Specialist in Internal Medicine. Lipids and Atherosclerosis Unit. Reina SofÃa University Hospital. Associated Professor of Medicine. University of Córdoba. Córdoba. Spain.
Abstract: ABSTRACT: Aim: Familial hypercholesterolemia (FH) patients are at high risk for premature coronary heart disease (CHD). Despite the use of statins, most patients do not achieve an optimal LDL-cholesterol goal. The aims of this study are to describe baseline characteristics and to evaluate Lipid Lowering Therapy (LLT) in FH patients recruited in SAFEHEART. Methods and Results: A cross-sectional analysis of cases recruited in the Spanish FH cohort at inclusion was performed. Demographic, lifestyle, medical and therapeutic data were collected by specific surveys. Blood samples for lipid profile and DNA were obtained. Genetic test for FH was performed through DNA-microarray. Data from 1852 subjects (47.5% males) over 19 years old were analyzed: 1262 (68.1%, mean age 45.6 years) had genetic diagnosis of FH and 590 (31.9%, mean age 41.3 years) were non-FH. Cardiovascular disease was present in 14% of FH and in 3.2% of non-FH subjects (P<0.001), and was significantly higher in patients carrying a null mutation compared with those carrying a defective mutation (15.7% vs. 11.5%, respectively, P< 0.05). Prevalence of current smokers was 28.4% in FH subjects. Most FH cases were receiving LLT (84%). Although 51.5% were receiving treatment expected to reduce LDL-C levels at least 50%, only 13.6% were on maximum statin dose combined with ezetimibe. Mean LDL-c level in treated FH cases was 186.5 mg/dl (SD: 65.6) and only 3.4% of patients reached and LDL-c under 100 mg/dl. The best predictor for LDL-c goal attainment was the use of combined therapy with statin and ezetimibe. CONCLUSION: Although most of this high risk population is receiving LLT, prevalence of cardiovascular disease and LDL-c levels are still high and far from the optimum LDL-c therapeutic goal. However, LDL-c levels could be reduced by using more intensive LLT such as combined therapy with maximum statin dose and ezetimibe.
Abstract: BACKGROUND AND AIMS: The aim of this study is to validate a semi-quantitative Food Frequency Questionnaire (FFQ) used for general population in Spain, in patients with familial hypercholesterolaemia (FH). SUBJECTS AND METHODS: : Subjects with genetic diagnosis of FH were randomly selected from the Spanish FH Registry. They completed an FFQ based in 113 food items at inclusion (FFQ1) and after 1 year (FFQ2), and a 3-day dietary records (DR) every 3 months. Detailed instruction about how to register foods and beverages was given by a trained nutritionist. Each DR and FFQ was systematically coded, and the daily nutrients intake in absolute, percentage and nutrient density terms were estimated using a software system based on food composition tables. Pearson correlation coefficient was calculated with correction-repeated measurements to assess the reproducibility of both FFQ and the four 3-day DRs, as well as the validity of FFQ comparing to the mean of 3 days' DR. RESULTS: A total of 112 subjects (58 females and 54 males, aged 43 ± 16 years) finished the study. There were no differences between FFQ1, FFQ2 and mean FFQ (FFQa) in mean absolute and percentage values of selected daily nutrients' intake. Comparison between FFQ1, FFQ2, FFQa and the mean of four 3-day DRs was statistically significant in all absolute values, but not in percentage or nutrient density terms. Corrected Pearson correlation coefficient ranged from 0.470 to 0.952 for mean values of all nutrients, except alcohol. CONCLUSION: This study demonstrated that FFQ is a reliable tool to assess the dietary pattern in FH patients.
Abstract: Ageing is an important determinant of atherosclerosis development rate, mainly by the creation of a chronic low-grade inflammation. Diet, and particularly its fat content, modulates the inflammatory response in the fasting and postprandial states. Our aim was to study the effects of dietary fat on the expression of genes related to inflammation (NF-κB, monocyte chemoattractant protein 1 (MCP-1), TNF-α and IL-6) and plaque stability (matrix metalloproteinase 9, MMP-9) during the postprandial state of twenty healthy, elderly people who followed three diets for 3 weeks each: (1) Mediterranean diet (Med Diet) enriched in MUFA with virgin olive oil; (2) SFA-rich diet; and (3) low-fat, high-carbohydrate diet enriched in n-3 PUFA (CHO-PUFA diet) by a randomised crossover design. At the end of each period, after a 12-h fast, the subjects received a breakfast with a composition similar to the one when the dietary period ended. In the fasting state, the Med Diet consumption induced a lower gene expression of the p65 subunit of NF-κB compared with the SFA-rich diet (P = 0·019). The ingestion of the Med Diet induced a lower gene postprandial expression of p65 (P = 0·033), MCP-1 (P = 0·0229) and MMP-9 (P = 0·041) compared with the SFA-rich diet, and a lower gene postprandial expression of p65 (P = 0·027) and TNF-α (P = 0·047) compared with the CHO-PUFA diet. Direct plasma quantification mostly reproduced the findings. Our data suggest that consumption of a Med Diet reduces the postprandial inflammatory response in mononuclear cells compared with the SFA-rich and CHO-PUFA diets in elderly people. These findings may be partly responsible for the lower CVD risk found in populations with a high adherence to the Med Diet.
Abstract: Coenzyme Q10 (CoQ) is a powerful antioxidant that reduces oxidative stress. We explored whether the quality of dietary fat alters postprandial oxidative DNA damage and whether supplementation with CoQ improves antioxidant capacity by modifying the activation/stabilization of p53 in elderly subjects. In this crossover study, 20 subjects were randomly assigned to receive three isocaloric diets during 4 weeks each: (1) Mediterranean diet (Med diet), (2) Mediterranean diet supplemented with CoQ (Med+CoQ diet), and (3) saturated fatty acid-rich diet (SFA diet). Levels of mRNAs were determined for p53, p21, p53R2, and mdm2. Protein levels of p53, phosphorylated p53 (Ser20), and monoubiquitinated p53 were also measured, both in cytoplasm and nucleus. The extent of DNA damage was measured as plasma 8-OHdG. SFA diet displayed higher postprandial 8-OHdG concentrations, p53 mRNA and monoubiquitinated p53, and lower postprandial Mdm2 mRNA levels compared with Med and Med+CoQ diets (p < 0.05). Moreover, Med+CoQ diet induced a postprandial decrease of cytoplasmatic p53, nuclear p-p53 (Ser20), and nuclear and cytoplasmatic monoubiquitinated p53 protein (p < 0.05). In conclusion, Med+CoQ diet improves oxidative DNA damage in elderly subjects and reduces processes of cellular oxidation. Our results suggest a starting point for the prevention of oxidative processes associated with aging.
Abstract: Context: IL1b (IL1B or IL1β), a key modulator of the immune response, exerts its functions mainly via IL6 regulation. Fatty meals cause transient hypertriglyceridemia and are considered to be proinflammatory, but the extent of these responses shows high interindividual susceptibility. Objective: We evaluated the influence of a genetic variant located in the promoter region of IL1B (-1473G/C) on fasting and postprandial lipids and IL6. Design, Setting, and Participants: A total of 477 people over age 65 yr were genotyped for IL1B -1473G/C, and we evaluated fasting lipids depending on genotype. Then, 88 healthy young men were also genotyped and were fed a saturated fatty acid-rich meal. Serial blood samples were drawn for 11 h after the meal, and lipid fractions and IL6 were assayed. Main Outcome and Interventions: Fasting lipids were studied in the aged persons. Fasting and postprandial measurements of lipids and IL6 were performed in the healthy young men. Results: In the aged persons, CC subjects (minor allele homozygotes) showed higher triglyceride (P = 0.002) and cholesterol (P = 0.011) levels. Healthy young male carriers of the minor C allele showed higher postprandial triglycerides (P = 0.037), and those carried into large triglyceride-rich lipoproteins (P = 0.004). In addition, they showed higher postprandial IL6 concentrations (P = 0.008). Conclusions: Our work shows that inflammatory genes may regulate fasting and postprandial lipids because the carriers of the minor allele of an IL gene variant have altered lipid metabolism. To reinforce these gene-phenotype findings, IL6 (the natural effector of IL1B) was increased in these persons.
Abstract: Glu298Asp polymorphism of the endothelial nitric oxide synthase (eNOS) gene (NOS3) has been characterized as a risk factor of hypertension and coronary artery disease. Previous studies suggest that the higher risk observed in T allele carriers is due to endothelial dysfunction associated with a lower eNOS activity and that acute consumption of phenol-rich olive oil ameliorates postprandial endothelial dysfunction by reducing oxidative stress and increasing nitric oxide bioavailability. Nevertheless, how these facts may interact in a population with altered endothelial function such as metabolic syndrome patients remains unknown.
Abstract: Heterozygous Familial Hypercholesterolemia (FH) is a genetic disorder characterized by a high risk of cardiovascular disease. Certain polymorphisms of the factor VII gene have been associated with the development of coronary artery disease and there is a known association between factor VII levels and polymorphic variants in this gene. To date, no study has evaluated the association between factor VII and coronary artery disease in patients with FH.
Abstract: OBJECTIVE: Genetic variants of ABCA1, an ATP-binding cassette (ABC) transporter, have been linked to altered atherosclerosis progression and fasting lipid concentration, mainly high-density lipoproteins and apolipoprotein A1; however, results from different studies have been inconsistent. METHODS AND RESULTS: To further characterize the effects of ABCA1 variants in human postprandial lipid metabolism, we studied the influence of 3 single nucleotide polymorphisms (i27943 [rs2575875]; i48168 [rs4149272]; R219K [rs2230806]) in the postprandial lipemia of 88 normolipidemic young men who were given a fatty meal. For i27943 and i48168 single nucleotide polymorphisms, fasting and postprandial values of apolipoprotein A1 were higher and postprandial lipemia was much lower in homozygotes for the major alleles, total triglycerides in plasma, and large triglyceride-rich lipoprotein triglycerides. These persons also showed a higher apolipoprotein A1/apolipoprotein B ratio. Major allele homozygotes for i48168 and i27943 showed additionally higher high-density lipoproteins and lower postprandial apolipoprotein B. CONCLUSIONS: Our work shows that major allele homozygotes for ABCA1 single nucleotide polymorphisms i27943 and i48168 have a lower postprandial response as compared to minor allele carriers. This finding may further characterize the role of ABCA1 in lipid metabolism.
Abstract: OBJECTIVE: To investigate the association of four common single nucleotide polymorphisms (SNPs) at ABCG5 (i7892A>G, i18429C>T, Gln604GluC>G, i11836G>A) and five at ABCG8 (5U145T>G, Tyr54CysA>G, Asp19HisG>C, i14222T>C, and Thr400LysG>T) with plasma lipids concentrations and to explore the interaction between those SNPs and smoking in patients with FH. METHODS AND RESULTS: ABCG5/G8 SNPs were genotyped in 500 subjects with genetic diagnosis of FH. Carriers of the minor A allele at the ABCG5_i11836G>A SNP displayed significantly higher HDL-C concentrations (P=0.023) than G/G subjects. In addition, carriers of the minor G allele at the ABCG5_Gln604GluC>G SNP had significantly lower VLDL-C (P=0.011) and lower TG (P=0.017) concentrations than homozygous C/C. Interestingly, a significant gene-smoking interaction was found, in which carriers of the minor alleles at ABCG5 (i7892A>G, i18429C>T, i11836G>A) SNPs displayed significantly lower HDL-C, higher TC and higher TG respectively, only in smokers. On the other hand, nonsmokers carriers of the minor alleles at ABCG5 (i18429C>T and Gln604GluC>G) SNPs had significantly lower TG concentrations (P=0.012 and P=0.035) compared with homozygous for the major allele. CONCLUSIONS: Our data support the notion that ABCG5/G8 genetic variants modulate plasma lipids concentrations in patients with FH and confirm that this effect could be influenced by smoking. Therefore, these results suggest that gene-environmental interactions can affect the clinical phenotype of FH.
Abstract: Postprandial oxidative stress is characterized by an increased susceptibility of the organism towards oxidative damage after consumption of a meal rich in lipids and/or carbohydrates. We have investigated whether the quality of dietary fat alters postprandial cellular oxidative stress and whether the supplementation with coenzyme Q(10) (CoQ) lowers postprandial oxidative stress in an elderly population. In this randomized crossover study, 20 participants were assigned to receive three isocaloric diets for periods of 4Â week each: (1) Mediterranean diet supplemented with CoQ (Med+CoQ diet), (2) Mediterranean diet (Med diet), and (3) saturated fatty acid-rich diet (SFA diet). After a 12-h fast, the volunteers consumed a breakfast with a fat composition similar to that consumed in each of the diets. CoQ, lipid peroxides (LPO), oxidized low-density lipoprotein (oxLDL), protein carbonyl (PC), total nitrite, nitrotyrosine plasma levels, catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities and ischemic reactive hyperaemia (IRH) were determined. Med diet produced a lower postprandial GPx activity and a lower decrease in total nitrite level compared to the SFA diet. Med and Med+CoQ diets induced a higher postprandial increase in IRH and a lower postprandial LPO, oxLDL, and nitrotyrosine plasma levels than the SFA diet. Moreover, the Med+CoQ diet produced a lower postprandial decrease in total nitrite and a greater decrease in PC levels compared to the other two diets and lower SOD, CAT, and GPx activities than the SFA diet.In conclusion, Med diet reduces postprandial oxidative stress by reducing processes of cellular oxidation and increases the action of the antioxidant system in elderly persons and the administration of CoQ further improves this redox balance.
Abstract: Background: The APOA1/C3/A4/A5 gene cluster encodes important regulators of fasting lipids, but the majority of lipid metabolism takes place in the postprandial state, and knowledge about gene regulation in this state is scarce. With the aim of characterizing possible regulators of lipid metabolism, we studied the effects of nine single nucleotide polymorphisms (SNPs) during postprandial lipid metabolism. Methods: Eighty-eight healthy young men were genotyped for APOA1 -2630 (rs613808), APOA1 -2803 (rs2727784), APOA1 -3012 (rs11216158), APOC3 -640 (rs2542052), APOC3 -2886 (rs2542051), APOC3 G34G (rs4520), APOA4 N147S (rs5104), APOA4 T29T (rs5092) and A4A5_inter (rs1263177) and were fed a saturated fatty acid-rich meal (1g fat/kg of weight, with 60% fat, 15% protein and 25% carbohydrate). Serial blood samples were extracted for 11 hours after the meal. Total cholesterol (CHOL) and fractions (high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL)), triacylglycerols (TG) in plasma, triacylglycerol-rich lipoproteins (TRL) (large TRL and small TRL), apolipoprotein A-I (APOA1) and apolipoprotein B (APOB) were determined. Results: APOA1 -2803 homozygotes for the minor allele and A4A5_inter carriers showed a limited degree of postprandial lipemia. Carriers of the rare alleles of APOA4 N147S and APOA4 T29T had lower APOA1 plasma concentration during this state. APOC3 -640 was associated with altered TG kinetics, but not its magnitude. Conclusions: We have identified new associations between SNPs in the APOA1/C3/A4/A5 gene cluster and altered postprandial lipid metabolism.
Abstract: OBJECTIVE: To investigate whether endothelium-dependent vasomotor function and plasma levels of cellular adhesion molecules are affected by diets with different fat quantity and quality during the postprandial state in subjects with the metabolic syndrome (MetS). METHODS: Patients were randomly assigned to one of four isoenergetic diets distinct in fat quantity and quality: high-SFA (HSFA); high-MUFA (HMUFA) and two low-fat, high-complex carbohydrate (LFHCC) diets, supplemented with 1.24g/day of long chain n-3 PUFA (LC n-3 PUFA) or placebo for 12 weeks each. Flow-associated vasodilatation of the brachial artery and postprandial plasma levels of total nitrites, nitric oxide (NO) synthase, soluble intercellular cell adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and P-selectin were assessed post-intervention. RESULTS: Post-intervention postprandial flow-associated vasodilatation was significantly higher after the HMUFA diet (P<0.05) compared to subjects adhering to the other three diets. Consistently, the postprandial NO synthase response significantly increased during the HMUFA compared with the HSFA and LFHCC (placebo) diets. Postprandial sICAM-1 levels were lower during the HMUFA than during the HSFA and LFHCC n-3 diets. CONCLUSIONS: Our data support the notion that the HMUFA diet improves postprandial endothelial cell function and decreases postprandial plasma sICAM-1 concentrations in patients with the MetS. These findings suggest that the postprandial state is important for understanding possible cardio-protective effects associated with the Mediterranean diet particularly in subject with the MetS.
Abstract: The interindividual variation in ApoE plasma concentration is considerable, mainly determined by apoE genotype and sex. However, a large amount of variability remains unexplained by these factors. We have evaluated whether the quantity and quality of dietary fat interacts with the apoE genotype and sex modifying ApoE plasma levels in young healthy subjects. Eighty-four volunteers (sixty-six apoE3/3, eight apoE4/3 and ten apoE3/2) were subjected to three dietary periods, each lasting 4 weeks. The first was a SFA-enriched diet (38 % fat and 20 % SFA), which was followed by a carbohydrate (CHO)-rich diet (30 % fat, < 10 % SFA and 55 % carbohydrate) or a MUFA-rich diet (38 % fat and 22 % MUFA) following a randomised crossover design. apoE2 carriers have the highest ApoE levels, whereas apoE4 individuals show the lowest concentration after the SFA, CHO and MUFA diets. Women had significantly higher ApoE concentration than men only after the consumption of the SFA diet. The SFA diet increased the ApoE plasma concentration when compared with the CHO- and MUFA-rich diets in women, but not in men. In women, but not in men, the shift from the SFA- to CHO- or MUFA-rich diets significantly decreased the ApoE concentration in apoE3/2 and apoE3/3 subjects, whereas no differences were observed in women with the apoE4/3 genotype. Sex and apoE genotype determine ApoE plasma levels; however, this effect is dependent on dietary fat.
Abstract: Traditional cardiovascular risk factors are associated with endothelial dysfunction. The vascular endothelium plays a key role in local vascular tone regulation and can be modulated by dietary fat. We propose to determine the chronic effect of three diets with different fat compositions on postprandial endothelial function and inflammatory biomarkers. Twenty healthy men followed three 4-week diets in a randomised cross-over design: a Western diet, rich in saturated fat (22 % SFA, 12 % MUFA and 0.4 % alpha-linolenic acid (ALA), all fractions are % of energy); a Mediterranean diet, rich in MUFA ( < 10 % SFA, 24 % MUFA and 0.4 % ALA); a low-fat diet enriched in ALA ( < 10 % SFA, 12 % MUFA and 2 % ALA). At the end of each dietary period all subjects underwent a postprandial study. Plasma concentrations of lipid parameters, soluble intercellular cell-adhesion molecule-1, soluble vascular cell-adhesion molecule-1 (sVCAM-1), nitrates and nitrites (NOx) and endothelial function studied by laser Doppler were examined at 0, 2, 4, 6 and 8 h. The endothelium-dependent vasodilatory response was greater 4 h after the ingestion of the MUFA-rich diet than after the SFA or ALA low-fat diets (P = 0.031). The 4 h postprandial plasma sVCAM-1 levels were lower after the MUFA meals than after the ALA low-fat diet (P = 0.043). The bioavailability of NOx was higher following the MUFA diet than after the SFA and ALA low-fat diets (P = 0.027). We found no differences in the other parameters measured. Chronic ingestion of a Mediterranean diet avoids the postprandial deterioration of endothelial function associated with Westernised diets in healthy individuals.
Abstract: BACKGROUND: Hemostasis is the result of a complex equilibrium between coagulation and fibrinolysis, and the influence of different dietary models on this equilibrium is not entirely known. OBJECTIVE: The objective was to compare the effects of the chronic intake of different dietary models on postprandial hemostasis. DESIGN: In a randomized crossover design, 20 healthy men consumed for 28 d each diets rich in monounsaturated fatty acids (MUFAs), saturated fatty acids (SFAs), and carbohydrates plus n-3 fatty acids (CHO/N3). Fasting and postprandial hemostatic factors (factor VII coagulant activity, plasminogen activator inhibitor-1, tissue-type plasminogen activator, d-dimer, and thromboxane B(2)) were measured; meal tests for the postprandial measures were based on butter, virgin olive oil, and walnuts for the SFA, MUFA, and CHO/N3 diets, respectively. RESULTS: There were no differences in the fasting variables after the dietary periods. After the 3 fatty meals were consumed, we observed an increase in thromboxane B(2) and d-dimer and a reduction in tissue plasminogen activator, irrespective of the dietary model. The MUFA or CHO/N3 meals lowered postprandial concentrations of factor VII coagulant activity, although the reduction was greater after the MUFA-enriched meal. The concentration of plasminogen activator inhibitor-1 was greater after the SFA meal than after the other 2 meals. CONCLUSIONS: The administration of a fatty meal induces a postprandial procoagulant tendency, irrespective of the type of fat consumed. However, the use of a dietary model rich in SFA creates a more procoagulant environment than does a model that includes MUFA or CHO/N3 as the source of fatty acids.
Abstract: AIM: To determine the effect of the type of mutation in low-density lipoprotein receptor gene and the risk factors associated with the development of premature cardiovascular disease (PCVD) in a large cohort of heterozygous familial hypercholesterolemia (hFH) subjects with genetic diagnosis in Spain. METHODS AND RESULTS: A cross-sectional study was conducted on 811 non-related FH patients (mean age 47.1+/-14 years, 383 males and 428 females) with a molecular defect in the low-density lipoprotein receptor (LDLR) gene from the Spanish National FH Register. Prevalence of PCVD was 21.9% (30.2% in males and 14.5% in women, P<0.001). Mean age of onset of cardiovascular event was 42.1 years in males and 50.8 years in females. Of those patients with PCVD, 59.5% of males and 27% of females suffered a second cardiovascular (CV) event. In multivariate analysis male gender, age, tobacco consumption (ever), and total cholesterol/HDL-cholesterol (TC/HDL-C) ratio were significantly associated with PCVD. Two hundred and twenty different mutations were found with a large heterogeneity. Patients carrying null-mutations had significantly higher frequency of PCVD and recurrence of CV events. No relationship with Lp(a) levels and genotype of Apo E were found. CONCLUSIONS: This study confirms the importance of identifying some classic risk factors such as smoking and TC/HDL-C ratio, and also the type of mutation in LDLR gene in order to implement early detection and intensive treatment for the prevention of cardiovascular disease in FH patients.
Abstract: Background:Familial hypercholesterolemia (FH) is associated with a high risk of coronary heart disease. Pharmacological treatment and diet are both essential for the management of FH. Foods rich in plant sterols (PS) may play an important role in the treatment of patients with these disorders.Objective:To test the effect of the intake of PS on low-density lipoprotein (LDL) concentration, endothelial function (EF) and LDL particle size in 30 patients with FH.Design:Randomized and crossover dietary intervention study.Setting:Tertiary outpatient care.Subjects:Thirty-eight were recruited, but only 30 were subjected to four low-fat dietary intervention periods, each of 4 weeks.Methods:Each intervention had a different content of cholesterol (<150 or 300 mg/day) and sitosterol (<1 or 2 g/day). Lipid response, EF and LDL particle size were analysed after the intervention.Results:Plasma sitosterol/cholesterol ratio was higher during both plant sterol-rich periods than during the low plant sterols periods. Basal sitosterol concentrations predicted the LDL-cholesterol response during the intake of plant sterol-enriched diets. The change in LDL-cholesterol was significantly greater in subjects in the upper and intermediate tertiles of basal plasma sitosterol concentrations (-21+/-8 mg/dl, P=0.03; -19+/-7 mg/dl, P=0.04, respectively) than in subjects in the lower tertile (8+/-5 mg/dl) when they changed from a low cholesterol diet to a low cholesterol plus plant sterol diet.Conclusion:Our study demonstrates that basal sitosterol values can predict hypolipidemic response in patients with FH.European Journal of Clinical Nutrition advance online publication, 18 April 2007; doi:10.1038/sj.ejcn.1602731.
Abstract: Both insulin resistance and dyslipidaemia are determined by genetic and environmental factors. Depending on their expression and their function, gene variants may influence either insulin action or dyslipidaemia. The purpose of this review was to give some examples from recent studies of gene variants that influence insulin signalling and the interaction between gene and diet to predispose insulin resistance. Recent findings indicate a major role for genetic susceptibility to the insulin resistance syndrome. Nutrition also plays an important role in the development and progression of the condition. Genetic background may interact with habitual dietary fat composition, affecting predisposition to the insulin resistance syndrome and individual responsiveness to changes in dietary fat intake. Due to the complex nature of gene-environment interactions, therefore, therapeutic dietary therapy may require a 'personalized' nutrition approach in the future. Although results have not always been consistent, gene variants that affect primary insulin action or dyslipidaemia, and particularly their interaction with the environment, are important modulators of glucose metabolism and insulin resistance syndrome.
Abstract: Several apo B polymorphic sites have been studied for their potential use as markers for CHD in the population and for potential gene-diet interactions. Our aim was to determine whether the presence of the -516C/T polymorphism in the APOB gene promoter modifies insulin sensitivity to dietary fat. We studied fifty-nine healthy volunteers (thirty men and twenty-nine women, thirty-six homozygotes for the -516C allele (C/C) (nineteen males and seventeen females) and twenty-three heterozygotes for the -516T allele (C/T) (eleven males and twelve females)). Subjects consumed three diets during the feeding study, 4 weeks each: an SFA-rich diet (38 % fat, 20 % SFA), followed by a carbohydrate (CHO)-rich diet (30 % fat, 55 % CHO) or a MUFA-rich diet (38 % fat, 22 % MUFA) following a randomised cross-over design. For each diet, we investigated peripheral insulin sensitivity with the insulin suppression test. Male carriers of the -516T allele showed a significantly greater decrease in steady-state plasma glucose concentrations when changing from the SFA-rich diet (9.18 (sd 1.35) mmol/l) to the MUFA (6.55 (sd 0.74) mmol/l) or the CHO (6.31 (sd 0.93) mmol/l) diets than did those who were homozygous for the C allele (P = 0.040). Furthermore, C/T subjects presented higher plasma NEFA values after consumption of the SFA diet compared with the MUFA and CHO diets (P = 0.001). This effect was not observed in females (P = 0.908). Our findings show that male carriers of the -516T allele, C/T, have a significant increase in insulin resistance after consumption of all diets, but the difference is more exaggerated after the SFA diet compared with the MUFA- and CHO-rich diets.
Abstract: To determine the influence of the factor VII gene polymorphisms, R353Q and 5'F7, on factor VII Ag plasma levels after the consumption of diets with different fat contents. METHODS: 59 healthy individuals (42 RR, 16 RQ, 1 QQ at the R353Q and 46 A1A1, 13 A1A2 at the 5'F7) consumed 3 diets during 4-weeks each: a Saturated diet (SAT) enriched in saturated fatty acid (SFA) (38% fat, 20% SFA), followed by a carbohydrate (CHO)-rich diet (30% fat, 55% CHO) or a Mediterranean diet (MEDIT) enriched in monounsaturated fatty acid (MUFA) (38% fat, 22% MUFA) following a randomized crossover design. Plasma lipids and FVII Ag plasma levels were determined at the end of each dietary period. RESULTS: After a SAT diet, RR homozygotes had greater concentrations of FVII Ag compared with MEDIT and CHO diets than did carriers of the minority Q allele (82.76 +/- 1.3 vs. 75.02 +/- 2.4, p = 0.001). The 5'F7 polymorphism behaved in a similar fashion (A1A1 81.98 +/- 1.4 vs. A1A2 75.37 +/- 2.4, p = 0.026). CONCLUSIONS: Our data show that carriers of the RR and/or A1A1 genotype present higher FVII Ag levels after the consumption of a SAT diet compared with the MEDIT and CHO rich diets.
Abstract: BACKGROUND: Oxidative stress associated with postprandial lipemia contributes to endothelial dysfunction, which shifts hemostasis to a more thrombogenic state. OBJECTIVE: We investigated whether a high concentration of phenols in olive oil can partly reverse this phenomenon. DESIGN: Twenty-one hypercholesterolemic volunteers received 2 breakfasts rich in olive oils with different phenolic contents (80 or 400 ppm) according to a randomized, sequential crossover design. Plasma concentrations of lipid fractions, factor VII antigen (FVIIag), activated factor VII (FVIIa), and plasminogen activator inhibitor-1 (PAI-1) activity were measured at baseline and postprandially. RESULTS: Concentrations of FVIIa increased less (P = 0.018) and plasma PAI-1 activity decreased more (P = 0.021) 2 h after the high-phenol meal than after the low-phenol meal. FVIIa concentrations 120 min after intake of the olive oil with a high phenol content correlated positively with fasting plasma triacylglycerols (P = 0.001), area under the curve (AUC) of triacylglycerols (P = 0.001), and AUC of nonesterified fatty acids (P = 0.024) and negatively with hydroxytyrosol plasma concentrations at 60 min (P = 0.039) and fasting HDL-cholesterol concentrations (P = 0.005). PAI-1 positively correlated with homeostasis model assessment of insulin resistance (P = 0.005) and fasting triacylglycerols (P = 0.025) and inversely with adiponectin (P = 0.026). In a multivariate analysis, the AUCs of nonesterified fatty acids (R(2) = 0.467; beta: 0.787; SE: 0.02; P < 0.001) and adiponectin (R(2) = 0.232; beta: -1.594; SE: 0.629; P < 0.05) were the strongest predictors of plasma FVIIa and PAI-1, respectively. CONCLUSIONS: A virgin olive oil with a high content of phenolic compounds changes the postprandial hemostatic profile to a less thrombogenic state.
Abstract: Interest in the Mediterranean diet (MD) has grown worldwide due to its link with greater longevity and lower cardiovascular disease rate, cancer and age cognitive decline. Despite the high complexity of its nutrients composition, olive oil emerges as its principal food, since it provides the higher percent of energy and a lot of bioactive compounds. In this review we will discuss the benefits of diets enriched in virgin olive oil, whose effects are probably due not only to its oleic acid content but also to its other potentially health-promoting components. Traditionally, the benefits of MD were linked to its effect on lipoprotein metabolism but today we realise that there exists a whole sheaf of other benefits, including the components of haemostasis: platelet function, thrombogenesis and fibrinolysis. A diet enriched in virgin olive oil can reduce the sensitivity of platelets to aggregation, decreasing von Willebrand and tromboxane B2 plasma levels. Moreover a particular interest has arisen about its capacity to decrease fasting Factor VII plasma levels and to avoid or modulate its postprandial activation. Also Tissue Factor expression in mononuclear cells could be reduced with the chronic intake of virgin olive oil and finally, studies performed in different experimental situation have shown that it could also increase fibrinolytic activity, reducing plasma concentration of Plasma Activator Inhibitor type-1.
Abstract: The Apolipoprotein A-V (apoA-V) gene promoter polymorphism -1131T>C modulates triacylglycerol (TG) concentrations. We evaluate whether this polymorphism could be involved in the interindividual variability observed during postprandial lipemia. Fifty-one healthy apo E3E3 male volunteers [12 with -1131CC/CT genotype, and 39 with -1131TT genotype] underwent a Vitamin A fat-load test consisting of 1g of fat/kg body weight and 60,000IU of Vitamin A. Blood samples were taken at time 0 and every hour until the 6th and every 2h and 30 min until the 11th. Cholesterol (Chol) and TG were determined in plasma and Chol, TG, ApoB-100, ApoB-48, and retinyl palmitate (RP) were determined in lipoprotein fractions. Data of postprandial lipemia revealed that subjects with the -1131CT/CC genotype had a higher postprandial response of total plasma TG (p=0.043), large triacylglycerol-rich lipoproteins-TG (TRL-TG) (p=0.002), large TRL-Chol (p=0.004), small TRL-Chol (p=0.004) and small TRL-RP (p=0.001) than subjects with the -1131TT genotype. The modifications observed in postprandial lipoprotein metabolism in subjects with the apoA-V -1131T>C polymorphism could be involved in the increased fasting plasma TG concentrations previously described in carriers of the C allele.
Abstract: Interest in the Mediterranean diet (MD) has grown worldwide. Despite the high complexity of its nutrients composition, olive oil emerges as its principal food, since it provides the higher percentage of energy and a lot of bioactive compounds. OBJECTIVE: In this review, we will discuss the benefits of diets enriched in virgin olive oil, whose effects are probably due not only to its oleic acid content but also to its other potentially health-promoting components. METHODS: Traditionally, the benefits of MD were linked to its effect on lipoprotein metabolism, but today we realise that there exists a whole sheaf of other benefits, including the components of haemostasis: platelet function, thrombogenesis and fibrinolysis. RESULTS: A diet enriched in virgin olive oil can reduce the sensitivity of platelets to aggregation, decreasing von Willebrand and thromboxane B2 plasma levels. Moreover, a particular interest has aroused about its capacity to decrease fasting factor VII plasma levels and to avoid or modulate its postprandial activation. In addition, tissue factor expression in mononuclear cells could be reduced with the chronic intake of virgin olive oil, and finally, studies performed in different experimental situation have shown that it could also increase fibrinolytic activity, reducing plasma concentration of plasma activator inhibitor type-1 (PAI-1). CONCLUSION: The MD is an alimentary model with a high content of monounsaturated fats that is capable of inducing a wide range of biological effects on the cardiovascular system. The application of modern focuses of study will dilucidate in the future the biological and clinical interest of these findings.
Abstract: INTRODUCTION AND OBJECTIVES: Many clinical and epidemiologic studies suggest that activated factor VII may be involved in the pathogenesis of coronary heart disease. Our objective was to determine the effect of a Mediterranean diet on plasma levels of activated factor VII in comparison to a low-fat diet and a diet rich in saturated fat. PATIENTS AND METHOD: The study population comprised 16 healthy normolipemic men who consumed 3 different diets in consecutive 28-day periods. The first diet was rich in saturated fat (38% calories as fat, 20% saturated fat), the second was a low-fat, high-carbohydrate diet (28% calories as fat, 10% saturated fat), and the third was enriched in monounsaturated fatty acids (38% calories as fat, 22% monounsaturated fat). At the end of each period, plasma concentrations of total cholesterol, HDL cholesterol, LDL cholesterol, total triglycerides, apolipoprotein A-I, apolipoprotein B, and glucose were measured. Activated factor VII was determined with a coagulation assay. RESULTS: The diet rich in saturated fat was associated with a significant increase in total cholesterol, LDL cholesterol, apolipoprotein AI, and apolipoprotein B in comparison to the other 2 diets. There were no significant differences between the carbohydrate-rich diet and the Mediterranean diet in any of the lipid parameters. The Mediterranean diet decreased plasma levels of factor VIIa in comparison to the diet rich in saturated fat (34.6+/-15.3 mU/mL vs 101.5+/-19.2 mU/mL; P<.05). CONCLUSIONS: In comparison to the diet rich in saturated fat or the high-carbohydrates diet, the Mediterranean diet decreased plasma concentrations of activated factor VII in healthy young men. This phenomenon may constitute another protective mechanism of the Mediterranean diet in reducing cardiovascular risk.
Abstract: OBJECTIVES: The goal of this study was to evaluate the effects of the phenolic content of virgin olive oil on endothelial reactivity. BACKGROUND: Endothelial-dependent vasodilatation is impaired during the postprandial state, and oxidative stress could play a key role in its development. METHODS: Twenty-one hypercholesterolemic volunteers received two breakfasts, using a randomized sequential crossover design. Both arms received the same olive oil, but one had its phenolic acid content reduced from 400 to 80 ppm. Ischemic reactive hyperemia (IRH) was measured with a laser-Doppler procedure at baseline and 2 h and 4 h after oil intake. Postprandial plasma concentrations of lipid fractions, lipoperoxides (LPO), 8-epi prostaglandin-F(2alpha), and nitrates/nitrites (NO(x)) were obtained at baseline and after 2 h of the fat meal. RESULTS: The intake of the polyphenol-rich breakfast was associated with an improvement in endothelial function, as well as a greater increase in concentrations of NO(x) (p < 0.001) and a lower increase in LPO (p < 0.005) and 8-epi prostaglandin-F2alpha (p < 0.001) than the ones induced by the low polyphenol fat meal. A positive correlation was found to exist between NO(x) and enhanced endothelial function at the second hour (r = 0.669; p < 0.01). Furthermore, a negative correlation was found between IRH and LPO (r = -0.203; p < 0.05) and 8-epi prostaglandin-F2alpha levels (r = -0.440; p < 0.05). CONCLUSIONS: A meal containing high-phenolic virgin olive oil improves ischemic reactive hyperemia during the postprandial state. This phenomenon might be mediated via reduction in oxidative stress and the increase of nitric oxide metabolites.
Abstract: AIMS: To investigate the role of HMG-CoA reductase inhibitor (statin) treatment during serum glucose variations on plasma oxidized LDL (ox-LDL) levels in obese patients with early Type 2 diabetes mellitus (T2D) and its relationship to endothelial biomarkers. METHODS: In a double-blind, randomized crossover study, 15 obese diet-treated T2D patients received cerivastatin (0.4 mg/day) or placebo for 3 months. Circulating ox-LDL levels were measured fasting and during a euglycaemic-hyperinsulinaemic clamp (approximately 5.5 mmol/l; EHC) and a hyperglycemic clamp (approximately 20 mmol/l; HC). An endothelium-dependent flow-mediated dilation (FMD) study was carried out and urinary albumin excretion (UAE) was measured at rest and during EHC. S-ICAM, s-VCAM and basal prothrombotic factors were also measured. RESULTS: During cerivastatin treatment, basal circulating ox-LDL levels decreased by 48% (P<0.001) compared with placebo. Serum ox-LDL levels decreased during EHC and remained unchanged during HC compared with the fasting state; with cerivastatin treatment these levels were lower compared with placebo both in the fasting state and during the clamp studies. FMD was higher with cerivastatin than with placebo (P<0.001) and the increments in FMD correlated with decrements in serum ox-LDL levels (r=0.78, P=0.001). Microalbuminuria increased during EHC but this was blunted during cerivastatin therapy compared with placebo (P<0.05). Basal sICAM-1 and sVCAM-1 levels decreased (P<0.01 and P<0.05, respectively). CONCLUSIONS: In early obese Type 2 diabetic patients, serum ox-LDL levels are influenced by short-term serum glucose variations and lowered with cerivastatin therapy. During cerivastatin treatment, improved flow-mediated endothelium-dependent dilation was associated with decrements in circulating ox-LDL levels and the hyperinsulinaemia-induced urinary albumin excretion was blunted.
Abstract: Paraoxonase 1 (PON 1) is an esterase with antioxidant properties that is present in HDL. Gln192Arg polymorphism (also named Q192R or Q/R) of the PON 1 gene that encodes this protein defines two alleles (Q and R). The R allele has been associated with higher cardiovascular risk. LDL size and susceptibility to oxidation also have been identified as cardiovascular risk factors. Our objective was to determine whether genetic variations in the Gln192Arg polymorphism influence LDL size and susceptibility to oxidation after the consumption of diets with different fat content. In our experiments, the participants (n = 98) underwent three 4-wk diets--one, saturated fat-enriched (SAT); another, monounsaturated fat-enriched (MONO); and a third, carbohydrate-enriched (CHO). We observed that LDL were smaller in the QQ group after the CHO diet vs. the SAT (P < 0.01) and MONO diets (P < 0.03). No differences in LDL size were found in QR/RR subjects. When we analyzed lag time of oxidation of LDL, we found that when carriers of the R allele (QR/RR) received the MONO diet, the lag period of LDL oxidation was longer as compared with the CHO diet. Otherwise, we found no differences in QQ homozygotes when we evaluated the lag time of oxidation of LDL after the three diets. These results suggest that the Glnl92Arg polymorphism of the paraoxonase gene influences LDL size and susceptibility to oxidation in response to diet.
Abstract: Impaired insulin action has been associated with diabetes, dyslipidemia and atherosclerotic vascular disease. The expression of insulin resistance results from the interaction of environmental and genetic factors. Human hepatic lipase (HL) is a lipolytic enzyme that plays a role in the metabolism of several lipoproteins, while insulin up-regulates the activity of HL via insulin-responsive elements in the HL promoter. We have examined the influence of -514 C/T polymorphism in the hepatic lipase gene promoter on insulin sensitivity in 59 healthy young subjects (30 males and 29 females). The volunteers were subjected to three dietary periods, each lasting four weeks. During the first period all subjects consumed a saturated fat (SFA)-enriched diet with 38% as fat (20% SFA, 12% monounsaturated fatty acids (MUFA) and 6% polyunsaturated fatty acids (PUFA)). In the second and third dietary periods, a randomized crossover design was used, consisting of a low fat, high carbohydrate diet (CHO diet) (< 10% SFA, 12% MUFA and 6% PUFA) and a high-MUFA, or Mediterranean diet, with < 10% SFA, 22% MUFA and 6% PUFA. We determined the in vivo insulin resistance using the insulin suppression test with somatostatin. Steady-state plasma glucose (SSPG) concentrations (a measure of insulin sensitivity) were significantly higher in men carriers of the -514T allele after the consumption of the SFA diet than after the CHO diet and the Mediterranean diet. This effect was not observed in women. Moreover, there were no significant differences in insulin sensitivity after the three diets in men and women with the CC genotype. In summary, our results show an improvement in insulin sensitivity in men with the -514T allele of the HL promoter polymorphism, when MUFA and carbohydrates are consumed instead of SFA fat.
Abstract: Scavenger receptor class B type I (SCARB1) was described as the first high-density lipoprotein receptor. Increasing evidence indicates that SCARB1 plays additional roles particularly in type 2 diabetes mellitus. Our aim was to determine whether the presence of an exon 1 (G-->A) polymorphism at the SCARB1 gene modifies the insulin sensitivity to dietary fat. METHODS: We studied 59 healthy volunteers (30 men and 29 women, 42 G/G homozygous and 17 G/A heterozygous). Subjects consumed three diets for 4 wk each: a saturated fatty acid (SFA)-rich diet (38% fat, 20% SFA), followed by a carbohydrate (CHO)-rich diet (30% fat, 55% CHO) or a monounsaturated fatty acid (MUFA)-rich diet (38% fat, 22% MUFA) after a randomized crossover design. For each diet, we investigated peripheral insulin sensitivity with the insulin suppression test. RESULTS: Steady-state plasma glucose after the MUFA diet was lower in G/A compared with G/G subjects (P = 0.030). This effect was not observed after CHO and SFA diets (P = 0.177 and 0.957, respectively). Plasma nonesterified free fatty acid values were lower in subjects carrying the A allele for all the diet periods. CONCLUSIONS: Our findings show that carriers of the G/A genotype have significant increases in insulin sensitivity after a MUFA-rich diet compared with G/G individuals.
Abstract: LDL particle size is dependent on both genetic factors and environmental factors such as dietary fat composition. The apolipoprotein E (apoE) genotype is a major genetic determinant of LDL size. Thus, the aim of this work was to study whether the apoE genotype interacts with the quantity and quality of dietary fat, modifying LDL size in young healthy subjects. Healthy subjects (n = 84; 66 apoE 3/3, 8 apoE 4/3, 10 apoE 3/2) were subjected to 3 dietary periods, each lasting 4 wk. The first was an SFA-enriched diet (38% fat, 20% SFA), which was followed by a carbohydrate (CHO)-rich diet (30% fat, < 10% SFA, 55% carbohydrate) or a monounsaturated fatty acid (MUFA) olive oil-rich diet (38% fat, 22% MUFA) following a randomized crossover design. At the end of each diet period, LDL particle size and plasma levels of total cholesterol, LDL cholesterol (LDL-C), HDL-C, apoB, apoA-I, and triacylglycerols were determined. LDL particle size was significantly higher (P < 0.04) in subjects with the apoE 4/3 genotype compared with those with apoE 3/3 and apoE 3/2 in the basal state. LDL size was smaller (P < 0.02) after the CHO diet than after the MUFA or SFA diets. After the CHO diet, a significant increase in LDL particle size (P < 0.035) was noted with respect to the MUFA diet in apoE 4/3 subjects, whereas a significant decrease was observed in the apoE 3/3 individuals (P < 0.043). In conclusion, a Mediterranean diet, high in MUFA-fat increases LDL particle size compared with a CHO diet, and this effect is dependent of apoE genotypes.
Abstract: BACKGROUND: The apolipoprotein E (APOE) gene promoter polymorphism (-219G-->T) has been associated with increased risk of myocardial infarction, premature coronary artery disease, and decreased plasma apolipoprotein E concentrations. OBJECTIVE: We aimed to determine in healthy subjects whether this polymorphism modifies the susceptibility of LDL to oxidation and the lipid response to the content and quality of dietary fat. DESIGN: Fifty-five healthy men with the APOE3/E3 genotype (7 GG, 38 GT, and 10 TT) completed 3 dietary periods, each lasting 4 wk. The first was a saturated fatty acid (SFA)-rich diet [38% fat-20% SFA and 12% monounsaturated fatty acid (MUFA)-and 47% carbohydrates (CHO)], which was followed by a CHO-rich diet (30% fat-<10% SFA and 12% MUFA-and 55% CHO) or a MUFA-rich diet (38% fat-<10% SFA and 22% MUFA-and 47% CHO) in a randomized crossover design. At the end of each dietary period, LDL oxidation susceptibility, lipids, and lipoproteins were measured. RESULTS: Compared with carriers of the G allele, TT subjects had a significantly (P < 0.05) shorter lag time after the SFA diet. The replacement of the SFA diet by the CHO or MUFA diet induced a greater increase (P < 0.05) in lag time in the TT subjects than in the GG or GT subjects. Carriers of the T allele had higher LDL-cholesterol (P < 0.05) and apolipoprotein B (P < 0.05) plasma concentrations after the SFA diet than did GG subjects. Compared with GG subjects, carriers of the T allele had a significantly (P < 0.05) greater decrease in LDL cholesterol and apolipoprotein B when they changed from the SFA to the CHO diet. CONCLUSION: The -219G-->T polymorphism may partially explain differences in individual responses to diet.
Abstract: BACKGROUND: Nuclear transcription factor kappaB (NF-kappaB) plays an important role in atherosclerosis by modulating gene expression. Postprandial lipemia has been correlated with an increase in NF-kappaB activation in vascular cells and it is associated with an increase in postprandial triacylglycerol-rich lipoproteins, which are involved in the development of atherosclerotic plaque. OBJECTIVE: The objective of this study was to determine the effect of the intakes of 3 different foods with different fat compositions on the postprandial activation of monocyte NF-kappaB. DESIGN: Eight healthy men followed a 4-wk baseline diet and then consumed 3 fat-load meals consisting of 1 g fat/kg body wt (65% fat) according to a randomized crossover design. Each meal had a different fatty acid composition, and the consumption of each meal was separated by 1 wk. The compositions of the 3 test meals were as follows: olive oil meal [22% saturated fatty acids (SFAs), 38% monounsaturated fatty acids (MUFAs), 4% polyunsaturated fatty acids (PUFAs), and 0.7% alpha-linolenic acid], butter meal (38% SFAs, 22% MUFAs, 4% PUFAs, and 0.7% alpha-linolenic acid), and walnut meal (20% SFAs, 24% MUFAs, 16% PUFAs, and 4% alpha-linolenic acid). RESULTS: Ingestion of the olive oil meal did not elicit NF-kappaB activation compared with ingestion of either the butter meal at 3 h (P <0.05) or the walnut meal at 9 h (P <0.05). There was no significant difference in the postprandial triacylglycerol response between the 3 meals. CONCLUSIONS: Consumption of an olive oil-enriched meal does not activate NF-kappaB in monocytes as do butter and walnut-enriched meals. This effect could enhance the cardioprotective effect of olive oil-enriched diets.
Abstract: Lipoprotein lipase (LPL) is one of the key enzymes in the metabolism of triacylglycerol-rich lipoproteins (TRL). We evaluated whether the association of LPL HindIII (H1/H2) and Serine447-Stop (S447X) polymorphisms may explain the interindividual variability observed during postprandial lipemia. Fifty-one healthy male volunteers (26 with the H2S447 genotype, 15 with the H1X447 genotype, and 10 with the H1S447 genotype) were subjected to a vitamin A-fat load test consisting of 1 g fat/kg body weight and 60,000 IU vitamin A. Blood was drawn every hour until the 6th hour and every 2 h and 30 min until the 11th hour. Data revealed that subjects that are homozygous for the H2 allele (H2H2) showed a higher postprandial response for small TRL, retinyl palmitate (RP), large TRL-RP, large TRL-B48, and small TRL-B48 levels. Furthermore, in the case of the S447X polymorphism, 447Ter carriers had a lower postprandial response for small TRL-RP, large TRL-B48, and small TRL-RP. Subjects with the LPL H2S447 genotype had higher plasma triacylglycerol, large TRL-triacylglycerol, large TRL-RP, small TRL-RP, and large TRL-B48 (P < 0.037) than H1X447 subjects. The modifications observed in postprandial lipoprotein metabolism in young normolipemic males with LPL polymorphism could be involved in the lower risk of coronary artery disease associated with the H1X447 genotype.
Abstract: Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), an autosomal dominant inherited disorder associated with an increased risk of premature atherosclerosis. The aim of this study was to characterize the LDLR mutations in a group of 476 apparently non-related Spanish FH patients. The promoter region and the 18 exons with their flanking intron sequences of the LDLR gene were screened by PCR-SSCP analysis and DNA sequencing. In addition, we tested for the presence of the mutation p.R3500Q in the gene coding for apolipoprotein B-100 (apo B-100). We found 77 mutations previously described, and 39 novel mutations affecting the LDLR gene: 8 missense, 5 nonsense, 15 frameshift, 5 splicing, 4 in frame, one nucleotide change in the non-coding sequence of exon 1, and one silent variant. We have identified al least one of these LDLR gene mutations in 329 subjects (69%). Four patients were homozygous, 4 patients were compound heterozygous, 48 patients were found to carry two different sequence variants in the same allele and 4 patients carried three different sequence variants in the same allele. Additionally, 4 subjects were carriers of the p.R3500Q mutation in the apo B gene. All of these findings indicate that there is a broad spectrum of mutations and sequence variants in the LDLR gene causing FH in Spain.
Abstract: BACKGROUND AND OBJECTIVE: We aimed to determine the diagnostic alternatives indicated by serum ferritin levels (2000 ng/ml, and to establish the clinical processes associated with very high levels (5000-10 000 ng/ml). PATIENTS AND METHOD: We retrospectively analyzed cases with serum levels of ferritin serum equal to or greater than 2000 ng/ml between March 2000 and November 2001. Data were obtained from the laboratory's computerized database. Patients' medical records were reviewed by means of a protocol which established the clinical conditions associated with these serum ferritin values. RESULTS: The study involved 135 patients with ferritin levels equal to or greater than 2000 ng/ml. Clinical syndromes included hematological diseases (45.9%), liver diseases (23%), chronic renal failure (17.78%), neoplastic diseases (10.4%), systemic inflammatory diseases (7.4%), chronic transfusions (7.4%), and non-HIV systemic infections (5.9%). Syndromes which are not usually associated with extreme serum ferritin levels were identified in 3.7% of the patients. The highest concentrations were seen in the systemic inflammatory disease group: 5856 (2492) ng/ml. Within this group, four patients with adult onset Still's disease (AOSD) displayed the highest mean ferritin levels: 11 322 (5474) ng/ml. CONCLUSIONS: Elevated serum ferritin levels act as a non-specific marker for a large number of disorders. In certain inflammatory diseases such as adult onset Still's disease (AOSD), this finding may be an important tool.
Abstract: It has recently been reported that carriers of the less common allele at the scavenger receptor class B type I (SR-BI) exon 1 polymorphism are more susceptible to the presence of saturated fatty acid in the diet because of a greater increase in LDL cholesterol. Our aim was to determine if this polymorphism could also influence postprandial lipoprotein metabolism, because the SR-BI has been described as a possible mediator in the intestinal absorption of triacylglycerols. Forty-seven normolipidemic volunteers who were homozygous for the E3 allele at the APOE gene were selected [37 homozygous for the common genotype (1/1) at the SR-BI exon 1 polymorphism and 10 heterozygous (1/2)]. They were given a fat-rich meal containing 1 g fat and 7 mg cholesterol per kg body weight and vitamin A 60,000 IU/m2 body surface. Fat accounted for 60% of calories, and protein and carbohydrates accounted for 15% and 25% of energy respectively. Blood samples were taken at time 0, every 1 h until 6 h, and every 2.5 h until 11 h. Total cholesterol and triacylglycerols in plasma, and cholesterol, triacylglycerols and retinyl palmitate in triacylglycerol-rich lipoproteins (large and small triacylglycerol-rich lipoproteins) were determined. Postprandial responses for triacylglycerols and retinyl palmitate in small triacylglycerol-rich lipoproteins were higher in 1/1 individuals than in 1/2 individuals. No other significant differences were noted. Our data show that the presence of the genotype 1/2 is associated with a lower postprandial lipemic response.
Abstract: BACKGROUND: The association between polymorphisms in the scavenger receptor class B type I (SRB-I) gene and variations in basal plasma concentrations of cholesterol in humans has recently been described. OBJECTIVE: The objective of the study was to determine whether the exon 1 variant (G-->A) at the SRB-I gene is associated with the lipid response to the content and quality of dietary fat in healthy subjects. DESIGN: We studied 97 healthy volunteers with exon 1 polymorphism [65 homozygous for allele 1 (1/1) and 32 heterozygous for allele 2 (1/2)]. Both groups consumed 3 diets lasting 4 wk each. The first was a saturated fatty acid (SFA)-rich diet (38% fat, 20% SFA), which was followed by a carbohydrate (Cho)-rich diet (30% fat, < 10% SFA, 55% carbohydrate) or a monounsaturated fatty acid (MUFA), olive oil-rich diet (38% fat, 22% MUFA) according to a randomized crossover design. At the end of each dietary period, plasma concentrations of triacylglycerol and of total, LDL, and HDL cholesterol were measured. RESULTS: Carriers of the 1/2 genotype had a trend toward higher concentrations of LDL cholesterol (P < 0.11) after the SFA-rich diet than did those who were homozygous for 1/1. Carriers of the mutation showed a significantly greater (P = 0.007) decrease in LDL-cholesterol concentrations (-23%) in changing from an SFA-rich diet to a Cho-rich diet than did noncarriers of the mutation (-16%). CONCLUSION: Carriers of the minority allele, 1/2, are more susceptible to the presence of SFA in the diet because of a greater increase in LDL cholesterol.
Abstract: BACKGROUND AND AIM: The effect of the quality of dietary fat on body composition is unknown. Our objective was to determine whether body composition is modified by the isocaloric substitution of a diet rich in saturated fat by a diet high in monounsaturated fat (Mediterranean diet) or a carbohydrate-rich diet in overweight subjects with hypercholesterolemia. METHODS AND RESULTS: The study involved 34 hypercholesterolemic males aged 18-63 years with a body mass index (BMI) of 28.2 (2.6), all of whom consumed a diet rich in saturated fat (SAT) for 28 days. They were then randomly divided into two groups of 17 subjects and underwent two dietary periods of 28 days each in a crossover design: a Mediterranean diet high in monounsaturated fat (MONO) and a carbohydrate-rich diet (CHO). The order of the diets was different for the two group. The CHO diet contained 57% CHO and 28% total fat (< 10% saturated fat, 12% monounsaturated fat and 6% polyunsaturated fat); the Mediterranean diet contained 47% CHO and 38% fat (< 10% saturated fat, 22% monounsaturated fat--75% of which was provided by olive oil- and 6% polyunsaturated fat). The variables measured at the end of each dietary intervention period were: 1) body composition by means of bioelectrical impedance; 2) plasma lipoproteins using enzymatic techniques; and 3) fatty acids in cholesterol esters by means of gas chromatography. BMI and the waist/hip ratio remained the same during the three dietary periods. A decrease in fat was observed when changing from a saturated fat diet (23.3 (6.3) kg) to a Mediterranean diet (20.8 (7.2) kg) (p < 0.05), or a carbohydrate-rich diet (20.6 (6.7) kg) (p < 0.05). Lean mass increased when changing from a SAT diet (58.4 (7.0) kg) to a CHO diet (60.2 (7.0) kg) (p < 0.05). CONCLUSION: The isocaloric substitution of a saturated fat-rich diet by a Mediterranean or carbohydrate-rich diet decreases total body fat in hypercholesterolemic males.
Abstract: The apolipoprotein E (apoE) gene promoter (-219G/T) polymorphism has been associated with increased risk of myocardial infarction, premature coronary heart disease, and decreased plasma apoE concentrations. We examined whether the -219G/T polymorphism could modify the postprandial response of triacylglycerol-rich lipoproteins (TRLs). Fifty-one healthy apoE 3/3 male volunteers (14GG, 29GT, and 8TT) were given a vitamin A fat-loading test consisting of 1 g of fat/kg body weight and 60,000 IU of vitamin A per m2 of body surface area. Blood samples were taken at time 0 and every hour until the sixth hour, and every 2 hours and 30 minutes until the eleventh hour. Cholesterol, triacylglycerols (TGs), and apoE were determined in plasma; and cholesterol, TG, apoB-100, apoB-48, and retinyl palmitate (RP) were analyzed in lipoprotein fractions. Postprandial lipemia data revealed that subjects with the -219TT genotype had a higher postprandial response of large TRL-cholesterol (P < 0.03), large TRL-triacylglycerols (P < 0.001), large TRL-RP (P < 0.004), and small TRL-apoB-48 (P < 0.03) than carriers of the -219G allele. Moreover, the -219TT subjects had the lowest postprandial levels of serum apoE (P < 0.05). In conclusion, the -219G/T polymorphism may influence TRL metabolism during the postprandial period, thus prolonging postprandial lipemia in subjects with the TT genotype.
Abstract: BACKGROUND: The response of plasma cholesterol to diet is modulated by endogenous and exogenous factors such as body mass, tobacco consumption, gender and the genetic background. Our purpose was to know whether the response degree depends on the concentration of cholesterol prior to the intervention and whether several polymorphisms modulating the cholesterol response to diet are actually involved in such response. PATIENTS AND METHOD: Seventy two males with hypercholesterolemia were administered three different 4-weeks duration diets. The first one was a saturated fat-enriched (SAT) diet. Then, in a randomized and crossed manner, subjects were categorized in two groups: one group received a diet with low fat but high complex carbohydrates contents (HCO); the another group received a monounsaturated fat-enriched diet (Mediterranean diet). In the third period, we inverted the diets of the previous period. We determined the prevalent genotypes of the following apoproteins: E, CIII, A-IV, A-I, B, A-IV 360. RESULTS: The diet with low fat contents and the Mediterranean diet led to a significant decrease of total cholesterol, LDL-c and HDL-c. Those at the upper LDL-c tertile, after the SAT diet, were found to have statistically significant greater decreases (absolute and relative values) with the Mediterranean and HCO diet. In the multivariate analysis, the only variable with an effect on the modification of LDL-c, after shifting a SAT to any hypolipidemic diet, were the levels of LDL-c at the end of a SAT diet. The allelic frequency of different apoproteins in the hyper-respondent group was not different from that in the hypo-respondent group (response displayed when going from a SAT period to any hypolipidemic diet). CONCLUSIONS: The decrease of LDL-c observed with hypolipidemic diets (low in fat contents or Mediterranean) was more significant in those individuals with hypercholesterolemia who had higher levels of LDL-c at the onset.
Abstract: BACKGROUND: There is considerable interindividual variability in the postprandial lipid response to a fat-rich meal, and genetic factors have been considered to account for some of these effects. We previously showed that the G-A mutation 5' to the apolipoprotein (apo) A-I gene was significantly associated with the LDL-cholesterol response to diet. OBJECTIVE: We evaluated whether this effect is mediated by mechanisms involving postprandial lipoprotein metabolism. DESIGN: Twenty-eight G/G and 23 G/A healthy male subjects, homozygotes for the apo E3 allele, were subjected to a vitamin A fat-loading test. Blood was drawn at time 0 and every hour for 11 h. RESULTS: There was a significant postprandial decrease in plasma cholesterol, LDL cholesterol, and apo B in G/G subjects but not in G/A subjects. A greater postprandial response in large triacylglycerol-rich lipoproteins (TRLs) and a smaller postprandial response in large TRL apo A-IV was observed in G/A than in G/G subjects. Retinyl palmitate in large and small TRL concentrations was similar for both genotypes. No significant genotype effects were detected for triacylglycerol concentrations in plasma, small TRL fraction, and apo A-I and HDL-cholesterol concentrations. CONCLUSION: Our data suggest that the G-A mutation affects the LDL-cholesterol response to diet by mechanisms involving postprandial lipoprotein cholesterol metabolism.
Abstract: BACKGROUND: The regulatory function of the endothelium is altered in hypercholesterolemia, and the subsequent endothelial dysfunction plays a central role in the development of atherosclerosis. OBJECTIVE: To determine whether endothelial function in hypercholesterolemic patients is affected by replacing a saturated fat-enriched diet with a low-fat, low-saturated fat diet (the U.S. National Cholesterol Education Program stage 1 [NCEP-1] diet) or a diet rich in monounsaturated fat (such as that common in Mediterranean countries). DESIGN: Intervention dietary study with a baseline phase and two randomized crossover dietary periods. SETTING: Hospital Universitario Reina SofÃa, Córdoba, Spain. PATIENTS: 22 hypercholesterolemic men. INTERVENTION: Patients followed a diet high in saturated fat, then were assigned in a crossover design to the NCEP-1 diet or a Mediterranean diet. Each dietary period lasted 28 days. MEASUREMENTS: Plasma P-selectin levels, lipid concentrations, and endothelial function. RESULTS: Compared with the saturated fat diet, flow-mediated dilatation increased during the Mediterranean diet but not during the NCEP-1 diet. In addition, levels of plasma cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, and P-selectin decreased during the NCEP-1 and Mediterranean diets. CONCLUSION: In hypercholesterolemic men, diets low in fat (especially saturated fat) and diets rich in monounsaturated fats improve endothelial function.
Abstract: OBJECTIVES: To study whether the presence of the polymorphism in the apolipoprotein E (apo E) gene influences the lipid profile in heart-transplant recipients. METHODS: A cohort of 103 recipients of heart transplant (93 men and 10 women, with a mean age of 47 +/- 13 years) under triple immunosuppressive therapy were submitted to a genetic study of the apo E gene region. Anthropometric and analytical data, including lipid profile and arterial blood pressure were collected prior to transplantation and 3, 6, 12, and 24 months after it. RESULTS: 65 subjects present the genotype E3E3, 27 the genotype E3E4, 6 the genotype E2E3, and 5 the genotype E2E4. Carriers of the E2 allele (that is, genotypes E3E2 and E4E2) had higher total plasma triglyceride (TG) levels after 3 months (3.47 +/- 1.88 mmol/liter p < 0.001) and after 1 year of transplantation (3.13 +/- 1.77 mmol/liter p < 0.05) than the other genotypes. There were no differences in the plasma levels of total cholesterol (TC), LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C). Multiple regression analysis revealed that the apoprotein E gene polymorphism determines 5% (p = 0.0425) and age 8.7% (p < 0.009) of the variants in TG levels. CONCLUSIONS: The presence of the E2 allele in heart-transplant recipients produces a greater rise in total TG plasma levels than the other genotypes.
Abstract: Most experts, specially from Anglo-Saxon countries, recommend a low fat diet in order to prevent cardiovascular diseases. However, mortality rate by ischemic cardiopathy is low in Mediterranean countries, probably because of the consumption of a Mediterranean diet, with a high level of monounsaturated fats provided by the olive oil. We have conducted this study in order to investigate the possible influence of this kind of diet on the oxidation of LDL in vitro, the key element for the development of atherosclerosis. Patients and methods: 41 healthy male subjects were submitted to three consecutive 4-week diets. The first was a saturated fat-rich diet (SAT diet, 38% fat, 20% saturated). This was followed by a low fat diet (NCEP-I, 28% fat, 10% saturated) and after that a Mediterranean diet (38% fat, 22% monounsaturated fat). Plasma levels of total cholesterol, LDL-c, HDL-c, triglycerides, apolipoproteins A-I and B, -tocopherol, and the in vitro susceptibility to oxidation of LDL particles. Both hypolipidemic diets produced a significant decrease in total cholesterol, LDL-c, and apo-B plasma levels. However, it was only the NCEP-I diet that revealed a decrease in the HDL-c. The shift from a saturated fat-rich diet, or a diet rich in carbohydrates, to a Mediterranean diet increased the resistance of LDL particles to oxidation increasing the lag time period (p < 0.038), and decreasing (p < 0.001) the progression rate of the curve of oxidation of LDL. Our results point out two positive consequences of the consumption of a Mediterranean diet by healthy young males, compared with the low fat diet recommended by most Anglo-Saxon experts. On the one hand, the Mediterranean diet increases HDL-c plasma levels, and on the other hand, it decreases the susceptibility of LDL to oxidation. This is why the Mediterranean diet must be recommended in order to prevent cardiovascular diseases.
Abstract: BACKGROUND: Cholesterol ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to apolipoprotein (apo) B-containing lipoproteins. The possible atherogenic role of this protein is controversial. Diet may influence plasma CETP concentrations. OBJECTIVE: The objective was to determine whether the changes in plasma lipids observed after consumption of 2 lipid-lowering diets are associated with changes in plasma CETP concentrations. DESIGN:: We studied 41 healthy, normolipidemic men over 3 consecutive 4-wk dietary periods: a saturated fatty acid-rich diet (SFA diet: 38% fat, 20% saturated fat), a National Cholesterol Education Program Step I diet (NCEP Step I diet: 28% fat, 10% saturated fat), and a monounsaturated fatty acid-rich diet (MUFA diet: 38% fat, 22% monounsaturated fat). Cholesterol content (27.5 mg/MJ) was kept constant during the 3 periods. Plasma concentrations of total, LDL, and HDL cholesterol; triacylglycerol; apo A-I and B; and CETP were measured at the end of each dietary period. RESULTS: Compared with the SFA diet, both lipid-lowering diets significantly decreased plasma total and LDL cholesterol, apo B, and CETP. Only the NCEP Step I diet lowered plasma HDL cholesterol. Positive, significant correlations were found between plasma CETP and total (r = 0.3868, P < 0.0001) and LDL (r = 0.4454, P < 0.0001) cholesterol and also between changes in CETP concentrations and those of total (r = 0.4543, P < 0.0001) and LDL (r = 0.4554, P < 0.0001) cholesterol. CONCLUSIONS: The isoenergetic substitution of a high-saturated fatty acid diet with an NCEP Step I or a high-monounsaturated fatty acid diet decreases plasma CETP concentrations.
Abstract: BACKGROUND: A study of the effect of smokers' diets on their atherogenic lipidic profile. SUBJECTS AND METHODS: 41 healthy males (32 non-smokers and 9 smokers) consumed consecutively a diet low in fat and rich in carbohydrates (28% total fat content < 10% saturated fats, and 57% carbohydrates), and a diet rich in monounsaturated fatty acids (38% total fat content with 22% monounsaturated fats). At the end of each dietary period, adhesion was confirmed by quantification of LDL cholesterol esters, plasma lipids and insulin levels. RESULTS: There were no significant differences between the age or the body mass of the groups of smokers or non-smokers. After both diets tobacco was found to have a significant effect on triglyceride levels (p < 0.0007), HDLc (p < 0.007), apo A-I (p < 0.02) and the LDLc/HDLc ratio (p < 0.005), revealing an interaction between diet and both HDLc levels (p < 0.004) and LDLc/HDLc ratios (p < 0.003). With the low fat and high monounsaturated fatty acid content diets smokers presented higher triglyceride levels (both with p < 0.0002) and LDLc/HDLc ratios (p < 0.0002 and p < 0.05, respectively) and lower levels of apo A-I (p < 0.002 and p < 0.004, respectively). However, in smokers the HDLc levels were only reduced after the low fat diet (p < 0.0003) and after the diet with a high monounsaturated fat content there was a rise in HDLc levels (p < 0.02) and a drop in the LDLc/HDLc ratio (p < 0.005) compared to the group of non-smokers. There were no significant differences in the insulin levels between groups. CONCLUSION: The atherogenic lipidic profile of smokers is due to an effect of tobacco on the lipidic metabolism. This atherogenic profile is accentuated with a low fat diet rich in carbohydrates and can be rectified to some degree with a diet with a high monounsaturated fatty acid content.
Abstract: BACKGROUND: For the most part, the benefits of monounsaturated-rich diets (MUFA-diet) have been related to their action on plasma lipid levels. However other non-lipidic effects could also be involved in their protective effects. One of these involves the decrease in plasma levels of plasminogen activator inhibitor type 1 (PAI-1), the main inhibitor of fibrinolysis. Given that the PAI-1 is of endothelial origin, one hypothesis is that the MUFA-diet could protect against CHD by modulating some endothelial components. METHODS AND RESULTS: Healthy male subjects (n = 25) received three different consecutive diets, each lasting 28 days: a low fat NCEP-I-diet, with 28% calories as fat, 10% saturated fat (SAT), 12% monounsaturated (MUFA) and 6% polyunsaturated (PUFA); a MUFA-diet, with 38% calories as fat, 10% SAT, 22% MUFA and 6% PUFA; and a SAT rich-diet (SAT-diet), with 38% calories as fat, 20% SAT, 12% MUFA and 6% PUFA. After each dietary period, the plasma lipid profile was determined, including total cholesterol, HDL cholesterol, LDL cholesterol, total triglyceride, apo A1, apo B plasma levels and conjugated diene formation, after incubation of LDL particles with Cu 5 microM/l. Endothelial products measured in plasma were von Willebrand factor (vWF), E-selectin, Thrombomodulin and Tissue Factor Pathway Inhibitor (TFPI) levels. We observed a decrease in vWF, PAI-1 and TFPI plasma levels and an increase in lag time of conjugated diene formation after the MUFA-diet. There was a positive correlation between the decreases in TFPI and vWF and the changes in total cholesterol, LDL-C, apo B plasma levels. The decrease in TFPI was negatively correlated with the increase in lag time of conjugated diene formation. PAI-1 plasma levels were positively correlated with total cholesterol, LDL-C and triglycerides and negatively correlated with HDL-C. CONCLUSIONS: Consumption of a Mediterranean-type MUFA-diet produces a decrease in plasma levels of vWF, TFPI and PAI-1 plasma levels in young healthy males. Given that these substances are of endothelial origin, one could suggest that the MUFA of the diet has a beneficial effect on endothelial function resulting in protective changes against thrombogenesis.
