Hypercholesterolemic Subjects Research Articles

Hypercholesterolemic patients have higher eryptosis and erythrocyte adhesion to human endothelium independently of statin therapy.

Phosphatidylserine (PS) externalization out of the membrane facilitates the eryptotic erythrocytes (EE) binding to endothelial cells (EC), potentially leading to atherosclerosis. Thus, the levels of eryptosis and interactions of EE-EC in hypercholesterolemic patients, either non-medicated or medicated, compared with healthy subjects were studied. A total of 56 subjects clustered into three groups: (control (n=20), hypercholesterolemic non-treated (HCNT) (n=15), and statin-treated (HCT) (n=21)) were enrolled in this cross-sectional study. Biochemical parameters were determined with validated and standard methods. PS exposure was estimated from annexin-V-binding, cell volume from forward scatter (FSC), and GSH from CMFDA fluorescence by flow cytometry. The erythrocyte-EC adhesion assay was performed by using the parallel-plate flow chamber technique. Higher PS externalization and adhesion of erythrocytes to EC (P<.05) was found in hypercholesterolemic subjects, regardless of statin treatment, compared with the control group. Although no correlation between FSC and PS externalization with other parameters was found, GSH was inversely correlated with erythrocyte adhesion, which was significantly correlated with total cholesterol, LDL-c, and apolipoprotein B. The link between hypercholesterolemia and eryptosis suggests a possible detrimental impact of this binomial on endothelial function with possible further development of atherosclerosis and microcirculation problems in hypercholesterolemic patients, independently of statin therapy.

Lipoprotein(a) in hereditary hypercholesterolemia: Influence of the genetic cause, defective gene and type of mutation

Background and aimsLipoprotein(a) [Lp(a)] concentration in heterozygous familial hypercholesterolemia (heFH) is not well established. Whether the genetic defect responsible for heFH plays a role in Lp(a) concentration is unknown.We aimed to compare Lp(a) in controls from a healthy population, in genetically diagnosed heFH and mutation-negative hypercholesterolemia subjects, and to assess the influence on Lp(a) of the genetic defect responsible for heFH. MethodsWe conducted a cross-sectional study, performed in a lipid clinic in Spain. We studied adults with suspected heFH and a genetic study of FH genes (LDLR, APOB, APOE and PCSK9) and controls from de Aragon Workers’ Health Study. HeFH patients from the Dyslipidemia Registry of the Spanish Atherosclerosis Society (SEA) were used as validation cohort. ResultsAdjusted geometric means (95% confidence interval) of Lp(a) in controls (n = 1059), heFH (n = 500), and mutation-negative subjects (n = 860) were 14.9 mg/dL (13.6, 16.4), 21.9 mg/dL (18.1, 25.6) and 37.4 mg/dL (33.3, 42.1), p < 0.001 in all comparisons. Among heFH subjects, APOB-dependent FH showed the highest Lp(a), 36.5 mg/dL (22.0, 60.8), followed by LDLR-dependent FH, 21.7 mg/dL (17.9, 26.4).These differences were also observed in heFH from the SEA cohort. The number of plasminogen-like kringle IV type−2 repeats of LPA, the hypercholesterolemia polygenic score or LDLc concentration did not explain these differences. In LDLR-dependent FH, Lp(a) levels were not different depending on the affected protein domain. ConclusionsLp(a) is elevated in mutation-negative subjects and in heFH. The concentration of Lp(a) in heFH varies in relation to the responsible gene. Higher Lp(a) in heFH is not explained by their higher LDLc.

Impact of high neutrophil-to-lymphocyte ratio on the cardiovascular benefit of PCSK9 inhibitors in familial hypercholesterolemia subjects with atherosclerotic cardiovascular disease: Real-world data from two lipid units

Background and aimsNeutrophil-to-lymphocyte ratio (NLR) is a novel inflammatory biomarker strongly associated with atherosclerotic cardiovascular disease (ASCVD). Our aim was to evaluate the role of NLR on pulse wave velocity (PWV) after adding-on proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9-i) in familial hypercholesterolemia (FH) subjects with ASCVD. Methods and resultsIn this prospective observational study, we evaluated 45 FH subjects with ASCVD on high-intensity statins plus ezetimibe and with an off-target LDL-C. Study population was divided into two groups according to the mean value of NLR. All patients received PCSK9-i therapy and obtained biochemical analysis as well as PWV evaluation at baseline and after six months of PCSK9-i. After six months of add-on PCSK9-i therapy, a significant reduction of TC, LDL-C, Non-HDL-C, Lp(a) and ApoB plasma levels was observed in the two groups; while low-NLR group exhibited a significant PWV reduction after six-month therapy with PCSK9-i (Δ −16.2%, p < 0.05), no significant changes in PWV were observed in the high-NLR group. ConclusionsOnly FH subjects with low-NLR experienced a significant reduction of PWV after PCSK9-i. Our findings suggest a role of NLR in predicting PCSK9-i effect in FH subjects with ASCVD.

Effects of monacolin K-containing nutraceutical on cholesterol homeostasis re-establishment and CVD risk reduction in hypercholesterolemic subjects.

Hypercholesterolemia is caused by cholesterol homeostasis (CH) disruption, and it contributes to cardiovascular diseases pathogenesis and progression. Status of CH can be assessed by measuring serum concentrations of non-cholesterol sterols (NCS) which serve as cholesterol synthesis and absorption surrogate markers. Monacolin K, isolated from red yeast rice, influences cholesterol synthesis by inhibiting HMG-CoA reductase activity and reduces serum total cholesterol (TC) concentration. This longitudinal study included 30 hypercholesterolemic patients, with systematic coronary risk estimation (SCORE) values <10%, who received 3-months-long supplementation with nutraceutical mixture containing monacolin K, and vitamins C, B1 and K2. Serum NCS were quantified by HPLC-MS/MS method. Atherogenic indexes were calculated from lipid status parameters concentrations. Albumin degradation inhibition test was conducted to estimate in vitro anti-inflammatory activity of the nutraceutical mixture, whereas in vitro antioxidant activity was measured in serum enriched with prooxidants and antioxidants. TC, LDL-cholesterol (LDL-C), and triglycerides (TG) concentrations (p<0.001), as well as atherogenic indexes and SCORE values (p<0.001, p<0.01, respectively) were lowered following the supplementation. Concentrations of cholesterol synthesis markers were decreased (p<0.001), whereas levels of cholesterol absorption markers remained unchanged after the supplementation. Reduction in cholesterol synthesis went alongside reductions in lipid status parameters and atherogenic indexes. In vitro analyses showed certain anti-inflammatory and antioxidant activity of the nutraceutical. These results suggest that supplementation with monacolin K containing nutraceutical favorably influences lipid status parameters and atherogenic indexes by acting on cholesterol synthesis. Anti-inflammatory and antioxidant effects of this unique nutraceutical mixture may exhibit beneficial pleiotropic effects.

Effect of Lactobacillus paracasei HII01 Supplementation on Total Cholesterol, and on the Parameters of Lipid and Carbohydrate Metabolism, Oxidative Stress, Inflammation and Digestion in Thai Hypercholesterolemic Subjects

Hypercholesterolemia is one of the leading causes of cardiovascular disease. Probiotics can help to improve high blood lipid levels in hypercholesterolemia patients. Lactobacillus paracasei has been reported to have beneficial effects in several subjects; however, there is a lack of studies on Thai hypercholesterolemic subjects. Thus, this study was conducted in order to investigate the effect of L. paracasei HII01 on cholesterol, oxidative stress, and other biomarkers. Fifty-two subjects were randomized into two groups: the L. paracasei treatment group and the placebo group. The study was conducted over an intervention period of 12 weeks of supplementation. The results show that L. paracasei HII01 significantly reduced the total cholesterol (TCH), triglycerides (TGs), tumor necrosis factor (TNF)-α and lipopolysaccharide (LPS) of the patients, and increased their HDL, total antioxidant capacity (TAC) and propionic acid compared to the placebo group. Moreover, the supplementation of L. paracasei HII01 significantly increased lactic acid, IL-10 and IFN-γ, and substantially decreased malondialdehyde (MDA) at the end of the treatment. The results suggest that L. paracasei HII01 improves the blood lipid profile, reduces oxidative stress, and is beneficial for health among Thai hypercholesterolemic subjects.

Effects of a Combination of Extracts from Olive Fruit and Almonds Skin on Oxidative and Inflammation Markers in Hypercholesterolemic Subjects: A Randomized Controlled Trial.

Hydroxytyrosol (HT) from olives and polyphenols from almond skin (ASPs) possess cardioprotective properties. This pilot study evaluates the effect of supplementation with a combination of olive fruit and almond skin extracts on low-density lipoprotein (LDL) cholesterol oxidation, lipid homeostasis, and inflammatory parameters in adults with moderate hypercholesterolemia. A randomized, parallel, double-blind, placebo-controlled pilot study of 8 weeks was performed. The extract group (EG) received the supplement with 7.5 mg HT +210 mg ASPs, and the control group (CG) received a placebo composed of maltodextrin. Oxidized LDL (oxLDL) levels and the oxLDL/LDL ratio were lower in the EG than in the CG after 8 weeks of treatment (18.76 ± 3.91 vs. 10.34 ± 4.22, P < .001 and 0.151 ± 0.025 vs. 0.08 ± 0.023, P < .001, respectively). Interleukin-1β levels were significantly higher in the CG than in the EG at week 4 (P = .004), IL-6 was significantly higher in the CG than in the EG at week 4 (P = .049), and IL-10 was significantly increased at week 4 in both groups (P = .002 for CG and P = .001 for EG). In conclusion, daily consumption of a combination of an olive fruit extract and an almond skin extract for 8 weeks seems to protect LDL from oxidation and to prevent inflammatory status in moderately hypercholesterolemic subjects.

Decreased Efficiency of Very-Low-Density Lipoprotein Lipolysis Is Linked to Both Hypertriglyceridemia and Hypercholesterolemia, but It Can Be Counteracted by High-Density Lipoprotein.

Impaired triglyceride-rich lipoprotein plasma catabolism is considered the most important factor for hypertriglyceridemia development. The aim of this study was to evaluate the impact of hypercholesterolemia and hypertriglyceridemia on the efficiency of lipoprotein lipase (LPL)-mediated very-low-density lipoprotein (VLDL)-triglyceride lipolysis and the role of high-density lipoprotein (HDL) in this process. Subjects with no history of cardiovascular disease (CVD) and untreated with lipid-lowering agents were recruited into the study and divided into normolipidemic, hypercholesterolemic, and hyperlipidemic groups. VLDL was isolated from serum and incubated with LPL in the absence or presence of HDL. For the hypercholesterolemic and hyperlipidemic groups, a significantly lower percentage of hydrolyzed VLDL-triglyceride was achieved compared to the normolipidemic group (p < 0.01). HDL enhanced the lipolysis efficiency in the hypercholesterolemic and hyperlipidemic groups on average by ~7% (p < 0.001). The lowest electrophoretic mobility of the VLDL remnants indicating the most effective lipolysis was obtained in the normolipidemic group (p < 0.05). HDL presence significantly reduced the electrophoretic mobility of the VLDL remnants for the hypercholesterolemic and hyperlipidemic groups (p < 0.05). The results of our study indicate that VLDL obtained from hypercholesterolemic and hyperlipidemic subjects are more resistant to lipolysis and are additional evidence of the need for early implementation of hypocholesterolemic treatment, already in asymptomatic CVD subjects.

EFFECTIVENESS AND SAFETY OF NUTRACEUTICAL COMPOUNDS ADDED TO EZETIMIBE TREATMENT IN HYPERTENSIVE AND HYPER–CHOLESTEROLEMIC SUBJECTS WITH STATIN–INTOLERANCE

Objective: The effectiveness of statins in the primary and secondary prevention of cardiovascular (CV) diseases has been widely proven. However, the onset of adverse events associated with their use, prevents to achieve the therapeutic targets recommended by the guidelines (GL) for the management of dyslipidaemia. In the event of statin intolerance, is recommend to use bile acid sequestrants, fibrates and ezetimibe in monotherapy, but their benefits in improving lipid pattern are quite modest. This study aims at evaluating the effectiveness and safety of a nutraceutical compound (NC) associated with ezetimibe (E) on the lipid profile in statin-intolerant patients with moderate-to-high CV risk Design and method: Ninety-six statin-intolerant hypertensive and hyper-cholesterolemic subjects treated with E 10 mg daily, were randomised in open label (n = 48) to take for 3 months a NC containing Monacolin K (MK) 5 mg, Berberine Hydrochloride, t-Resveratrol, Quercetin, and Chromium, in the form of a gastro-resistant tablet that improves enteric bio-accessibility and bio-availability of these substances. The control group (n = 48), took only E in monotherapy at the same dosage; both groups followed a standardised lipid-lowering diet. The total serum cholesterol (TC), low density lipoprotein cholesterol (LDLC), high density lipoprotein cholesterol (HDLC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatinine phosphokinase (CPK) levels were compared at the follow-up in both groups using Student's t-test. Results: TC and LDL levels reduced in both groups, but there lower in the group treated with E+ NC vs E alone (-25.9 vs -15%, p &lt; 0.05 and -38.7 vs. -21.0%, p &lt; 0.05, respectively). No changes were observed in either group regarding to a decrease in TG (-9.4 vs. -11.7%, NS) and an increase in HDLC (+ 4.2 vs. +1.1%, NS). The AST, ALT and CPK levels increased in the E + NC compared to the control group, but were still within the acceptable range. There was no difference for the lipid-lowering treatment between gender, and no patient withdrawn the study. Conclusions: In hypertensive and hyper-cholesterolemic subjects with statin-intolerance, the E + NC combination therapy is well-tolerated and effective in the short term in improving TC and LDLC levels.

Effect of PCSK9 inhibitors on pulse wave velocity and monocyte-to-HDL-cholesterol ratio in familial hypercholesterolemia subjects: results from a single-lipid-unit real-life setting

AimsSubjects with familial hypercholesterolemia (FH) are characterized by an increased amount of low-density lipoprotein cholesterol (LDL-C) that promotes a continuous inflammatory stimulus. Our aim was to evaluate the effect of PCSK9-i on inflammatory biomarkers, neutrophil-to-lymphocyte ratio, monocyte-to-high-density lipoprotein ratio (MHR), and on early atherosclerosis damage analyzed by pulse wave velocity (PWV) in a cohort of FH subjects.MethodsIn this prospective observational study, we evaluated 56 FH subjects on high-intensity statins plus ezetimibe and with an off-target LDL-C. All subjects were placed on PCSK9-i therapy and obtained biochemical analysis as well as PWV evaluation at baseline and after six months of PCSK9-i therapy.ResultsAfter six months of add-on PCSK9-i therapy, only 42.9% of FH subjects attained LDL-C targets. As expected, a significant reduction of LDL-C (− 49.61%, p < 0.001) was observed after PCSK9-i therapy. Neutrophil count (NC) and MHR were reduced by PCSK9-i (-13.82% and -10.47%, respectively, p value for both < 0.05) and PWV significantly decreased after PCSK9-i therapy (− 20.4%, p < 0.05). Finally, simple regression analyses showed that ∆ PWV was significantly associated with ∆ LDL-C (p < 0.01), ∆ NC and ∆ MHR (p value for both < 0.05).ConclusionsIn conclusion, PCSK9-i therapy significantly improved lipid and inflammatory profiles and PWV values in FH subjects; our results support the positive effect of PCSK9-i in clinical practice.

Virgin Olive Oil Phenolic Compounds Modulate the HDL Lipidome in Hypercholesterolaemic Subjects: A Lipidomic Analysis of the VOHF Study.

ScopeThe lipidomic analysis of high‐density lipoprotein (HDL) could be useful to identify new biomarkers of HDL function.Methods and resultsA randomized, controlled, double‐blind, crossover trial (33 hypercholesterolaemic subjects) is performed with a control virgin olive oil (VOO), VOO enriched with its own phenolic compounds (FVOO), or VOO enriched with additional phenolic compounds from thyme (FVOOT) for 3 weeks. HDL lipidomic analyses are performed using the Lipidyzer platform. VOO and FVOO intake increase monounsaturated‐fatty acids (FAs) and decrease saturated and polyunsaturated FAs in triacylglyceride (TAG) species, among others species. In contrast, FVOOT intake does not induce these FAs changes. The decrease in TAG52:3(FA16:0) after VOO intake and the decrease in TAG52:5(FA18:2) after FVOO intake are inversely associated with changes in HDL resistance to oxidation. After FVOO intake, the decrease in TAG54:6(FA18:2) in HDL is inversely associated with changes in HDL cholesterol efflux capacity.ConclusionVOO and FVOO consumption has an impact on the HDL lipidome, in particular TAG species. Although TAGs are minor components of HDL mass, the observed changes in TAG modulated HDL functionality towards a cardioprotective mode. The assessment of the HDL lipidome is a valuable approach to identify and characterize new biomarkers of HDL function.

ANGPTL3 Inhibition With Evinacumab Results in Faster Clearance of IDL and LDL apoB in Patients With Homozygous Familial Hypercholesterolemia—Brief Report

The mechanism by which evinacumab, a fully human monoclonal antibody directed against ANGPTL3 (angiopoietin-like 3 protein) lowers plasma LDL (low-density lipoprotein) cholesterol levels in patients with homozygous familial hypercholesterolemia is unknown. We investigated apoB (apolipoprotein B) containing lipoprotein kinetic parameters in patients with homozygous familial hypercholesterolemia, before and after treatment with evinacumab. Approach and Results: Four patients with homozygous familial hypercholesterolemia underwent apoB kinetic analyses in 2 centers as part of a substudy of a trial evaluating the efficacy and safety of evinacumab in patients with homozygous familial hypercholesterolemia. The enrichment of apoB with the stable isotope (5,5,5-2H3)-Leucine was measured in VLDL (very LDL), IDL (intermediate-density lipoprotein), and LDL at different time points before and after intravenous administration of 15 mg/kg evinacumab. Evinacumab lowered LDL-cholesterol by 59±2% and increased IDL apoB and LDL apoB fractional catabolic rate in all 4 homozygous familial hypercholesterolemia subjects, by 616±504% and 113±14%, respectively. VLDL-apoB production rate decreased in 2 of the 4 subjects. In this small study, ANGPTL3 inhibition with evinacumab is associated with an increase in the fractional catabolic rate of IDL apoB and LDL apoB, suggesting that evinacumab lowers LDL-cholesterol predominantly by increasing apoB-containing lipoprotein clearance from the circulation. Additional studies are needed to unravel which factors are determinants in this biological pathway. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04722068.

Higher levels of eryptosis and erythrocyte adhesion to vascular endothelium in hypercholesterolemic subjects regardless statin therapy: a pilot study

Higher levels of eryptosis and erythrocyte adhesion to vascular endothelium in hypercholesterolemic subjects regardless statin therapy: a pilot study

Modulation of human intestinal microbiota in a clinical trial by consumption of a β-D-glucan-enriched extract obtained from Lentinula edodes.

The aim of this study was to evaluate the hypocholesterolemic, immune- and microbiota-modulatory effect of a mushroom extract in hypercholesterolemic subjects. A randomized, controlled, double-blind, and parallel clinical trial was carried out with subjects from 18 to 65years old (n = 52) with untreated mild hypercholesterolemia. Volunteers consumed a β-D-glucan-enriched (BGE) mixture (10.4g/day) obtained from shiitake mushrooms (Lentinula edodes) ensuring a 3.5g/day of fungal β-D-glucans or a placebo incorporated in three different commercial creams. This mixture showed hypocholesterolemic activities in vitro and in animal studies. After eight weeks intervention, no significant differences in lipid- or cholesterol-related parameters were found compared to placebo subjects as well as before and after the BGE mixture administration. No inflammatory or immunomodulatory responses were noticed and no changes in IL-1β, IL-6, TNF-α or oxLDL were recorded. However, consumption of the BGE mixture was safe and managed to achieve the dietary fibre intake recommended as cardiovascular protective diet. Moreover, the BGE mixture modulated the colonic microbiota differently compared to placebo. Microbial community composition varied from before to after the intervention with several genera being positively or negatively correlated with some biomarkers related to cholesterol metabolism. These results suggested a relation between cholesterol metabolism, microbiota and BGE administration. Nevertheless, the precise significance of this differential modulation was not fully elucidated and requires further studies.

Interactions of Oxysterols with Atherosclerosis Biomarkers in Subjects with Moderate Hypercholesterolemia and Effects of a Nutraceutical Combination (Bifidobacterium longum BB536, Red Yeast Rice Extract) (Randomized, Double-Blind, Placebo-Controlled Study).

Background: Oxysterol relationship with cardiovascular (CV) risk factors is poorly explored, especially in moderately hypercholesterolaemic subjects. Moreover, the impact of nutraceuticals controlling hypercholesterolaemia on plasma levels of 24-, 25- and 27-hydroxycholesterol (24-OHC, 25-OHC, 27-OHC) is unknown. Methods: Subjects (n = 33; 18–70 years) with moderate hypercholesterolaemia (low-density lipoprotein cholesterol (LDL-C:): 130–200 mg/dL), in primary CV prevention as well as low CV risk were studied cross-sectionally. Moreover, they were evaluated after treatment with a nutraceutical combination (Bifidobacterium longum BB536, red yeast rice extract (10 mg/dose monacolin K)), following a double-blind, randomized, placebo-controlled design. We evaluated 24-OHC, 25-OHC and 27-OHC levels by gas chromatography/mass spectrometry analysis. Results: 24-OHC and 25-OHC were significantly correlated, 24-OHC was correlated with apoB. 27-OHC and 27-OHC/total cholesterol (TC) were higher in men (median 209 ng/mL and 77 ng/mg, respectively) vs. women (median 168 ng/mL and 56 ng/mg, respectively); 27-OHC/TC was significantly correlated with abdominal circumference, visceral fat and, negatively, with high-density lipoprotein cholesterol (HDL-C). Triglycerides were significantly correlated with 24-OHC, 25-OHC and 27-OHC and with 24-OHC/TC and 25-OHC/TC. After intervention, 27-OHC levels were significantly reduced by 10.4% in the nutraceutical group Levels of 24-OHC, 24-OHC/TC, 25-OHC, 25-OHC/TC and 27-OHC/TC were unchanged. Conclusions: In this study, conducted in moderate hypercholesterolemic subjects, we observed novel relationships between 24-OHC, 25-OHC and 27-OHC and CV risk biomarkers. In addition, no adverse changes of OHC levels upon nutraceutical treatment were found.

LDL-cholesterol lowering and clinical outcomes in hypercholesterolemic subjects with and without a familial hypercholesterolemia phenotype: Analysis from the secondary prevention 4S trial

Background and aimsTrial evidence for the benefits of cholesterol-lowering is limited for familial hypercholesterolemia (FH) patients, since they have not been the focus of large outcome trials. We assess statin use in coronary artery disease (CAD) subjects with low-density lipoprotein cholesterol (LDL-C) ≥4.9 mmol/L with or without an FH phenotype. MethodsThe 4S trial randomized hypercholesterolemic CAD patients to simvastatin or placebo. We first stratified participants into baseline LDL-C <4.9 and ≥ 4.9 mmol/L; next, based on the DLCN criteria for FH, the latter group was stratified into four subgroups by presence of none, one or both of “premature CAD” and “family history of CAD”. Participants having both are defined as having an FH phenotype. Results2267 and 2164 participants had LDL-C <4.9 and ≥ 4.9 mmol/L, respectively. Mortality endpoints and major coronary events (MCE) were significantly reduced with simvastatin versus placebo in both groups over 5.4 years, but the latter derived greater absolute risk reductions (ARR) (4.1–4.3% for mortality endpoints, versus 2.5–2.8%).LDL-C reductions were similar among the 4 subgroups with levels ≥4.9 mmol/L. Participants with FH phenotype (n = 152) appeared to derive greater relative benefits with simvastatin than the other three subgroups (all-cause death: 84% relative risk reduction, p = 0.046; MCE: 55% reduction, p = 0.0297); statistical interaction was non-significant. Participants with FH phenotype derived greater ARR than any other group with simvastatin versus placebo (all-cause mortality: 6.6% ARR; MCE 13.2%; versus 3.8% and 8.3%, respectively, among participants with LDL-C ≥4.9 mmol/L but without features suggestive of FH). ConclusionsThe FH phenotype appeared to be associated with greater clinical benefits from a given magnitude of LDL-C reduction as compared to individuals without FH phenotype.

Efficacy of Probiotic Milk Formula on Blood Lipid and Intestinal Function in Mild Hypercholesterolemic Volunteers: A Placebo-control, Randomized Clinical Trial.

Several studies have reported that probiotics could modulate host lipid metabolism via altering the intestinal microbiota. Hence, the current study was aimed to assess the efficacy of a mixture of probiotic-contained milk formula (PMF) with three different bacterial strains [Lactobacillus acidophilus (La5), Lactobacillus casei (TMC), Bifidobacterium lactis (Bb12)] on lipid profile and intestinal function in healthy mild hypercholesterolemic volunteers. Totally, 40 healthy mild hypercholesterolemic subjects (180-220mg/dL) were randomly assigned into two groups as placebo or experimental group. All the subjects were requested to drink either PMF (experimental) or skimmed milk drink formula-placebo (30g mixed with 200mL of water) for 10weeks and continued by 2weeks of the follow-up period. Supplementation of PMF for 10weeks significantly improved (p<0.05) the fecal weight, fecal movement (decreased fecal gastrointestinal passing time) by improving intestinal microbiota (increasing beneficial bacterial species like Lactobacillus, Bifidobacterium spp.), and lag time of low-density lipoprotein (LDL) oxidation. Also, intake of PMF substantially reduced (p<0.05) the levels of total cholesterol (TC; 8.1%) and low-density lipoprotein cholesterol (LDL-c; 10.4%) and thus showcasing its cardioprotective efficacy. PMF considerably improves gastrointestinal function by modulating fecal movement, intestinal microbiota, and decrease cholesterol and might be helpful in the management of hypercholesterolemia.

Genetics of Hypercholesterolemia: Comparison Between Familial Hypercholesterolemia and Hypercholesterolemia Nonrelated to LDL Receptor.

Severe hypercholesterolemia (HC) is defined as an elevation of total cholesterol (TC) due to the increase in LDL cholesterol (LDL-C) >95th percentile or 190 mg/dl. The high values of LDL-C, especially when it is maintained over time, is considered a risk factor for the development of atherosclerotic cardiovascular disease (ASCVD), mostly expressed as ischemic heart disease (IHD). One of the best characterized forms of severe HC, familial hypercholesterolemia (FH), is caused by the presence of a major variant in one gene (LDLR, APOB, PCSK9, or ApoE), with an autosomal codominant pattern of inheritance, causing an extreme elevation of LDL-C and early IHD. Nevertheless, an important proportion of serious HC cases, denominated polygenic hypercholesterolemia (PH), may be attributed to the small additive effect of a number of single nucleotide variants (SNVs), located along the whole genome. The diagnosis, prevalence, and cardiovascular risk associated with PH has not been fully established at the moment. Cascade screening to detect a specific genetic defect is advised in all first- and second-degree relatives of subjects with FH. Conversely, in the rest of cases of HC, it is only advised to screen high values of LDL-C in first-degree relatives since there is not a consensus for the genetic diagnosis of PH. FH is associated with the highest cardiovascular risk, followed by PH and other forms of HC. Early detection and initiation of high-intensity lipid-lowering treatment is proposed in all subjects with severe HC for the primary prevention of ASCVD, with an objective of LDL-C <100 mg/dl or a decrease of at least 50%. A more aggressive reduction in LDL-C is necessary in HC subjects who associate personal history of ASCVD or other cardiovascular risk factors.

Analysis of HDL-microRNA profile in heterozygous familial hypercholesterolemia subjects with LDL receptor null or defective mutation

Analysis of HDL-microRNA profile in heterozygous familial hypercholesterolemia subjects with LDL receptor null or defective mutation

Genetically determined hypercholesterolaemia results into premature leucocyte telomere length shortening and reduced haematopoietic precursors

Leucocyte telomere length (LTL) shortening is a marker of cellular senescence and associates with increased risk of cardiovascular disease (CVD). A number of cardiovascular risk factors affect LTL, but the correlation between elevated LDL cholesterol (LDL-C) and shorter LTL is debated: in small cohorts including subjects with a clinical diagnosis of familial hypercholesterolaemia (FH). We assessed the relationship between LDL-C and LTL in subjects with genetic familial hypercholesterolaemia (HeFH) compared to those with clinically diagnosed, but not genetically confirmed FH (CD-FH), and normocholesterolaemic subjects. LTL was measured in mononuclear cells-derived genomic DNA from 206 hypercholesterolaemic subjects (135 HeFH and 71 CD-FH) and 272 controls. HeFH presented shorter LTL vs. controls (1.27 ± 0.07 vs. 1.59 ± 0.04, P = 0.045). In particular, we found shorter LTL in young HeFH as compared to young controls (<35 y) (1.34 ± 0.08 vs. 1.64 ± 0.08, P = 0.019); moreover, LTL was shorter in statin-naïve HeFH subjects as compared to controls (1.23 ± 0.08 vs. 1.58 ± 0.04, P = 0.001). HeFH subjects presented shorter LTL compared to LDL-C matched CD-FH (1.33 ± 0.05 vs. 1.55 ± 0.08, P = 0.029). Shorter LTL was confirmed in leucocytes of LDLR-KO vs. wild-type mice and associated with lower abundance of long-term haematopoietic stem and progenitor cells (LT-HSPCs) in the bone marrow. Accordingly, HeFH subjects presented lower circulating haematopoietic precursors (CD34 + CD45dim cells) vs. CD-FH and controls. We found (i) shorter LTL in genetically determined hypercholesterolaemia, (ii) lower circulating haematopoietic precursors in HeFH subjects, and reduced bone marrow resident LT-HSPCs in LDLR-KO mice. We support early cellular senescence and haematopoietic alterations in subjects with FH.

Analysis of steatosis biomarkers and inflammatory profile after adding on PCSK9 inhibitor treatment in familial hypercholesterolemia subjects with nonalcoholic fatty liver disease: A single lipid center real-world experience

Background and aimsNonalcoholic fatty liver disease (NAFLD) may be crucial in subjects with familial hypercholesterolemia (FH). We aimed to evaluate the effect of the inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9-i) on steatosis biomarkers such as triglyceride-glucose index (TyG) and hepatic steatosis index (HSI) and analyse the role of TG/HDL in this population before and after adding-on PCSK9-i. Methods and resultsIn this observational study, we evaluated 26 genetically confirmed FH patients with NAFLD and an LDL-C off-target despite high-intensity statins plus ezetimibe. All patients added PCSK9-i treatment and obtained biochemical analysis and TyG and HSI evaluation at baseline and after six months of PCSK9-i. No difference of steatosis biomarkers was found after adding-on PCSK9-i therapy. In a secondary analysis, we divided the study population in two groups according to TG/HDL median value: high TG/HDL group (H-TG/HDL) and low TG/HDL group (L-TG/HDL). TyG and HSI were significantly lower in the L-TG/HDL than H-TG/HDL group (for TyG 9.05 ± 0.34 vs 9.51 ± 0.32; for HSI 38.43 ± 1.35 vs 41.35 ± 1.83, p value for both < 0.05). After six months of PCSK9-i therapy, TyG and HSI were significantly reduced in the L-TG/HDL group after PCSK9-i therapy (−7.5% and −8.4% respectively, p value for both < 0.05) and these biomarkers were lower compared to H-TG/HDL group (for TyG 8.37 ± 0.14 vs 9.19 ± 0.12; for HSI 35.19 ± 1.32 vs 39.48 ± 1.33, p value for both < 0.05). ConclusionIn conclusion, PCSK9-i therapy significantly ameliorate steatosis biomarkers in FH patients with low TG/HDL; our results appear to be consistent with a beneficial role of PCSK9-i on steatosis biomarkers in FH subjects with NAFLD.