Recent Update on the Development of PCSK9 Inhibitors for Hypercholesterolemia Treatment.

The proprotein convertase subtilisin/kexin-type 9 (PCSK9) binds to low-density lipoprotein receptors (LDLR), thereby trafficking them to lysosomes upon endocytosis and enhancing intracellular degradation to prevent their recycling. As a result, the levels of circulating LDL cholesterol (LDL-C) increase, which is a prominent risk factor for developing atherosclerotic cardiovascular diseases (ASCVD). Thus, PCSK9 has become a promising therapeutic target that offers a fertile testing ground for new drug modalities to regulate plasma LDL-C levels to prevent ASCVD. In this review, we have discussed the role of PCSK9 in lipid metabolism and briefly summarized the current clinical status of modalities targeting PCSK9. In particular, a detailed overview of peptide-based PCSK9 inhibitors is presented, which emphasizes their structural features and design, therapeutic effects on patients, and preclinical cardiovascular disease (CVD) models, along with PCSK9 modulation mechanisms. As a promising alternative to monoclonal antibodies (mAbs) for managing LDL-C, anti-PCSK9 peptides are emerging as a prospective next generation therapy.

High-sensitivity C-reactive protein and low-density lipoprotein cholesterol association with incident of cardiovascular events: Isfahan cohort study.

BACKGROUND: There are many studies on high-sensitivity C-reactive protein (hs-CRP) association with cardiovascular disease (CVD); however, just a few studies investigated whether the low-density lipoprotein cholesterol (LDL-C) could participate in hs-CRP prognostic strength. This study aimed to determine the alliance of hs-CRP and LDL-C in different concentrations in occurrence cardiovascular events in the Isfahan Cohort Study (ICS). METHODS: 3277 participants aged 35 and above were included in the current analysis. We evaluated the association of elevated hs-CRP levels (≥ 3 mg/dL) and CVD events including myocardial infarction, ischemic heart disease, stroke, CVD, CVD mortality, and all-cause mortality in those with LDL-C ≥ or < 130 mg/dL Cox frailty models was used to determine possible interactions. RESULTS: In both crude and fully adjusted models, there was no significant interaction between LDL-C and hs-CRP levels with the incidence of MI, stroke, CVD mortality, and all-cause death. Neither elevated LDL-C alone nor elevated CRP alone were associated with the risk of all cardiovascular events and all-cause death. However, participants with elevated concentrations of both hs-CRP and LDL-C had a greater risk of ischemic heart disease (IHD) (hazards ratio (HR) 1.44; 95% CI 1.03-2.02) and CVD (HR 1.36; 95% CI 1.01-1.83) than those with low LDL-C and hs-CRP. CONCLUSION: These results indicate that despite a null association between elevated levels of CRP or LDL-C alone and CVD events, concurrent rise in LDL-C and hs-CRP levels is associated with higher risk of IHD and CVD.

Analysis of the acrolein-modified sites of apolipoprotein B-100 in LDL.

We have reported that acrolein-conjugated low-density lipoprotein (Acro-LDL) uptake by scavenger receptor class A type 1 (SR-A1) can mediate macrophage foam cell formation. The purpose of this study was to determine which amino acid residues of apoB protein in LDL are conjugated with acrolein. Acro-apoB was prepared by incubation of LDL with acrolein (10 to 60 µM) at 37 °C for 7 days. Identification of acrolein-conjugated amino acid residues in apoB was performed using LC-MS/MS. The levels of acrolein-conjugated amino acid residues of apoB as well as crosslinking apoB increased in proportion to acrolein concentration. The level of LDL uptake by macrophages was parallel with the acrolein-conjugated monomer apoB. Acrolein-conjugated amino acid residues in apoB were C212, K327, K742, K949, K1087, H1923, K2634, K3237 and K3846. The NH2-teriminal four amino acid residues (C212, K327, K742 and K949) were located at the scavenger receptor SR-A1 recognition site, suggesting that these four acrolein-conjugated amino acids are involved in the rapid uptake of Acro-LDL by macrophages. It is proposed that the rapid uptake of LDL by macrophages is dependent on acrolein conjugation of four amino acids residues at the scavenger receptor recognition site of apoB in LDL.

Genetic variants in the FAM3C gene are associated with lipid traits in Chinese children.

BACKGROUND: Previous studies have related FAM3C gene with childhood bone health, and the regulation of lipid metabolism in hepatocytes. The present case-control study aimed to analyze the association of FAM3C genetic variants with overweight/obesity and lipid traits among Chinese children. METHODS: Two genetic variants (rs7776725 and rs7793554) within the FAM3C gene were genotyped in 3305 Chinese children aged 6-18 years. RESULTS: In the whole study population, the T-allele of rs7776725 and A-allele of rs7793554 within the FAM3C gene were associated with 40.2% (95% CI: 11.6-76.1%; P = 0.004) and 29.1% (6.9-56.0%; P = 0.008) increased risk of dyslipidemia, higher triglyceride (P = 0.014 and P = 0.001) and lower HDL-C (P = 0.015 and P = 0.003). In addition, we found that rs7776725 interacted with sex on dyslipidemia (Pfor interaction = 0.004), and sex-stratified analyses showed that it was significantly associated with dyslipidemia only in girls (P = 8.78 × 10-5). The variant also showed nominally significant interactions with sex on total cholesterol and LDL-C (Pfor interaction = 0.012 and 0.008). CONCLUSION: We found that FAM3C genetic variants were associated with dyslipidemia and lipid traits among Chinese children. In addition, we found significant gene-by-sex interactions. Our findings provided evidence supporting the role of FAM3C gene in regulating lipid metabolism in humans. IMPACT: FAM3C genetic variants were associated with dyslipidemia and lipid traits among Chinese children. In addition, we found significant gene-by-sex interactions. FAM3C/rs7776725 was associated with dyslipidemia and lipid traits only in girls. Our findings provided evidence supporting the role of FAM3C gene in regulating lipid metabolism in humans.

Efeito do treinamento aeróbio em parâmetros cardiorrespiratórios, hemodinâmicos e autonômicos de pacientes com doença renal crônica em hemodiálise / Effect of aerobic training on cardiorespiratory, hemodynamic, and autonomic parameters of chronic kidney disease patients on hemodialysis

A doença renal crônica (DRC) é uma condição clínica de alto risco cardiovascular e os pacientes nos estágios mais avançados da doença que dependem de terapia renal substitutiva frequentemente tem prejuízo cardiorespiratório, níveis elevados de pressão arterial (uso de múltiplas medicações para controle), modulação autonômica prejudicada e graus variados de inflamação. Deste modo este estudo tem como objetivo verificar se o exercício físico aeróbio intradialítico tem impacto em modificar estas alterações. Os pacientes foram selecionados em duas unidades de hemodiálise em São Luís do Maranhão, Brasil, entre junho de 2016 e outubro de 2019, e foram alocados conforme aceitação em grupo controle (GC) e grupo exercício (GE). O GE foi submetido a treinamento aeróbio com bicicleta por um período de 12 semanas. Avaliação física antropométrica, teste de caminhada de 6 minutos (TC6m), ecocardiograma, eletrocardiograma com análise da variabilidade da frequência cardíaca e medidas laboratoriais foram realizadas incluindo interleucina 6 (IL6) antes e após 12 semanas em ambos os grupos. Trinta e um pacientes foram avaliados 15 pacientes no grupo controle (GC) e 16 pacientes no grupo exercício (GE). Após 12 semanas de treinamento houve diminuição da pressão arterial sistólica do grupo exercício em relação ao basal (129,8 ± 9,41mmHg vs 112,00 ± 12,0 mmHg p = 0,03). Não houve alterações na composição corporal e na maioria dos exames laboratoriais, exceto pelo aumento do KTV (índice de adequação de diálise) e diminuição do LDL colesterol no grupo exercício em relação ao grupo controle. No entanto, os níveis de HDL colesterol aumentaram (39,92 ± 6,1 mg/dL vs 48,00 ± 7,85 mg/dL p = 0,02) e IL6 diminuíram (4,56 ± 1,2 pg / mL vs 2,14 ± 1,0 pg / mL p = 0,02). Houve aumento da distância percorrida no teste de caminhada no grupo exercício (473,80 ± 98,6 metros vs 573,50 ± 74,22 metros p = 0,01). Na avaliação ecocardiográfica, verificou-se que no GE houve diminuição da pressão da artéria pulmonar estimada (31,38 ± 2,9 mmhg vs 24,2 ± 1,7 mmhg p = 0,001). Houve melhora na modulação autonômica no GE (RMSSD 11,7 ± 4,2 vs 18,4 ± 5,7 p=0,02), LFnu (52,9 ± 17,2 vs 32,0 ± 18,2 p=0,02) e HFnu (48,1 ± 17,2 vs 68,0 ± 18,2 p=0,01). Não foram evidenciados efeitos adversos e não houve abandono do treinamento. Baseados nestes resultados, é possível concluir que o exercício aeróbio intradialítico por 12 semanas pode melhorar parâmetros cardiorrespiratórios, hemodinâmicos e autonômicos, com boa aderência e sem eventos adversos, podendo ser usado como medida coadjuvante para melhora clínica destes pacientes.

Chronic kidney disease (CKD) is a clinical condition of high cardiovascular risk and patients in the more advanced stages of the disease who depend on renal replacement therapy often experience cardiorespiratory impairment, high blood pressure levels (use of multiple medications for control), modulation impaired autonomy and varying degrees of inflammation. Thus, this study aims to verify whether intradialytic aerobic exercise has an impact on modifying these variables. The patients were selected in two hemodialysis units in São Luís do Maranhão, Brazil, between May 2016 and October 2019, and were allocated according to acceptance in the control group (CG) and exercise group (EG). The group exercise was submitted to aerobic exercise with bicycle for a period of 12 weeks. Anthropometric physical evaluation, 6-minute walk test (6MWT), echocardiogram, electrocardiogram with analysis of heart rate variability (VFC) and laboratory measurements were performed including interleukin 6 (IL6) before and after 12 weeks in both groups. Thirty-one patients were evaluated 15 patients in the control group (CG) and 16 patients in the exercise group (EG). After 12 weeks of training, there was a decrease in systolic blood pressure in the exercise group compared to baseline (129.8 ± 9.41 mmHg vs 112.00 ± 12.0 mmhg p = 0.03). There were no changes in body composition and in most laboratory tests, except for an increase in KTV (dialysis adequacy index) and a decrease in LDL cholesterol in the exercise group compared to the control group. However, HDL cholesterol levels increased (39.92 ± 6.1 mg / dL vs 48.00 ± 7.85 mg / dL p = 0.02) and IL6 decreased (4.56 ± 1.2 pg / mL vs 2.14 ± 1.0 pg / mL p = 0.02). There was an increase in the distance covered in the walking test in the exercise group (473.80 ± 98.6 m vs 573.50 ± 74.22 m p = 0,01). In the echocardiographic evaluation, it was found that in the EG there was a decrease in the estimated pulmonary artery pressure (31.38 ± 2.9 mmhg vs 24.2 ± 1.7 mmhg p = 0.001). There was an improvement in autonomic modulation in the EG (RMSSD 11.7 ± 4.2 vs 18.4 ± 5.7 p = 0.02), LFnu (52.9 ± 17.2 vs 32.0 ± 18.2 p = 0.02) and HFnu (48.1 ± 17.2 vs 68.0 ± 18.2 p = 0.01). There were no adverse effects and training was not abandoned. Based on these results, it is possible to conclude that intradialytic aerobic exercise for 12 weeks can improve cardiorespiratory, hemodynamic, and autonomic parameters, with good adherence and without adverse events, and can be used as a supporting measure for the clinical improvement of these patients.

Role of the adaptive immune system in atherosclerosis.

Atherosclerosis, the pathology underlying heart attacks, strokes and peripheral artery disease, is a chronic inflammatory disease of the artery wall initiated by elevated low-density lipoprotein (LDL) cholesterol levels. LDL accumulates in the artery wall, where it can become oxidized to oxLDL. T cell responses to ApoB, a core protein found in LDL and other lipoproteins, are detectable in healthy mice and people. Most of the ApoB-specific CD4T cells are FoxP3+ regulatory T cells (Treg). In the course of atherosclerosis development, the number of ApoB-reactive T cells expands. At the same time, their phenotype changes, showing cell surface markers, transcription factors and transcriptomes resembling other T-helper lineages like Th17, Th1 and follicular helper (TFH) cells. TFH cells enter germinal centers and provide T cell help to B cells, enabling antibody isotype switch from IgM to IgG and supporting affinity maturation. In people and mice with atherosclerosis, IgG and IgM antibodies to oxLDL are detectable. Higher IgM antibody titers to oxLDL are associated with less, IgG antibodies with more atherosclerosis. Thus, both T and B cells play critical roles in atherosclerosis. Modifying the adaptive immune response to ApoB holds promise for preventing atherosclerosis and reducing disease burden.

The beneficial effects of nutraceuticals and natural products on small dense LDL levels, LDL particle number and LDL particle size: a clinical review.

Cardiovascular diseases (CVDs) are globally the major causes of morbidity and mortality. Evidence shows that smaller and denser low-dense lipoprotein (sdLDL) particles are independent atherogenic risk factors for CVD due to their greater susceptibility to oxidation, and permeability in the endothelium of arterial walls. sdLDL levels are an independent risk factor and of more predictive value than total LDL-C for the assessment of coronary artery disease and metabolic syndrome. Functional food ingredients have attracted significant attention for the management of dyslipidemia and subsequently increase cardio-metabolic health. However, to date there is no study that has investigated the effect of these bioactive natural compounds on sdLDL levels. Therefore, the aim of the present review is to summarize the evidence accrued on the effect of special dietary ingredients such as omega-3 polyunsaturated fatty acids, nutraceuticals and herbal medicines on the levels of sdLDL, LDL particle number, and LDL particle size. Based on the results of the existing clinical trials this review suggests that natural products such as medicinal plants, nutraceuticals and omega-3 fatty acids can be used as adjunct or complementary therapeutic agents to reduce sdLDL levels, LDL particle numbers or increase LDL particle size and subsequently may prevent and treat CVD, with the advantage that theses natural agents are generally safe, accessible, and inexpensive.

Precipitated sdLDL: An easy method to estimate LDL particle size.

BACKGROUND: LDL-C lowering is the main measure in cardiovascular disease prevention but a residual risk of ischemic events still remains. Alterations of lipoproteins, specially, increase in small dense LDL (sdLDL) particles are related to this risk. OBJECTIVE: To investigate the potential use of sdLDL cholesterol concentration (sdLDL-C) isolated by an easy precipitation method and to assess the impact of a set of clinical and biochemical variables determined by NMR on sdLDL concentration. METHODS: sdLDL-C and NMR lipid profile were performed in 85 men samples. Association among them was evaluated using Pearson coefficients (rxy ). A multivariate regression was performed to identify the influence of NMR variables on sdLDL-C. RESULTS: A strong association between sdLDL-C and LDLLDL-P (rxy  = 0.687) and with LDL-Z (rxy  = -0.603) was found. The multivariate regression explained a 56.8% in sdLDL-C variation (P = 8.77.10-12). BMI, ApoB, triglycerides, FFA, and LDL-Z showed a significant contribution. The most important ones were ApoB and LDL-Z; a 1nm increase (LDL-Z) leads to decrease 126 nmol/L in sdLDL-C. CONCLUSION: The association between sdLDL-C, LDL-Z, and LDL-P is clear. From a large number of variables, especially LDL-Z and apoB influence on sdLDL-C. Results show that the smaller the LDL size, the higher their cholesterol concentration. Therefore, sdLDL-C determination by using this easy method would be useful to risk stratification and to uncover cardiovascular residual risk.

Interaction of lipoprotein(a) with low-density lipoprotein cholesterol on first incident acute myocardial infarction.

OBJECTIVE: To evaluate the interaction effects between lipoprotein (a) (Lp(a)) and low-density lipoprotein cholesterol (LDL-C) on first incident acute myocardial infarction (AMI) among Chinese Han population. METHODS: 1522 cases and 1691 controls were retrospectively analyzed. All subjects were grouped by Lp(a) or LDL-C level. RESULTS: Compared with reference group (LDL-C < 2.6 mmol/L and in the 1st quintile of Lp(a)), multivariable-adjusted analysis revealed that OR(95%CI) of first incident AMI for higher LDL-C alone is 2.66(1.78-3.98); that ORs(95%CI) for higher Lp(a) alone are 1.51(1.07-2.15), 1.84(1.28-2.64), 1.86(1.30-2.67) and 2.66(1.88-3.76) across the Lp(a) quintiles; and that ORs(95%CI) for both higher LDL-C and higher Lp(a) are 3.95(2.64-5.92), 3.20(2.21-4.64), 5.64(3.80-8.36) and 7.48(4.90-11.44) which were greater than the sum of the risks of both alone across the Lp(a) quintiles. Relative excess risks due to interaction were 1.78(95% CI, 0.12-3.44, P = 0.036) and 3.01(0.58-5.44, P = 0.015) at the 4th and 5th quintile of Lp(a), confirming the presence of additive interaction between Lp(a) and LDL-C on initial AMI. CONCLUSIONS: Lp(a) interacts with LDL-C in first incident AMI on additive scale in Chinese Han population. The risk of initial AMI from exposure of elevated Lp(a) combined with elevated LDL-C is much greater than the sum of the risks from that of both alone.

LDL as a therapeutic objective. / LDL como objetivo terapéutico.

The incidence of atherosclerotic cardiovascular disease has increased in the developed countries. Dyslipidemia is a primary major risk factor for atherosclerotic cardiovascular disease and LDL lowering is one of the main objectives. Although treatment goals for dyslipidemias should be personalized in every patient, statins are cost-effective in primary and secondary prevention of atherosclerotic cardiovascular disease. New treatments with higher power and greater decreases in LDL, PSCK9 inhibitors, have made a new breakthrough in atherosclerotic cardiovascular disease treatment. The 2019 guidelines for de management of dyslipidemias: lipid modification to reduce cardiovascular risk (European Society of Cardiology/European Atherosclerosis Society) with the level of evidence and the strength of the recommendations can facilitate the best decisions and benefits to our patients in clinical practice.

Association of exposure to phthalates with cardiometabolic risk factors in children and adolescents: a systematic review and meta-analysis.

Recent studies revealed controversial results on the association of exposure to phthalates with cardiometabolic risk factors in children and adolescents. Therefore, this systematic review and meta-analysis was conducted in this regard. At first, we searched English-language papers in Scopus, Web of Science, and PubMed databases, with no restriction of time, till the end of the year 2018. We performed a comprehensive literature search for association between phthalate exposure and cardiometabolic risk factors including obesity, hypertension, hyperglycemia, and dyslipidemia. Among 99 published papers found in scientific databases, 17 cohort, 15 cross-sectional, and three case-control studies were included in the meta-analysis. We observed a significant association between the concentrations of phthalates and their metabolites with body mass index (BMI), BMI z-score, waist circumference (WC), and low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and glucose in serum. In addition, significant association was observed between prenatal phthalate exposure and birth weight. To the best of our knowledge, this is the first meta-analysis of its kind. It shows positive association between phthalate exposure and some cardiometabolic risk factors in children and adolescents. Therefore, prevention of exposure to phthalates and reduction of their use should be underscored in strategies for primordial prevention of cardiovascular diseases. Recent studies revealed controversial results on the association of exposure to phthalates with cardiometabolic risk factors in children and adolescents. Therefore, this systematic review and meta-analysis was conducted in this regard.

Molecular Insights into the Mechanisms Underlying the Cholesterol- Lowering Effects of Phytosterols.

Dietary phytosterols, which comprise plant sterols and stanols, reduce plasma Low-Density Lipoprotein-Cholesterol (LDL-C) levels when given 2 g/day. Since this dose has not been reported to cause health-related side effects in long-term human studies, food products containing these plant compounds are used as potential therapeutic dietary options to reduce LDL-C and cardiovascular disease risk. Several mechanisms have been proposed to explain the cholesterol-lowering action of phytosterols. They may compete with dietary and biliary cholesterol for micellar solubilization in the intestinal lumen, impairing intestinal cholesterol absorption. Recent evidence indicates that phytosterols may also regulate other pathways. Impaired intestinal cholesterol absorption is usually associated with reduced cholesterol transport to the liver, which may reduce the incorporation of cholesterol into Very-Low- Density Lipoprotein (VLDL) particles, thereby lowering the rate of VLDL assembly and secretion. Impaired liver VLDL production may reduce the rate of LDL production. On the other hand, significant evidence supports a role for plant sterols in the Transintestinal Cholesterol Excretion (TICE) pathway, although the exact mechanisms by which they promote the flow of cholesterol from the blood to enterocytes and the intestinal lumen remains unknown. Dietary phytosterols may also alter the conversion of bile acids into secondary bile acids, and may lower the bile acid hydrophobic/hydrophilic ratio, thereby reducing intestinal cholesterol absorption. This article reviews the progress to date in research on the molecular mechanisms underlying the cholesterol-lowering effects of phytosterols.

Oxidized-LDL is a useful marker for predicting the very early coronary artery disease and cardiovascular outcomes.

AIM: The link of oxidized-low-density lipoprotein (ox-LDL) with premature coronary artery disease (CAD) has previously been less examined. Materials & methods: A total of 1217 patients with angiography-proven CAD were consecutively enrolled and divided into very-early CAD (VECAD), early CAD and late CAD subgroups. And 72 normal control of VECAD were examined. All the subjects were followed-up for an average of 31 months. RESULTS: Patients with VECAD had higher ox-LDL levels; and logistic regression analysis indicated that ox-LDL was an independent risk factor for VECAD among patients with CAD (adjusted odds ratio: 1.024; p < 0.001). The Kaplan-Meier analysis revealed that VECAD patients had lower event-free survival (p < 0.01, respectively). CONCLUSION: Elevated plasma ox-LDL level is independently associated with the presence and cardiovascular events in VECAD patients, suggesting that ox-LDL may be a prognostic predictor for VECAD.

Lipoprotein Particle Profiles, Standard Lipids, and Peripheral Artery Disease Incidence.

BACKGROUND: Despite strong and consistent prospective associations of elevated low-density lipoprotein (LDL) cholesterol concentration with incident coronary and cerebrovascular disease, data for incident peripheral artery disease (PAD) are less robust. Atherogenic dyslipidemia characterized by increased small LDL particle (LDL-P) concentration, rather than total LDL cholesterol content, along with elevated triglyceride-rich lipoproteins and low high-density lipoprotein (HDL) cholesterol (HDL-C), may be the primary lipid driver of PAD risk. METHODS: The study population was a prospective cohort study of 27 888 women ≥45 years old free of cardiovascular disease at baseline and followed for a median of 15.1 years. We tested whether standard lipid concentrations, as well as nuclear magnetic resonance spectroscopy-derived lipoprotein measures, were associated with incident symptomatic PAD (n=110) defined as claudication and/or revascularization. RESULTS: In age-adjusted analyses, while LDL cholesterol was not associated with incident PAD, we found significant associations for increased total and small LDL-P concentrations, triglycerides, and concentrations of very LDL (VLDL) particle (VLDL-P) subclasses, increased total cholesterol (TC):HDL-C, low HDL-C, and low HDL particle (HDL-P) concentration (all P for extreme tertile comparisons <0.05). Findings persisted in multivariable-adjusted models comparing extreme tertiles for elevated total LDL-P (adjusted hazard ratio [HRadj] 2.03; 95% CI, 1.14-3.59), small LDL-P (HRadj 2.17; 95% CI, 1.10-4.27), very large VLDL-P (HRadj 1.68; 95% CI, 1.06-2.66), medium VLDL-P (HRadj 1.98; 95% CI, 1.15-3.41), and TC:HDL-C (HRadj, 3.11; 95% CI, 1.67-5.81). HDL was inversely associated with risk; HRadj for extreme tertiles of HDL-C and HDL-P concentration were 0.30 ( P trend < 0.0001) and 0.29 ( P trend < 0.0001), respectively. These components of atherogenic dyslipidemia, including small LDL-P, medium and very large VLDL-P, TC:HDL-C, HDL-C, and HDL-P, were more strongly associated with incident PAD than incident coronary and cerebrovascular disease. Finally, the addition of LDL-P and HDL-P concentration to TC:HDL-C measures identified women at heightened PAD risk. CONCLUSIONS: In this prospective study, nuclear magnetic resonance-derived measures of LDL-P, but not LDL cholesterol, were associated with incident PAD. Other features of atherogenic dyslipidemia, including elevations in TC:HDL-C, elevations in triglyceride-rich lipoproteins, and low standard and nuclear magnetic resonance-derived measures of HDL, were significant risk determinants. These data help clarify prior inconsistencies and may elucidate a unique lipoprotein signature for PAD compared to coronary and cerebrovascular disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/ . Unique Identifier: NCT00000479.

Remnant-Like Particle Cholesterol, Low-Density Lipoprotein Triglycerides, and Incident Cardiovascular Disease.

BACKGROUND: Hypertriglyceridemia is associated with increased remnant-like particle cholesterol (RLP-C) and triglycerides in low-density lipoprotein (LDL-TG). Recent studies have focused on atherogenicity of RLP-C, with few data on LDL-TG. OBJECTIVES: The aim of this study was to examine associations of RLP-C and LDL-TG with incident cardiovascular disease (CVD) events and genetic variants in the ARIC (Atherosclerosis Risk In Communities) study. METHODS: Fasting plasma RLP-C and LDL-TG levels were measured in 9,334 men and women without prevalent CVD. Participants were followed for incident CVD events (coronary heart disease and ischemic stroke) for up to 16 years. Associations between LDL-TG and RLP-C levels and genetic variants were assessed by whole-exome sequencing using single-variant analysis for common variants and gene-based burden tests for rare variants; both an unbiased and a candidate gene approach were explored. RESULTS: RLP-C and LDL-TG levels were correlated with triglyceride levels (r = 0.85 and r = 0.64, p < 0.0001). In minimally adjusted analyses, RLP-C and LDL-TG were associated with CVD risk, but in models adjusted for traditional risk factors including lipids, only LDL-TG was associated with incident CHD (hazard ratio: 1.28; 95% confidence interval: 1.10 to 1.50) and stroke (hazard ratio: 1.47; 95% confidence interval: 1.13 to 1.92). A common APOE variant, rs7412, had the strongest association with LDL-TG and RLP-C (p < 5 × 10-8). CONCLUSIONS: RLP-C and LDL-TG levels were predictive of CVD and associated with APOE variants. LDL-TG may represent a marker of dysfunctional remnant lipoprotein metabolism associated with increased CVD risk. Further research is needed to determine whether LDL-TG plays a causal role in CVD and may be a target for therapy.

Experimental challenges regarding the in vitro investigation of the nanoparticle-biocorona in disease states.

Toxicological evaluation of nanoparticles (NPs) requires the utilization of in vitro techniques due to their number and diverse properties. Cell culture systems are often lacking in their ability to perform comparative toxicity assessment due to dosimetry issues and capacity to simulate in vivo environments. Upon encountering a physiological environment, NPs become coated with biomolecules forming a biocorona (BC), influencing function, biodistribution, and toxicity. Disease-induced alterations in the biological milieu can alter BC formation. This study evaluates the role of low-density lipoprotein (LDL) in altering macrophage responses to iron oxide (Fe3O4) NPs. BCs were formed by incubating Fe3O4 NPs in serum-free media, or 10% fetal bovine serum with or without LDL present. Following exposures to a normalized dose (25 µg/mL), macrophage association of Fe3O4 NPs with a LDL-BC was enhanced. TNF-α mRNA expression and protein levels were differentially induced due to BCs. Cell surface expression of SR-B1 was reduced following all Fe3O4 NPs exposures, while only NPs with an LDL-BC enhanced mitochondrial membrane potential. These findings suggest that elevations in LDL may contribute to distinct BC formation thereby influencing NP-cellular interactions and response. Further, our study highlights challenges that may arise during the in vitro evaluation of disease-related variations in the NP-BC.

Intake of Fatty Fish Alters the Size and the Concentration of Lipid Components of HDL Particles and Camelina Sativa Oil Decreases IDL Particle Concentration in Subjects with Impaired Glucose Metabolism.

SCOPE: Intake of long-chain n-3 PUFAs affects the lipoprotein subclass profile, whereas the effect of shorter chain n-3 PUFAs remains unclear. We investigated the effect of fish and camelina sativa oil (CSO) intakes on lipoprotein subclasses. METHODS AND RESULTS: Altogether, 79 volunteers with impaired glucose metabolism were randomly assigned to CSO, fatty fish (FF), lean fish (LF), or control group for 12 weeks. Nuclear magnetic resonance spectroscopy was used to determine lipoprotein subclasses and their lipid components. The average HDL particle size increased in the FF group (overall p = 0.032) as compared with the control group. Serum concentrations of cholesterol in HDL and HDL2 (overall p = 0.024 and p = 0.021, respectively) and total lipids and phospholipids in large HDL particles (overall p = 0.012 and p = 0.019, respectively) increased in the FF group, differing significantly from the LF group. The concentration of intermediate-density lipoprotein (IDL) particles decreased in the CSO group (overall p = 0.033) as compared with the LF group. CONCLUSION: Our study suggests that FF intake causes a shift toward larger HDL particles and increases the concentration of lipid components in HDL, which may be associated with the antiatherogenic properties of HDL. Furthermore, CSO intake decreases IDL particle concentration. These changes may favorably affect cardiovascular risk.

The association between serum copper concentrations and cardiovascular disease risk factors in children and adolescents in NHANES.

Copper is an essential element in human beings, alterations in serum copper levels could potentially have effect on human health. To date, no data are available regarding how serum copper affects cardiovascular disease (CVD) risk factors in children and adolescents. We examined the association between serum copper levels and CVD risk factors in children and adolescents. We analyzed data consisting of 1427 subjects from a nationally representative sample of the US population in the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014. The CVD risk factors included total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, fasting glucose, glycohemoglobin, fasting insulin, and blood pressure. Multivariate and generalized linear regressions were performed to investigate associations adjusted for age, gender, ethnicity, poverty:income ratio (PIR), BMI, energy intake, and physical activity. We found significant associations between serum copper and total cholesterol (coefficient = 0.132; 95% CI 0.081, 0.182; P for trend < 0.001), glycohemoglobin (coefficient = 0.044; 95% CI 0.020, 0.069; P < 0.001), and fasting insulin (coefficient = 0.730; 95% CI 0.410, 1.050; P < 0.001) among the included participants. Moreover, in the generalized linear models, subjects with the highest copper levels demonstrated a 0.83% (95% CI 0.44%, 1.24%) greater increase in serum total cholesterol (p for trend < 0.001) when compared to participants with the lowest copper concentrations. Our results provide the first epidemiological evidence that serum copper concentrations are associated with total cholesterol concentrations in children and adolescents. However, the underlying mechanisms still need further exploration.

Critical Review on the Analytical Techniques for the Determination of the Oldest Statin-Atorvastatin-in Bulk, Pharmaceutical Formulations and Biological Fluids.

Statins are a group of medicines that can help to lower the level of low-density lipoprotein (LDL) cholesterol "bad cholesterol" in the blood. Having a high level of LDL cholesterol is potentially dangerous, as it can lead to a hardening and narrowing of arteries (atherosclerosis) and cardiovascular disease (CVD), atorvastatin is one of the oldest member of the statin family and is used in the treatment of dyslipidemia and the prevention of CVD. Atorvastatin was first made in August 1985 and from 1996 to 2012 under the trade name Lipitor, atorvastatin became the world's best-selling drug. Numerous analytical methodologies are available for the quantification of atorvastatin and its content in pharmaceutical preparations and in biological fluids.