HDL Triglycerides: A New Marker of Metabolic and Cardiovascular Risk.

While cholesterol content in high-density lipoproteins (HDLs) is a well-established inverse marker of cardiovascular risk, the importance of HDL-triglyceride (HDL-TG) concentration is not well known. We aim to examine plasma HDL-TG concentrations, assessed by 1H-NMR, in patients with metabolic diseases and their association with classical biomarkers. In this cross-sectional study, we included 502 patients with type 2 diabetes or metabolic syndrome attending the lipid unit of our University Hospital. The presence of arteriosclerotic plaques was assessed by ultrasonography. A complete lipoprotein profile was performed by 1H-NMR (Liposcale test). HDL-TG was strongly positively correlated with total triglycerides, glycerol, and fatty liver index, while a strong negative correlation was observed with HDL-cholesterol (HDL-C) and HDL-particle number (HDL-P). HDL-TG was associated with all triglyceride-rich lipoprotein parameters and had an opposite association with HDL-C and HDL-P. It was also significantly correlated with circulating cholesterol ester transfer protein (CETP). HDL-TG concentrations were higher as metabolic syndrome components increased. HDL-TG was also higher with worsening glucose metabolism. Patients with carotid plaques also showed higher HDL-TG. In contrast to HDL-C, HDL-TG is directly associated with metabolism and arteriosclerotic vascular alterations. HDL-TG should be considered a biomarker of metabolic and cardiovascular risk and could be a marker of HDL dysfunction.

Negative effect of a low-carbohydrate, high-protein, high-fat diet on small peripheral artery reactivity in patients with increased cardiovascular risk.

Low-carbohydrate diets have become increasingly popular for weight loss. Although they may improve some metabolic markers, particularly in type 2 diabetes mellitus (T2D) or the metabolic syndrome (MS), their net effect on arterial wall function remains unclear. The objective was to evaluate the relation between dietary macronutrient composition and the small artery reactive hyperaemia index (saRHI), a marker of small artery endothelial function, in a cohort of patients at increased cardiovascular (CV) risk. The present cross-sectional study included 247 patients. Diet was evaluated by a 3-d food-intake register and reduced to a novel low-carbohydrate diet score (LCDS). Physical examination, demographic, biochemical and anthropometry parameters were recorded, and the saRHI was measured in each patient. Individuals in the lowest LCDS quartile (Q1, 45 % carbohydrate; 20 % protein; 32 % fat) had higher saRHI values than those in the top quartile (Q4, 29 % carbohydrate, 24 % protein, 40 % fat; 1.66 (sd 0.41) v. 1.52 (sd 0.22), P= 0.037). These results were particularly strong in patients with the MS (Q1 = 1.82 (sd 0.32) v. Q4 = 1.61 (sd 027); P= 0.021) and T2D (Q1 = 1.78 (sd 0.31) v. Q4 = 1.62 (sd 0.35); P= 0.011). Multivariate analysis demonstrated that individuals in the highest LCDS quartile had a significantly negative coefficient of saRHI, which was independent of confounders (OR -0.85; 95 % CI 0.19, 0.92; P= 0.031). These findings suggest that a dietary pattern characterised by a low amount of carbohydrate, but high amounts of protein and fat, is associated with a poorer small artery vascular reactivity in patients with increased CV risk.

Small artery dilation and endothelial markers in cardiovascular risk patients.

BACKGROUND: The use of methods based on reactive hyperaemia of small distal arteries to assess endothelial function (EF) is increasing; however, the mechanisms regulating vascular function in large and small arteries are probably different. We studied the correlations between the hyperaemia reactivity of small peripheral arteries determined by peripheral artery tonometry (PAT) and the levels of serum biomarkers of EF, inflammation and oxidation in patients with cardiovascular (CV) risk factors. METHODS: Four hundred and seven patients with intermediate CV risk were recruited into a cross-sectional study to examine whether soluble endothelial, inflammatory and lipid oxidative biomarkers correlate with small artery reactive hyperaemia index (saRHI) values, which were measured by PAT. RESULTS: A significant correlation was found between saRHI values and the concentrations of soluble E-selectin (sE-selectin) and soluble vascular cell adhesion molecule 1 (sVCAM-1). These correlations were stronger when only non-metabolic syndrome patients (46%) were analysed (r = -0·310, P < 0·0001; r = -0·264, P < 0·0001, respectively). In this subgroup, the oxidised low-density lipoprotein/LDL (oxLDL/LDL) was also correlated with saRHI (r = -0·193, P = 0·009). A stepwise regression study showed that sE-selectin was the only biomarker significantly correlated with saRHI values (P < 0·0001). In multivariate linear regression analysis, this relationship was still strong when the main confounding covariates were taken into consideration. CONCLUSIONS: Elevated levels of sE-selectin and, to a smaller degree, sVCAM-1 and oxLDL/LDL are associated with lower postischemic reactivity in the small distal arteries. sE-selectin is the main determinant biomarker of saRHI as assessed by regression analysis. The presence of multiple risk factors weakens this association.

Plasma expression of microRNA-425-5p and microRNA-451a as biomarkers of cardiovascular disease in rheumatoid arthritis patients.

To validate in a cohort of 214 rheumatoid arthritis patients a panel of 10 plasmatic microRNAs, which we previously identified and that can facilitate earlier diagnosis of cardiovascular disease in rheumatoid arthritis patients. We identified 10 plasma miRs that were downregulated in male rheumatoid arthritis patients and in patients with acute myocardial infarction compared to controls suggesting that these microRNAs could be epigenetic biomarkers for cardiovascular disease in rheumatoid arthritis patients. Six of those microRNAs were validated in independent plasma samples from 214 rheumatoid arthritis patients and levels of expression were associated with surrogate markers of cardiovascular disease (carotid intima-media thickness, plaque formation, pulse wave velocity and distensibility) and with prior cardiovascular disease. Multivariate analyses adjusted for traditional confounders and treatments showed that decreased expression of microRNA-425-5p in men and decreased expression of microRNA-451 in women were significantly associated with increased (ß = 0.072; p = 0.017) and decreased carotid intima-media thickness (ß = -0.05; p = 0.013), respectively. MicroRNA-425-5p and microRNA-451 also increased the accuracy to discriminate patients with pathological carotid intima-media thickness by 1.8% (p = 0.036) in men and 3.5% (p = 0.027) in women, respectively. In addition, microRNA-425-5p increased the accuracy to discriminate male patients with prior cardiovascular disease by 3% (p = 0.008). Additionally, decreased expression of microRNA-451 was significantly associated with decreased pulse wave velocity (ß = -0.72; p = 0.035) in overall rheumatoid arthritis population. Distensibility showed no significant association with expression levels of the microRNAs studied. We provide evidence of a possible role of microRNA-425-5p and microRNA-451 as useful epigenetic biomarkers to assess cardiovascular disease risk in patients with rheumatoid arthritis.

FABP4 plasma levels are increased in familial combined hyperlipidemia.

The lipid profile of familial combined hyperlipidemia (FCHL) shares some characteristics with atherogenic dyslipidemia seen in diabetes, metabolic syndrome, and obesity. Adipocyte fatty acid-binding protein 4 (FABP4) appears to be a determinant of atherogenic dyslipidemia. We examined relationships between FABP4 plasma concentrations, dyslipidemia, and metabolic variables in patients with FCHL. We studied 273 unrelated FCHL patients and 118 control subjects. FABP4 was higher in FCHL than controls, with mean levels of 21.8 (10.1) microg/l and 19.2 (9.2) microg/l, respectively (adjusted P= 0.012). In FCHL, FABP4 correlated to body mass index (BMI), waist circumference, insulin levels, and homeostasis model assessment (HOMA) index (all P< 0.05), but not to lipid levels, whereas in obese patients, FABP4 correlated to triglyceride levels (r = 0.303, P= 0.014) and very low density lipoprotein size (r = 0.502, P = 0.001), as determined by nuclear magnetic resonance. Associations of FABP4 with BMI and waist circumference, but not with insulin levels, persisted in this subgroup. Plasma FABP4 does not influence the lipid phenotype of FCHL. In a small subgroup of obese FCHL, FABP4 levels were associated with triglyceride-rich lipoproteins independent of insulin resistance. These results support a hyperlipidemic mechanism of FCHL different from similar metabolic conditions where fat mass is strongly related to FABP4 and hypertriglyceridemia.

Efficacy of therapeutic lifestyle changes on lipid profiles assessed by NMR in children with familial and non-familial hypercholesterolemia.

BACKGROUND AND AIMS: The first line of therapy in children with hypercholesterolaemia is therapeutic lifestyle changes (TLSC). The efficacy of lifestyle intervention in children with familial hypercholesterolaemia (FH), where LDL-C levels are genetically driven, deserves a focused study. AIMS: To evaluate the impact of a lifestyle education program, focused on food patterns and physical activity, on lipid profiles assessed by nuclear magnetic resonance (NMR) in children with FH vs. non-FH. METHODS: Phase 1 was a cross-sectional study of baseline characteristics, and phase 2 was a prospective TLSC intervention study. In total, the study included 238 children (4 to 18 years old; 47% girls) attending the lipid unit of our hospital due to high cholesterol levels. Eighty-five were diagnosed with FH (72% genetic positive), and 153 were diagnosed with non-Familial hypercholesterolaemia. A quantitative food frequency questionnaire (FFQ) including 137 items was used. Physical activity (PA) was assessed by the Minnesota questionnaire. The lipid profile was assessed using the 2D-1H-NMR (Liposcale test). A total of 127 children (81 in the FH group) participated in the prospective phase and were re-assessed after 1 year of the TLSC intervention, consisting of education on lifestyle changes delivered by a specialized nutritionist. RESULTS: The FH and non-FH groups were similar in anthropometry and clinical data, except that those in the FH were slightly younger than those in the non-FH group. Both the FH and non-FH groups showed a similar diet composition characterized by a high absolute calorie intake and a high percentage of fat, mainly saturated fat. The PA was below the recommended level in both groups. After one year of TLSC, the percentage of total and saturated fats was reduced, and the amount of fiber increased significantly in both groups. The percentage of protein increased slightly. The number of children engaged in at least 1 hour/day of PA increased by 56% in the FH group and by 53% in the non-FH group, and both these increases were significant. The total and small-LDL particle numbers were reduced in both groups, although the absolute change was greater in the FH group than in the non-FH group. CONCLUSIONS: Educational strategies to implement TLSC in children lead to empowerment, increased adherence, and overall metabolic improvement in children with high blood cholesterol, including those with FH.

Assessment of arterial stiffness variables in patients with rheumatoid arthritis: A mediation analysis.

We aimed to study arterial stiffness variables in patients with rheumatoid arthritis (RA), specifically considering their associations with path model mediation analysis. We examined arterial stiffness expressed by the pulse wave velocity (PVW), augmentation index (AIx), distensibility, and clinical and biochemical characteristics in a cohort of 214 RA patients. Variable associations were analysed using multivariate linear regression analysis. We also used path model mediation analysis for PWV variable. Our results indicate that age, systolic blood pressure (SBP), and body mass index (BMI) were significantly associated with PWV, and collectively accounted for 32% of PWV variability. The parallel mediation analysis showed that SBP and BMI accounted for 21% and 7% (a total of 28%) of the total effect of age on PWV, respectively, indicating a partial mediation effect. The associated variables with AIx were age and tender joint count, while those with distensibility were BMI and sex, overall accounting for 16.5% and 4.7% of the variation in AIx and distensibility, respectively. We observed no associations of arterial stiffness with inflammatory variables, disease activity and duration, or cholesterol levels. In conclusion, in our population of RA patients, age is the most important variable that determines the increase in PWV. We have also shown that a significant proportion of the negative effects of age on PWV occurs through increases in SBP and BMI. In our study, lipid and inflammation variables were not associated with an increase in arterial stiffness.

Low-density lipoprotein net charge is a risk factor for atherosclerosis in lupus patients independent of lipid concentrations.

AIMS: Patients with systemic lupus erythematosus (SLE) suffer from accelerated atherosclerosis. Their most common cause of death is a cardiovascular disease (CVD), in spite of the presence of moderate lipid alterations and normal cardiovascular risk scores. However, cholesterol still accumulates in the arteries of SLE patients, so we aim to identify additional factors that may help explain the residual risk that exists in these patients. We focus on investigating whether the net charge contributes significantly to both the development and the progression of atherosclerosis in patients with SLE. METHODS: The lipoproteins from 78 patients with SLE and 32 controls were isolated via sequential ultracentrifugation. Lipoprotein subclasses distributions were analyzed via nuclear magnetic resonance spectroscopy and the net charges of very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) were measured using a Zetasizer Nano-ZS. The degree of atherosclerosis (carotid intima-media thickness [cIMT]) was determined in all the participants. RESULTS: Each lipoprotein class exhibited a negative net charge. IDL and LDL net charge correlated negatively with cIMT (r = -0.274, P = 0.034; r = -0.288; P = 0.033, respectively) in patients with SLE. This effect was independent of age, body mass index (BMI), gender, tobacco consumption, high-sensitivity C-reactive protein (hsCRP), lipid concentration and lipoprotein particle number. LDL net charge explained 4% of the cIMT variability among these patients; this contribution was also independent of age, BMI, gender, tobacco consumption, lipids levels, apolipoproteins and hsCRP. CONCLUSIONS: Low-density lipoprotein net charge may be considered a new independent contributor to subclinical atherosclerosis in SLE patients. The observed relationship was independent of lipid concentrations and extends the prominent role that IDL and LDL play in cardiovascular risk.

The Circulating GRP78/BiP Is a Marker of Metabolic Diseases and Atherosclerosis: Bringing Endoplasmic Reticulum Stress into the Clinical Scenario.

BACKGROUND: Glucose-regulated protein 78/Binding immunoglobulin protein (GRP78/BiP) is a protein associated with endoplasmic reticulum stress and is upregulated by metabolic alterations at the tissue-level, such as hypoxia or glucose deprivation, and it is hyper-expressed in fat tissue of obese individuals. OBJECTIVE: To investigate the role of the GRP78/BiP level as a metabolic and vascular disease biomarker in patients with type 2 diabetes (DM), obesity and metabolic syndrome (MS). METHODS: Four hundred and five patients were recruited, of whom 52.5% were obese, 72.8% had DM, and 78.6% had MS. The intimae media thickness (cIMT) was assessed by ultrasonography. The plasma GRP78/BiP concentration was determined, and its association with metabolic and vascular parameters was assessed. Circulating GRP78/BiP was also prospectively measured in 30 DM patients before and after fenofibrate/niacin treatment and 30 healthy controls. RESULTS: In the cross-sectional study, the GRP78/BiP level was significantly higher in the patients with obesity, DM, and MS. Age-, gender- and BMI-adjusted GRP78/BiP was directly associated with LDL-cholesterol, non-HDL-cholesterol, triglycerides, apoB, and cIMT. GRP78/BiP was positively associated to carotid plaque presence in the adjusted model, irrespective of obesity, DM and MS. In the prospective study, nicotinic acid treatment produced a significant reduction in the GRP78/BiP levels that was not observed with fenofibrate. CONCLUSIONS: GRP78/BiP plasma concentrations are increased in patients with both metabolic derangements and subclinical atherosclerosis. GRP78/BiP could be a useful marker of metabolic and cardiovascular risk.

The Obemat2.0 Study: A Clinical Trial of a Motivational Intervention for Childhood Obesity Treatment.

The primary aim of the Obemat2.0 trial was to evaluate the efficacy of a multicomponent motivational program for the treatment of childhood obesity, coordinated between primary care and hospital specialized services, compared to the usual intervention performed in primary care. This was a cluster randomized clinical trial conducted in Spain, with two intervention arms: motivational intervention group vs. usual care group (as control), including 167 participants in each. The motivational intervention consisted of motivational interviewing, educational materials, use of an eHealth physical activity monitor and three group-based sessions. The primary outcome was body mass index (BMI) z score increments before and after the 12 (+3) months of intervention. Secondary outcomes (pre-post intervention) were: adherence to treatment, waist circumference (cm), fat mass index (z score), fat free mass index (z score), total body water (kg), bone mineral density (z score), blood lipids profile, glucose metabolism, and psychosocial problems. Other assessments (pre and post-intervention) were: sociodemographic information, physical activity, sedentary activity, neuropsychological testing, perception of body image, quality of the diet, food frequency consumption and foods available at home. The results of this clinical trial could open a window of opportunity to support professionals at the primary care to treat childhood obesity. The clinicaltrials.gov identifier was NCT02889406.

Variables associated with subclinical atherosclerosis in a cohort of rheumatoid arthritis patients: Sex-specific associations and differential effects of disease activity and age.

OBJECTIVE: To advance the study of variables associated with subclinical atherosclerosis in rheumatoid arthritis (RA) with special consideration for the degree of disease activity, age and gender. METHODS: The carotid intima-media thickness (cIMT) and the presence of carotid atherosclerotic plaques along with clinical and biochemical characteristics were determined in 214 RA patients. RESULTS: Adjusted analysis reveals that men had a 0.059 mm significantly increased cIMT compared with women (p = 0.001; R2 = 3.8%) and that age was associated with cIMT (ß = 0.0048 mm; p = 0.0001; R2 = 16%). Interestingly, we observed a significant interaction between gender and age. Thus, the effect of age on cIMT was significantly increased (12%) in men compared with women (p-value for interaction term = 0.041). Moreover, adjusted multivariable linear regression analysis revealed that disease activity score (DAS28) was significantly associated with cIMT in women (ß = 0.021; p = 0.018: R2 = 0.03) but not men. In particular, women with high disease activity had a 0.079 mm increased cIMT compared with women in remission (p = 0.026). In addition, men in remission had a 0.134 mm increased cIMT compared with women in remission (p = 0.003; R2 = 8.7%). Active patients did not exhibit differences in cIMT values. Furthermore, 43% of patients presented carotid plaques. The variables independently associated with carotid plaques were age, smoking, health assessment questionnaire, erythrocyte sedimentation rate and rheumatoid factor (p<0.0001; R2 = 46%). CONCLUSION: In our cohort of patients with RA, DAS28 and age are differentially associated with cIMT in men and women. Our findings could explain the contradictory results that have previously been published in the literature.

Lipoprotein profile assessed by 2D-1H-NMR and subclinical atherosclerosis in children with familial hypercholesterolaemia.

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is underdiagnosed in children. In addition to lipid concentrations, lipoprotein particle quantity and quality could influence cardiovascular risk. We aimed to perform a comprehensive plasma lipid study, including lipoprotein particle number and size assessment by two-dimensional nuclear magnetic resonance (2D-1H-NMR), in children with FH compared to non-affected children and to evaluate the clinical value of these factors as subclinical atherosclerosis biomarkers. METHODS: One hundred eighty-three children participating in the broad "Hypercholesterolemia Early Detection Programme" (Decopin Project) were recruited. They were categorized as FH, if they had either a positive genetic test or clinical certainty, or as control children (CCh). Medical history, anthropometry and clinical variables were recorded. Standard biochemical measurements were performed. The lipoprotein profile was studied by 2D-1H-NMR. Carotid intima-media thickness (cIMT) was assessed by sonography in 177 children. RESULTS: FH children had a significant 36% increase in LDL particles. The small LDL fraction was increased by 33% compared to CCh. The relative relationship between large, medium and small LDL and the mean LDL particle size was similar between FH children and CCh. The total and small LDL particle numbers were directly associated with and contributed to the determination of the mean cIMT according to bivariate and multivariate analyses in FH children. CONCLUSIONS: The higher cholesterol levels of FH children are due to an overall increased number of all LDL particle subclasses, including a notable 33% increase in small LDL. Total and small LDL particle number shows a good correlation with cIMT in FH children.

Lipid and lipoprotein parameters for detection of familial hypercholesterolemia in childhood. The DECOPIN Project. / Valor de los parámetros lipídicos y apoproteicos para la detección de hipercolesterolemia familiar en la infancia. Proyecto DECOPIN.

BACKGROUND: Familial hypercholesterolaemia (FH) in children is under-detected and is difficult to diagnose in clinical practice. The aim of this study was to evaluate clinical, biochemical and vascular imaging variables in order to detect children and adolescents with FH. METHODS: A total of 222 children aged 4-18 years old were recruited to participate in a project for the early detection of FH (The DECOPIN Project). They were distributed into 3groups: FH, if genetic study or clinical criteria were positive (n=91); Polygenic hypercholesterolaemia (PH) if LDL-Cholesterol >135mg/dL without FH criteria (n=23), and Control group (CG) if LDL-C <135mg/dL (n=108). Data were collected from family history, anthropometric data, and clinical variables. The usual biochemical parameters, including a complete lipid profile were analysed. The carotid intima-media thickness (cIMT) and thickness of Achilles tendons were determined using ultrasound in all participants. RESULTS: A total of 91 children had a diagnosis of FH, 23 with PH, and 108 with CG. Children with FH had higher concentrations of total cholesterol, LDL-C, ApoB/ApoA1 ratio, and cholesterol-year score, than the other groups. HDL-C was lower in the FH group than in the CG. Thickness of the Achilles tendon and cIMT did not show any differences between groups, although a greater cIMT trend was observed in the FH group. ApoB/ApoA1 ratio >0.82 was the parameter with the highest sensitivity and specificity to predict the presence of mutation in children with FH. CONCLUSIONS: Although LDL-C is the main biochemical parameter used to define FH, the ApoB/ApoA1 ratio (>0.82) may be a useful tool to identify children with FH and a positive mutation.

Clinical and pathophysiological evidence supporting the safety of extremely low LDL levels-The zero-LDL hypothesis.

While the impact of very low concentrations of low-density lipoprotein cholesterol (LDL-C) on cardiovascular prevention is very reassuring, it is intriguing to know what effect these extremely low LDL-C concentrations have on lipid homoeostasis. The evidence supporting the safety of extremely low LDL levels comes from genetic studies and clinical drug trials. Individuals with lifelong low LDL levels due to mutations in genes associated with increased LDL-LDL receptor (LDLR) activity reveal no safety issues. Patients achieving extremely low LDL levels in the IMPROVE-IT and FOURIER, and the PROFICIO and ODYSSEY programs seem not to have an increased prevalence of adverse effects. The main concern regarding extremely low LDL-C plasma concentrations is the adequacy of the supply of cholesterol, and other molecules, to peripheral tissues. However, LDL proteomic and kinetic studies reaffirm that LDL is the final product of endogenous lipoprotein metabolism. Four of 5 LDL particles are cleared through the LDL-LDLR pathway in the liver. Given that mammalian cells have no enzymatic systems to degrade cholesterol, the LDL-LDLR pathway is the main mechanism for removal of cholesterol from the body. Our focus, therefore, is to review, from a physiological perspective, why such extremely low LDL-C concentrations do not appear to be detrimental. We suggest that extremely low LDL-C levels due to increased LDLR activity may be a surrogate of adequate LDL-LDLR pathway function.

[Intraabdominal fat redistribution in long-term continuous positive airway pressure treatment in obstructive sleep apnea patients]. / Redistribución de grasa intraabdominal en el tratamiento a largo plazo con presión positiva continua de la vía aérea en los pacientes con síndrome de apnea-hipopnea durante el sueño.

BACKGROUND AND OBJECTIVE: Obesity is the main risk factor for obstructive sleep apnoea (OSA). The aim was to evaluate the long-term effect of continuous positive airway pressure (CPAP) on intraabdominal fat distribution in OSA patients. PATIENTS AND METHODS: Fifty OSA patients with and 35 without CPAP treatment criteria were followed-up for 2 years. Visceral and subcutaneous adipose tissue (VAT and SAT) and preaortic intraabdominal fat (PIF) were assessed by sonography. RESULTS: In the non CPAP treated group, SAT and VAT mean values didn't change, while a significantly PIF growth was observed (55.19 [23.44] vs. 63.45 [23.94] mm, P=.021). In the CPAP treated group, VAT and PIF mean were not changed, while SAT decreased significantly (11.29 [5.69] vs. 10.47 [5.71] mm, P=.012). CONCLUSIONS: Long-term CPAP treatment produces intraabdominal fat redistribution and is associated with an anthropometric profile of lower cardiovascular risk in OSA patients.

[Long-term effects of continuous positive airway pressure treatment on subclinical atherosclerosis in obstructive sleep apnoea syndrome]. / Efecto a largo plazo del tratamiento con presión positiva continua de la vía aérea sobre la arteriosclerosis subclínica en el síndrome de apnea-hipopnea durante el sueño.

BACKGROUND AND OBJECTIVE: Obstructive sleep apnoea (OSA) is associated with an increased risk of cardiovascular disease. Our objective was to evaluate subclinical atherosclerosis in OSA patients and the effect of continuous positive airway pressure (CPAP) treatment on carotid intima-media thickness (cIMT). PATIENTS AND METHOD: We included 125 patients with suspected OSA. After polysomnography, 107 patients were diagnosed with OSA; 58 of these met the criteria for CPAP treatment. cIMT was measured by ultrasonography at baseline in all patients and after 2 years of follow up in 50 patients on CPAP and 35 without CPAP treatment. RESULTS: The average cIMT was significantly thicker in OSA than in non-OSA patients (665±120 vs. 581±78µm, P=.005) and did not differ according to OSA severity. Atheromatous carotid plaque was more prevalent in OSA than non-OSA patients (48 vs. 2%, P=.004). Among OSA patients, the mean cIMT remained stable over time in the group without CPAP, whereas cIMT decreased markedly in the CPAP group (679±122 vs. 631±117µm, P<.0001). CONCLUSIONS: Increased cIMT was associated with presence of OSA, but not with its severity. Carotid ultrasound in OSA is a reliable marker of atherosclerosis. CPAP treatment with CPAP in OSA reduces cIMT and cardiovascular risk.

Impact of epidermal fatty acid binding protein on 2D-NMR-assessed atherogenic dyslipidemia and related disorders.

BACKGROUND: The role of circulating FABP5 on metabolic alterations is under active evaluation. On the other hand, FABP5 SNPs (rs454550 and rs79370435) seem to modulate its effect. OBJECTIVES: Our aim was to examine the role of circulating FABP5 levels and its main SNPs in atherogenic dyslipidemia (AD) assessed by 2D-Nuclear Magnetic Resonance (NMR) and related metabolic and inflammation markers. We hypothesized that circulating FABP5 may be a biomarker for metabolic risk. METHODS: We studied 459 subjects admitted to the metabolism unit because of lipid metabolism disturbances and/or associated disorders. After a 6-week lipid-lowering drug wash-out period, anamnesis and physical examination were performed. Carotid intime-media thickness (cIMT) was measured by ultrasound. FABP5, FABP4, lipids, metabolic proteins, and enzymes were determined by biochemical methods. The lipid profile was assessed by NMR. The rs454550 and rs79370435 FABP5 gene variants were also determined. RESULTS: The FABP5 plasma levels were positively correlated with adiposity, glucose metabolism, and lipolysis parameters and were associated with AD, as assessed by NMR. There was a significant positive correlation between hsCRP and FABP5. The presence of type 2 diabetes, obesity, metabolic syndrome, or AD was associated with higher FABP5 plasma levels (P < .005). The FABP5 concentrations, but not those of FABP4, were higher in patients with carotid plaques. FABP5 was a main determinant of plaque presence according to logistic regression analysis. The rare rs454550 allele was hyper-represented in nonobese subjects (P = .011). CONCLUSIONS: FABP5 is a biomarker of adiposity-associated metabolic derangements that include AD thus underscoring the concomitant presence of inflammation. FABP5 is associated with increased subclinical atherosclerosis.

Circulating PCSK9 in patients with type 2 diabetes and related metabolic disorders.

BACKGROUND: PCSK9 is a pivotal molecule in the regulation of lipid metabolism. Previous studies have suggested that PCSK9 expression and its function in LDL receptor regulation could be altered in the context of diabetes. The aim was to assess PCSK9 plasma levels in patients with type 2 diabetes (T2DM) and other related metabolic disorders as well as its relation to the metabolomic profile generated by nuclear magnetic resonance (NMR) and glucose homeostasis. METHODS: There were recruited a total of 457 patients suffering from T2DM and other metabolic disorders (metabolic syndrome (MetS), obesity and atherogenic dyslipidaemia (AD) and other disorders). Anamnesis, anthropometry and physical examinations were conducted, and vascular and abdominal adiposity imaging were carried out. Biochemical studies were performed to determine PCSK9 plasma levels 6 weeks after lipid lowering drug wash-out in treated patients. A complete metabolomic lipid profile was also generated by NMR. The rs505151 and rs11591147 genetic variants of PCSK9 gene were identified in patients. RESULTS: The results showed that PCSK9 levels are increased in patients with T2DM and MetS (14% and 13%; p<0.005, respectively). Circulating PCSK9 levels were correlated with an atherogenic lipid profile and with insulin resistance parameters. PCSK9 levels were also positively associated with AD, as defined by lipoprotein particle number and size. The rs11591147 genetic variant resulted in lower levels of circulating PCSK9 and LDL cholesterol (LDL-C). CONCLUSIONS: PCSK9 plasma levels are increased in T2DM and MetS patients and are associated with LDL-C and other parameters of AD and glucose metabolism.

Effect of Functional Bread Rich in Potassium, γ-Aminobutyric Acid and Angiotensin-Converting Enzyme Inhibitors on Blood Pressure, Glucose Metabolism and Endothelial Function: A Double-blind Randomized Crossover Clinical Trial.

Because it has been suggested that food rich in γ-aminobutyric acid (GABA) or angiotensin-converting enzyme inhibitor (ACEI) peptides have beneficial effects on blood pressure (BP) and other cardiovascular risk factors, we tested the effects of low-sodium bread, but rich in potassium, GABA, and ACEI peptides on 24-hour BP, glucose metabolism, and endothelial function.A randomized, double-blind, crossover trial was conducted in 30 patients with pre or mild-to-moderate hypertension, comparing three 4-week nutritional interventions separated by 2-week washout periods. Patients were randomly assigned to consume 120 g/day of 1 of the 3 types of bread for each nutritional intervention: conventional wheat bread (CB), low-sodium wheat bread enriched in potassium (LSB), and low-sodium wheat bread rich in potassium, GABA, and ACEI peptides (LSB + G). For each period, 24-hour BP measurements, in vivo endothelial function, and biochemical samples were obtained.After LSB + G consumption, 24-hour ambulatory BP underwent a nonsignificant greater reduction than after the consumption of CB and LSB (0.26 mm Hg in systolic BP and -0.63 mm Hg in diastolic BP for CB; -0.71 mm Hg in systolic BP and -1.08 mm Hg in diastolic BP for LSB; and -0.75 mm Hg in systolic BP and -2.12 mm Hg in diastolic BP for LSB + G, respectively). Diastolic BP at rest decreased significantly during the LSB + G intervention, although there were no significant differences in changes between interventions. There were no significant differences between interventions in terms of changes in in vivo endothelial function, glucose metabolism, and peripheral inflammatory parameters.Compared with the consumption of CB or LSB, no greater beneficial effects on 24-hour BP, endothelial function, or glucose metabolism were demonstrated after the consumption of LSB + G in a population with pre or mild-to-moderate hypertension. Further studies are warranted to clarify the effect of GABA on BP, preferably using a specific design for noninferiority trials and ambulatory BP monitoring as a measure of BP.This study was registered at Current Controlled Trials as ISRCTN31436822.