Hypercholesterolemic Individuals Research Articles

Abstract 4132968: CCR5 modulation enhances M-MDSCs functionality in early atherosclerosis

Background: The role of immune suppressive microenvironment, promulgated by the presence of Myeloid Derived Suppressor Cells (MDSC) have been the major focus of research delineating the underlying mechanisms of cardiovascular diseases (CVD). CCR5, a chemokine receptor, has been associated with both immunosuppressive and inflammatory phenotypes, however, the possible role of CCR5 pertaining to MDSCs in the development of atherosclerosis has not been elucidated yet. Therefore, we investigated the therapeutic potential of CCR5 modulation in early atherosclerosis progression. Methods: CCR5 receptor-ligand expression was studied with flow cytometry, real time PCR and immunocytochemistry in 65 individuals (25 Healthy controls, 20 young hypercholesterolemic individuals, and 20 stable [Coronary Artery Disease] CAD patients). To induce atherosclerosis, mice were fed high fat diet (HFD) for 6 weeks following partial ligation of left carotid artery in C57BL6 mice. MDSCs phenotype and functionality were assessed using CCR5 inhibitor in vitro (10 -8 M) and in vivo (i.p 3ng/day for 15 days) . M-MDSCs phenotype switch, atherosclerotic lesion development and plaque phenotype was studied in vivo . Results: We observed CCR5 elevation on Monocytic-MDSCs in the early phase of atherosclerosis. M-MDSCs displayed an intermediate phenotype with expression of both pro and anti-inflammatory mediators in early atherosclerosis, a similar trend was observed in inflammatory cytokines stimulated M-MDSCs ( in vitro ). Notably, DAPTA treatment shifted phenotype of M-MDSCs to anti-inflammatory profile with elevated expression of IL-10 and reduced expression of IFNγ, IL4, and IL22. Further, CCR5 modulation expanded IL10+M-MDSC in vivo . Additionally, DAPTA reduced the migratory potential, reduced cholesterol uptake and improved the functionality (suppression of T cell) of M-MDSCs. Blocking CCR5 with DAPTA led to the formation of stable plaque in HFD-fed mice. Conclusion: Increased expression of CCR5 coupled with inflammatory cytokine secretion by regulatory cells lead to dysfunctional M-MDSCs in CVD risk factor population. Possibly this dysfunctionality contributes to the development and progression of CVD including atherosclerosis. Our findings show targeting of CCR5 with DAPTA reduces atherogenesis, increases plaque stabilization and corrects phenotypic alterations in immune suppressive M-MDSCs. The functionality and phenotype of M-MDSCs in atherosclerosis, may be ameliorated by targeting CCR5.

Development of DNA-Based Lateral Flow Assay for Detection of LDLR Gene Mutation for Familial Hypercholesterolemia.

The techniques for detecting single nucleotide polymorphisms (SNP) require lengthy and complex experimental procedures and expensive instruments that may only be available in some laboratories. Thus, a deoxyribonucleic acid (DNA)-based lateral flow assay (LFA) was developed as a point-of-care test (POCT) diagnostic tool for genotyping. In this study, single nucleotide variation (E101K) in the low-density lipoprotein receptor (LDLR) gene leading to familial hypercholesterolemia (FH) was chosen as a model. Hypercholesterolemic individuals (n = 103) were selected from the Malaysian Cohort project (UKM Medical Molecular Biology Institute) while the control samples were selected from the Biobank (UKM Medical Molecular Biology Institute). The DNA samples were isolated from whole blood. Polymerase chain reaction (PCR) amplification process was performed using bifunctional labelled primers specifically designed to correspond to the variant that differentiates wild-type and mutant DNA for visual detection on LFA. The variant was confirmed using Sanger sequencing, and the sensitivity and specificity of the LFA detection method were validated using the Agena MassARRAY® technique. Out of 103 hypercholesterolemic individuals, 5 individuals (4.8%) tested positive for E101K, LDLR mutation and the rest, including healthy control individuals, tested negative. This result was concordant with Sanger sequencing and Agena MassARRAY®. These five individuals could be classified as Definite FH, as the DNA diagnosis was confirmed. The sensitivity and specificity of the variant detection by LFA is 100% compared to results using the genotyping method using Agena MassARRAY®. The developed LFA can potentially be used in the POC setting for detecting the E101K variant in the LDLR gene. This LFA can also be used to screen family members with E101K variant in the LDLR gene and is applicable for other SNP's detection.

Adherence of Candida albicans to fibrin-clot matrices in a rat model for type 2 diabetes

Individuals with type 2 diabetes are at increased risk for the development of infective endocarditis and septic thrombosis. Adherence to fibrin clot matrices by Candida albicans is the initial step in initiation of the infective processes. Clots made from lean (Fa/fa) and obese (fa/fa) Zucker rat plasma were used to measure adherence of yeast grown at environmental temperature and human body temperature. Adherence to clots by C. albicans was influenced both by source of plasma and temperature of yeast growth. Amphotericin B was effective in diminishing the candidal binding to lean but not obese clots. The degree of fungal surface hydrophobicity did not correlate with adherence to clots. However, Candida adherence to clots from both lean and obese Zucker rats was inhibited by the pretreatment of cells with mannose. These findings indicate that treatment of thrombi-associated candidal infections with ergosterol-targeting drugs e.g., amphotericin B alone in hypercholesterolemic individuals may have decreased clinically efficacy.

A four-week dietary intervention with mycoprotein-containing food products reduces serum cholesterol concentrations in community-dwelling, overweight adults: A randomised controlled trial

BackgroundSubstituting dietary meat and fish for mycoprotein, a fungal-derived food source rich in protein and fibre, decreases circulating cholesterol concentrations in laboratory-controlled studies. However, whether these findings can be translated to a home-based setting, and to decrease cholesterol concentrations in overweight and hypercholesterolemic individuals, remains to be established. ObjectiveWe investigated whether a remotely-delivered, home-based dietary intervention of mycoprotein-containing food products would affect various circulating cholesterol moieties and other markers of cardio-metabolic health in overweight (BMI >27.5 kg·m-2) and hypercholesterolaemic (>5.0 mmol·L-1) adults. MethodsSeventy-two participants were randomized into a controlled, parallel-group trial conducted in a free-living setting, in which they received home deliveries of either meat/fish control products (CON; n=39; BMI 33±1 kg·m-2; 13 males, 26 females) or mycoprotein-containing food products (MYC; n=33; BMI 32±1 kg·m-2; 13 males, 20 females) for 4 weeks. Fingertip blood samples were collected and sent via postal service before and after the dietary intervention period and analysed for concentrations of serum lipids, blood glucose and c-peptide. ResultsSerum total cholesterol concentrations were unchanged throughout the intervention in CON, but decreased by 5±2% in MYC (from 5.4±0.2 to 5.1±0.2 mmol·L-1; P<0.05). Serum low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol concentrations were also unchanged in CON, but decreased in MYC by 10±3% and 6±2% (both by 0.3±0.1 mmol·L-1; P<0.05). Serum high-density lipoprotein cholesterol and free triglyceride concentrations were unaffected in CON or MYC. Post-intervention, MYC displayed lower mean blood glucose (3.7±0.2 versus 4.3±0.2 mmol·L-1) and c-peptide (779±76 vs. 1064±86 pmol·L-1) concentrations (P<0.05) vs. CON. ConclusionsWe show that a home-based dietary intervention of mycoprotein-containing food products effectively lowers circulating cholesterol concentrations in overweight, hypercholesterolemic adults. This demonstrates that mycoprotein consumption is a feasible and ecologically valid dietary strategy to improve markers of cardio-metabolic health in an at-risk population under free living conditions. Clinical trial registrationNCT04773483 (https://classic.clinicaltrials.gov/ct2/show/NCT04773483)

The effect of water-soluble tomato concentrate on elevated serum cholesterol in the middle-aged and elderly Chinese individuals.

Water-soluble tomato concentrate (WSTC) has demonstrated beneficial effect on blood flow in healthy populations. The prospective, randomized, double-blind, and placebo-controlled clinical trial was conducted to explore the impact of WSTC on individuals with elevated cholesterol levels. Sixty participants aged 35-65 with high cholesterol were enrolled and evenly divided into a treatment group (FFG) and a placebo group (PCG). Over a 60-day period comprising a 45-day treatment phase followed by a 15-day observational follow-up. Participants in the FFG received 300 mg daily of Fruitflow tablets, while the PCG were received placebos. The study showed that there were no significant differences in baseline parameters between the FFG and PCG (p > 0.05). Post-intervention, the FFG exhibited significant reductions in systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 4.2% (SBP, p < 0.001) and 3.8% (DBP, p = 0.015), respectively, compared to the PCG (p = 0.041). These reductions were sustained during the follow-up period. In contrast, the PCG showed no significant changes in SBP and DBP (p > 0.05). Stratified analysis by hypertension status revealed a significant SBP reductions both hypertensive and non-hypertensive FFG subjects (p < 0.05), with a trend towards DBP reduction. No significant changes in SBP and DBP were observed in the PCG. Moreover, the FFG group showed a significant increase in high-density lipoprotein (HDL) cholesterol (p < 0.05), along with a marked reduction in both weight and body mass index (BMI) (p < 0.05). The FFG also showed decreased levels of homocysteine, high-sensitivity C-reactive protein, and fasting blood glucose compared to the PCG (p < 0.05). In conclusion, WSTC has the potential to lower blood pressure and cardiovascular risk profiles in hypercholesterolemic individuals, presenting a viable non-harmacological option for enhancing cardiovascular health. Clinical trial registration: https://www.chictr.org.cn/showproj.html?proj=27052, identifier ChiCTR1800015904.

Cholesterol reprograms glucose and lipid metabolism to promote proliferation in colon cancer cells

Hypercholesterolemia is often correlated with obesity which is considered a risk factor for various cancers. With the growing population of hypercholesterolemic individuals, there is a need to understand the role of increased circulatory cholesterol or dietary cholesterol intake towards cancer etiology and pathology. Recently, abnormality in the blood cholesterol level of colon cancer patients has been reported. In the present study, we demonstrate that alteration in cholesterol levels (through a high-cholesterol or high-fat diet) increases the incidence of chemical carcinogen-induced colon polyp occurrence and tumor progression in mice. At the cellular level, low-density lipoprotein cholesterol (LDLc) and high-density lipoprotein cholesterol (HDLc) promote colon cancer cell proliferation by tuning the cellular glucose and lipid metabolism. Mechanistically, supplementation of LDLc or HDLc promotes cellular glucose uptake, and utilization, thereby, causing an increase in lactate production by colon cancer cells. Moreover, LDLc or HDLc upregulates aerobic glycolysis, causing an increase in total ATP production through glycolysis, and a decrease in ATP generation by OXPHOS. Interestingly, the shift in the metabolic status towards a more glycolytic phenotype upon the availability of cholesterol supports rapid cell proliferation. Additionally, an alteration in the expression of the molecules involved in cholesterol uptake along with the increase in lipid and cholesterol accumulation was observed in cells supplemented with LDLc or HDLc. These results indicate that colon cancer cells directly utilize the cholesterol associated with LDLc or HDLc. Moreover, targeting glucose metabolism through LDH inhibitor (oxamate) drastically abrogates the cellular proliferation induced by LDLc or HDLc. Collectively, we illustrate the vital role of cholesterol in regulating the cellular glucose and lipid metabolism of cancer cells and its direct effect on the colon tumorigenesis.Graphical

A Review of Progress on Targeting LDL Receptor-Dependent and -Independent Pathways for the Treatment of Hypercholesterolemia, a Major Risk Factor of ASCVD.

Since the discovery of the LDL receptor in 1973 by Brown and Goldstein as a causative protein in hypercholesterolemia, tremendous amounts of effort have gone into finding ways to manage high LDL cholesterol in familial hypercholesterolemic (HoFH and HeFH) individuals with loss-of-function mutations in the LDL receptor (LDLR) gene. Statins proved to be the first blockbuster drug, helping both HoFH and HeFH individuals by inhibiting the cholesterol synthesis pathway rate-limiting enzyme HMG-CoA reductase and inducing the LDL receptor. However, statins could not achieve the therapeutic goal of LDL. Other therapies targeting LDLR include PCSK9, which lowers LDLR by promoting LDLR degradation. Inducible degrader of LDLR (IDOL) also controls the LDLR protein, but an IDOL-based therapy is yet to be developed. Among the LDLR-independent pathways, such as angiopoietin-like 3 (ANGPTL3), apolipoprotein (apo) B, apoC-III and CETP, only ANGPTL3 offers the advantage of treating both HoFH and HeFH patients and showing relatively better preclinical and clinical efficacy in animal models and hypercholesterolemic individuals, respectively. While loss-of-LDLR-function mutations have been known for decades, gain-of-LDLR-function mutations have recently been identified in some individuals. The new information on gain of LDLR function, together with CRISPR-Cas9 genome/base editing technology to target LDLR and ANGPTL3, offers promise to HoFH and HeFH individuals who are at a higher risk of developing atherosclerotic cardiovascular disease (ASCVD).

Differences in Bacterial Small RNAs in Stool Samples from Hypercholesterolemic and Normocholesterolemic Subjects.

Cholesterol metabolism is important at the physiological level as well as in several diseases, with small RNA being an element to consider in terms of its epigenetic control. Thus, the aim of this study was to identify differences between bacterial small RNAs present at the gut level in hypercholesterolemic and normocholesterolemic individuals. Twenty stool samples were collected from hypercholesterolemic and normocholesterolemic subjects. RNA extraction and small RNA sequencing were performed, followed by bioinformatics analyses with BrumiR, Bowtie 2, BLASTn, DESeq2, and IntaRNA, after the filtering of the reads with fastp. In addition, the prediction of secondary structures was obtained with RNAfold WebServer. Most of the small RNAs were of bacterial origin and presented a greater number of readings in normocholesterolemic participants. The upregulation of small RNA ID 2909606 associated with Coprococcus eutactus (family Lachnospiraceae) was presented in hypercholesterolemic subjects. In addition, a positive correlation was established between small RNA ID 2149569 from the species Blautia wexlerae and hypercholesterolemic subjects. Other bacterial and archaeal small RNAs that interacted with the LDL receptor (LDLR) were identified. For these sequences, the prediction of secondary structures was also obtained. There were significant differences in bacterial small RNAs associated with cholesterol metabolism in hypercholesterolemic and normocholesterolemic participants.

Comparison of Plasma Metabolome Response to Diets Enriched in Soybean and Partially-Hydrogenated Soybean Oil in Moderately Hypercholesterolemic Adults-A Pilot Study.

Partially-hydrogenated fat/trans fatty acid intake has been associated with adverse effects on cardiometabolic risk factors. Comparatively unexplored is the effect of unmodified oil relative to partially-hydrogenated fat on the plasma metabolite profile and lipid-related pathways. To address this gap, we conducted secondary analyses using a subset of samples randomly selected from a controlled dietary intervention trial involving moderately hypercholesterolemic individuals. Participants (N = 10, 63 ± 8 y, BMI, 26.2 ± 4.2 kg/m2, LDL-C, 3.9 ± 0.5 mmol/L) were provided with diets enriched in soybean oil (SO) and partially-hydrogenated soybean oil (PHSO). Plasma metabolite concentrations were determined using an untargeted approach and pathway analysis using LIPIDMAPS. Data were assessed using a volcano plot, receiver operating characteristics curve, partial least square-discrimination analysis and Pearson correlations. Among the known metabolites higher in plasma after the PHSO diet than the SO diet, the majority were phospholipids (53%) and di- and triglycerides (DG/TG, 34%). Pathway analysis indicated upregulation of phosphatidylcholine synthesis from DG and phosphatidylethanolamine. We identified seven metabolites (TG_56:9, TG_54:8, TG_54:7, TG_54:6, TG_48:5, DG_36:5 and benproperine) as potential biomarkers for PHSO intake. These data indicate that TG-related metabolites were the most affected lipid species, and glycerophospholipid biosynthesis was the most active pathway in response to PHSO compared to SO intake.

Cardiovascular disease onset in old people with severe hypercholesterolemia

Background and aimsFamilial hypercholesterolemia (FH) variants are associated with higher atherosclerotic cardiovascular disease risk (ASCVD) even when compared with other forms of severe hypercholesterolemia, especially in young people. Lipid lowering therapies (LLT) may change hypercholesterolemia natural history. This study aimed at evaluating factors associated with occurrence of ASCVD in old severe hypercholesterolemics diagnosed or not with FH and undergoing LLT. MethodsHypercholesterolemic individuals ≥60 years participating on a genetic cascade screening for FH were divided in 4 groups (2 × 2) according to the presence (variant+) or not (variant-) of FH genetic variants and previous ASCVD (ASCVD+ and ASCVD-). Biomarkers associated with new incident ASCVD events were tested using Cox models. Continuous data shown as medians (%25; %75). ResultsFrom 4,111 genotyped individuals, 377 (9.1%) were elderly [age 66 (63; 71) years], 28.9% males, 42.7% variant+, 32.1% with previous ASCVD, LLT duration 9 (5; 16) years, and on treatment LDL-cholesterol 144 (109; 200) mg/dL. After 4.8 (7; 3) years of follow up there were 47 incident events (12.4%, 2.7% patient/year). The annualized event rates were 0.8% (95% CI 0.36%; 1.70%), 2.3% (95% CI 1.3%; 4.1%), 5.2% (95% CI 2.8%; 9.7%) and 6.3% (95% CI 4.0%; 10.0%) respectively for groups variant-/ASCVD-, variant+/ASCVD-, variant-/ASCVD+ and, variant+/ASCVD+ (p log rank p < 0.001). Only presence of previous ASCVD was independently associated with incident ASCVD [hazard ratio 3.236 (95%CI 1.497–6.993, p = 0.003)]. No interaction was found for previous ASCVD and variants. ConclusionsIn old severe hypercholesterolemic individuals undergoing long-term LLT previous ASCVD was associated with incident events while FH causing variants were not.

Characterization of microbial communities from gut microbiota of hypercholesterolemic and control subjects.

In recent years, several studies have evidenced the importance of the microbiome to host physiology as metabolism regulator, along with its potential role in triggering various diseases. In this study, we analyzed the gut microbiota in hypercholesterolemic (cases) and normocholesterolemic (controls) individuals to identify characteristic microbial signature for each condition. Stool samples were obtained from 57 adult volunteers (27 hypercholesterolemic and 30 controls). The taxonomic profiling of microbial communities was performed using high-throughput sequencing of 16S rRNA V3-V4 amplicons, followed by data analysis using Quantitative Insights Into Microbial Ecology 2 (QIIME2) and linear discriminant analysis (LDA) effect size (LEfSe). Significant differences were observed in weight, height, body mass index (BMI) and serum levels of triglycerides, total cholesterol and low-density lipoprotein cholesterol (LDL-C) between the groups (p<0.05). LEfSe showed differentially abundant prokaryotic taxa (α=0.05, LDA score > 2.0) in the group of hypercholesterolemic individuals (Methanosphaera, Rothia, Chromatiales, Clostridiales, Bacillaceae and Coriobacteriaceae) and controls (Faecalibacterium, Victivallis and Selenomonas) at various taxonomic levels. In addition, through the application of Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2 (PICRUSt2), the predominance of pathways related to biosynthesis in hypercholesterolemic patients was established, compared to controls in which degradation pathways were predominant. Finally, in the analysis of co-occurrence networks, it was possible to identify associations between the microorganisms present in both studied groups. Our results point out to unique microbial signatures, which likely play a role on the cholesterol metabolism in the studied population.

Impact of Phenol-Enriched Olive Oils on Serum Metabonome and Its Relationship with Cardiometabolic Parameters: A Randomized, Double-Blind, Cross-Over, Controlled Trial.

Phenol-rich foods consumption such as virgin olive oil (VOO) has been shown to have beneficial effects on cardiovascular diseases. The broader biochemical impact of VOO and phenol-enriched OOs remains, however, unclear. A randomized, double-blind, cross-over, controlled trial was performed with thirty-three hypercholesterolemic individuals who ingested for 3-weeks (25 mL/day): (1) an OO enriched with its own olive oil phenolic compounds (PCs) (500 ppm; FOO); (2) an OO enriched with its own olive oil PCs (250 ppm) plus thyme PCs (250 ppm; FOOT); and (3) a VOO with low phenolic content (80 ppm). Serum lipid and glycemic profiles, serum 1H-NMR spectroscopy-based metabolomics, endothelial function, blood pressure, and cardiovascular risk were measured. We combined OPLS-DA with machine learning modelling to identify metabolites discrimination of the treatment groups. Both phenol-enriched OO interventions decreased the levels of glutamine, creatinine, creatine, dimethylamine, and histidine in comparison to VOO one. In addition, FOOT decreased the plasma levels of glycine and DMSO2 compared to VOO, while FOO decreased the circulating alanine concentrations but increased the plasma levels of acetone and 3-HB compared to VOO. Based on these findings, phenol-enriched OOs were shown to result in a favorable shift in the circulating metabolic phenotype, inducing a reduction in metabolites associated with cardiometabolic diseases.

Improvement in cardiometabolic risk markers following an oatmeal diet is associated with gut microbiota in mildly hypercholesterolemic individuals

Cardiovascular diseases have been the leading cause of death worldwide for decades. Some animal studies have indicated that oatmeal could improve gut microbiota and cardiometabolic risk markers. However, vivo evidence remained limited, especially in individuals with mild hypercholesterolemia. Our purpose was to explore the beneficial effects of oatmeal on serum lipids, oxidative stress and inflammation levels, and their correlations with gut microbiota and short-chain fatty acids (SCFAs) in mildly hypercholesterolemic individuals. The study was a randomized, single-blind, placebo-controlled trial. A total of 62 qualified participants were randomly divided into control group and oatmeal group with a 45-day follow-up. 16S rDNA and Gas-Chromatography Mass Spectrometry were employed respectively to measure the changes in gut microbiota and SCFAs at the start and the end of the intervention period. Cardiometabolic risk markers were assayed via commercial kits. The results suggested that oatmeal could significantly decrease serum total cholesterol (TC) (−8.59 %, p = 0.013), low density lipoprotein cholesterol (LDL-c) (−12.97 %, p = 0.004) and non-high density lipoprotein cholesterol (non-HDL-c) (−10.98 %, p = 0.040) level. In terms of oxidative stress, oatmeal significantly increased serum total antioxidant capacity (T-AOC) (21.98 %, p < 0.001), superoxide dismutase (SOD) (15.53 %, p = 0.044) levels and decreased concentration of malondialdehyde (MDA) (−19.11 %, p = 0.033) compared with control group. While no significant effect was observed in inflammatory factors. SCFAs results indicated that oatmeal could significantly increase serum acetic acid, propionic acid and valeric acid. The results of 16S rDNA showed that there was a significant difference in the alteration of β-diversity between groups throughout the whole trial. Oatmeal resulted in the increases of Akkermansia, Dialister, Faecalibacterium, Barnesiella, Agathobacter, Lactobacillus and the decrease of Ruminococcaceae-MK4A214-group. Correlation analysis further suggested that the lipids regulation effect of oatmeal may be mainly mediated by Lactobacillus and Dialister, as well as some SCFAs (e.g., acetic acid and propionic acid), while Barnesiella and Akkermansia may play a crucial role in ameliorating oxidative stress level. In conclusion, despite of its small sample size, the present study is the first clinical trial performed in Chinese individuals with mild hypercholesterolemia to explore the effects of oatmeal on serum lipids, oxidative stress, inflammation levels, and gut microbiota. The results demonstrated that oatmeal could induce some beneficial changes in serum lipids, oxidative stress, gut microbiota composition and SCFAs. Correlation analysis further extended our understanding of the role of gut microbiota and SCFAs in improving cardiometabolic risk markers.

ROSuvastatin and Amlodipine as free or fixed combination on theRApeutic taRgets and treatment Adherence in hypertensive, hypercholesterolemic individuals. ROSA RARA: a spontaneous, observational study conducted by italian outpatient cardiologists

Background: Hypertension and LDL hypercholesterolemia often coexist, and their effective treatment has favorable implications for cardiovascular health. We aimed at defining the impact of amlodipine and rosuvastatin as free or fixed combinations on blood pressure (BP) and LDL-cholesterol, and the satisfaction with treatment, in hypertensive individuals with LDL hypercholesterolemia. Methods: A spontaneous longitudinal observational study was conducted at Italian cardiology outpatients clinics. Eligible individuals (age ≥ 18y, informed consent, stable 5 or 10 mg amlodipine therapy in addition to a RAAS inhibitor, stable 10 or 20 mg rosuvastatin therapy) underwent home and office BP and LDL-cholesterol assessment at 12 and 24 weeks. BP and LDL-cholesterol control rates and satisfaction with the fixed combination were assessed. Results: 285 participants were enrolled (51%M; 67 ± 10y; 94 on the free combination). At 12 weeks, mean BP and LDL-cholesterol were reduced in both groups, with higher hypertension control rates in the fixed combination group; at 24 weeks they were further reduced compared with baseline, and home systolic BP was lower in the fixed than the free combination group (121.9 ± 17.6 vs 129.4 ± 8.5 mmHg; p = 0.03). Patients in the fixed combination reported higher satisfaction with this regimen than with the free combination. Conclusions: The fixed combination of calcium channel blocker and statin appears to have advantages in terms of clinical efficacy and patients’ satisfaction.

Statins effect on insulin resistance after a meal and exercise in hypercholesterolemic pre-diabetic individuals.

AimTo study if statins, a widely prescribed, inexpensive medication to prevent coronary artery diseases may cause insulin resistance (IR).MethodsFasted (HOMA‐IR) and post‐meal insulin resistance were assessed in 21 pre‐diabetic hypercholesterolemic individuals treated with statins (STA trial). Measurements were compared to another trial conducted 96 h after statin withdrawal using placebo pills (PLAC trial). Trials were duplicated 16–18 h after a bout of moderate‐intensity exercise (500 kcal of energy expenditure) to reduce IR and better appreciate statin effects (EXER+STA and EXER+PLAC trials).ResultsStatin withdrawal did not affect fasting (HOMA‐IR; 2.35 ± 1.05 vs. 2.18 ± 0.87 for STA vs. PLAC trials; p = 0.150) or post‐meal insulin resistance (i.e., Matsuda‐index, STA 6.23 ± 2.83 vs. PLAC 6.49 ± 3.74; p = 0.536). A bout of aerobic exercise lowered post‐meal IR (p = 0.043), but statin withdrawal did not add to the exercise actions (p = 0.564). Statin withdrawal increased post‐meal plasma free glycerol concentrations (0.136 ± 0.073 vs. 0.185 ± 0.090 mmol·L−1 for STA vs. PLAC trials; p < 0.001) but not plasma free fatty acids or fat oxidation (p = 0.981, and p = 0.621, respectively). Post‐meal fat oxidation was higher in the exercise trials (p = 0.002).ConclusionsWithdrawal of statin medication does not affect fasting or post‐meal insulin resistance in pre‐diabetic hypercholesterolemic individuals. Furthermore, statin use does not interfere with the beneficial effects of exercise on lowering IR.

Effects of Oat Beta-Glucan Intake on Lipid Profiles in Hypercholesterolemic Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

(1) Background: hyperlipidemia is one of the cardiovascular diseases which becomes a great threat to the health of people worldwide. Oat beta-glucan is reported to have a beneficial effect on lowering blood lipids. To probe the effect of oat beta-glucan consumption on serum lipid profiles (total cholesterol, total triglyceride, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol), we carried out a systematic search on randomized controlled trials of oat beta-glucan intervention on hypercholesterolemic individuals. (2) Methods: the pieces of literature were obtained from PubMed, Scopus, Cochrane Library, Web of Science, and the Embase from inception to 28 February 2022. The results were presented with the weighted mean difference (WMD) with a 95% CI. The random-effects or fixed-effects model was applied according to the heterogeneity. The subgroup analysis and meta-regression were used to identify the source of heterogeneity. (3) Results: thirteen trials with 927 participants were included in our meta-analysis. Overall, oat beta-glucan supplementation significantly reduced levels of TC (pooled WMD = −0.24 mmol/L; 95%CI: −0.28 to −0.20 mmol/L), LDL-c (pooled WMD = −0.27 mmol/L; 95%CI: −0.35 to −0.20 mmol/L). Furthermore, beta-glucan consumption did not show significant effects on TG (pooled WMD = −0.04 mmol/L; 95%CI: −0.13 to 0.05 mmol/L), HDL-c (pooled WMD = 0.00 mmol/L; 95%CI: −0.05 to 0.05 mmol/L). Subgroup analysis indicated that critical factors, such as disease severity of participants, the daily intervention of oat beta-glucan, source of oat beta-glucan, and duration of intervention had impacts on outcomes. (4) Conclusions: oat beta-glucan intake may significantly decrease the level of TC and LDL-c while no significant changes in TG and HDL-c were observed. This meta-analysis supports the health benefits of oat beta-glucan, especially for its cholesterol-lowering features, although it has some inevitable limitations.

Effects of an Optimized Aged Garlic Extract on Cardiovascular Disease Risk Factors in Moderate Hypercholesterolemic Subjects: A Randomized, Crossover, Double-Blind, Sustainedand Controlled Study.

The consumption of aged black garlic (ABG) has been related to improvements in several cardiovascular disease (CVD) risk factors. However, the extent of the beneficial effects depends on the garlic aging process and the amount and type of chemical compounds accumulated. The main objective of this study was to assess the effect of daily intake of a well-characterized ABG extract with a standardized S-allyl-L-cysteine (SAC) yield in combination with dietary recommendations regarding CVD risk factors in individuals with moderate hypercholesterolemia. Sixty-seven hypercholesterolemic individuals with low-density lipoprotein cholesterol levels ≥115 mg/dL were randomized in a crossover, double-blind, sustained, and controlled intervention study. The participants consumed 250 mg (1.25 mg SAC)/tablet/day ABG or a placebo for 6 weeks, with 3 weeks of washout. Blood and pulse pressure and other CVD risk biomarkers were determined at the beginning and end of each intervention. At 6 weeks, ABG extract reduced diastolic blood pressure (DBP) (mean (95% CI) −5.85 (−10.5; −1.3) mm Hg) compared to the placebo, particularly in men with a DBP > 75 mm Hg. The consumption of an improved ABG extract with 1.25 mg of SAC decreased DBP, particularly in men with moderate hypercholesterolemia. The potential beneficial effects of ABG may contribute to obtaining an optimal DBP.

Abstract 9323: Molecular Defects Are Not Associated With Occurrence of Cardiovascular Events in Older Individuals With Familial Hypercholesterolemia on Lipid Lowering Therapy

Introduction: Familial hypercholesterolemia (FH) is a genetic disorder associated with early onset atherosclerotic cardiovascular disease (ASCVD). However, lipid lowering therapies (LLT) may change FH natural history. There is scant data about elderly (≥60 years) with FH. Hypothesis: FH molecular defect may not influence on ASCVD risk after LLT in older individuals. Methods: Older hypercholesterolemic individuals were divided into 4 groups (2X2) according to the presence (FH +) or not of genetic variants (FH-) and previous or not clinical ASCVD (ASCVD+ and ASCVD-). Association of biomarkers with ASCVD onset was tested using Cox models. Results: From 4,111 genotyped individuals, 377 (9.1%) were elderly [age 66 (63; 71)] years, 28.9% men, 42.7% FH+, LDL-C on LLT 144 (109; 200) mg/dL, median LLT duration 9 (5;16) years. Overall ASCVD was present in 32.1%, and 62.1% and 34.5% had ASCVD of early onset in FH+ and FH- respectively. FH-/ASCVD+ (n=161), FH+/ASCVD- (n=95), FH-/ASCVD+ (n=55) and FH+/ASCVD+(n=66) were followed by 4.8(7;3) years and 51 new ASCVD events (2.8/100 patients/year) occurred. No differences were seen regarding age, hypertension, body mass index, current use, duration, and intensity of LLT and LDL-C at the last follow-up visit. In univariate analysis there was an association of male gender (p = 0.002), presence of genetic variants (p = 0.006), diabetes (p = 0.006), smoking (p = 0.028) and previous ASCVD (p = 0.000) with new ASCVD event. There was no association of LLT and current or previous lipid profile, except with HDL-C at diagnosis (p=0.014), with ASCVD event. Table 1 shows that after multivariate analysis the genetic defect was not associated with occurrence of ASCVD events. Conclusion: Although FH is associated with a higher risk of early ASCVD even when compared to other hypercholesterolemics, in older individuals after LLT the presence of genetic defects was not associated with the occurrence of new events.

Past, Present, and Future of Familial Hypercholesterolemia Management.

Familial hypercholesterolemia (FH) is a monogenic form of severe hypercholesterolemia that, if left untreated, is associated with early onset of atherosclerosis. FH derives from genetic variants that lead to inefficient hepatic clearance of low-density lipoprotein (LDL) particles from the circulation. The FH phenotype is encountered in approximately 1 of every 300 people. The risk of atherosclerotic cardiovascular disease (ASCVD) is higher in those with FH than in normolipidemic individuals and in those with polygenic hypercholesterolemia. FH is usually diagnosed by clinical scores that consider hypercholesterolemia, family history of early ASCVD and hypercholesterolemia, and cutaneous stigmata. Genetic diagnosis is important and should be offered to individuals suspected of FH. Family cascade screening is important to identify asymptomatic hypercholesterolemic individuals. Despite the high risk of ASCVD, this risk is heterogenous in heterozygous FH and depends not only on high LDL cholesterol (LDL-C) but also on other risk biomarkers. Risk can be evaluated by considering biomarkers such as male sex, late-onset therapy (> age 40), LDL-C > 310 mg/dL, low high-density lipoprotein cholesterol, elevated lipoprotein(a), obesity, diabetes, and hypertension by using specific risk equations and by detecting subclinical coronary atherosclerosis. Statins are the main therapy for FH and change the natural history of ASCVD; however, most individuals persist with elevated LDL-C. PCSK9 inhibitors provide robust and safe LDL-C lowering in FH, although elevated costs preclude their widespread use. Newer therapies such as ANGPTL3 inhibitors add intensive LDL-C lowering for refractory forms of FH. Finally, while it is possible to normalize LDL-C in people with FH, the disease unfortunately is still severely underdiagnosed and undertreated.

Effect of phytosterols in the treatment of hypercholesterolemia in adults – systematic review with meta-analysis / Efeitos dos fitoesteróis no tratamento da hipercolesterolemia em adultos – revisão sistemática com metanálise

Increased plasma total cholesterol (TC) and LDL-cholesterol (low-density lipoprotein) are considered risk factors for coronary disease. Phytosterols are among the dietary options for decreasing serum concentrations of TC and LDL-c by up to 15%.To evaluate the scientific evidence on the use of phytosterols in the treatment of hypercholesterolemia in adults.A systematic meta-analysis of the Medline, Embase, Web of Service, VHL, PUBMED, Scopus, Cochrane Library and LILACS databases was performed between November and December 2016. The PICO strategy was used. Inclusion criteria were randomized clinical trials with adults of both sexes using phytosterols longer than 4 weeks intervention. Exclusion criteria were animal and in vitro studies, humans less than 18 years old and individuals with other diseases (cancer, metabolic syndromes, diabetes mellitus, hypertension, renal disease, liver diseases). The risk of bias was assessed by two reviewers. The primary outcomes investigated were TC and LDL-cholesterol. Statistical analyses were conducted using the RevMan 5.3. The standardized effect size was used to estimate the standardized mean difference and 95% CI of TC and LDL-c.Twenty-seven randomized controlled trials were included in this systematic review and 26 studies in the meta-analysis of TC and LDL-cholesterol. The meta-analyzes showed an association with the reduction in plasma TC (-2.54 [-3.04; -2.03]) and LDL-c (-2.8 [-2.63; -1.53]) after intervention with the vegetable esters.The consumption of 1.5 to 2.0 g/day of phytosterols promotes reduction of TC and LDL-c in hypercholesterolemic individuals, regardless of the way they are consumed.