small LDL particle concentration decreased (from 523.4±170.2 to 362.8±119.7, normal 63.8-1719.6, p<0.01) and LDL particle size increased (from 20.6±0.5 to 21.2±0.3, normal 19.9 -21.6, p<0.01). By contrast, HDL profiles became more atherogenic after remission of TBIR: small HDL particle concentration increased (from 4.6±2.6 to 8.2±4.3, normal 6.6-19.3, p<0.01); the largest HDL particle concentration decreased (from 1.5±0.8 to 0.7±0.7, normal 0-1.2, p<0.01), and HDL particle size decreased (from 10.3±0.4 to 9.6±0.5, normal 8.4-9.9, p<0.001). Conclusions: Active TBIR is a pro-inflammatory state characterized by excess consumption of C3 and C4. Inflammation may contribute to an unfavorable LDL particle profile that improves after remission. However, lack of insulin signaling through the insulin receptor during active TBIR likely leads to an anti-atherogenic HDL profile that returns to normal levels when insulin signaling is restored after remission. Future studies will further investigate the role of insulin resistance and inflammation in CVD risk. Presentation: 6/3/2024

Factors associated with seizure response in adults with epilepsy on a modified Atkins diet

PurposeThis study investigated factors associated with improved seizure control in adults with epilepsy following a modified Atkins diet (MAD). MethodsFollow-up data collected from participants enrolled in a prospective study between March 2016 and November 2023 was analyzed. Demographic and clinical differences between diet responders and non-responders were evaluated. MAD response was defined as ≥ 50 % reduction in seizure frequency from baseline. ResultsMAD use led to clinical response in 48 % of study participants with 2–3 month follow-up and in 56 % of study participants with 6 month follow-up. No significant differences were found for gender, age at diet initiation, age at epilepsy diagnosis, or for number of current or past medications tried. However, a significant relationship emerged between epilepsy type and diet response at 6 months with a response of 100 % seen in adults with generalized epilepsy and a response of only 42 % in adults with focal epilepsy (p = 0.004). Those who responded to the diet showed non-significant increases in many of the measured lipid biomarkers. Levels of apolipoprotein-B and small low-density lipoprotein particles showed significant increases from baseline after 3 months in responders compared to non-responders (p = 0.004 and 0.049, respectively). ConclusionsThese findings support the continued use of MAD particularly for seizure management in adults with generalized epilepsy and highlight potential mechanisms of clinical response involving lipoprotein and energy metabolism.

Short-term effects of gastric bypass versus sleeve gastrectomy on high LDL cholesterol: The BASALTO randomized clinical trial

BackgroundThere has been a substantial increase in the use of laparoscopic sleeve gastrectomy (SG) to treat morbid obesity despite observational evidence demonstrating the superiority of Roux-en-Y gastric bypass (RYGB) for reducing low-density lipoprotein (LDL) cholesterol. The main aim was to ascertain whether high LDL cholesterol levels should be considered when selecting the most appropriate surgical procedure for each patient (RYGB or SG).MethodsIn this single-center, randomized clinical trial using intention-to-treat analysis, 38 patients with severe obesity and elevated levels of LDL cholesterol were randomly assigned to undergo RYGB or SG. The primary outcome was LDL cholesterol remission at 12 months, defined as LDL cholesterol < 3.36 nmol/l without lipid-lowering medications. Secondary outcomes included changes in weight, other comorbidities, qualitative lipoprotein traits, cholesterol esters, glycoproteins, cholesterol absorption and synthesis metabolites and complications.ResultsIntention-to-treat analysis revealed that LDL cholesterol remission occurred in 66.6% of RYGB patients compared to 27.8% of SG patients (p = 0.019). Among patients completing follow-up, RYGB demonstrated superior remission (80.0% vs. 29.4%, p = 0.005). Exclusive benefits of RYGB included a reduction in large, medium, and small LDL particles. Cholesterol absorption markers showed differential behavior after both techniques: campesterol (Δ −15.2 µg/mg, 95% CI −30.2 to −0.1) decreased after RYGB, and sitosterol (Δ 21.1 µg/mg, 95% CI 0.9 to 41.2), cholestanol (Δ 30.6 µg/mg, 95% CI 14.8 to 57.9) and campesterol (Δ 18.4 µg/mg, 95% CI 4.4 to 32.3) increased after SG. No differences in weight loss, cholesterol esters, glycoproteins, cholesterol synthesis metabolites or postoperative complications were observed between techniques.ConclusionIn conclusion, RYGB is superior to SG in terms of short-term of high LDL cholesterol remission. Furthermore, RYGB also led to a greater improvement in lipoprotein parameters that confer an atherogenic profile. Therefore, the presence of elevated levels of LDL cholesterol should be considered when determining the optimal bariatric surgery procedure for each patient.Trial registrationClinicaltrials.gov number, NCT03975478).Graphical abstract

Obesity and Sex as Determinants of Atherogenic Risk Associated with High-Density (HDL) and Low-Density Lipoprotein (LDL) Subfractions in Adolescents: A Population-based Study Based on Health Survey of Sao Paulo

Background: Worldwide, obesity in adolescents is an epidemiological concern. Overweight and obesity are associated with comorbidities in adult life, such as increased risk of hypertension and other non-communicable diseases. This study investigated possible differences between traditional lipid markers and Low-Density Lipoprotein (LDL) and High-Density Lipoprotein (HDL) subfractions in a population-wide representative sample of Brazilian adolescents. Methods: The individuals included in the study comprise a subsample of the 2015 Health Survey of São Paulo (ISA-Capital 2015). LDL and HDL particle sizes were determined by the Lipoprint® System (Quantimetrix Corporation). Results: 272 Brazilian adolescents with a mean age of 15.2 ± 2.2 years, of which 47.8% (n = 130) are boys. Analysis of LDL subfractions showed an increase in LDL 2 content in girls (5.7% vs. 5.1%; p = 0.047). This result was associated with a higher content of large LDL in girls (17.8% vs. 13.5%; p &lt; 0.001) and a significant, lower content of small LDL (1.7% vs. 3.4%; p = 0.002). When obesity was considered, we observed that regardless of being overweight, girls had higher large and small LDL than boys. However, when a large to small LDL ratio was calculated, girls with no excess weight had higher values than boys with no excess weight (10.6 vs. 9.3; p = 0.038), and these had lower LDL ratio than overweight boys (9.3 vs. 13.5; p = 0.016). On the other hand, boys had higher HDL 2 content than girls (8.9% vs. 8.0%; p = 0.017), which was associated with increased large HDL values in boys (1.9% vs. 1.7%; p = 0.047). Regression analysis was performed according to gender, the sum of very low-density lipoprotein (VLDL) + intermediate density lipoprotein (IDL) C + IDL B subfractions was adjusted for age and body mass index (BMI), showing that girls had lower atherogenic lipid profile (β = 0.987; CI = 0.977-0.998; p = 0.017) than boys. When the regression analysis was performed according to BMI, large LDL in adolescents with no excess weight presented a lower atherogenic lipid profile (β = 1.040; CI = 1.000-1.082; p = 0.049), adjusted for age and sex, than overweight adolescents. Conclusion: Regardless of excess weight, girls showed a cardioprotective profile more associated with a favorable distribution of LDL subfractions than boys, reinforcing the relevance of evaluating qualitative aspects of lipoproteins in addition to the traditional cholesterol content.

Lipoprotein subclasses are associated with Hepatic steatosis: insights from the prospective multicenter imaging study for the evaluation of chest pain (PROMISE) clinical trial

ObjectivesTo determine the relationship between lipoprotein particle size/number with hepatic steatosis (HS), given its association with traditional lipoproteins and coronary atherosclerosis. MethodsIndividuals with available CT data and blood samples enrolled in the PROMISE trial were studied. HS was defined based on CT attenuation. Lipoprotein particle size/number were measured by nuclear magnetic resonance spectroscopy. Principal components analysis (PCA) was used for dimensionality reduction. The association of PCA factors and individual lipoprotein particle size/number with HS were assessed in multivariable regression models. Associations were validated in an independent cohort of 59 individuals with histopathology defined HS. ResultsIndividuals with HS (n=410/1,509) vs those without (n=1,099/1,509), were younger (59±8 vs 61±8 years) and less often females (47.6 % vs 55.9 %). All PCA factors were associated with HS: factor 1 (OR:1.36, 95 %CI:1.21–1.53), factor 3 (OR:1.75, 95 %CI:1.53–2.02) and factor 4 (OR:1.49; 95 %CI:1.32–1.68) were weighted heavily with small low density lipoprotein (LDL) and triglyceride-rich (TRL) particles, while factor 2 (OR:0.86, 95 %CI:0.77–0.97) and factor 5 (OR:0.74, 95 %CI:0.65–0.84) were heavily loaded with high density lipoprotein (HDL) and larger LDL particles. These observations were confirmed with the analysis of individual lipoprotein particles in PROMISE. In the validation cohort, association between HS and large TRL (OR: 8.16, 95 %CI:1.82–61.98), and mean sizes of TRL- (OR: 2.82, 95 %CI:1.14–9.29) and HDL (OR:0.35, 95 %CI:0.13–0.72) were confirmed. ConclusionsLarge TRL, mean sizes of TRL-, and HDL were associated with radiographic and histopathologic HS. The use of lipoprotein particle size/number could improve cardiovascular risk assessment in HS.

Decreased Circulating Very Small Low-Density Lipoprotein is Likely Causal for Age-Related Macular Degeneration

Abnormal changes in metabolite levels in serum or plasma have been highlighted in several studies in age-related macular degeneration (AMD), the leading cause of irreversible vision loss. Specific changes in lipid profiles are associated with an increased risk of AMD. Metabolites could thus be used to investigate AMD disease mechanisms or incorporated into AMD risk prediction models. However, whether particular metabolites causally affect the disease has yet to be established. A 3-tiered analysis of blood metabolites in the United Kingdom (UK) Biobank cohort to identify metabolites that differ in AMD patients with evidence for a putatively causal role in AMD. A total of 72376 donors from the UK Biobank cohort including participants with AMD (N=1353) and non-AMD controls (N=71023). We analyzed 325 directly measured or derived blood metabolites from the UK Biobank for 72376 donors to identify AMD-associated metabolites. Genome-wide association studies for 325 metabolites in 98316 European participants from the UK Biobank were performed. The causal effects of these metabolites in AMD were tested using a 2-sample Mendelian randomization approach. The predictive value of these measurements together with sex and age was assessed by developing a machine learning classifier. Evaluating metabolic biomarkers associated with AMD susceptibility and investigating their potential causal contribution to the development of the disease. This study noted age to be the prominent risk factor associated with AMD development. While accounting for age and sex, we identified 84 metabolic markers as significantly (false discovery rate-adjusted P value < 0.05) associated with AMD. Lipoprotein subclasses comprised the majority of the AMD-associated metabolites (39%) followed by several lipoprotein to lipid ratios. Nineteen metabolites showed a likely causative role in AMD etiology. Of these, 6 lipoproteins contain very small, very low-density lipoprotein (VLDL), and phospholipids to total lipid ratio in medium VLDL. Based on this we postulate that depletion of circulating very small VLDLs is likely causal for AMD. The risk prediction model constructed from the metabolites, age and sex, identified age as the primary predictive factor with a much smaller contribution by metabolites to AMD risk prediction. This study underscores the pronounced role of lipids in AMD susceptibility and the likely causal contribution of particular subclasses of lipoproteins to AMD. Our study provides valuable insights into the metabopathological mechanisms of AMD disease development and progression.

Effect of Hormone Therapy on Lipoprotein Subfractions in Early and Late Postmenopausal Women.

The Early vs Late Intervention Trial with Estradiol (ELITE) showed that hormone therapy (HT) reduced atherosclerosis progression among early but not late postmenopausal women (PMW). Determined by time-since-menopause (1) HT effects on lipids and lipoprotein particle subfractions (LPs), (2) associations of estradiol (E2) level with lipids and LPs, (3) associations of lipids and LPs with atherosclerosis progression. Randomized controlled trial stratified by time-since-menopause. Academic institution. Healthy postmenopausal women. Oral E2 with/without sequential vaginal progesterone. Standard lipids and 21 LPs quantitated by ion mobility every 6 months. Among 562 PMW (240 early, 322 late), HT significantly increased total triglycerides (TG), high-density lipoprotein (HDL) cholesterol, small low-density lipoproteins (LDL), large HDL, and TG/C ratio in LDL and HDL and decreased LDL-cholesterol, total very low density lipoproteins (VLDL), small VLDL, intermediate-density lipoproteins, large LDL, and LDL peak diameter. HT showed no lipid or LP differences between time-since-menopause. Associations of E2 level with lipids and LPs explained the HT effects. Despite the nonsignificant P interaction by time-since-menopause, we observed that very small LDL and total HDL LPs were associated with atherosclerosis progression in late PMW. HT effects on standard lipids and LPs are consistent with the literature. HT has similar effect on lipids and LPs in early and late PMW. Novel findings include discordant effects of HT on TG and VLDL particles, which can be explained by increased catabolism of atherogenic remnants of TG-rich lipoproteins. Our findings extend the well-known HT effects on standard lipids and LPs that may contribute to the beneficial effects on atherosclerosis progression in PMW.

A two-sample Mendelian randomization study explores metabolic profiling of different glycemic traits

We assessed the causal relation of four glycemic traits and type 2 diabetes liability with 167 metabolites using Mendelian randomization with various sensitivity analyses and a reverse Mendelian randomization analysis. We extracted instruments for fasting glucose, 2-h glucose, fasting insulin, and glycated hemoglobin from the Meta-Analyses of Glucose and Insulin-related traits Consortium (n = 200,622), and those for type 2 diabetes liability from a meta-analysis of multiple cohorts (148,726 cases, 965,732 controls) in Europeans. Outcome data were from summary statistics of 167 metabolites from the UK Biobank (n = 115,078). Fasting glucose and 2-h glucose were not associated with any metabolite. Higher glycated hemoglobin was associated with higher free cholesterol in small low-density lipoprotein. Type 2 diabetes liability and fasting insulin were inversely associated with apolipoprotein A1, total cholines, lipoprotein subfractions in high-density-lipoprotein and intermediate-density lipoproteins, and positively associated with aromatic amino acids. These findings indicate hyperglycemia-independent patterns and highlight the role of insulin in type 2 diabetes development. Further studies should evaluate these glycemic traits in type 2 diabetes diagnosis and clinical management.

Causal relationship between metabolites and embolic stroke: based on Mendelian randomization and metabolomics.

This research employed Mendelian randomization (MR) methods to explore whether metabolites are causally associated with embolic stroke of undetermined source (ESUS). Genome-Wide Association Study (GWAS) data regarding metabolites and ESUS were downloaded from the database. Metabolites were employed as exposure factors, ESUS served as the outcome variable, and single nucleotide polymorphisms (SNPs) exhibiting significant association with ESUS were chosen as instrumental variables. The causal association between exposure factor metabolites and the outcome variable ESUS was assessed using two methods: MR-Egger regression and inverse variance-weighted (IVW) analysis. A causal relationship was observed between X-11593--O-methylascorbate* and ESUS, indicating a protective factor. Moreover, a causal relationship was identified between cholesterol esters in large very-low-density lipoprotein (VLDL), cholesterol esters in medium low-density lipoprotein (LDL), concentration of medium LDL particles, phospholipids in medium LDL, phenylalanine, total cholesterol in small LDL, total lipids in medium LDL and ESUS, representing risk factor. Funnel plots exhibited a symmetrical distribution of SNPs, while pleiotropic tests (p > 0.05) and leave-one-out tests indicated that the results were relatively stable. Metabolites are causally associated with ESUS. LDL and VLDL-related metabolites are identified as risk factors for ESUS.

Protective effect of phospholipids in lipoproteins against diabetic kidney disease: A Mendelian randomization analysis.

The etiology of diabetic kidney disease is complex, and the role of lipoproteins and their lipid components in the development of the disease cannot be ignored. However, phospholipids are an essential component, and no Mendelian randomization studies have yet been conducted to examine potential causal associations between phospholipids and diabetic kidney disease. Relevant exposure and outcome datasets were obtained through the GWAS public database. The exposure datasets included various phospholipids, including those in LDL, IDL, VLDL, and HDL. IVW methods were the primary analytical approach. The accuracy of the results was validated by conducting heterogeneity, MR pleiotropy, and F-statistic tests. MR-PRESSO analysis was utilized to identify and exclude outliers. Phospholipids in intermediate-density lipoprotein (OR: 0.8439; 95% CI: 0.7268-0.9798), phospholipids in large low- density lipoprotein (OR: 0.7913; 95% CI: 0.6703-0.9341), phospholipids in low- density lipoprotein (after removing outliers, OR: 0.788; 95% CI: 0.6698-0.9271), phospholipids in medium low- density lipoprotein (OR: 0.7682; 95% CI: 0.634-0.931), and phospholipids in small low-density lipoprotein (after removing outliers, OR: 0.8044; 95% CI: 0.6952-0.9309) were found to be protective factors. This study found that a higher proportion of phospholipids in intermediate-density lipoprotein and the various subfractions of low-density lipoprotein, including large LDL, medium LDL, and small LDL, is associated with a lower risk of developing diabetic kidney disease.

Gender-Dependent Associations between Serum Betatrophin Levels and Lipoprotein Subfractions in Diabetic and Nondiabetic Obese Patients.

Betatrophin, also known as angiopoietin-like protein 8 (ANGPTL8), mainly plays a role in lipid metabolism. To date, associations between betatrophin and lipoprotein subfractions are poorly investigated. For this study, 50 obese patients with type 2 diabetes (T2D) and 70 nondiabetic obese (NDO) subjects matched in gender, age, and body mass index (BMI) as well as 49 gender- and age-matched healthy, normal-weight controls were enrolled. Serum betatrophin levels were measured with ELISA, and lipoprotein subfractions were analyzed using Lipoprint gel electrophoresis. Betatrophin concentrations were found to be significantly higher in the T2D and NDO groups compared to the controls in all subjects and in females, but not in males. We found significant positive correlations between triglyceride, very low density lipoprotein (VLDL), large LDL (low density lipoprotein), small LDL, high density lipoprotein (HDL) -6-10 subfractions, and betatrophin, while negative correlations were detected between betatrophin and IDL, mean LDL size, and HDL-1-5. Proportion of small HDL was the best predictor of betatrophin in all subjects. Small LDL and large HDL subfractions were found to be the best predictors in females, while in males, VLDL was found to be the best predictor of betatrophin. Our results underline the significance of serum betatrophin measurement in the cardiovascular risk assessment of obese patients with and without T2D, but gender differences might be taken into consideration.

Causal role of lipid metabolome on the risk of ischemic stroke, its etiological subtypes, and long-term outcome: A Mendelian randomization study

Background and aimsThe lipid profile is consistently associated with coronary artery disease (CAD) and ischemic stroke (IS). However, the lipoprotein subfractions have not been deeply explored in stroke subtypes, especially in IS outcome. MethodsWe performed two-sample Mendelian randomization (MR) analysis using 92 lipid traits measured by nuclear magnetic resonance in 115,000 subjects from the UK Biobank. Data for genetic associations with IS, its subtypes, and long-term outcome (LTO) were obtained from three cohorts of European ancestry: GIGASTROKE (73,652 cases, 1,234,808 controls), GODS (n = 1791) and GISCOME (n = 6165). Results obtained using CARDIoGRAMPlusC4D were used to identify differences with CAD. ResultsGenetically determined low concentration of medium high-density lipoprotein (HDL) particles (odds ratio (OR) = 0.92, 95% CI 0.88–0.96; p = 3.6 × 10−4) and its cholesterol content (OR = 0.92, 95% CI 0.88–0.96; p = 1.9 × 10−4) showed causal associations with an increased risk of stroke. Genetic predisposition to high apolipoprotein (apo)B to apoA-I ratio was causally associated with an increased risk of IS (OR = 1.12, 95% CI 1.06–1.18, p = 1.1 × 10−4), and a highly suggestive association was found between non-esterified cholesterol in low-density lipoprotein (LDL) and increased risk of atherothrombotic stroke (LAS) (OR = 1.35, 95% CI 1.10–1.66; p = 4.0 × 10−3). Low cholesterol in small and medium LDL was suggestively associated with poor LTO. ConclusionsOur results support that low medium HDL concentration was causally associated with an increased stroke risk, while high levels of non-esterified cholesterol in LDL were suggestively associated with an increased risk of LAS and with a better LTO.

Relationship between the cholesterol and triglyceride content of lipoprotein subclasses and carotid intima-media thickness: A cross-sectional population-based study

BackgroundThe association between lipoprotein subclasses and carotid intima-media thickness (cIMT) progression has yet to be fully evaluated. We assessed which lipoprotein subclasses were associated with maximum cIMT levels in the general population. MethodsIn this study, cholesterol and triglyceride content of 20 lipoprotein subclasses were analyzed using gel permeation high-performance liquid chromatography (GP-HPLC) in 864 Japanese women and men (mean age 57 y, free of chronic liver or kidney diseases and off lipid-lowering, hormone replacement, or adrenocorticosteroid medications). Univariate and multivariate regression analyses and univariate and partial correlation analyses were performed to examine the relationships between lipoprotein subclasses and maximum cIMT levels. ResultsAfter adjusting for age, sex, systolic blood pressure, smoking, diabetes, and anti-hypertensive agents, elevated low-density lipoprotein (LDL)-2 and −3 cholesterol (particle diameter 25.5 nm and 23.0 nm, respectively; medium and small LDL) were associated with higher maximum cIMT levels in both women and men (all p for trend < 0.05). These associations were significant even after participants taking anti-diabetic or anti-hypertensive agents were excluded. No significant associations were found between any triglyceride subclasses and maximum cIMT levels. ConclusionsSmaller LDL particle cholesterol values are the most atherogenic lipoprotein parameter.

Improvement of lipid and lipoprotein profiles in children and adolescents with cystic fibrosis on CFTR modulator therapy

BackgroundAssociation of a high-fat diet with increased risks of cardiovascular disease (CVD) and type 2 diabetes, has prompted evaluation of lipids in people with CF (pwCF). However, most evidence on dyslipidemia was published before CF transmembrane conductance regulator (CFTR) modulators became a standard of care. The main goal of this study was to investigate the effect of CFTR modulator therapies on lipid and lipoprotein profiles in children and adolescents with CF. MethodsBlood samples were collected from 153 pwCF (10.1 ± 4.7 years of age) and 60 age-matched controls. Most pwCF were pancreatic insufficient on pancreatic enzyme replacement therapy. By the end of the study, 65% of CF participants were on CFTR modulator therapy for >1 month. The results of traditional and advanced lipid testing in pwCF were correlated with clinical and dietary information. ResultsTotal cholesterol and low-density lipoprotein (LDL) cholesterol were significantly lower in pwCF compared to non-CF participants. Those not receiving CFTR modulators also had significantly lower high-density lipoprotein (HDL) cholesterol and HDL particle number than controls. Individuals with CF on modulator therapy had significantly higher concentrations of anti-atherogenic HDL cholesterol and HDL particles along with lower levels of atherogenic large very-low density lipoprotein (VLDL) particles, total and small LDL particles, and triglycerides compared to those without CFTR modulator therapy. ConclusionCFTR modulator therapy has a beneficial effect on dyslipidemia in CF. It remains to be seen if these positive changes translate into decreased CVD risk later in life given the increasing life expectancy in CF.

The benefits of measuring the size and number of lipoprotein particles for cardiovascular risk prediction: A systematic review and meta-analysis

ObjectiveCardiovascular risk (CVR) is conventionally calculated by measuring the total cholesterol content of high-density lipoproteins (HDL) and low-density lipoproteins (LDL). The purpose of this systematic review was to assess the CVR associated with LDL and HDL particle size and number as determined by nuclear magnetic resonance (NMR) spectroscopy. Material and methodsA literature search was performed using the electronic databases MEDLINE and Scopus. All cohort and case–control studies published before January 1, 2019 that met the following inclusion criteria were included: HDL-P, LDL-P, HDL-Z and/or LDL-Z measured by NMR spectroscopy; cardiovascular event as an outcome variable; risk of cardiovascular events expressed as odds ratios or hazard ratios; only adult patients. A meta-analysis was performed for each exposure variable (4 for LDL and 5 for HDL) and for each exposure measure (highest versus lowest quartile and 1-standard deviation increment). ResultsThis review included 24 studies. Number of LDL particles was directly associated with CVR: risk increased by 28% with each standard deviation increment. LDL particle size was inversely and significantly associated with CVR: each standard deviation increment corresponded to an 8% risk reduction. CVR increased by 12% with each standard deviation increase in number of small LDL particles. HD, particle number and size were inversely associated with CVR. ConclusionLarger particle size provided greater protection, although this relationship was inconsistent between studies. Larger number of LDL particles and smaller LDL particle size are associated with increased CVR. Risk decreases with increasing number and size of HDL particles.

Indications for omega-3 fatty acid supplementation in prevention of cardiovascular disease: From fish to pharmaceuticals.

To explore the evidence for omega-3 fatty acid (O3FA) supplementation in primary and secondary prevention of cardiovascular disease (CVD). PubMed, Cochrane reviews, and Google Scholar were searched for meta-analyses and reviews related to O3FAs and CVD. Salient, recent randomized controlled trials referenced in these reviews were retrieved. Current lipid guidelines were reviewed. Most O3FAs are derived from marine or aquatic microalgae, which are consumed by fish. The essential fatty acids eicosapentaenoic acid and docosahexaenoic acid are mainly sourced from fish, with a small fraction coming from plants. Omega-3 fatty acids modestly lower triglyceride levels, but the major impact on CVD is through a variety of other mechanisms related to cell membrane function, antioxidant properties, and reduction of atherogenic small low-density lipoprotein cholesterol particles. Guidelines continue to recommend eating 2 servings of fish per week. There is little evidence of benefit of O3FAs in primary prevention of CVD. Given that 40% of Canadians have insufficient levels and that these low levels may be associated with other chronic diseases over time, supplementation with O3FAs could be considered, particularly in those with hypertriglyceridemia, in those who eat no fish, or for vegetarians or vegans. Doses up to 1 g daily are considered safe. For secondary prevention after statin optimization, if triglyceride levels are between 1.5 and 5.6 mmol/L, guidelines recommend with level 1A evidence taking 2 g of icosapent ethyl twice a day. This is also recommended in primary prevention for patients with diabetes and hypertriglyceridemia and additional CVD risk factors. As fish stocks dwindle over time, preserving fisheries for developing countries and obtaining O3FA from microalgal or genetically modified plant sources may become important. All guidelines recommend at least 2 servings of oily fish per week, although benefit from O3FAs is mostly seen in secondary prevention. Fish oil and combination preparations of eicosapentaenoic acid and docosahexaenoic acid have failed to show benefit at any dose at any level of prevention in patients who are appropriately prescribed statins. High-dose eicosapentaenoic acid shows substantial benefit in selected patients taking statins who have high triglyceride levels.

Supplementation with a β-glucan tablet has no effect on hyperlipidemia: a randomized, placebo-controlled clinical trial

BackgroundClinical evidence has suggested that the oat-soluble fiber β-glucan might have lipid-lowering effects. ObjectivesThe present clinical trial was conducted to evaluate the efficacy and safety of high-medium molecular weight β-glucan on serum low-density lipoprotein (LDL) cholesterol and other lipid subfractions in subjects with hyperlipidemia. MethodsA randomized double-blinded trial was performed to assess the efficacy and safety of β-glucan supplementation in reducing lipid levels. Subjects with LDL cholesterol levels of >3.37 mmol/L when treated or not with a statin were randomly assigned to receive 1 of 3 daily doses of a tableted formulation of β-glucan (1.5, 3, or 6 g) or placebo. The primary efficacy end point was the change from baseline to 12 wk in LDL cholesterol. Secondary end points of lipid subfractions and safety were also assessed. ResultsA total of 263 subjects were enrolled; 66 subjects were assigned to each of the 3 β-glucan groups, and 65 subjects were assigned to the placebo group. The mean change from baseline to 12 wk in serum LDL cholesterol level was 0.08, 0.11, and −0.04 mmol/L in the 3 β-glucan groups (P = 0.23, 0.18, and 0.72 compared with the placebo group, respectively) and −0.10 mmol/L in the placebo group. The changes in total cholesterol, small LDL cholesterol subclass particle concentration, non–high-density lipoprotein cholesterol, apolipoprotein B, very low–density lipoprotein cholesterol, and high-sensitivity C-reactive protein were also not significant in the β-glucan groups when compared with the placebo group. Gastrointestinal adverse events were reported in 23.4%, 34.8%, and 66.7% of patients in the β-glucan groups and in 36.9% of patients in the placebo group (P < 0.0001 for the overall comparison across the 4 groups). ConclusionsIn subjects with LDL cholesterol levels of >3.37 mmol/L, a tablet formulation of β-glucan was not effective in reducing LDL cholesterol concentration or other lipid subfractions when compared with a placebo.This trial was registered at clinicaltrials.gov as NCT03857256.

Lipoprotein Subfractions Associated with Endothelial Function in Previously Healthy Subjects with Newly Diagnosed Sleep Apnea-A Pilot Study.

Obstructive sleep apnea (OSA) activates several pathophysiological mechanisms which can lead to the development of vascular diseases. Endothelial dysfunction (ED) is an initial step in the development of atherosclerosis. The association between ED and OSA has been described in several studies, even in previously healthy subjects. High-density lipoproteins (HDL) were generally considered to be atheroprotective, and low-density lipoprotein (LDL) to be an atherogenic component of lipoproteins. However, recent findings suggest a pro-atherogenic role of small HDL subfractions (8-10) and LDL subfractions (3-7). This study aimed to evaluate the relationship between endothelial function and lipid subfractions in previously healthy OSA subjects. We prospectively enrolled 205 subjects with sleep monitoring. Plasma levels of triacylglycerols, total cholesterol, LDL, HDL, and their subfractions were assessed. Endothelial function was determined using peripheral arterial tonometry, and reperfusion hyperemia index (RHI) was assessed. Plasma levels of small and intermediate HDL subfractions have statistically significant pro-atherogenic correlations with endothelial function (p = 0.015 and p = 0.019). In other lipoprotein levels, no other significant correlation was found with RHI. In stepwise multiple linear regression analysis, small HDL (beta = -0.507, p = 0.032) was the only significant contributor in the model predicting RHI. In our studied sample, a pro-atherogenic role of small HDL subfractions in previously healthy subjects with moderate-to-severe OSA was proven.

Triglyceride content of lipoprotein subclasses and kidney hemodynamic function and injury in adolescents with type 1 diabetes

AimsElevated triglycerides (TG) are associated with development and progression of kidney disease, and TG distributions across lipoprotein subclasses predict kidney dysfunction in adults with type 1 diabetes (T1D). Little is known regarding these relationships in youth. MethodsIn this single center study conducted from October 2018–2019, lipid constituents from lipoprotein subclasses were quantified by targeted nuclear magnetic resonance spectroscopy. Glomerular filtration rate (GFR), renal plasma flow (RPF), afferent arteriolar resistance (RA), efferent arteriolar resistance (RE), intraglomerular pressure (PGLO), urine albumin-to-creatinine ratio (UACR), and chitinase-3-like protein 1 (YKL-40), a marker of kidney tubule injury, were assessed. Cross-sectional relationships were assessed by correlation and multivariable linear regression (adjusted for age, sex, HbA1c) models. ResultsFifty youth with T1D (age 16 ± 3 years, 50 % female, HbA1c 8.7 ± 1.3 %, T1D duration 5.7 ± 2.6 years) were included. Very-low-density lipoprotein (VLDL)-TG concentrations correlated and associated with intraglomerular hemodynamic function markers including GFR, PGLO, UACR, as did small low-density lipoprotein (LDL)-TG and small high-density lipoprotein (HDL)-TG. YKL-40 correlated with all lipoprotein subclasses. ConclusionTG within lipoprotein subclasses, particularly VLDL, associated with PGLO, GFR, albuminuria, and YKL-40. Lipid perturbations may serve as novel targets to mitigate early kidney disease.

The benefits of measuring the size and number of lipoprotein particles for cardiovascular risk prediction: A systematic review and meta-analysis

ObjectiveCardiovascular risk (CVR) is conventionally calculated by measuring the total cholesterol content of high-density lipoproteins (HDL) and low-density lipoproteins (LDL). The purpose of this systematic review was to assess the CVR associated with LDL and HDL particle size and number as determined by nuclear magnetic resonance (NMR) spectroscopy. Material and methodsA literature search was performed using the electronic databases MEDLINE and Scopus. All cohort and case–control studies published before January 1, 2019 that met the following inclusion criteria were included: HDL-P, LDL-P, HDL-Z and/or LDL-Z measured by NMR spectroscopy; cardiovascular event as an outcome variable; risk of cardiovascular events expressed as odds ratios or hazard ratios; only adult patients. A meta-analysis was performed for each exposure variable (4 for LDL and 5 for HDL) and for each exposure measure (highest versus lowest quartile and 1-standard deviation increment). ResultsThis review included 24 studies. Number of LDL particles was directly associated with CVR: risk increased by 28% with each standard deviation increment. LDL particle size was inversely and significantly associated with CVR: each standard deviation increment corresponded to an 8% risk reduction. CVR increased by 12% with each standard deviation increase in number of small LDL particles. HD, particle number and size were inversely associated with CVR. ConclusionLarger particle size provided greater protection, although this relationship was inconsistent between studies. Larger number of LDL particles and smaller LDL particle size are associated with increased CVR. Risk decreases with increasing number and size of HDL particles.