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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.

Resumen Introduccion La hipercolesterolemia familiar (HF) infantil esta infradiagnosticada y su diagnostico no es facil en la practica clinica. El objetivo fue evaluar que caracteristicas clinicas, bioquimicas y de imagen vascular pueden ayudarnos a detectar a ninos/as y adolescentes con hipercolesterolemia afectados de HF. Metodos Doscientos veintidos ninos y adolescentes de entre 4 y 18 anos fueron reclutados para participar en un proyecto de deteccion precoz de HF (proyecto DECOPIN). La HF se diagnostico por criterios geneticos o clinicos. Se definio hipercolesterolemia poligenica (HP) cuando el c-LDL >135 mg/dl pero sin criterios clinicos ni geneticos de HF. Participantes con c-LDL Resultados Noventa y un ninos fueron diagnosticados de HF y 23 de HP, y 108 como GC. El grupo HF presento mayores concentraciones de CT, c-LDL, indice ApoB/ApoA1 e indice colesterol ano. El c-HDL fue menor en grupo HF que en el GC. Si bien el c-LDL fue el parametro mas definitorio de HF, el indice ApoB/ApoA1 > 0,82 fue el que de forma aislada mostro mayor sensibilidad y especificad para predecir la presencia de mutacion en el grupo de ninos HF. El grosor de los tendones de Aquiles no mostro diferencias entre grupos. El GIMc fue mayor en los ninos HF sin diferencias significativas. Conclusiones Los niveles de c-LDL son el marcador de HF. Un indice ApoB/ApoA1 > 0,82 puede ser una herramienta util para decidir el estudio genetico en ninos con sospecha de HF.

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.

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.

Background: Cardiovascular disease (CVD) risk is increased in Rheumatoid arthritis (RA) patients, and therefore, improved approaches for its early detection are needed. An accelerated atherosclerosis is considered the cause of the increase CVD risk. As microRNAs (miRNAs) are increasingly recognized as critical regulators in atherosclerosis and possess excellent stability in plasma, this study focused on using miRNAs as noninvasive CVD risk biomarkers in RA patients. Objectives: To identify plasmatic miRNAs in RA patients that can facilitate earlier diagnosis of CVD and provide insight regarding the increase risk for CVD observed in these patients. Methods: A discovery and validation studies were performed. To discover miRNAs candidates, we first compared plasmatic profiles of 754 miRNAs in 7 RA patients without CVD, in 7 patients with acute myocardial infarction (AMI) but without RA, and in 7 healthy controls matched for age and for classical CV risk factors. miRNAs commonly expressed in the two group of patients but differentially expressed from the controls were selected as miRNA candidates for validation. Selected miRNAs were validated in independent serum samples from 214 RA patients (validation cohort) by studying its association with subclinical atherosclerosis measured by carotid intima-media thickness (cIMT). Plasma profile of miRNAs in the discovery study was analyzed using validated TaqMan Open Array miRNA panels which enables the quantification of 754 human miRNAs. Differential expression analysis was performed with Expression Suite software and selected miRNAs candidates were validated in the validation study by real-time PCR with LNA™ microRNA qPCR assays and analyzed with 2–DCt method. KrusKal-Wallis test, Dunns post-test and linear regression were used for statistical analyses. Results: In the discovery study we were able to measure 379 (50%) of the miRNAs represented in the array. We observed than 10 miRNAs (miRNA-Let-7a, miRNA-96, miRNA-381, miRNA-451a, miRNA-518d, miRNA-425-5p, miRNA-572, miRNA-190b, miRNA-708, and miRNA-1180) were expressed at the same level in RA and AMI patients but were significantly downregulated compared with controls. These 10 miRNAs were selected as potentially miRNAs associated with the increase risk of CVD in RA patients. Four of those miRNAs were expressed at very low level and were discarded for the validation study. In the validation study with 214 plasma samples from RA patients, we observed that two of the six candidate miRNAs (miRNA-425-5p and miRNA-451a) were significantly associated with cIMT. Thus, adjusted multivariable linear regression analysis showed that miRNA-425-5p and miRNA-451a independently explained 1.4% of the cIMT variability. Furthermore, adjusted regression estimates of the effect of miRNA-425-5p and miRNA-451a on cIMT were β = 0.029mm; p = 0.037 and β = -0.035 mm; p = 0.039, respectively. No other miRNA candidate exhibited association with cIMT values. Furthermore we observed that miRNA-425-5p was significantly correlated with ESR (r=-0.136; p=0.024) and miRNA-451a with DAS28 (r=0.19; p=0.003), ESR (r=0.23; p=0.0001), CRP (r=0.15; p=0.016) and fibrinogen (r=0.28; p=0.0001). miRNAs concentrations were not affected by any of the AR treatments. No association was observed between the presence of carotid plaque and the expression level of the microRNAs tested. Conclusion: In the present study, we have identified miRNA-425-5p and miRNA-451 as potentially miRNAs involved in the CVD risk observed in RA patients. Acknowledgement: The authors thank the patients and healthy controls for their participation in the study Disclosure of Interests: SILVIA PAREDES Speakers bureau: Bristol, Roche, Amgen, Pfiser, Abbvie, lilly, UCB, Delia Taverner Speakers bureau: amgen, pfiser, Bristol, Lilly, Roche, Raimon Ferre: None declared, Josep Maria Alegret Speakers bureau: Daichii, Lluis Masana Consultant for: amgen, daichii, sanofi, Speakers bureau: AMGEN, SANOFI, MYLAN, Joan Carles Vallve: None declared

While cholesterol content in high-density lipoproteins (HDLs) is a well-established inverse marker of cardiovascular risk, the importance of HDL&ndash, 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.

Resumen Antecedentes y objetivo El sindrome de apnea-hipopnea durante el sueno (SAHS) es un factor de riesgo de arteriosclerosis. Nuestro objetivo fue evaluar la arteriosclerosis subclinica en los pacientes con SAHS y el efecto del tratamiento con continuous positive airway pressure (CPAP, «presion positiva continua de la via aerea superior») sobre el grosor intima-media carotideo (GIMc). Pacientes y metodo Se incluyeron 125 pacientes con sospecha de SAHS. Despues de la polisomnografia, 107 pacientes fueron diagnosticados de SAHS; 58 cumplian criterios de tratamiento con CPAP. El GIMc se midio mediante ecografia a nivel basal y a los 2 anos de seguimiento en 50 pacientes con SAHS en tratamiento con CPAP y 35 SAHS sin criterio de CPAP. Resultados Los valores del GIMc fueron superiores en los pacientes con SAHS respecto a los que no tenian SAHS (665 ± 120 frente a 581 ± 78 μm, p = 0,005), sin asociarse con su nivel de gravedad. La presencia de placas de ateroma fue mas prevalente en los SAHS que en los no SAHS (48 frente a 2%, p = 0,004). En los pacientes con SAHS, la media del GIMc permanecio estable durante el seguimiento en el grupo sin CPAP, y en el grupo tratado con CPAP disminuyo significativamente (679 ± 122 frente a 631 ± 117 μm, p Conclusiones Los pacientes con SAHS presentan un mayor grado de arteriosclerosis subclinica y no se asocia con su gravedad. La ecografia carotidea en el SAHS es un marcador fiable de arteriosclerosis. El tratamiento con CPAP en el SAHS disminuye el GIMc y el riesgo cardiovascular.

Resumen Fundamento y objetivo La obesidad es el principal factor de riesgo del sindrome de apneas-hipopneas del sueno (SAHS). El objetivo es evaluar el efecto de la continuous positive airway pressure (CPAP, «presion positiva continua de la via aerea» a largo plazo en pacientes con SAHS sobre la grasa intraabdominal. Pacientes y metodos Se incluyeron 50 pacientes SAHS con criterio de CPAP y 35 SAHS no candidatos a CPAP con un seguimiento de 2 anos. El visceral adipose tissue (VAT, «tejido adiposo visceral»), el subcutaneous adipose tissue (SAT, «tejido adiposo subcutaneo») y la preaortic intraabdominal fat (PIF, «grasa intraabdominal preaortica») se midieron mediante ecografia. Resultados En el grupo SAHS no candidatos a CPAP, la media del SAT y del VAT no cambio durante el seguimiento, pero se observo un aumento del PIF (55,19 [23,44] frente a 63,45 [23,94] mm, p = 0,021). En los pacientes SAHS tratados con CPAP, la media del VAT y del PIF no se modifico, pero el SAT disminuyo a los 2 anos del tratamiento con CPAP (11,29 [5,69] frente a 10,47 [5,71] mm, p = 0,012). Conclusiones El tratamiento con CPAP a largo plazo en los pacientes SAHS produce una redistribucion de la grasa intraabdominal y se asocia a un perfil antropometrico de menor riesgo cardiovascular.

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 did not 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.

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.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.The results showed that PCSK9 levels are increased in patients with T2DM and MetS (14% and 13%; p0.005, 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).PCSK9 plasma levels are increased in T2DM and MetS patients and are associated with LDL-C and other parameters of AD and glucose metabolism.

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.

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.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-Cholesterol135mg/dL without FH criteria (n=23), and Control group (CG) if LDL-C135mg/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.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 ratio0.82 was the parameter with the highest sensitivity and specificity to predict the presence of mutation in children with FH.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.

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.

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.

Background Rheumatoid arthritis (RA) is the most common chronic inflammatory condition and is characterized by an increase risk in cardiovascular (CV) disease. Carotid intima-media thickness (cIMT) is a surrogate marker of CV disease and many studies have evaluated the relationship between cIMT and RA disease activity with contradictory results. Objectives To evaluate in RA patients the association between both cIMT and carotid plaque presence and clinical RA features and analytical measurements. Methods We selected 214 RA patients according to the American College of Rheumatology criteria. Conventional clinical evaluation and analytical measurements were performed, including a standard lipid profile. We used My Lab 50 X-Vision sonograph to measure cIMT and atherosclerotic plaque presence Results No differences between men and women regarding age, body mass index, glycaemia, LDL-C and TG were observed. However, men had a significantly higher waist circumference, systolic and diastolic BP and lower levels of HDLc. On the other hand, women had significantly higher values of DAS28 (3.7 vs 2.99), HAQ, and VSG with no differences in other inflammatory variables (rheumatoid factor, ACPA, CRP or fibrinogen). Moreover, 74% of patients had pathological cIMT without gender differences and 43% had plaque presence in the carotid artery with a significant higher percentage in men (57%) than women (36%). Overall, men had significantly higher cIMT (0.678 vs 0.627 mm) but when disease activity (DAS28) was considered, we observed that such difference was due to patients that were in remission or in low activity. Men and women with moderate and high disease activity had no statistical differences in cIMT. Furthermore, across women cIMT was significantly higher in those with high disease activity compared with remission. This effect was not observed in men. Multivariate linear regression with cIMT showed a significant interaction between age and gender, so that the effect of age on cIMT was significantly more pronounced in men than in women. Conclusions We have described that in our RA cohort, disease activity measured with DAS28 and age are differentially associated with cIMT in men and women. Our results could explain the contradictory results published in the literature and it can be justified by a higher incidence of RA in women and by the hormonal-genetic status. Disclosure of Interest None declared

Background and aims Obesity is associated with increased cardiovascular risk. However, the impact of morbid obesity on vascular structure and function is not well understood. This study was designed to appraise subclinical atherosclerosis markers, including carotid intima media thickness (cIMT), endothelial function, and arterial wall stiffness, and their determinants, in morbidly obese patients. Methods and results In this cross-sectional study 194 overweight and obese patients were distributed in morbid-obese patients (MOP, n = 110), obese (OP, n = 84) and overweight patients (OwP, n = 33) groups. Demography, anthropometry, clinical and standard biochemical data were recorded. cIMT, endothelial function, defined as the small artery reactivity index (saRHI), and artery wall rigidity, studied by the augmentation index, were determined. More than 50% of the MOP, OP and OwP had a cIMT above the 75th percentile per age and gender. No differences in cIMT or saRHI were observed, although overweight and obese patients (OOP) had higher arterial rigidity compared with the morbid-obese patients. In a multivariate regression test, while cholesterol was the main determinant of cIMT in overweight and obese patients, glucose metabolism was the determinant in MOP. Conclusion More than half of the population have a cIMT above general population ranges. OwP, OP and MOP have similar cIMT and saRHI. However, OOP have greater arterial wall rigidity. Dysglycemia is the main factor associated with subclinical atherosclerosis in MOP.

Background 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 metabolic syndrome (MS), their net effect on vascular function remains unclear. Objective Evaluate the relation between dietary macronutrient composition and the small artery reactive hyperaemia index (saRHI), a marker of small artery vascular function, in a cohort of MS patients. Design This cross-sectional study included 160 MS patients. Diet was evaluated by a 3-day food-intake register and reduced to a novel low-carbohydrate diet score (LCDS). Physical examination, demographic, biochemical and anthropometry parameters were recorded, and saRHI was measured in each patient. Results Individuals in the lowest LCDS quartile (Q1; 45% carbohydrate, 19% protein, 31% fat) had higher saRHI values than those in the top quartile (Q4; 30% carbohydrate, 25% protein, 43% fat) (1.84 ± 0.42 vs. 1.55 ± 0.25, P = .012). These results were similar in T2D patients (Q1 = 1.779 ± 0.311 vs. Q4 = 1.618 ± 0.352, P = .011) and also in all of the MS components, except for low HDLc. Multivariate analysis demonstrated that individuals in the highest LCDS quartile, that is, consuming less carbohydrates, had a significantly negative coefficient of saRHI which was independent of confounders (HR: −0.747; 95%CI: 0.201, 0.882; P = .029). Conclusions These data suggest that a dietary pattern characterized by a low amount of carbohydrate, but reciprocally higher amounts of fat and protein, is associated with poorer vascular reactivity in patients with MS and T2D.

OBJECTIVE To evaluate circulating adipocyte and epidermal fatty acid-binding protein (FABP4 and FABP5) concentrations in patients with obstructive sleep apnea (OSA), as well as the effects of continuous positive airway pressure (CPAP) treatment. METHODS Our cross-sectional study included 125 patients. After polysomnography, 58 participants met the criteria for CPAP treatment and were included in a closed cohort study of 8 weeks of CPAP treatment. General anthropometric and biochemical data and circulating FABP4 and FABP5 levels were determined in all patients at baseline and after CPAP treatment in those receiving this therapy. RESULTS Circulating FABP4 but not FABP5 levels were higher in patients with OSA (P = 0.003). FABP4 but not FABP5 values were associated with parameters of OSA severity independently of age, gender, adiposity and insulin resistance (P < 0.05). FABP4 but not FABP5 concentrations were determinants of OSA presence (OR: 1.11, P = 0.010) and severity (OR: 1.06, P = 0.020). After CPAP treatment, FABP4 levels decreased in the more severe patients (P = 0.019), while FABP5 levels increased in all patients (P < 0.001). CONCLUSIONS FABP4 is directly associated with obstructive sleep apnea severity and did not change with continuous positive airway pressure treatment, while FABP5 was not associated with obstructive sleep apnea severity and increased with continuous positive airway pressure treatment. FABP4 and FABP5 have different associations with obstructive sleep apnea. FABP4 but not FABP5 could be considered a marker of metabolic alterations in obstructive sleep apnea patients.

OBJECTIVE Some individuals with cardiovascular risk are unable to achieve even the lower internationally recommended level of physical activity (PA). We aimed to study the impact of a lower-than-advised level of PA on small artery vascular function and oxidative stress in overweight and obese postmenopausal women. METHODS Forty-seven overweight and obese postmenopausal women completed a 4-month program of 1-hour low-intensity PA for 2 days per week. Before and after the intervention, PA level (metabolic equivalent tasks/h/wk), endogenous antioxidant status (superoxide dismutase and erythrocyte lysate and glutathione peroxidase erythrocyte lysate concentrations, superoxide dismutase plasma and glutathione peroxidase plasma [GPXa] activities, and oxidized low-density lipoprotein), asymmetrical dimethylarginine concentrations, endothelial function by small artery reactive hyperemia index (saRHI), and resting heart rate (RHR) were assessed. RESULTS After the intervention, a significant increase in GPXa and decreases in asymmetrical dimethylarginine concentrations and RHR (P < 0.001 for all) were observed. Increases in PA were positively associated with increases in saRHI (r = 0.330, P = 0.027) and GPXa (r = 0.299, P = 0.05) and a decrease in RHR (r = -0.297, P = 0.047). Multivariate analyses showed that the independent predictors of saRHI improvement were an increase in PA (β = 2.63; 95% CI, 1.24-4.19; P = 0.019), a decrease in RHR (β = 1.96; 95% CI, 1.01-5.03; P = 0.048), and an increase in GPXa (β = 2.64; 95% CI, 1.18-5.08; P = 0.021). CONCLUSIONS Even low-intensity PA improves antioxidant capacity, RHR, and saRHI in postmenopausal women. Advising postmenopausal women to increase their PA at any level seems warranted based on our preliminary and hypothesis-generating data.

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 ± 78 μm, 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 ± 117 μm, p 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.

Resumen Introduccion La hipercolesterolemia familiar (HF) heterocigota es un trastorno genetico del metabolismo de las lipoproteinas que conlleva un riesgo cardiovascular (RCV) muy elevado. El estudio de la pared arterial y su funcion son de especial interes en pacientes con HF. La rigidez arterial esta asociada a un incremento del RCV. El objetivo del estudio fue determinar la rigidez arterial en pacientes con HF y su asociacion con parametros bioquimicos y vasculares. Metodos Se incluyeron 125 pacientes con HF y 59 controles sanos (GC). Se obtuvieron datos clinicos, antropometricos y parametros bioquimicos. Se determino la rigidez arterial basada en el indice de aumento ajustado por 75 latidos por minuto (IAx@75), mediante tonometria arterial periferica, el grosor intima-media carotideo (GIMc) y el indice tobillo-brazo (ITB). Resultados Los pacientes con HF presentaron un incremento significativo en el IAx@75 con respecto a GC (9,8 ± 18,3 vs. 2,4 ± 11,1%; p = 0,011), tambien un mayor GIMc (0,758 ± 0,280 vs. 0,635 ± 0,160 mm; p Conclusiones Los pacientes con HF presentan rigidez arterial incrementada. El IAx@75 esta asociado con las concentraciones de Apo-B100 y es un determinante del GIMc. El IAx@75 podria utilizarse como marcador precoz de RCV en pacientes con HF.

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.

Background and aims Abdominal obesity (AO) is associated with endothelial function (EF) alteration and increased global cardiovascular (CV) risk. Therapeutic lifestyle changes (TLSC) reduce CV risk, but the impact on EF assessed by peripheral artery tonometry (PAT) is unknown. In this study, we aimed to prospectively assess the effects of TLSC on EF measured by PAT in increased CV risk patients with AO. Methods and results 150 patients with AO and moderate CV risk were randomized to groups receiving a one-year intervention of either conventional medical care (control group, CG) or an intensive TLSC program (intervention group, IG). Vascular studies (EF by PAT, intima-media thickness (IMT)) and lifestyle (LS) assessment were performed before and after intervention. The PAT ratio improved in the IG and worsened in the CG. The global CV risk was reduced ( P = 0.017) in the IG due to a significant decrease in systolic blood pressure ( P P = 0.013). More individuals in the IG than in the CG quit smoking ( P = 0.001) and increased their physical activity ( P = 0.014). The improvement in at least two LS components was associated with a PAT ratio increase (2.44 IC: 95% 0.99–6.00, P = 0.051). The PAT ratio increase determined less IMT progression (−1.1 IC: 95% 0.91–1.00, P = 0.053). Conclusions Good adherence to a TLSC program reduces global CV risk and determines PAT ratio improvement. The PAT ratio increase is the main determinant of lower IMT progression.

Resumen Introduccion y objetivos Analizar el impacto de cambios de estilo de vida en la concentracion plasmatica de adipocyte fatty acid-binding protein (FABP4) en pacientes con riesgo cardiovascular. Metodos Se incluyo a 140 pacientes con riesgo cardiovascular sin enfermedad cardiovascular previa en un estudio prospectivo de 1 ano de duracion para evaluar el impacto de cambios terapeuticos de estilo de vida (tabaco, educacion nutricional y actividad fisica) en el riesgo cardiovascular. Resultados Las variaciones de la FABP4 se asociaron inversamente con cambios en la actividad fisica (MET·h/sem). La FABP4 se redujo significativamente en los pacientes que aumentaron su actividad fisica, mientras que aumento en quienes la disminuyeron. Los cambios observados en la FABP4 tambien se asociaron con modificaciones en el indice de masa corporal y la resistencia a la insulina; sin embargo, las correlaciones entre actividad fisica y FABP4 permanecieron significativas tras ajustarlas por variables de confusion. Los cambios en la actividad fisica fueron los principales predictores de las modificaciones en la FABP4. La disminucion de FABP4 se asocio directamente con reducciones de colesterol ligado a las lipoproteinas de baja densidad y apolipoproteina B. Dejar de fumar y la composicion de la dieta no modificaron las concentraciones de FABP4. Conclusiones La concentracion plasmatica de FABP4 puede reducirse aumentando la actividad fisica aerobica. La actividad fisica actua sobre las concentraciones de FABP4 independientemente de la reduccion de peso. Si se pudiera establecer un papel causal de la FABP4 en las alteraciones metabolicas y vasculares, nuestros resultados anadirian un nuevo efecto positivo tanto de la actividad fisica como de la reduccion de la obesidad en el riesgo metabolico y cardiovascular.

Resumen Introduccion Los cambios terapeuticos sobre el estilo de vida (CTEV) reducen el riesgo cardiovascular (RCV), pero el efecto sobre la funcion endotelial (FE) es desconocido. El objetivo de este estudio fue evaluar prospectivamente el efecto de los CTEV sobre la FE en pacientes con RCV incrementado y obesidad abdominal (OA). Metodos Ciento cincuenta pacientes con OA y RCV incrementado fueron aleatorizados a una intervencion de un ano de control medico convencional (grupo control, GC) o a un programa intensivo de CTEV (grupo intervencion, GI). El estudio vascular, bioquimico y de valoracion del estilo de vida se realizo antes y despues del periodo de intervencion. Resultados El indice de hiperemia reactiva (RHI) mejoro en el GI y empeoro en el GC. El RCV se redujo (p = 0,017) en el GI debido a una disminucion significativa en la presion arterial sistolica (p Conclusiones La buena adherencia a los CTEV redujo el RCV y determino una mejoria en el RHI. El incremento del RHI fue el principal determinante de la menor progresion de cIMT.

Resumen Introduccion Los niveles plasmaticos de la proteina FABP4 son superiores en pacientes con diabetes tipo 2 (DT2), obesidad y sindrome metabolico. La disfuncion endotelial es una caracteristica comun en el desarrollo de las enfermedades vasculares asociadas a las alteraciones metabolicas. El objetivo del trabajo es estudiar la relacion entre FABP4 circulante y la funcion endotelial en pacientes con elevado riesgo cardiovascular (RCV). Metodos Doscientos cincuenta y siete pacientes (57,29 ± 10,66 anos) con RCV incrementado. Se determino FABP4 plasmatica. En el estudio vascular se valoro la funcion endotelial mediante el indice de la hiperemia reactiva (IHR) por tonometria arterial periferica, el grosor de la intima-media carotideo (GIM) y el indice tobillo-brazo (ITB). Las caracteristicas antropometricas y los biomarcadores endoteliales, de inflamacion y de oxidacion fueron determinados. Resultados FABP4 se asocio negativamente con la funcion endotelial medida por IHR (r = -0,226; p = 0,027) en los pacientes DT2. No se observo ninguna asociacion significativa con GIM e ITB en este grupo. Se observo una asociacion inversa y significativa de IHR a traves de los terciles de FABP4 (p = 0,023). En el modelo de regresion lineal, FABP4 fue el unico predictor de IHR en DT2 (p Conclusiones Los niveles aumentados de FABP4 circulante se asocian a una peor funcion endotelial, medida por IHR en pacientes DT2. Nuestro trabajo sugiere un efecto directo de FABP4 plasmatica en el endotelio vascular en pacientes DT2.

Eur J Clin Invest 2012; 42 (1): 34–41 Abstract 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

Aim: In heterozygous familial hypercholesterolaemic (FH) patients, study of the arterial wall and its function are of particular interest. Arterial stiffness has been shown to be associated with increased cardiovascular risk (CVR). In this study, we examined arterial stiffness in FH patients and its association with biochemical and vascular parameters.Methods: In this cross-sectional study, we included 125 FH patients (20-60 years old) and 59 gender- and age-matched healthy controls (CG). Clinical, anthropometry and biochemical data were obtained. Arterial stiffness determined based on the augmentation index (AIx) was assessed with peripheral artery tonometry. Carotid intima-media thickness (cIMT) and ankle-brachial index (ABI) were also assessed.Results: FH patients displayed a significant increase in AIx with respect to CG subjects (9.6±17.2 vs. 2.6±10.3%, P= 0.011). FH patients also had a thicker cIMT (0.758±0.280 vs. 0.635±0.160 mm, P< 0.001), while their ABIs were not different from CG subjects. AIx values were positively correlated with LDLc, non-HDLc, apolipoprotein B100, triglyceride and sE-selectin levels. Moreover, apolipoprotein B100-rich particles, along with systolic blood pressure and glucose levels, were the main determinants of AIx. In addition, we found that AIx (β= 0.224, P= 0.014) was an independent determinant of cIMT.Conclusions: FH patients have increased arterial stiffness, despite advancements in typical clinical management. AIx is clearly associated with apolipoprotein B100 concentrations, and it is a determinant of cIMT. AIx can be utilised as a vascular risk marker in FH patients.

Resumen Antecedentes Los niveles circulantes de FABP4 se han asociado a alteraciones metabolicas y se han considerado un biomarcador predictivo de desarrollo de sindrome metabolico (SM) independiente de la adiposidad y la resistencia a la insulina en sujetos asiaticos no diabeticos. Objetivo Evaluar la relacion entre los cambios en los niveles circulantes de FABP4 y la regresion o progresion de SM en sujetos incluidos en un programa global de cambios terapeuticos de estilo de vida. Pacientes y metodos En este estudio prospectivo de 1 ano de duracion se incluyeron 140 sujetos con obesidad abdominal y riesgo cardiovascular global aumentado. Se evaluo la asociacion entre los cambios en los niveles de FABP4 y la evolucion del diagnostico de SM y sus componentes. Tambien se analizaron cambios en otros parametros bioquimicos, marcadores antropometricos y parametros vasculares. Resultados Se observo un aumento en los niveles de FABP4 asociado a la progresion de SM y una reduccion de los niveles de FABP4 asociada a regresion de SM. El aumento en los niveles de FABP4 se asocio con la aparicion tanto de hipertrigliceridemia como de colesterol-HDL bajo, mientras que las reducciones de FABP4 se asociaron con la desaparicion de los criterios de SM de obesidad abdominal, colesterol-HDL bajo y glicemia basal. Los predictores de progresion de SM fueron aumentos en el perimetro abdominal y las concentraciones de insulina. Las disminuciones de FABP4 fueron el unico predictor independiente de regresion de SM. Conclusiones Las variaciones en la concentracion plasmatica de FABP4 se asocian a la progresion o regresion de SM. Dado el impacto de FABP4 sobre diversos componentes de SM no podemos descartar una relacion causal entre el descenso de FABP4 y la regresion de SM.

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 P0.05), 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.

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 (β = 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 (β = 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

Introduccion La via de senalizacion del acido retinoico (AR) media la transcripcion inducida por ligando de genes del metabolismo lipidico a traves de los receptores nucleares, receptor X de retinoico y receptor de AR, y del coactivador proteina de union al AR tipo II. Se ha establecido una asociacion entre esta via de senalizacion y las alteraciones lipidicas en trastornos como la hiperlipemia familar combinada y la hiperlipemia inducida por el tratamiento con inhibidores de la proteasa (IP) en pacientes con infeccion por el virus de la inmunodeficiencia humana (VIH). Nuestro objetivo ha sido comprobar la hipotesis segun la cual el gen CRABP2 estaria involucrado en la modulacion de la dislipemia. Sujetos y metodos Se ha realizado un estudio de asociacion del polimorfismo -394T>C del promotor de CRABP2 en 3 poblaciones independientes (299 individuos sanos, 182 pacientes con infeccion por el VIH y 151 pacientes con hipercolesterolemia familiar [HF]). Todas las analiticas se determinaron en ausencia de tratamiento hipolipemiante. Se realizo ANOVA ajustando por edad, indice de masa corporal, sexo, y uso de IP cuando fue necesario. Resultados La frecuencia del alelo C fue del 0,03 en los 3 grupos estudiados. Entre los individuos sanos, los portadores del alelo C presentaban un aumento en la concentracion de colesterol total del 9% (p = 0,027) y de colesterol unido a lipoproteinas de baja densidad (cLDL) del 13% (p = 0,020). En los pacientes infectados por el VIH, se realizo un analisis multivariante de 4 medidas tomadas durante 1 ano, y se observo que los valores de cLDL eran significativamente mas elevados en los portadores del alelo C (p = 0,001), y que estos oscilaban entre el 10 y el 31%. Asimismo, los pacientes HF portadores del alelo C presentaban un aumento significativo en la concentracion de cLDL del 16% (p = 0,038). El alelo C estaba sobrerrepresentado en individuos hipercolesterolemicos (p = 0,001). Conclusiones Nuestros resultados muestran que el gen CRABP2 , involucrado en la via de senalizacion del acido retinoico, esta asociado con elevadas concentraciones de cLDL en plasma.

Supplemental Digital Content is available in the text, 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

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.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.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.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).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.

Clinical data on the role as a lipokine of de novo lipogenesis-derived palmitoleic acid (C16:1n-7cis) in serum non-esterified fatty acids (palmitoleate) are scarce. We aimed to assess whether palmitoleate relates to cardiometabolic risk.In this cross-sectional study we included 358 individuals aged 30-65-years at high cardiovascular risk. We tested the association of palmitoleate (determined by gas chromatography) with metabolic syndrome (MS) and its components (defined by ATPIII criteria), fatty liver index (a surrogate of non-alcoholic fatty liver disease [NAFLD]), and subclinical atherosclerosis (determined as ultrasound-measured carotid intima-media thickness and arterial stiffness). Palmitoleate concentration was higher in women compared with men (median ± range interquartile, 1.36 ± 0.96 vs. 0.97 ± 0.77 μmol/L respectively, P0.001). In both genders palmitoleate concentration was associated with a higher prevalence of MS: men, odds ratio [OR: 1.12 (95%CI: 1.03; 1.23, P = 0.010)]; women [OR: 1.07 (95%CI: 1.03; 1.13, P = 0.005)], and all of its components except low HDL-cholesterol and hypertriglyceridemia. Palmitoleate was also associated with increased risk of NAFLD in both men [OR: 1.12 (95%CI: 1.03; 1.29, P = 0.031)] and women [OR: 1.11 (95%CI: 1.05; 1.19, P = 0.001)]. No associations with subclinical atherosclerosis were detected.Our observational data supports a relationship between de novo lipogenesis-derived circulating palmitoleic acid (palmitoleate) and increased cardiometabolic risk.

Background and aims Circulating FABP4 is strongly associated with metabolic and cardiovascular risk (CVR) and has been proposed as a new risk biomarker. Several FABP4 gene polymorphisms have been associated with protein expression in vitro and metabolic and vascular alterations in vivo . The aim of this study is to evaluate the impact of FABP4 polymorphisms on FABP4 plasma levels and subclinical arteriosclerosis in patients with obesity, metabolic syndrome (MS) or type 2 diabetes (T2DM). Methods and results We studied 440 individuals with obesity, MS, T2DM or other cardiovascular risk conditions who attended the vascular medicine and metabolism unit of our hospital. Anamnesis, physical examination and anthropometry data were recorded. Standard biochemical parameters were determined. Plasma FABP4 concentrations were measured. Carotid intima-media thickness (cIMT) was assessed using ultrasonography. The following FABP4 gene single-nucleotide polymorphisms (SNPs) were analyzed: rs3834363, rs16909233, rs1054135, rs77878271, rs10808846 and rs8192688. None of the studied gene allele variants were hyper-represented in patients grouped according the presence of metabolic alterations nor were they associated with the FABP4 concentration. The FABP4 gene variants did not determine cIMT differences between the groups. In a multivariate analysis, gender and BMI, but not gene variants, significantly determined plasma FABP4 concentrations. Conclusions In clinical settings, the circulating FABP4 levels are determined by the acquired metabolic derangements and not genetic variation.

Background: The widespread use of protease inhibitors (PI) has been associated with abnormalities in the lipid profile of HIV-1-infected patients. Treatment simplification approaches in which PI are replaced by nevirapine (NVP) have been shown to improve PI-related toxicity. Objective: To assess the impact on plasma lipids of replacing the PI by NVP in HIV-1 infected patients with lipodystrophy. Methods: We studied 34 patients with lipodystrophy who had been the first to be enrolled in a prospective, randomized trial of continuing current treatment, or replacing PI with NVP. Sixteen patients replaced their PI with NVP and 18 continued their current PI-containing treatment. Total, low density lipoprotein (LDL), very low density lipoprotein (VLDL), intermediate density lipoprotein and high density lipoprotein (HDL) cholesterol and triglyceride levels, the size and particle number of LDL were determined at baseline and after 24 weeks, by nucleic magnetic resonance spectroscopy. Findings: After 24 weeks of replacing the PI with NVP, we observed a reduction of total cholesterol (P = 0.028), LDL-cholesterol (P = 0.001), the number of circulating LDL particles (P = 0.003) and the VLDL-1 triglyceride level (P = 0.032). A concomitant significant increase was observed in both HDL-cholesterol level (P = 0.002) and HDL particle size (P

A moderate level of physical activity (PA), such as a daily 30-min walk, reduces cardiovascular risk. There is a lack of evidence about the cardiovascular benefits of PA below this recommendation of minimum PA level.We aimed to study the impact of a lower level of PA on cardiovascular health.Sixty-four overweight/obese men and women were enrolled in a community programme consisting of 4 months of 1h, low-intensity PA two days per week. Before and after the intervention, PA level (METs/h/wk), endogenous antioxidant status (SOD and GPX concentration and activity and oxidised LDL), ADMA concentrations, endothelial function by small artery reactive hyperaemia index (saRHI), and resting heart rate (RHR) were assessed.After the intervention, significant increases in saRHI (P=0.031), SOD and GPX activities, and a decrease in ADMA plasma concentrations, and RHR (P0.001 for all) were observed. Increases in PA were positively associated with increases in saRHI (r=0.341, P=0.022), GPx (r=0.303, P=0.047) and decreases in RHR (r=-0.302, P=0.047). Multivariate analyses showed that independent predictors of saRHI improvement were an increase in PA (2.65, 95%CI: 1.21-4.01), decrease in RHR (1.91, 95%CI: 1.01-4.98), and an increase in GPx (2.61, 95%CI: 1.16-5.01).In obese and overweight men and women, an increase in PA, even below the minimal international recommendations, improves antioxidant capacity, RHR and peripheral small artery reactivity.

10.1177/0961203313517405 The aim of this study is to determine if circulating fatty acid-binding protein 4 (FABP4) plasma levels are a possible marker of metabolic risk in SLE patients. Circulating levels of adipose FABP4 are associated with adiposity, insulin resistance (IR), metabolic syndrome, diabetes and cardiovascular diseases. Patients affected by systemic lupus erythematosus (SLE) show an accelerated atherosclerosis that cannot be entirely explained by traditional cardiovascular risk factors. Sixty consecutive patients with SLE and 34 non-SLE age-matched controls were recruited for the study. Total plasma lipids and circulating FABP4 were determined. Subclinical atherosclerosis was evaluated by measuring carotid intimae-media thickness (c-IMT) by sonography, and the distribution of lipoprotein subclasses was analysed by nuclear magnetic resonance (NMR) spectroscopy. In the SLE group, FABP4 was associated with IR, atherogenic dyslipidaemia, as measured by NMR, and the presence of subclinical atherosclerosis. In multivariate analyses FABP4 was associated with increased c-IMT independent of the inflammatory state of the patient. In sum, circulating FABP4 is involved in the metabolic disturbances of SLE affecting lipid metabolism and IR, and it could be a biomarker of atherosclerosis in this population.

10.1016/j.jnutbio.2014.02.004 Dietary long-chain n-3 polyunsaturated fatty acids (LCn-3PUFA) improve endothelial function in medium-large-sized arteries, but effects on small peripheral arteries, responsible for most arterial resistance, are little known. We investigated the effects of increasing LCn-3PUFA intake with the usual diet on small artery reactive hyperemia index (saRHI). Within a clinical trial evaluating the effects of 1 year of intensive lifestyle intervention versus standard care on cardiovascular markers in subjects at risk, we selected 108 participants regardless of treatment allocation (n=47 standard care; n=61 intensive intervention) with complete baseline and follow-up information on dietary, clinical, saRHI and biochemical data, including biomarkers of inflammation and endothelial activation. At the end of follow-up, saRHI increased across tertiles of change in dietary LCn-3PUFA. Subjects in the top tertile (increased LCn-3PUFA intake) increased serum ApoA1 and decreased hs-CRP, serum TNF-a, sICAM-1, sVCAM-1 and oxLDL from baseline. After pooling data, in unadjusted models, changes in saRHI significantly correlated to changes in LCn-3PUFA intake and ApoA1 (directly) and changes in systolic blood pressure, waist circumference, TNF-a, sVCAM-1 and sE-selectin (inversely). In a multivariate model, changes in dietary LCn-3PUFA were significantly associated with changes in saRHI [. B=0.08 (95% confidence interval=0.083-0.291) for an increase by 100 mg/day]. Systolic blood pressure was inversely associated with saRHI changes [. B=-0.203 (-0.441 to -0.029) for a 9-mmHg increase]. We conclude that increased dietary consumption of LCn-3PUFA might be a cost-effective strategy to improve peripheral vasoactivity.

10.1007/s11695-012-0729-6 Background: Endothelial dysfunction is a major underlying mechanism for the elevated cardiovascular risk associated with increased body weight. We aimed to assess the impact of weight loss induced by an intensive very-low-calorie diet (VLCD) on arterial wall function in severely obese patients (SOP). Methods: Thirty-four SOP were admitted to the metabolic ward of the hospital for a 3-week period. A VLCD characterized by a liquid diet providing 800 kcal/day was administered. The small artery reactivity to postischemic hyperemia index (saRHI), a surrogate marker of endothelial function, was assessed before and 1 week after hospital discharge. Anthropometry and biochemical parameters were also measured. Obese and non-obese age- and gender-matched groups were recruited for baseline comparisons. Results: SOP had significantly lower saRHI compared with obese and non-obese individuals. SaRHI significantly increased after the intervention in SOP (1.595 ± 0.236 vs. 1.737 ± 0.417, p = 0.015). A significant improvement in glucose (p = 0.026), systolic blood pressure (p = 0.049), LDLc (p < 0.001), and inflammatory parameters was observed. Body weight loss was associated with a higher saRHI (r = -0.385, p = 0.033), and it was the main determinant of saRHI variation independently of confounders (ß -0.049, IC 95 % -0.091-0.008, p = 0.021). Conclusions: Weight loss induced by a VLCD in SOP improved small artery reactivity, and it was associated with the amelioration of metabolic and inflammation markers. Endothelial dysfunction may be softened by body weight loss interventions and useful in the management of cardiovascular risk factors in SOP.

This study analyses in depth lipid and lipoprotein changes in 20 HIV-infected patients on an efavirenz-containing regimen, either as initial therapy or as a substitute for a protease inhibitor. Total plasma lipids and the distribution of subclasses of lipoproteins were analysed at baseline and after 48 weeks by nuclear magnetic resonance spectroscopy, and showed a mean increase of 20% in HDL-cholesterol in both regimens. Up to 85% of patients significantly improved their atherogenic index (LDL/HDL ratio).

Our objective was to assess the number of patients with an indication for lipid-lowering therapy according to their non-HDL cholesterol (N-HDL-C) (130 mg/dL) concentrations despite on-target LDL (≤100 mg/dL) values determined using ultracentrifugation (UC) or direct enzymatic methods (DM).In 1590 patients we studied the lipid profile using standard biochemical methods and sequential UC (N = 637) or triglyceride (TG) independent DM (N = 953). The indications for lipid-lowering therapy were compared by evaluating the real LDL concentration or N-HDL-C concentration.The LDL/N-HDL-C correlation significantly decreased with increasing triglyceride concentrations: normal (r = 0.924, p 0.001), 150-400 mg/dL (r = 0.825, p 0.001) and higher than 400 mg/dL (r = 0.460, p 0.001) (p 0.001). The percentage of patients with an N-HDL-C concentration above the recommended level, despite having an LDL concentration that was on target, also increased significantly across the TG tertiles (3.1%, 15.6% and 57.%, respectively; p 0.001). Of the patients with a TG level above 400 mg/dL and an LDL concentration that was on target, 86% had an N-HDL-C concentration above 130 mg/dL. Of the patients with a TG level above 400 and an N-HDL-C concentration qualifying for therapy, 40% had an LDL concentration that was on target. The ApoB concentration had a stronger concordance with the LDL concentration than N-HDL-C.Using the N-HDL-C concentration as a therapeutic target in hypertriglyceridemic patients almost doubled the number of patients requiring treatment. The ApoB concentration had a better association with LDL when determining the need for lipid-lowering therapy.

Objective: In macrophages, adipocyte fatty acid-binding protein (FABP4) coordinates key events in oxidized LDL-induced foam cell formation, such as cholesterol trafficking and inflammatory responses. Nrf2 is a redox-sensitive transcription factor with antioxidant and anti-inflammatory properties. We investigated the involvement of the Nrf2 signaling pathway in FABP4-upregulation in response to aldehydes that are derived from polyunsaturated fatty acid (PUFA) oxidation. Methods and results: Using RT-PCR and western blotting, we found that the aldehyde 2,4-decadienal (2,4-DDE) produced a marked increase in FABP4 mRNA and protein levels. 2,4-DDE acts at the transcriptional level of FABP4 by promoting mRNA synthesis and prolonging the half-life of the de novo synthesized mRNA. 2,4-DDE consistently enhanced nuclear translocation of phosphorylated Nrf2, which was mediated by the activation of the Akt and ERK signaling pathways. A chromatin immunoprecipitation assay showed the in vivo binding of activated Nrf2 to a newly identified ARE site in the human FABP4 promoter. Conclusions: We propose an Akt and ERK/Nrf2-dependent FABP4 upregulation pathway in response to PUFA oxidation end-products in human macrophages. These results open a new avenue for putative therapeutic targets addressed to control atherogenesis.