Common Variants in Cholesterol Synthesis- and Transport-Related Genes Associate with Circulating Cholesterol Responses to Intakes of Conventional Dairy Products in Healthy Individuals.

BACKGROUND: Dairy intake has been associated with varying impacts on circulating cholesterol concentrations across nutritional epidemiology and intervention studies, with findings attributed mainly to differences in the nature of dairy products consumed or study designs. The contribution of the genomic architecture to such observations has yet to be revealed. OBJECTIVE: We assessed the impact of multiple common genetic variations in cholesterol-related genes on responses of serum cholesterol to the recommended amount of dairy product intake in Canada. METHODS: In a multicenter, randomized crossover design, 101 normolipidemic adults (n = 29 men and 72 women), with a mean ± SD age of 41.7 ± 16.7 y and a body mass index (BMI, in kg/m(2)) of 25.9 ± 4.3 consumed 3 servings/d of dairy [375 mL 1% milk-fat (MF) milk, 175 g 1.5% MF yogurt, and 30 g of 34% MF cheese] or energy-matched control products (juice, cashews, and cookies) provided within a prudent background diet for 4 wk each, separated by a 4- to 8-wk washout period. Serum lipid variables were determined by standard enzymatic methods by using an autoanalyzer. Candidate single nucleotide polymorphisms were assessed by TaqMan genotyping assay. RESULTS: The responsiveness of serum total cholesterol (TC) and LDL cholesterol to the dairy compared with the control diet was associated with individuals' genotypes. The cholesterol transport gene ATP-binding cassette subfamily G, member 5 (ABCG5) rs6720173-GG homozygotes had higher concentrations of TC (+0.18 mmol/L; P = 0.0118) and LDL cholesterol (+0.17 mmol/L; P = 0.0056) relative to C-allele carriers (-0.07 and -0.06 mmol/L, respectively). The bile acid synthesis gene cholesterol 7α-hydroxylase (CYP7A1) rs3808607-G-allele carriers had higher TC (+0.20 to +0.28 mmol/L; P = 0.0026) and LDL cholesterol (+0.19 mmol/L for GT genotype; P = 0.0260) relative to TT homozygotes (-0.11 and -0.03 mmol/L, respectively). In addition, the cholesterol synthesis gene 7-dehydrocholesterol reductase (DHCR7) rs760241-A-allele carriers had higher LDL cholesterol (+0.26 mmol/L; P = 0.0399) relative to GG homozygotes (+0.06 mmol/L). CONCLUSION: Genetic variations in ABCG5, CYP7A1, and DHCR7 may contribute to differing responses of serum cholesterol to dairy intake among healthy adults. This trial was registered at clinicaltrials.gov as NCT01444326.

High-Molecular-Weight ß-Glucan Decreases Serum Cholesterol Differentially Based on the CYP7A1 rs3808607 Polymorphism in Mildly Hypercholesterolemic Adults.

BACKGROUND: ß-Glucan, a soluble fiber with viscous property, has a documented cholesterol-lowering effect. The molecular weight (MW) of ß-glucan, which contributes to viscosity, and an individual's genotype might influence the cholesterol-lowering efficacy of ß-glucan. OBJECTIVES: This study was designed to determine whether the cholesterol-lowering efficacy of barley ß-glucan varied as a function of MW and the daily dose consumed. Our second aim was to determine whether any gene-diet interactions are associated with the cholesterol-lowering efficacy of ß-glucan. METHODS: In a randomized controlled crossover trial, 30 mildly hypercholesterolemic adults [12 men and 18 women, aged 27-78 y; body mass index (in kg/m(2)): 20-40; total cholesterol (TC): 5.0-8.0 mmol/L; LDL cholesterol: 2.7-5.0 mmol/L] were randomly assigned to receive a breakfast that contained either barley ß-glucan at 3 g high MW (HMW)/d, 5 g low MW (LMW)/d, or 3 g LMW/d or a control diet, each for 5 wk. The washout period between the phases was 4 wk. Fasting blood samples were collected at the start and end of each phase for blood lipid analysis and genotyping. RESULTS: Consumption of 3 g HMW ß-glucan/d lowered TC by -0.12 mmol/L (95% CI: -0.24, -0.006 mmol/L) compared with the control diet (P= 0.0046), but the LMW ß-glucan, at either 3 g/d or 5 g/d, did not change serum cholesterol concentrations. This effect of HMW ß-glucan was associated with gene-diet interaction, whereby individuals with the single nucleotide polymorphism (SNP) rs3808607-G allele (GG or GT) of the cytochrome P450 family 7 subfamily A member 1 gene (CYP7A1) had greater responses to 3 g HMW ß-glucan/d in lowering TC than TT carriers (P= 0.0006). CONCLUSIONS: The HMW ß-glucan rather than LMW ß-glucan reduced circulating TC effectively in mildly hypercholesterolemic adults. The cholesterol-lowering effect of ß-glucan may also be determined by the genetic characteristics of an individual. These data show that individuals carrying theCYP7A1SNP rs3808607-G allele are more responsive to the cholesterol-lowering effect of ß-glucan with HMW than TT carriers. This trial was registered atclinicaltrials.govasNCT01408719.

Evaluating immunotherapeutic outcomes in triple-negative breast cancer with a cholesterol radiotracer in mice.

Evaluating the response to immune checkpoint inhibitors (ICIs) remains an unmet challenge in triple-negative breast cancer (TNBC). The requirement for cholesterol in the activation and function of T cells led us to hypothesize that quantifying cellular accumulation of this molecule could distinguish successful from ineffective checkpoint immunotherapy. To analyze accumulation of cholesterol by T cells in the immune microenvironment of breast cancer, we leveraged the PET radiotracer, eFNP-59. eFNP-59 is an analog of cholesterol that our group validated as an imaging biomarker for cholesterol uptake in preclinical models and initial human studies. In immunocompetent mouse models of TNBC, we found that elevated uptake of exogenous labeled cholesterol analogs functions as a marker for T cell activation. When comparing ICI-responsive and -nonresponsive tumors directly, uptake of fluorescent cholesterol and eFNP-59 increased in T cells from ICI-responsive tumors. We discovered that accumulation of cholesterol by T cells increased in ICI-responding tumors that received anti-PD-1 checkpoint immunotherapy. In patients with TNBC, tumors containing cycling T cells had features of cholesterol uptake and trafficking within those populations. These results suggest that uptake of exogenous cholesterol analogs by tumor-infiltrating T cells allows detection of T cell activation and has potential to assess the success of ICI therapy.

Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

BACKGROUND: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. MAIN BODY: This selection of highlights provides commentary on 19 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals. CONCLUSION: Trends in radiochemistry and radiopharmacy are highlighted. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field in many aspects.

Effect of dietary sphingomyelin on absorption and fractional synthetic rate of cholesterol and serum lipid profile in humans.

BACKGROUND: Diets enriched with sphingolipids may improve blood lipid profiles. Studies in animals have shown reductions in cholesterol absorption and alterations in blood lipids after treatment with sphingomyelin (SM). However, minimal information exists on effect of SM on cholesterol absorption and metabolism in humans. The objective was to assess the effect of SM consumption on serum lipid concentrations and cholesterol metabolism in healthy humans. METHODS: Ten healthy adult males and females completed a randomized crossover study. Subjects consumed controlled diets with or without 1 g/day SM for 14 days separated by at least 4 week washout period. Serum lipid profile and markers of cholesterol metabolism including cholesterol absorption and synthesis were analyzed. RESULTS: Serum triglycerides, total, LDL- and VLDL- cholesterol were not affected while HDL cholesterol concentrations were increased (p = 0.043) by SM diet consumption. No change in cholesterol absorption and cholesterol fractional synthesis rate was observed with supplementation of SM compared to control. Intraluminal cholesterol solubilization was also not affected by consumption of SM enriched diet. CONCLUSIONS: In humans, 1 g/day of dietary SM does not alter the blood lipid profile except for an increased HDL-cholesterol concentration and has no effect on cholesterol absorption, synthesis and intraluminal solubilization compared to control. TRIAL REGISTRATION: Clinicaltrials.gov # NCT00328211.

Predicting efficacy of immunotherapy in mice with triple negative breast cancer using a cholesterol PET radiotracer.

Predicting the response to cancer immunotherapy remains an unmet challenge in triple-negative breast cancer (TNBC) and other malignancies. T cells, the major target of current checkpoint inhibitor immunotherapies, accumulate cholesterol during activation to support proliferation and signaling. The requirement of cholesterol for anti-tumor functions of T cells led us to hypothesize that quantifying cellular accumulation of this molecule could distinguish successful from ineffective checkpoint immunotherapy. To analyze accumulation of cholesterol by T cells in the immune microenvironment of breast cancer, we leveraged a novel positron emission tomography (PET) radiotracer, FNP-59. FNP-59 is an analog of cholesterol that our group has validated as an imaging biomarker for cholesterol uptake in pre-clinical models and initial human studies. In immunocompetent mouse models of TNBC, we found that elevated uptake of exogenous labeled cholesterol analogs functions as a marker for T cell activation. When comparing immune checkpoint inhibitor (ICI)-responsive EO771 tumors to non-responsive AT-3 tumors, we found significantly higher uptake of a fluorescent cholesterol analog in T cells of the ICI-responsive tumors both in vitro and in vivo. Using the FNP-59 radiotracer, we discovered that accumulation of cholesterol by T cells increased further in ICI-responding tumors that received ant-PD-1 checkpoint immunotherapy. We verified these data by mining single cell sequencing data from patients with TNBC. Patients with tumors containing cycling T cells showed gene expression signatures of cholesterol uptake and trafficking. These results suggest that uptake of exogenous cholesterol analogs by tumor-infiltrating T cells predict T cell activation and success of ICI therapy.

Musculoskeletal disorder risk assessment tool use: A Canadian perspective.

Canadian ergonomics professionals from the Association of Canadian Ergonomists (ACE) and Board of Canadian Registered Safety Professionals (BCRSP) participated in a web-based survey of their awareness, use, and factors influencing use of ergonomics musculoskeletal disorder (MSD) risk assessment tools. A total of 791 respondents (21.0% response rate) participated in the survey. Certified ergonomics professionals represented an important subpopulation of MSD risk assessment tool users, however; the vast majority (86.4%) of users within Canada were certified safety professionals. Average tool use varied between ACE and BCRSP groups, where ACE respondents on average use more tools than BCRSP respondents, however the top 10 tools used were similar between the groups. Over 45% of assessment tools were learned at school and average tool use was not influenced by years of experience or continuing education.

Low-carbohydrate vegan diets in diabetes for weight loss and sustainability: a randomized controlled trial.

BACKGROUND: Low-carbohydrate, high animal fat and protein diets have been promoted for weight loss and diabetes treatment. We therefore tested the effect of a low-carbohydrate vegan diet in diabetes as a potentially healthier and more ecologically sustainable low-carbohydrate option. OBJECTIVES: We sought to compare the effectiveness of a low-carbohydrate vegan diet with a moderate-carbohydrate vegetarian diet on weight loss and metabolic measures in diabetes. METHODS: One hundred and sixty-four male and female participants with type 2 diabetes were randomly assigned to advice on either a low-carbohydrate vegan diet, high in canola oil and plant proteins, or a vegetarian therapeutic diet, for 3 mo, with both diets recommended at 60% of calorie requirements. Body weight, fasting blood, blood pressure, and 7-d food records, to estimate potential greenhouse gas emissions, were obtained throughout the study with tests of cholesterol absorption undertaken at baseline and end of study on 50 participants. RESULTS: Both low-carbohydrate vegan and vegetarian diets similarly but markedly reduced body weight (-5.9 kg; 95% CI: -6.5, -5.28 kg; and -5.23 kg; 95% CI: -5.84, -4.62 kg), glycated hemoglobin (-0.99%; 95% CI: -1.07, -0.9%; and -0.88%; 95% CI: -0.97, -0.8%), systolic blood pressure (-4 mmHg; 95% CI: -7, -2 mmHg; and -6 mmHg; 95% CI: -8, -3 mmHg), and potential greenhouse gas emissions, but only for potential greenhouse gas emissions was there a significant treatment difference of -0.63 kgCO2/d (95% CI: -0.99, -0.27 kgCO2/d) favoring the low-carbohydrate vegan diet. CONCLUSIONS: Low-carbohydrate vegan and vegetarian diets reduced body weight, improved glycemic control and blood pressure, but the more plant-based diet had greater potential reduction in greenhouse gas emissions. TRIAL REGISTRATION NUMBER: clinicaltrials.gov identifier NCT02245399.

Guidelines for the content and format of PET brain data in publications and archives: A consensus paper.

It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data. To facilitate comparison of findings across studies, we first recommend publication standards for tracer characteristics, image acquisition, image preprocessing, and outcome estimation for PET neuroimaging data. The co-authors of this paper, representing more than 25 PET centers worldwide, voted to classify information as mandatory, recommended, or optional. Second, we describe a framework to facilitate data archiving and data sharing within and across centers. Because of the high cost of PET neuroimaging studies, sample sizes tend to be small and relatively few sites worldwide have the required multidisciplinary expertise to properly conduct and analyze PET studies. Data sharing will make it easier to combine datasets from different centers to achieve larger sample sizes and stronger statistical power to test hypotheses. The combining of datasets from different centers may be enhanced by adoption of a common set of best practices in data acquisition and analysis.

Low and moderate-fat plant sterol fortified soymilk in modulation of plasma lipids and cholesterol kinetics in subjects with normal to high cholesterol concentrations: report on two randomized crossover studies.

BACKGROUND: Although consumption of various plant sterol (PS)-enriched beverages is effective in lowering plasma cholesterol, the lipid-lowering potential of PS in a soymilk format has not been investigated thoroughly. Therefore, to evaluate the efficacy of PS-enriched soy beverages on plasma lipids and cholesterol kinetics, we conducted two separate 28 d dietary controlled cross-over studies. In study 1, the cholesterol-lowering efficacy of a low-fat (2 g/serving) PS enriched soy beverage was examined in 33 normal cholesterolemic subjects in comparison with 1% dairy milk. In study 2, we investigated the efficacy of a moderate-fat (3.5 g/serving) PS-enriched soy beverage on plasma cholesterol concentrations and cholesterol kinetic responses in 23 hypercholesterolemic subjects compared with 1% dairy milk. Both the low and moderate-fat PS-enriched soymilk varieties provided 1.95 g PS/d. Endpoint plasma variables were analyzed by repeated-measures ANOVA using baseline values as covariates for plasma lipid measurements. RESULTS: In comparison with the 1% dairy milk control, the low-fat soy beverage reduced (P < 0.05) total and LDL-cholesterol by 10 and 13%, respectively. Consumption of the moderate-fat PS-enriched soy beverage reduced (P < 0.05) plasma total and LDL-cholesterol by 12 and 15% respectively. Fasting triglycerides were reduced by 9.4% following consumption of the moderate-fat soy beverage in comparison with the 1% dairy milk. Both low and moderate-fat PS-enriched soy varieties reduced (P < 0.05) LDL:HDL and TC:HDL ratios compared with the 1% dairy milk control. Consumption of the moderate-fat PS-enriched soymilk reduced (P < 0.05) cholesterol absorption by 27%, but did not alter cholesterol synthesis in comparison with 1% dairy milk. CONCLUSION: We conclude that, compared to 1% dairy milk, consumption of low and moderate-fat PS-enriched soy beverages represents an effective dietary strategy to reduce circulating lipid concentrations in normal to hypercholesterolemic individuals by reducing intestinal cholesterol absorption. TRIAL REGISTRATION (CLINICALTRIALS.GOV): NCT00923403 (Study 1), NCT00924391 (Study 2).

The Manitoba Personalized Lifestyle Research (TMPLR) study protocol: a multicentre bidirectional observational cohort study with administrative health record linkage investigating the interactions between lifestyle and health in Manitoba, Canada.

INTRODUCTION: Lifestyle factors, such as diet, physical activity and sleep, are associated with the development of many chronic diseases. The objective of The Manitoba Personalized Lifestyle Research study is to understand how these lifestyle factors interact with each other and with other factors, such as an individual's genetics and gut microbiome, to influence health. METHODS: An observational study of adults, with extensive phenotyping by objective health and lifestyle assessments, and retrospective assessment of early life experiences, with retrospective and prospective utilisation of secondary data from administrative health records. STUDY POPULATION: A planned non-random convenience sample of 840 Manitobans aged 30-46 recruited from the general population, stratified by sex (equal men and women), body mass index (BMI; 60% of participants with a BMI>25 kg/m2) and geography (25% from rural areas). These stratifications were selected based on Manitoba demographics. MEASUREMENTS: Lifestyle factors assessed will include dietary pattern, physical activity, cardiovascular fitness, and sleep. Factors such as medical history, socioeconomic status, alcohol and tobacco consumption, cognition, stress, anxiety, and early life experiences will also be documented. A maternal survey will be performed. Body composition and bone density will be measured by dual energy X-ray absorptiometry. Blood pressure, pulse wave velocity, and augmentation index will be measured on two consecutive days. Chronic disease risk biomarkers will be measured in blood and urine samples. DNA will be extracted for genetic analysis. A faecal sample will be collected for microbiome analysis. Participants may provide their Manitoba personal health information number to link their study data with administrative health records. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the University of Manitoba Health Research Ethics Board (protocol # HS18951; 05/01/2016). Data analysis, release of results and publication of manuscripts are scheduled to start in early 2019. Additional information at www.TMPLR.ca. TRIAL REGISTRATION NUMBER: NCT03674957; Pre-results.

Conjugated linoleic acids: why the discrepancy between animal and human studies?

Conjugated linoleic acids (CLA) are positional and geometric isomers of linoleic acid. In animals, CLA consumption reduces body fat but results in humans are less conclusive. This review of the literature on CLA and loss of body fat or body weight in humans was conducted to explore the reasons for the discrepancy between animal and clinical trials. It indicates that the incongruity between human and animal data is largely related to methodological differences in the experimental design, including age and gender and, to a lesser extent, to CLA dose and isomers. The relatively unknown metabolic fate of CLA in humans may also be a contributing factor that helps explain the lack of consistency for CLA efficacy across studies.

Guar gum and similar soluble fibers in the regulation of cholesterol metabolism: current understandings and future research priorities.

The hypocholesterolemic effects associated with soluble fiber consumption are clear from animal model and human clinical investigations. Moreover, the modulation of whole-body cholesterol metabolism in response to dietary fiber consumption, including intestinal cholesterol absorption and fecal sterol and bile acid loss, has been the subject of many published reports. However, our understanding of how dietary fibers regulate molecular events at the gene/protein level and alter cellular cholesterol metabolism is limited. The modern emphasis on molecular nutrition and rapid progress in 'high-dimensional' biological techniques will permit further explorations of the role of genetic polymorphisms in determining the variable interindividual responses to soluble fibers. Furthermore, with traditional molecular biology tools and the application of 'omic' technology, specific insight into how fibers modulate the expression of genes and proteins that regulate intestinal cholesterol absorption and alter hepatic sterol balance will be gained. Detailed knowledge of the molecular mechanisms by which soluble fibers reduce plasma cholesterol concentrations is paramount to developing novel fiber-based "cocktails" that target specific metabolic pathways to gain maximal cholesterol reductions.

Gallium-68: methodology and novel radiotracers for positron emission tomography (2012-2017).

Commercial 68Ge/68Ga generators provide a means to produce positron emission tomography agents on site without use of a cyclotron. This development has led to a rapid growth of academic literature and patents ongallium-68 (68Ga). As 68Ga positron emission tomography agents usually involve a targeting moiety attached to a metal chelator, the development lends itself to the investigation of theragnostic applications; the 68Ga-based diagnostic is utilized to determine if the biological target is present and, if so, a therapeutic isotope (e.g., 177Lu, 225Ac) can be complexed with the same scaffold to generate a corresponding radiotherapeutic. This review considers patents issued between 2012 and 2017 that contain a 68Ga-labeled molecule indexed by Chemical Abstract Services (a division of the American Chemical Society).

Modulating Sterol Concentrations in Infant Formula Influences Cholesterol Absorption and Synthesis in the Neonatal Piglet.

Formula-fed infants present higher cholesterol synthesis rates and lower circulating cholesterol during the postnatal feeding period compared to breast-fed infants, though the mechanisms underlying this phenotype are not fully understood. Typical infant formulas contain vegetable-based fats, inherently including phytosterols (PS), which are structurally similar to cholesterol and may interfere with their absorption. A seven-day old piglets model was used to test the inhibitory effects of PS on cholesterol absorption during postnatal feeding. Following feeding for 21 days with milk-based formulas containing PS and cholesterol levels resembling those in formulas or human-milk, apparent cholesterol digestibility was analyzed in ileal digesta, and cholesterol, PS, and cholesterol synthesis markers were analyzed in plasma and liver samples. Ileal cholesterol digestibility content was increased in the piglets fed low PS formulas and the rate of the hepatic cholesterol synthesis, as determined by the lathosterol-to-cholesterol ratios (L:C), was decreased in the piglets fed LP-formulas and corresponded to reduced nuclear expression of SREBP2 relative to those fed HP-formulas. These results are consistent with the hypothesis that PS in formula can inhibit cholesterol absorption and enhance cholesterol synthesis. Whether or not this leads to entrainment of cholesterol synthesis later in life via early programming awaits further research.

Comparison of the impact of SFAs from cheese and butter on cardiometabolic risk factors: a randomized controlled trial.

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 clinicaltrials.gov as NCT02106208.

Fluorine-18 patents (2009-2015). Part 2: new radiochemistry.

Fluorine-18 ((18)F) is one of the most common positron-emitting radionuclides used in the synthesis of positron emission tomography radiotracers due to its ready availability, convenient half-life and outstanding imaging properties. In Part 1 of this review, we presented the first analysis of patents issued for novel radiotracers labeled with fluorine-18. In Part 2, we follow-up with a focus on patents issued for new radiochemistry methodology using fluorine-18 issued between January 2009 and December 2015.

CYP7A1-rs3808607 and APOE isoform associate with LDL cholesterol lowering after plant sterol consumption in a randomized clinical trial.

BACKGROUND: The benefits of plant sterols (PSs) for cholesterol lowering are hampered by large heterogeneity across individuals, potentially because of genetic polymorphisms. OBJECTIVE: We investigated the impact of candidate genetic variations on cholesterol response to PSs in a trial that recruited individuals with high or low endogenous cholesterol synthesis, estimated by lathosterol to cholesterol (L:C) ratio. DESIGN: Mildly hypercholesterolemic adults preselected as possessing either high endogenous cholesterol synthesis (n = 24; mean ± SEM: L:C ratio = 2.03 ± 0.39 µmol/mmol) or low endogenous cholesterol synthesis (n = 39; mean ± SEM: L:C ratio = 0.99 ± 0.28 µmol/mmol) consumed 2 g PS/d or a placebo for 28 d by using a dual-center, single-blind, randomized crossover design. Cholesterol synthesis and change in cholesterol absorption were measured with stable isotopic tracers. Candidate single-nucleotide polymorphisms and apolipoprotein E (APOE) isoform were assessed by TaqMan genotyping assay. RESULTS: The cholesterol fractional synthesis rate was higher (P < 0.001) in participants with high endogenous cholesterol synthesis (mean ± SEM: placebo: 9.16% ± 0.47%; PSs: 9.74% ± 0.47%) than in participants with low endogenous cholesterol synthesis (mean ± SEM placebo: 5.72% ± 0.43%; PS: 7.10% ± 0.43%). Low-density lipoprotein (LDL) cholesterol lowering in response to PSs was associated with individuals' genotypes. Cholesterol 7 alpha-hydroxylase (CYP7A1-rs3808607) T/T homozygotes showed no LDL cholesterol lowering (mean ± SEM: -0.05 ± 0.07 mmol/L, P = 0.9999, n = 20), whereas the presence of the G-allele associated with LDL cholesterol response in a dose-dependent fashion (mean ± SEM G/T: -0.22 ± 0.06 mmol/L, P = 0.0006, n = 35; G/G: -0.46 ± 0.12 mmol/L, P = 0.0009, n = 8). Similarly, APOE ɛ3 carriers (mean ± SEM: -0.13 ± 0.05 mmol/L, P = 0.0370, n = 40) responded less than APOE ɛ4 carriers (mean ± SEM: -0.31 ± 0.07 mmol/L, P < 0.0001, n = 23). Moreover, genoset CYP7A1-rs3808607 T/T/APOE ɛ3 was associated with nonresponsiveness (mean ± SEM: +0.09 ± 0.08 mmol/L, P = 0.9999, n = 14). rs5882 in cholesteryl ester transfer protein (CETP) and rs4148217 in ATP-binding cassette subfamily G member 8 (ABCG8) did not associate with LDL cholesterol lowering. Cholesterol absorption decreased as a result of PS consumption, but this decrease was not related to circulating LDL cholesterol concentrations, cholesterol synthesis phenotype, or genotypes. CONCLUSION: CYP7A1-rs3808607 and APOE isoform are associated with the extent of reduction in circulating LDL cholesterol in response to PS consumption and could serve as potential predictive genetic markers to identify individuals who would derive maximum LDL cholesterol lowering with PS consumption. The trial was registered at clinicaltrials.gov as NCT01131832.

Coronary heart disease and upper airway obstruction.

Coronary heart disease (CHD) is a leading cause of death among middle-aged men. In the same age group the spectrum of upper airway obstruction from habitual snoring to obstructive sleep apnoea syndrome (OSAS) is frequent. In several studies snoring was found to be an important risk factor for ischaemic heart disease. The prevalence of OSAS in patients with CHD, profile of risk factors and ventricular arrhythmias was determined in a prospective manner in 78 patients with stenosis of one or more coronary arteries at coronary arterography. OSAS was found in 27 patients (34.6%). Mean respiratory disturbance index (RDI) was 23.9. RDI increased with higher age. No significant differences in both groups could be found in ventricular arrhythmias, left ventricular ejection fraction and risk factors, except hyperuricaemia and adiposity. OSAS is frequent in patients with CHD and may be an additional risk factor besides the known coronary risk factors. Patients with the combination of CHD and OSAS have to be regarded as a group at particular risk because of several interactions between OSAS and coronary haemodynamics. Furthermore the microstructure of sleep in patients with nocturnal myocardial ischaemia is disturbed.

Arterial hypertension and sleep apnoea: effect of the angiotensin-converting enzyme (ACE) inhibitor cilazapril on continuously measured blood pressure during sleep and wakefulness.

Male patients with arterial hypertension and obstructive sleep-related breathing disorders (mean age 50 y, Body Mass Index (BMI) 32.4 kg m-2, Respiratory Disturbance Index (RDI) 47.2 and systolic/diastolic blood pressure (SBD/DBD) 162/103 mmHg) were examined before and after 8 days of treatment with the long-acting angiotensin-converting-enzyme (ACE) inhibitor cilazapril 2.5 mg vs. placebo in a double-blind design with parallel groups. Cardiorespiratory polysomnography was carried out at night; during daytime wakefulness patients submitted to examinations of physical and mental exertion. Cilazapril reduced the mean pressure during the entire examination period (day and night) by 9.55 (SD +/- 7.13) mmHg, compared to 4.57 (SD +/- 7.20) mmHg for placebo (P < 0.006), independently from systematic changes of heart rate (x = -3.3 and -3.5 bpm, respectively). During REM sleep, mean arterial pressure was significantly reduced by 8.63 (SD +/- 10.1) mmHg, compared to a reduction on placebo of 3.17 (SD 9.6) mmHg (P = 0.023). Under psychometric strain, the mean arterial pressure was reduced by 15.31 (SD +/- 8.7) mmHg with cilazapril; under placebo medication by 6.19 (SD +/- 7.3) mmHg (P < 0.0001). Heart rate was not significantly changed.