Rocío Mateo-Gallego

Grosor íntima-media carotídeo en sujetos sin factores de riesgo cardiovascular

El grosor intima-media de la arteria carotida permite la cuantificacion del engrosamiento arterial en fases preclinicas de la enfermedad, pero no se conoce sus valores en poblacion sin factores de riesgo cardiovascular. El objetivo es describir la distribucion y los factores determinantes del grosor intima-media carotideo en poblacion sana y sin factores de riesgo cardiovascular. Estudiamos el grosor intima-media carotideo de 138 sujetos (64 varones y 74 mujeres) de 20-79 anos de edad distribuidos homogeneamente segun edad y sexo. El limite superior de la normalidad de la media del grosor intima-media oscilo entre 0,59 y 0,95 mm en varones y entre 0,52 y 0,93 mm en mujeres. Los valores maximos oscilaron entre 0,81 y 1,11 mm en varones y entre 0,66 y 1,13 mm en mujeres. Los principales factores determinantes del grosor intima-media fueron edad, sexo masculino, presion arterial sistolica y colesterol de las lipoproteinas de baja densidad.

Carotid Intima-Media Thickness in Subjects With No Cardiovascular Risk Factors

Measurement of the carotid intima-media thickness enables arterial wall thickening to be quantified during preclinical disease stages. However, little is known about how the thickness varies in individuals with no cardiovascular risk factors. The objective of this study was to report on the range of carotid intima-media thicknesses observed in a population of healthy subjects with no cardiovascular risk factors and to identify parameters that influence it. The carotid intima-media thickness was assessed in 138 subjects (64 men and 74 women) aged 20-79 years whose age and sex were homogeneously distributed. The upper limit of normal for the mean carotid intima-media thickness ranged from 0.59-0.95 mm in men and from 0.52-0.93 mm in women. The upper limit for the maximum thickness varied from 0.81-1.11 mm in men and from 0.66-1.13 mm in women. The main parameters determining the intima-media thickness were age, male sex, systolic blood pressure and low-density lipoprotein cholesterol level.

Fatty acids in serum phospholipids and carotid intima-media thickness in Spanish subjects with primary dyslipidemia

BACKGROUND Low rates of incident ischemic heart disease (IHD) and cardiac death occur in Spain despite a high prevalence of cardiovascular risk factors. High consumption of unsaturated fatty acid-rich foods, such as olive oil, nuts, and seafood, might underlie this paradox. OBJECTIVE We investigated whether serum phosphatidylcholine enrichment in oleic, linoleic, alpha-linolenic, and n-3 (omega-3) long-chain polyunsaturated fatty acids (as biomarkers of olive oil, seed oil, walnut, and fish intake, respectively) relate to carotid atherosclerosis in Spanish subjects at risk of IHD. DESIGN In a cross-sectional study, we measured fatty acid concentrations in serum phosphatidylcholine and measured carotid intima-media thickness (IMT) by using ultrasound in 451 asymptomatic subjects (261 men, 190 women; mean age: 45 y) with primary dyslipidemia. Main and secondary outcomes were mean and maximum IMT in the common carotid artery (CCA) and other carotid segments, respectively. RESULTS Phosphatidylcholine fatty acid composition was similar to that reported for other Spanish populations. Multiple regression analyses showed that proportions of oleic and docosahexaenoic acids were inversely related to mean CCA IMT (P < 0.02, all) after adjustment for several confounders. In similar models, alpha-linolenic acid related inversely to mean and maximum internal carotid artery IMT (P < 0.05 for all). Linoleic and eicosapentaenoic acids were unrelated to IMT. CONCLUSIONS Higher phospholipid proportions of oleic, alpha-linolenic, and docosahexaenoic acids showed inverse associations with IMT at specific carotid segments in subjects with primary dyslipidemia. High intakes of healthy fats might explain, in part, the Spanish paradox of low IHD rates in the face of a high burden of cardiovascular risk factors.

Apolipoprotein E gene mutations in subjects with mixed hyperlipidemia and a clinical diagnosis of familial combined hyperlipidemia.

OBJECTIVE Rare mutations in the APOE gene, undetectable with the usual genotyping technique, are responsible for dominant familial dysbetalipoproteinemia (FD) and therefore could be easily misclassified as familial combined hyperlipidemia (FCHL). We aimed to identify APOE mutations associated with dominant combined hyperlipoproteinemia and to establish their frequency in subjects with a clinical diagnosis of FCHL. METHODS AND RESULTS In 279 unrelated subjects with FCHL in whom a functional LDLR mutation was excluded, sequencing of the entire APOE gene detected 9 carriers of a rare mutation: 5 subjects (1.8%) with the R136S mutation (arginine at residue 136 changed to serine) and 4 subjects (1.4%) with the p.Leu149del mutation, a 3-bp inframe deletion that results in the loss of leucine at position 149. Both genetic defects were detected with similar frequency (2.5% and 1.3%, respectively) in an independent group of 160 FCHL subjects from other locations in Spain. Family studies demonstrated cosegregation of these APOE mutations with hyperlipoproteinemia. R136S carriers showed dysbetalipoproteinemia, while the lipid phenotype of p.Leu149del carriers was IIa or IIb. CONCLUSIONS Rare APOE mutations are responsible for approximately 3.5% of FCHL cases in our population. APOE R136S and p.Leu149del induce autosomal dominant FD and a phenotype indistinguishable from FCHL, respectively.

Beneficial effects of omega-3 fatty acids in the proteome of high-density lipoprotein proteome

BackgroundOmega-3 poly-unsaturated fatty acids (ω-3 PUFAs) have demonstrated to be beneficial in the prevention of cardiovascular disease, however, the mechanisms by which they perform their cardiovascular protection have not been clarified. Intriguingly, some of these protective effects have also been linked to HDL. The hypothesis of this study was that ω-3 PUFAs could modify the protein cargo of HDL particle in a triglyceride non-dependent mode. The objective of the study was to compare the proteome of HDL before and after ω-3 PUFAs supplemented diet.MethodsA comparative proteomic analysis in 6 smoker subjects HDL before and after a 5 weeks ω-3 PUFAs enriched diet has been performed.ResultsAmong the altered proteins, clusterin, paraoxonase, and apoAI were found to increase, while fibronectin, α-1-antitrypsin, complement C1r subcomponent and complement factor H decreased after diet supplementation with ω-3 PUFAs. Immunodetection assays confirmed these results. The up-regulated proteins are related to anti-oxidant, anti-inflammatory and anti-atherosclerotic properties of HDL, while the down-regulated proteins are related to regulation of complement activation and acute phase response.ConclusionsDespite the low number of subjects included in the study, our findings demonstrate that ω-3 PUFAs supplementation modifies lipoprotein containing apoAI (LpAI) proteome and suggest that these protein changes improve the functionality of the particle.

Serum ferritin is a major determinant of lipid phenotype in familial combined hyperlipidemia and familial hypertriglyceridemia

Familial combined hyperlipidemia (FCH) and familial hypertriglyceridemia (FHTG) share pathogenic mechanisms and a high interaction with components of the metabolic syndrome. The metabolic syndrome associates increased serum ferritin concentration and high cardiovascular risk. The objective was to describe the frequency of iron overload and the relationship between serum ferritin and the phenotype in patients with FCH and FHTG. The study was composed of 211 consecutive unrelated patients aged at least 18 years with primary hypertriglyceridemia, 149 with FCH, and 62 with FHTG. The prevalence of the metabolic syndrome and hyperferritinemia was very high in both hypertriglyceridemic groups (51.7% and 20.1% in FCH and 62.9% and 16.1% in FHTG, respectively), without significant statistical differences between them. Serum ferritin concentration did not show any significant association with the number of metabolic syndrome criteria. Subjects in the highest tertile of ferritin concentration (ferritin >200 mug/L) presented higher concentrations of triglycerides and liver enzymes than subjects in the first tertile of ferritin concentration (ferritin <90 mug/L). The highest positive correlation coefficient for triglycerides was found with ferritin in FCH and in FHTG subjects (R = 0.317 [P < .001] when combined). Ferritin was also the covariate that showed the highest independent association with triglycerides in FCH and FHTG. In contrast, ferritin was not associated with carotid intima-media thickness. In summary, serum ferritin is commonly increased in FCH and in FHTG, it is not related with the presence of metabolic syndrome, and it is highly correlated with liver enzymes.

Omega-3 Fatty Acids and HDL. How Do They Work in the Prevention of Cardiovascular Disease?

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) from marine origin have been strongly associated with cardiovascular protection, even at low doses ( < 1g/d). Despite the research performed in this promising area, basic aspects, such as the ideal doses and the mechanisms by which ω-3 PUFAs act, are not precisely defined. The best known biological property of ω-3 PUFAs is their hypotriglyceridemic effect, but other cardioprotective actions, such as reduction of arrhythmia susceptibility, antithrombotic, antiinflammatory and antioxidant effects, improvement of endothelial function, and delayed atherosclerosis development have received an increased interest in recent years. Some of these actions are also ascribable to high-density lipoproteins (HDL). Abundant epidemiological evidence links increasing HDL-cholesterol concentrations to cardiovascular protection. Recently, the protein cargo (proteome) of HDL particles has been attributed a key role in their functionality. In this review, we summarize the main effects of ω-3 PUFAs on HDL-cholesterol, HDL subfractions, and its main proteins, apolipoproteins (apo) AI and AII. The shared cardioprotective actions of ω-3 PUFAs and HDL are reviewed as well.

The p.Leu167del Mutation in APOE Gene Causes Autosomal Dominant Hypercholesterolemia by Down-regulation of LDL Receptor Expression in Hepatocytes

CONTEXT The p.Leu167del mutation in the APOE gene has been associated with hyperlipidemia. OBJECTIVES Our objective was to determine the frequency of p.Leu167del mutation in APOE gene in subjects with autosomal dominant hypercholesterolemia (ADH) in whom LDLR, APOB, and PCSK9 mutations had been excluded and to identify the mechanisms by which this mutant apo E causes hypercholesterolemia. DESIGN The APOE gene was analyzed in a case-control study. SETTING The study was conducted at a University Hospital Lipid Clinic. PATIENTS OR OTHER PARTICIPANTS Two groups (ADH, 288 patients; control, 220 normolipidemic subjects) were included. INTERVENTION We performed sequencing of APOE gene and proteomic and cellular experiments. MAIN OUTCOME MEASURE To determine the frequency of the p.Leu167del mutation and the mechanism by which it causes hypercholesterolemia. RESULTS In the ADH group, nine subjects (3.1%) were carriers of the APOE c.500_502delTCC, p.Leu167del mutation, cosegregating with hypercholesterolemia in studied families. Proteomic quantification of wild-type and mutant apo E in very low-density lipoprotein (VLDL) from carrier subjects revealed that apo E3 is almost a 5-fold increase compared to mutant apo E. Cultured cell studies revealed that VLDL from mutation carriers had a significantly higher uptake by HepG2 and THP-1 cells compared to VLDL from subjects with E3/E3 or E2/E2 genotypes. Transcriptional down-regulation of LDLR was also confirmed. CONCLUSIONS p.Leu167del mutation in APOE gene is the cause of hypercholesterolemia in the 3.1% of our ADH subjects without LDLR, APOB, and PCSK9 mutations. The mechanism by which this mutation is associated to ADH is that VLDL carrying the mutant apo E produces LDLR down-regulation, thereby raising plasma low-density lipoprotein cholesterol levels.

Common genetic variants contribute to primary hypertriglyceridemia without differences between familial combined hyperlipidemia and isolated hypertriglyceridemia.

Background—The majority of hypertriglyceridemias are diagnosed as familial combined hyperlipidemia (FCHL) and primary isolated hypertriglyceridemias. The contribution of common genetic variants in primary hypertriglyceridemias and the genetic difference between FCHL and isolated hypertriglyceridemias have not been thoroughly examined. Methods and Results—This study involved 580 patients with hypertriglyceridemias and 403 controls. Of the 37 single nucleotide polymorphisms examined, 12 located in 10 genes showed allelic and genotype frequency differences between hypertriglyceridemias and controls. The minor alleles of APOE, APOA5, GALNTN2, and GCKR variants were positively correlated with plasma triglycerides, whereas minor alleles of ADIPOR2, ANGPTL3, LPL, and TRIB1 polymorphisms were inversely associated. Body mass index, glucose, sex, rs328 and rs7007797 in LPL, rs662799 and rs3135506 in APOA5, and rs1260326 in GCKR explained 36% of the variability in plasma triglycerides, 7.3% of which was attributable to the genetic variables. LPL, GCKR, and APOA5 polymorphisms fit dominant, recessive, and additive inheritance models, respectively. Variants more frequently identified in isolated hypertriglyceridemias were rs7412 in APOE and rs1800795 in IL6; rs2808607 in CYP7A1 and rs3812316 and rs17145738 in MLXIPL were more frequent in FCHL. The other 32 single nucleotide polymorphisms presented similar frequencies between isolated hypertriglyceridemias and FCHL. Conclusions—Common genetic variants found in LPL, APOA5, and GCKR are associated with triglycerides levels in patients with primary hypertriglyceridemias. FCHL and isolated hypertriglyceridemias are probably trace to an accumulation of genetic variants predisposing to familial and sporadic hypertriglyceridemias or to hypertriglyceridemias and hypercholesterolemia in case of FCHL.

Prevalence of metabolic syndrome and cardiovascular disease in a hypertriglyceridemic population

BACKGROUND We aim to study the prevalence of metabolic syndrome (MS), hypertension and diabetes, and their relationship to cardiovascular disease in subjects with hypertriglyceridemia. METHODS This is an observational cross-sectional study, uncontrolled and multicentre study. Selected subjects were patients with hypertriglyceridemia (triglycerides, TG, ≥ 200 mg/dl) visited in the Lipid Units of the Spanish Arteriosclerosis Society who met the inclusion criteria. Prevalence of MS (ATPIII and IDF criteria, MS-ATPIII or MS-IDF), hypertension and diabetes were studied. The presence of cardiovascular disease (CVD) was also determined. RESULTS The results showed that individuals referred for hypertriglyceridemia had a high prevalence of MS-ATPIII 79.6% and MS-IDF 75.2%. The prevalence of MS was independent of plasma triglyceride levels. The prevalence of hypertension and diabetes were 50.9% and 33.5%, respectively. The prevalence of diabetes was double than in the general population. The prevalence of CVD was 14.6%. 95.9% of CVD events were found in patients with MS-ATPIII and only 4.1% in the group without MS-ATPIII, significant differences. CONCLUSIONS Hypertriglyceridemia is associated to the metabolic syndrome and diabetes, as well as the risk of CVD, independently of the levels of triglycerides. Hypertriglyceridemia may be an important marker in the screening of these severe metabolic and vascular abnormalities.