Higher LDL-cholesterol Concentrations Research Articles

Cardiovascular outcomes in patients with homozygous familial hypercholesterolaemia on lipoprotein apheresis initiated during childhood: long-term follow-up of an international cohort from two registries

Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by extremely high plasma LDL cholesterol from birth, causing atherosclerotic cardiovascular disease at a young age. Lipoprotein apheresis in combination with lipid-lowering drugs effectively reduce LDL cholesterol, but long-term health outcomes of such treatment are unknown. We aimed to investigate the long-term cardiovascular outcomes associated with lipoprotein apheresis initiated in childhood or adolescence. In this cohort study, data were drawn from the HoFH International Clinical Collaboration (HICC) and the international registry for Children with Homozygous Hypercholesterolemia on Lipoprotein Apheresis (CHAIN). An overall cohort included patients diagnosed with HoFH aged 0-18 years who were alive and in follow-up between Jan 1, 2010, and Nov 8, 2021, and whose high plasma LDL cholesterol concentrations made them eligible for lipoprotein apheresis. To compare cardiovascular outcomes, patients who initiated lipoprotein apheresis in childhood (lipoprotein apheresis group) and patients who only received lipid-lowering drugs (pharmacotherapy-only group) were matched by sex and untreated plasma LDL cholesterol concentrations. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischaemic stroke, percutaneous coronary intervention, coronary artery bypass grafting, aortic valve replacement, peripheral artery disease, carotid endarterectomy, angina pectoris, and supra-aortic or aortic stenosis (collectively referred to as atherosclerotic cardiovascular disease), for which survival analyses were performed in the matched cohort. Cox regression analyses were used to compare disease-free survival between cohorts and to calculate hazard ratio (HR) and 95% CI adjusted for sex, age at diagnosis, untreated plasma LDL cholesterol concentration, and number of lipid-lowering therapies other than lipoprotein apheresis. The overall cohort included 404 patients with a median age at diagnosis of 6·0 years (IQR 3·0-9·5) and median untreated plasma LDL cholesterol of 17·8 mmol/L (14·7-20·8). The matched cohorts included 250 patients (125 patients per group), with a median untreated LDL cholesterol of 17·2 mmol/L (14·8-19·7). Mean reduction in plasma LDL cholesterol concentrations between baseline and final follow-up was greater in the lipoprotein apheresis group (-55% [95% CI -60 to -51] vs -31% [-36 to -25]; p<0·0001). Patients in the lipoprotein apheresis group had longer atherosclerotic cardiovascular disease-free survival (adjusted HR 0·52 [95% CI 0·32-0·85]) and longer cardiovascular death-free survival (0·0301 [0·0021-0·4295]). Cardiovascular death was more common in the pharmacotherapy-only group than in the lipoprotein apheresis group (ten [8%] vs one [1%]; p=0·010), whereas median age at coronary artery bypass grafting was lower in the lipoprotein apheresis group than in the pharmacotherapy-only group (15·0 years [IQR 12·0-24·0] vs 30·5 years [19·0-33·8]; p=0·037). Among patients with HoFH, lipoprotein apheresis initiated during childhood and adolescence is associated with reduced long-term risk of atherosclerotic cardiovascular disease and death, and clear benefits of early initiation of high-frequency treatment on reducing plasma cholesterol were found. Consensus recommendations are now needed to guide more widespread and timely use of lipoprotein apheresis for children with HoFH, and research is required to further optimise treatment and ensure benefits of early and aggressive treatment delivery are balanced against effects on quality of life. Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; European Atherosclerosis Society; and the US National Heart, Lung, and Blood Institute, National Institutes of Health.

Associations of LDL Cholesterol, Non-HDL Cholesterol, and Apolipoprotein B With Cardiovascular Disease Occurrence in Adults: Korean Genome and Epidemiology Study.

Despite the superiority of non-HDL cholesterol (non-HDL-C) and apolipoprotein B (ApoB) as lipid markers for atherosclerotic cardiovascular disease (ASCVD), these are only suitable as secondary markers. We compared LDL cholesterol (LDL-C), non-HDL-C, and ApoB concentrations with respect to the occurrence of cardiovascular disease in adults enrolled in the Korean Genome and Epidemiology Study (KoGES). We used information on age; sex; medical history; family history of ASCVD; current lipid-lowering therapy; current smoking status; and creatinine, total cholesterol, HDL-C, LDL-C, triglyceride, and ApoB concentrations from 5,872 KoGES participants without ASCVD. New ASCVD development was monitored during the 8-year follow-up period. Adjusted hazard ratios (aHRs) for ASCVD of LDL-C, non-HDL-C, and ApoB concentrations were calculated based on the multivariate Cox regression analyses. The participants were also grouped as low and high according to the median values for each lipid marker, and calculated aHRs of each group combined by two lipid makers. ApoB showed the highest aHR per 1-SD for ASCVD (1.26; 95% confidence interval [CI], 1.11-1.43), followed by non-HDL-C (1.25; 95% CI, 1.11-1.41) and LDL-C (1.20; 95% CI, 1.06-1.37). The group with low LDL-C and high ApoB concentrations had a significantly higher aHR for ASCVD (1.61; 95% CI, 1.05-2.48) compared to the reference group values (low LDL-C and low ApoB concentrations). The aHR for the group with high LDL-C and low ApoB concentrations was not significant (1.30; 95% CI, 0.79-2.16). ApoB, non-HDL-C, and LDL-C are independent risk factors for ASCVD. Increases in the aHR per 1-SD for ASCVD were more strongly affected by ApoB, followed by non-HDL-C and LDL-C. Participants with low LDL-C and high ApoB concentrations showed increased ASCVD risk. For individuals with ASCVD risk factors, even those presenting normal LDL-C concentrations, measuring ApoB concentrations can provide useful information for better evaluation of ASCVD risk.

Postprandial dyslipidemia after a standardized high-fat meal in BMI-matched healthy individuals, and in subjects with prediabetes or type 2 diabetes

A relationship between postprandial hyperlipidemia and glucose homeostasis/cardiovascular diseases has been suggested. We investigated postprandial plasma lipid patterns after a standardized high-fat meal and their association with glucose homeostasis and subclinical atherosclerosis. Using matching by BMI, 32 healthy individuals with normal glucose tolerance (NGT), 21 subjects with impaired glucose tolerance (IGT), and 20 subjects with drug-naïve type 2 diabetes (T2D) were enrolled. Plasma concentrations of triglycerides (TGs), apolipoprotein-B (ApoB), ApoB48, ApoB100, glucose, and insulin at baseline and 1, 2, 3, 4, 5, 6, and 8h after a standardized meal (1041.03kcal with 70.99g of fat) were measured. Body composition, abdominal visceral fat area, and resting energy expenditure (REE) were measured using dual energy X-ray absorptiometry, computed tomography, and indirect calorimetry, respectively. The intima-media thickness (IMT) of the carotid artery and the ankle-brachial index (ABI) were used to detect subclinical atherosclerosis. Baseline data and area under the curve (AUC) of plasma concentrations of TGs, ApoB, and ApoB48 in the IGT and T2D groups were higher than in the NGT group. The peak TG concentrations after the meal was observed at 5h in subjects with IGT and T2D, while healthy subjects showed the highest concentrations at 4h. In multivariable analysis, high abdominal visceral fat area and low HDL-cholesterol concentrations were independently associated with the AUCTG and AUCApoB after adjusting for confounders including baseline TG and the REE. High LDL-cholesterol and high HbA1c concentrations were also associated with the AUCApoB. Furthermore, high AUCTG and AUCApoB values were independent factors for an increased carotid IMT and a low ABI after adjusting for relevant variables. Abdominal visceral obesity and low HDL-cholesterol concentrations were associated with increased post load excursions of TGs and ApoB in this series. These elevated concentrations of TGs and ApoB were linked with subclinical atherosclerosis.

WHO/International Society of Hypertension risk prediction charts versus the UK Prospective Diabetes Study risk engine for cardiovascular risk assessment among patients with type 2 diabetes: a comparative study

BackgroundPatients with type 2 diabetes are at increased risk of developing cardiovascular diseases, and assessment of cardiac risk is important for preventive strategies. We compared the performance of two cardiac assessment tools to predict 10-year cardiovascular risk. MethodsThis was a retrospective study of patients with type 2 diabetes who attended two primary-health-care centres in the Gaza Strip from Sept 15 to Nov 15, 2019. We excluded patients who had any existing cardiovascular disease. 10-year cardiovascular risk assessment was done with two risk assessment tools: the WHO/International Society of Hypertension (WHO/ISH) risk prediction charts and the UK Prospective Diabetes Study (UKPDS) risk engine. We also assessed the need for prescribing statins based on the documented risk. FindingsOf 350 patients assessed, 200 were eligible for the study. WHO/ISH charts classified 135 (68%) patients as being at low of cardiac events and the UKPDS risk engine classified 100 (50%). WHO/ISH assigned 40 (20%) people to the low to moderate 10-year risk category compared with 52 (26%) assigned by the UKPDS risk engine. Agreement between the two tools was poor (p=0·01). 12 (6%) patients who were classified as being at very low 10-year cardiac risk by WHO/ISH were classified as being at very high risk when assessed by the UKPDS risk engine. Furthermore, 150 (75%) of individuals who were categorised as having low cardiac risk by WHO/ISH had higher LDL-cholesterol concentrations than the therapeutic target of 100 mg/dL. Meanwhile, the UKPD risk engine, which uses a higher number of parameters for assessment, identified these individuals as having moderate to high risk. Based on risk documented in the medical records, 33 patients needed statin therapy of whom 12 (36%) patients were receiving this treatment. Among the remaining 167 patients who did not need statin therapy, treatment was prescribed for 57 (34%). InterpretationThere is a significant discrepancy between the WHO/ISH risk charts and the UKPDS risk engine in assigning cardiac risk. Sensitivity in identifying patients with treatable levels of LDL cholesterol and diastolic blood pressure was low for both tools. Furthermore, a lack of clear local protocols led to incorrect or unnecessary prescribing. This study showed that there is a need to reconsider the use of assessment tools either by adding a new tool or by improving assessments with the current tools. FundingNone.

NMR-Based Lipid Metabolite Profiles to Predict Outcomes in Patients Undergoing Interventional Therapy for a Hepatocellular Carcinoma (HCC): A Substudy of the SORAMIC Trial.

Simple SummaryA hepatocellular carcinoma (HCC) is the most common cause of death in patients suffering from chronic liver diseases. In order to improve the prediction of outcomes in HCC patients, there is a need for new biomarkers. This pilot study aimed at identifying serum metabolites for the prediction of outcomes of HCC patients using nuclear magnetic resonance (NMR) spectroscopy. This analysis revealed that high serum concentrations of myo-inositol or dimethylamine were associated with an improved overall survival. In contrast, high concentrations of total cholesterol, LDL-cholesterol and LDL particles (LDL-P) were associated with a decreased overall survival. The identification of novel biomarkers using this NMR-based technology holds promise for opening new directions in the conduction of interventional trials in HCCs.Background: This exploratory study aimed to evaluate lipidomic and metabolomic profiles in patients with early and advanced HCCs and to investigate whether certain metabolic parameters may predict the overall survival in these patients. Methods: A total of 60 patients from the prospective, randomized-controlled, multicenter phase II SORAMIC trial were included in this substudy; among them were 30 patients with an early HCC who underwent radiofrequency ablation combined with sorafenib or a placebo and 30 patients with an advanced HCC who were treated with a selective internal radiation therapy (SIRT) plus sorafenib vs. sorafenib alone. The blood serum of these patients was analyzed using a standardized nuclear magnetic resonance (NMR) platform. All tested metabolites were correlated with the overall survival. Results: The overall survival (OS) was significantly higher in patients with an early HCC (median OS: 34.0 months) compared with patients with an advanced HCC (median OS: 12.0 months) (p < 0.0001). Patients with high serum concentrations of myo-inositol (MI) had a higher overall survival compared with patients with low concentrations (21.6 vs. 13.8 months) with a Pearson correlation coefficient of 0.331 (p = 0.011). Patients with high serum concentrations of dimethylamine had a higher overall survival compared with patients with low concentrations (25.1 vs. 19.7 months) with a Pearson correlation coefficient of 0.279 (p = 0.034). High concentrations of total cholesterol, LDL-cholesterol and LDL particles (LDL-P) were associated with a decreased overall survival. Conclusions: NMR-based lipidomic and metabolomic profiling has the potential to identify individual metabolite biomarkers that predict the outcome of patients with an HCC exposed to non-invasive therapeutic management.

MicroRNA-148a regulates low-density lipoprotein metabolism by repressing the (pro)renin receptor.

High plasma LDL cholesterol (LDL-c) concentration is a major risk factor for atherosclerosis. Hepatic LDL receptor (LDLR) regulates LDL metabolism, and thereby plasma LDL-c concentration. Recently, we have identified the (pro)renin receptor [(P)RR] as a novel regulator of LDL metabolism, which regulates LDLR degradation and hence its protein abundance and activity. In silico analysis suggests that the (P)RR is a target of miR-148a. In this study we determined whether miR-148a could regulate LDL metabolism by regulating (P)RR expression in HepG2 and Huh7 cells. We found that miR-148a suppressed (P)RR expression by binding to the 3’-untranslated regions (3’-UTR) of the (P)RR mRNA. Mutating the binding sites for miR-148a in the 3’-UTR of (P)RR mRNA completely abolished the inhibitory effects of miR-148a on (P)RR expression. In line with our recent findings, reduced (P)RR expression resulted in decreased cellular LDL uptake, likely as a consequence of decreased LDLR protein abundance. Overexpressing the (P)RR prevented miR-148a-induced reduction in LDLR abundance and cellular LDL uptake. Our study supports a new concept that miR-148a is a regulator of (P)RR expression. By reducing (P)RR abundance, miR-148a decreases LDLR protein abundance and consequently cellular LDL uptake.

Triglyceride-glucose index is a predictor of incident chronic kidney disease: a population-based longitudinal study.

Insulin resistance is one of the risks of chronic kidney disease (CKD). The triglyceride-glucose index (TyG index) has been suggested as a marker of moderate insulin resistance. We aimed to investigate the association between TyG index and incident CKD. In this historical cohort study of 11,712 participants (6026 men and 5686 women), we investigated the impact of TyG index on incident CKD. CKD was defined as estimated GFR less than 60mL/min/1.73m2 and/or proteinuria detected by dipstick test in fasting morning urine. TyG index was calculated as ln [fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2]. Cox proportional hazard models were performed to investigate the impact of TyG index on incident CKD, adjusting for age, BMI categories, waist circumference, smoking status, exercise, logarithm of alcohol consumption, systolic blood pressure, serum albumin, hemoglobin A1c, hyperuricemia, low HDL-cholesterol concentration, high LDL-cholesterol concentration, CRP, creatinine, and gamma-glutamyltransferase. During the median 4.0-year follow-up duration for men and 3.7-year follow-up duration for women, 261 participants (120 men and 141 women) developed CKD. In Cox proportional hazard model, TyG index presented the significant risks for incident CKD in both men and women (men, hazard ratio 1.32, 95% confidence interval 1.02-1.70, p = 0.036, women, hazard ratio 1.50, 95% confidence interval 1.05-2.13, p = 0.024). This study revealed that TyG index can be a predictor of incident CKD.

The emerging concept of "individualized cholesterol-lowering therapy": A change in paradigm.

High LDL-cholesterol concentrations constitute a risk for atherosclerotic cardiovascular disease. By consensus, cholesterol-lowering therapy is initiated with a statin that reduces endogenous cholesterol synthesis, upregulates hepatic LDL receptor activity, increases LDL clearance and lowers LDL-cholesterol concentrations in the bloodstream. The efficacy of statin treatment is dose dependent and achieves a risk reduction of up to 50%. However, a substantial body of evidence suggests that a quarter of statin-treated patients do not respond adequately as a result of low endogenous cholesterol synthesis. In humans fractional cholesterol absorption varies from 20% to 80%. High cholesterol absorbers, which are characterized by a low-to-normal cholesterol synthesis, exhibit poor responsiveness to statin treatment. On the other hand, the cholesterol absorption inhibitor ezetimibe effectively reduces serum cholesterol levels in these patients. On this background, we suggest to "get personal" and individualize cholesterol-lowering therapies, according to the individual's status of cholesterol synthesis and absorption.

DIET-INDUCED PREDIABETES: EFFECTS ON OXIDATIVE STRESS AND INFLAMMATORY BIOMARKERS AS AGENTS FOR VASCULAR COMPLICATIONS IN RENAL FUNCTION

Ponte Academic JournalFeb 2019, Volume 75, Issue 2 DIET-INDUCED PREDIABETES: EFFECTS ON OXIDATIVE STRESS AND INFLAMMATORY BIOMARKERS AS AGENTS FOR VASCULAR COMPLICATIONS IN RENAL FUNCTIONAuthor(s): Andile Khathi ,Mluleki Luvuno, Musa MabandlaJ. Ponte - Feb 2019 - Volume 75 - Issue 2 doi: 10.21506/j.ponte.2019.2.9 Abstract:Studies in our laboratory have shown that prolonged ingestion of a high fat high carbohydrate diet (HFHC) results in the development of pre-diabetes that is characterized by moderate hyperglycaemia. However, the effects of moderate hyperglycaemia, as seen in a HFHC-diet induced pre-diabetes rat model on renal function have not fully been characterized. Therefore, we investigated the changes in renal function on a HFHC diet-induced prediabetes rat model through the evaluation of markers of inflammation and oxidative stress. Animals were randomly assigned to the following diets ad libitum during experimentation: standard rat chow (ND+H2O) and high-fat high-carbohydrate supplemented with fructose (HFHC+Fructose). We measured glycosylated haemoglobin (HbA1c), lipid profile, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx1), tumor necrosis factor-alpha (TNF-α), interlukin-6 (IL-6), aldosterone concentration and mean arterial pressure. An increase in HbA1c, triglyceride (TG) and LDL-cholesterol concentration in the HFHC+Fructose diet group that occurred in parallel to an increase in MDA concentration and a decrease in SOD and GPx1 concentration was observed. This change was accompanied by an increase in TNF-α, IL-6, aldosterone concentration and mean arterial pressure. Therefore, the presence of high HbA1c, TG and LDL-cholesterol concentration that co-exists with elevated MDA concentration and lower anti-oxidant concentration suggests potential damage in renal tissue due to oxidative stress. High TNF-α and IL-6 concentration increases the risk for inflammation and development of vascular complications as evidenced by the increase in mean arterial pressure and aldosterone concentration. Altogether, chronic ingestion of the HFHC+Fructose diet increase apoptotic markers that induce glycation of proteins, dyslipidemia, oxidative stress, inflammatory condition and high blood pressure. Therefore, early management of these markers during prediabetes may prevent the onset of kidney dysfunction and circumvent development of vascular complications. Download full text:Check if you have access through your login credentials or your institution Username Password

LIMA1: A Newly Identified Player in the Field of Cholesterol Control

Higher concentrations of LDL cholesterol (LDL-C) are causally linked to risk for cardiovascular disease (CVD). Correspondingly, lowering cholesterol leads to a proportional lowering of risk in randomized control trials. Thus, a key objective of CVD risk mitigation is lipid lowering—and the lower, the better. The Odyssey randomized control trial suggests that there is no LDL-C concentration too low for safety, and those achieving the lowest values displayed the greatest risk reduction. What complicates the matter is the multifaceted nature of lipid homeostasis. Although approximately half of cholesterol variability is controlled by genetic variability (other factors being diet and lifestyle), only a small percentage of risk has been linked to genetic variance. Furthermore, lipid screening is poor at identifying individuals with genetic lipidemias. For example, it …

Changes in socio-economic status and lipoproteins in Chilean adolescents: a 16-year longitudinal study.

The present longitudinal study assessed whether changes in socio-economic status (SES) from infancy to adolescence were associated with plasma lipoprotein concentrations in adolescence, of which low HDL-cholesterol (HDL-C) and high LDL-cholesterol (LDL-C), TAG and total cholesterol (TC) concentrations are associated with higher cardiovascular risk. SES, assessed using the modified Graffar Index, was calculated at 1, 5, 10 and 16 years. Principal components factor analysis with varimax rotation extracted two orthogonal SES factors, termed 'environmental capital' and 'social capital'. Generalized linear models were used to analyse associations between environmental and social capital at 1 and 16 years and outcomes (HDL-C, LDL-C, TAG, TC) at 16 years, as well as changes in environmental and social capital from 1-5, 5-10, 10-16 and 1-16 years, and outcomes at 16 years. Santiago, Chile.ParticipantsWe evaluated 665 participants from the Santiago Longitudinal Study enrolled at infancy in Fe-deficiency anaemia studies and examined every 5 years to age 16 years. Social capital in infancy was associated with higher HDL-C in adolescence. Environmental capital in adolescence was associated with higher LDL-C and TC during adolescence. Changing environmental capital from 1-16 years was associated with higher LDL-C. Changing environmental capital from 1-5 and 1-16 years was associated with higher TC. Improvements in environmental capital throughout childhood were associated with less healthy LDL-C and TC concentrations in adolescence. We found no evidence of associations between changing environmental capital and HDL-C or TAG, or changing social capital and HDL-C, LDL-C, TAG or TC.

Smoking Habit Effect on Total Cholesterol Levels

Introduction and Aims: Smoking habits have an adverse effect on fat profiles, including high concentrations of LDL cholesterol. Nicotine in cigarettes is one of the substances that interfere with cholesterol metabolism in the body. This study aims to find out more about the relationship of smoking habit to total cholesterol levels. Methods: This research is a survey research using cross-sectional study design. The respondents in this study are active smokerresidents of Bintara XIV. The data collected in this research is using Biosensor method.Analysis of the data performed is univariate and bivariate analysis by using the ANOVA test SPSS for Windows 17. Result: The result of the ANOVA analysis is p = 0.000 (p &lt; 0.05) which means there is influence of two variables analyzed and there is a relationship between them. Conclusions: There is influence between smoking habits of respondent with a total cholesterol level of respondent. Respondents with high smoking intensity tend to have high total cholesterol levels. The results of this study are expected to be used as a base for further research todetermine the effect of smoking intensity oneach lipid profile on laboratory examination.Â

CHANGE OF SOME BIOCHEMICAL INDICES DEPENDING ON EXPOSURE LOAD IN STAFF WORKERS IN CONTACT WITH VINYL CHLORIDE

Introduction. The paper presents the results of a survey of 42 experienced workers of a chemical enterprise exposed to vinyl chloride (VC). The purpose of the study is to establish the characteristics of changes in some biochemical indices in workers exposed to vinyl chloride, depending on the exposure load. Material and methods. A neurological, general therapeutic, ultrasound examination, biochemical studies with the determination of lipid profile, lipid peroxidation, and antioxidant protection, neurotransmitters was executed. The toxic exposure load (TEL) for the entire period of internship has been determined. Non-parametric methods of statistical analysis with the determination of the Mann-Whitney U-test were used. Results. Clinical manifestations of employees working in contact with VC included asthenic disorder with cognitive impairment and autonomic dysfunction syndrome, arterial hypertension, and gastrointestinal diseases. The prevalence of cognitive impairments and hypertension has been established to increases with an extremely high level of exposure load. In individuals with an extremely high level of exposure, higher concentrations of LDL cholesterol, atherogenic index (AI) and serotonin levels, and a decrease in the level of ceruloplasmin were noted. An ultrasound examination of the liver revealed an increase in the anteroposterior size of the right lobe in the group of experienced workers who were in contact with VC, compared with the control (p = 0.03). Discussion. Among the indices of lipid metabolism, pro-atherogenic cholesterol fractions are a more sensitive marker, reflecting the degree of exposure to VC. A decrease in the concentration of ceruloplasmin is probably associated with a weakening of the antioxidant defense mechanisms with an increase in the level of TEL. Increased serotonin levels in individuals with extremely high levels of TEL, confirms the prevalence of cognitive impairment in this group. In the group of individuals with extremely high levels of TEL, a statistically significant increase in LDL cholesterol, IA, a decrease in ceruloplasmin concentration, an increase in serotonin serum levels due to impaired metabolic and protective functions of the liver as a result of prolonged contact with VC were noted.

The Ossabaw Pig Is a Suitable Translational Model to Evaluate Dietary Patterns and Coronary Artery Disease Risk

BackgroundAnimal models that mimic diet-induced human pathogenesis of chronic diseases are of increasing importance in preclinical studies. The Ossabaw pig is an established model for obesity-related metabolic disorders when fed extreme diets in caloric excess. ObjectiveTo increase the translational nature of this model, we evaluated the effect of diets resembling 2 human dietary patterns, the Western diet (WD) and the Heart Healthy Diet (HHD), without or with atorvastatin (−S or +S) therapy, on cardiometabolic risk factors and atherosclerosis development. MethodsOssabaw pigs (n = 32; 16 boars and 16 gilts, aged 5–8 wk) were randomized according to a 2 × 2 factorial design into 4 groups (WD−S, WD+S, HHD−S, and HHD+S) and were fed the respective diets for 6 mo. The WD (high in saturated fat, cholesterol, and refined grain) and the HHD (high in unsaturated fat, whole grain, and fruit and vegetables) were isocaloric [38% of energy (%E) from fat, 47%E from carbohydrate, and 15%E from protein]. Body composition was determined by using dual-energy X-ray absorptiometry, serum fatty acid (FA) profiles by gas chromatography, cardiometabolic risk profile by standard procedures, and degree of atherosclerosis by histopathology. ResultsSerum FA profiles reflected the predominant dietary FA. Pigs fed the WD had 1- to 4-fold higher concentrations of LDL cholesterol, non-HDL cholesterol, HDL cholesterol, high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor α (TNF-α), alkaline phosphatase (ALP), and alanine aminotransferase (ALT) compared with HHD-fed pigs (all P-diet < 0.05). Statin therapy significantly lowered concentrations of LDL cholesterol (−39%), non-HDL cholesterol (−38%), and triglycerides (−6%) (P-statin < 0.02). A greater degree of atheromatous changes (macrophage infiltration, foam cells, fatty streaks) and lesion incidence was documented in the coronary arteries (P-diet < 0.05), as well as 2- to 3-fold higher lipid deposition in the aortic arch or thoracic aorta of WD- compared with HHD-fed pigs (P-diet < 0.001). ConclusionOssabaw pigs manifested a dyslipidemic and inflammatory profile accompanied by early-stage atherosclerosis when fed a WD compared with an HHD, which was moderately reduced by atorvastatin therapy. This phenotype presents a translational model to examine mechanistic pathways of whole food–based dietary patterns on atherosclerosis development.

Comparison of the impact of SFAs from cheese and butter on cardiometabolic risk factors: a randomized controlled trial1–3

Background: Controversies persist concerning the association between intake of dietary saturated fatty acids (SFAs) and cardiovascular disease risk.Objective: We compared the impact of consuming equal amounts of SFAs from cheese and butter on cardiometabolic risk factors.Design: In a multicenter, crossover, randomized controlled trial, 92 men and women with abdominal obesity and relatively low HDL-cholesterol concentrations were assigned to sequences of 5 predetermined isoenergetic diets of 4 wk each separated by 4-wk washouts: 2 diets rich in SFAs (12.4–12.6% of calories) from either cheese or butter; a monounsaturated fatty acid (MUFA)–rich diet (SFAs: 5.8%, MUFAs: 19.6%); a polyunsaturated fatty acid (PUFA)–rich diet (SFAs: 5.8%, PUFAs: 11.5%); and a low-fat, high-carbohydrate diet (fat: 25%, SFAs: 5.8%).Results: Serum HDL-cholesterol concentrations were similar after the cheese and butter diets but were significantly higher than after the carbohydrate diet (+3.8% and +4.7%, respectively; P < 0.05 for both). LDL-cholesterol concentrations after the cheese diet were lower than after the butter diet (−3.3%, P < 0.05) but were higher than after the carbohydrate (+2.6%), MUFA (+5.3%), and PUFA (+12.3%) diets (P < 0.05 for all). LDL-cholesterol concentrations after the butter diet also increased significantly (from +6.1% to +16.2%, P < 0.05) compared with the carbohydrate, MUFA, and PUFA diets. The LDL-cholesterol response to treatment was significantly modified by baseline values (P-interaction = 0.02), with the increase in LDL cholesterol being significantly greater with butter than with cheese only among individuals with high baseline LDL-cholesterol concentrations. There was no significant difference between all diets on inflammation markers, blood pressure, and insulin-glucose homeostasis.Conclusions: The results of our study suggest that the consumption of SFAs from cheese and butter has similar effects on HDL cholesterol but differentially modifies LDL-cholesterol concentrations compared with the effects of carbohydrates, MUFAs, and PUFAs, particularly in individuals with high LDL cholesterol. In contrast, SFAs from either cheese or butter have no significant effects on several other nonlipid cardiometabolic risk factors. This trial was registered at http://clinicaltrials.gov as NCT02106208.

Psoriasis and Cardiovascular Risk-Do Promising New Biomarkers Have Clinical Impact?

Epidemiological studies suggest an increased prevalence of cardiovascular disease (CVD) in patients with psoriasis (PS). Therefore, emphasis has lately been laid on the necessity for clinical evaluation of the risk of CVD in these patients. The systemic inflammatory markers C-reactive protein (CRP) and interleukin- (IL-) 6, which have long been used to predict future CVD in the general population, are increased manyfold in patients with PS. Lipid abnormalities characterized by elevated triglycerides, low HDL cholesterol, and higher concentrations of LDL cholesterol and its oxidized form are also prevalent in patients. There is a need for additional laboratory markers for the assessment of cardiovascular status of patients with PS. Due to frequent comorbid overweight and obesity, biologically active compounds produced by adipocytes may have an impact on monitoring the status of the cardiovascular system of patients with PS. For this purpose, two adipokines, adiponectin and leptin, have been most extensively studied. The review focuses on some inflammatory and oxidative stress aspects in patients with PS through the analysis of the impact of prominent adipokines and oxidized low-density lipoprotein (oxLDL) to assess their eligibility for clinical practice as markers of CVD risk in patients with PS.

Mutational screening in the LDLR gene among patients presenting familial hypercholesterolemia in the Southeast of Brazil.

Familial hypercholesterolemia (FH) is a dominant, autosomal disease characterized by high LDL levels in blood plasma, and is caused by a defect in the gene encoding the LDL receptor (LDLR). The clinical diagnosis is based on personal and familial history, physical examination findings, and measures of high LDL cholesterol concentrations. LDLR is a cell-surface glycoprotein that controls the level of blood plasma cholesterol and triglyceride by LDLR-mediated endocytosis. Here we sequenced the entire LDLR gene-coding region to screen for mutations in 32 patients diagnosed with FH, and we have found 20 mutations including synonymous, missense, and intronic mutations. Six of them were characterized as pathogenic mutations (D178Y, C184Y, S326C, C681X, IVS7+10G>C, and IVS11-10G>A). We have also found one intronic mutation not described so far (IVS11-63C>A). Our study corroborates the broad spectrum of mutations distributed along the entire LDLR gene, and we suggest that the genes APOB and PCSK9 should also be screened for mutations when considering the diagnosis of FH. It is already known that different types of mutations are directly associated with the phenotype heterogeneity presented by patients. Considering that Brazilian population is highly admixed, it is important to determine the geographic spectrum of LDLR mutations to provide information on the prognosis and treatment of each FH patient.

Non-targeted metabolomics combined with genetic analyses identifies bile acid synthesis and phospholipid metabolism as being associated with incident type 2 diabetes.

Identification of novel biomarkers for type 2 diabetes and their genetic determinants could lead to improved understanding of causal pathways and improve risk prediction. In this study, we used data from non-targeted metabolomics performed using liquid chromatography coupled with tandem mass spectrometry in three Swedish cohorts (Uppsala Longitudinal Study of Adult Men [ULSAM], n = 1138; Prospective Investigation of the Vasculature in Uppsala Seniors [PIVUS], n = 970; TwinGene, n = 1630). Metabolites associated with impaired fasting glucose (IFG) and/or prevalent type 2 diabetes were assessed for associations with incident type 2 diabetes in the three cohorts followed by replication attempts in the Cooperative Health Research in the Region of Augsburg (KORA) S4 cohort (n = 855). Assessment of the association of metabolite-regulating genetic variants with type 2 diabetes was done using data from a meta-analysis of genome-wide association studies. Out of 5961 investigated metabolic features, 1120 were associated with prevalent type 2 diabetes and IFG and 70 were annotated to metabolites and replicated in the three cohorts. Fifteen metabolites were associated with incident type 2 diabetes in the four cohorts combined (358 events) following adjustment for age, sex, BMI, waist circumference and fasting glucose. Novel findings included associations of higher values of the bile acid deoxycholic acid and monoacylglyceride 18:2 and lower concentrations of cortisol with type 2 diabetes risk. However, adding metabolites to an existing risk score improved model fit only marginally. A genetic variant within the CYP7A1 locus, encoding the rate-limiting enzyme in bile acid synthesis, was found to be associated with lower concentrations of deoxycholic acid, higher concentrations of LDL-cholesterol and lower type 2 diabetes risk. Variants in or near SGPP1, GCKR and FADS1/2 were associated with diabetes-associated phospholipids and type 2 diabetes. We found evidence that the metabolism of bile acids and phospholipids shares some common genetic origin with type 2 diabetes. Metabolomics data have been deposited in the Metabolights database, with accession numbers MTBLS93 (TwinGene), MTBLS124 (ULSAM) and MTBLS90 (PIVUS).

Consumption of takeaway meals and risk markers for coronary heart disease, type 2 diabetes, and obesity in children aged 9–10 years: a cross-sectional study

BackgroundFrequent consumption of takeaway meals is associated with increased risks of coronary heart disease, type 2 diabetes, and obesity in adults, but little is known about such risks in childhood. This study aimed to assess whether consumption of takeaway meals is linked to chronic disease in childhood. MethodsA cross-sectional study of UK schoolchildren aged 9–10 years (Year 5) was carried out in a sample of 85 primary schools in London, Birmingham, and Leicester, with a high prevalence of ethnic minority pupils (black African-Caribbean or South Asian). All children in Year 5 classes were invited to participate. Children self-reported their frequency of consumption of takeaway meals, completed a 24 h dietary recall, had anthropometric measurements taken, and provided a fasting blood sample. Analyses were done with multilevel linear modelling allowing for clustering at school level. Ethics approval was obtained and written informed consent secured for all participants. FindingsAmong 3679 invited children, 2529 participated (69% response rate), of whom 1948 (77%) had complete data (1023 girls, 52%). They included similar numbers of children of white European (n=475), black African-Caribbean (496), South Asian (495), and other ethnic origins (482); 499 (26%) never or hardly ever consumed a takeaway meal, 894 (46%) did so less than once per week, and 555 (28%) once or more per week. In analyses adjusted for age, sex, month, school, ethnic group, and socioeconomic status, children who reported eating a takeaway meal once or more per week had higher mean total cholesterol and LDL cholesterol, by 0·09 mmoL/L (95% CI 0·01–0·18) and by 0·10 mmoL/L (0·02–0·18), respectively, than did children who never or hardly ever ate a takeaway meal; their mean fat mass index was also higher (by 5·06%, 95% CI 0·53–9·79). Mean total cholesterol, LDL cholesterol, and fat mass index in the never or hardly ever group were 4·44 mmoL/L, 2·58 mmoL/L, and 2·01 kg/m5, respectively. Children who reported more frequent consumption of takeaway meals had substantially higher intakes of energy, fat (percent of energy), and saturated fat (percent of energy), and lower starch, protein, and micronutrient intakes. InterpretationFrequent consumption of takeaway meals in childhood is common and is associated with higher intakes of saturated fat and higher concentrations of LDL cholesterol. This research adds to growing evidence of the adverse health effects of takeaway meals. FundingThis research was supported by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (South London) and by grants from Diabetes UK and the Wellcome Trust.

PP.28.19

Objective: Adipose tissue is an active endocrine organ with autocrine/paracrine and endocrine metabolic functions. The aim of the study is to investigate the levels of leptin, adiponectin and lipids in patients with Essential Arterial Hypertension (EAH) and abdominal obesity (AO) depending on genes polymorphism of PPAR-γ2 (Pro12Ala) and ACE (I/D). Design and method: Study involved 110 EAH I-III stages patients with AO 1–3 grades severity: 56.4% women, 43.6% men; mean age 53.3 ± 6.05 years. Alleles of angiotensin converting enzyme – ACE (I/D) and peroxisome proliferator-activated receptor-γ2 – PPAR-γ2 (Pro12Ala) genes were studied with PCR. Overweight/AO determined according to ATP III, NCEP criteria. Control group included 50 healthy individuals. Leptin and Adiponectin plasma levels were detected by ELISA. Lipids investigated by total cholesterol (TC), triglycerides (TG), high and low density levels cholesterol (HDL, LDL). Leptin-resistance (LR) was determined by the ratio of leptin/TG (>2.7). Results analyzed according to the ESC/ESH 2013 guidelines. Results: Leptin level increased 2.48–3.35 times (61.4 ± 9.34 ng/ml, p = 0,024) in women with EAH III, AO 2–3 with decrease of adiponectin from 82.0 ± 3.05 to 73.6 ± 2.34 ng/ml, p = 0.025. Leptin in men elevated according to EAH and AO severity, remaining 2.2 times lower than in women (27.4 ± 6.54 ng/ml, p < 0.05). The levels of TC, TG, LDL and LR were 1.27–2.24 times higher in EAH II-III women than in men (p < 0.05). Atherogenic dyslipidemia type IIb (Frederickson) prevailed in 87.1% overweight and AO EAH patients, especially in ACE gene’ D-allele carriers and PPAR-γ2 Pro12-genotype. Leptin level was 1.28–3.78 times (p < = 0.048–0.008) higher in D-allele female carriers of ACE gene and in Pro12-genotype carriers of PPAR-γ2 gene (regardless of gender). DD-genotype and Pro-allele associated with 23.1–39.8% (p < 0.05) higher concentrations of LDL cholesterol, Pro12-genotype – with 23.9% (p = 0.048) higher content of TC and 2.23 times (p < 0.01) higher LR in men. Leptin synthesis and LR data increased 1.26–4.71 times (p < = 0,021–0,001) in EAH with AO DD-genotype carriers of ACE gene and Pro12- genotype of PPAR-γ2 gene. Conclusions: Hyperleptinemia, leptin-resistance, dyslipidemia in EAH and AO patients correlates with the allelic status of the ACE (I/D) and PPAR-γ2 (Pro12Ala) genes.