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.

Efficacy of therapeutic lifestyle changes on lipid profiles assessed by NMR in children with familial and non-familial hypercholesterolemia / Eficacia de los cambios terapéuticos en el estilo de vida en el perfil lipídico evaluado por RMN en niños con hipercolesterolemia familiar y no familiar

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

Antecedentes y objetivos: La primera línea de terapia en niños con hipercolesterolemia son los cambios terapéuticos en el estilo de vida (TLSC). La eficacia de la intervención en el estilo de vida en niños con hipercolesterolemia familiar (HF), en los que los niveles de LDL-C son generados genéticamente, merece un estudio específico. Objetivos: Evaluar el impacto de un programa de educación sobre el estilo de vida, centrado en los patrones alimentarios y la actividad física, sobre el perfil lipídico evaluado por resonancia magnética nuclear (RMN) en niños con HF versus no HF. Métodos: La fase 1 fue un estudio transversal de las características basales, y la fase 2 fue un estudio prospectivo de intervención mediante TLSC. En total, el estudio incluyó a 238 niños (de 4 a 18 años; 47% niñas) que asistieron a la unidad de lípidos de nuestro hospital debido a los altos niveles de colesterol. Ochenta y cinco fueron diagnosticados con HF (72% genéticamente positivos), y 153 fueron diagnosticados de no HF. Se utilizó un cuestionario cuantitativo de frecuencia de alimentos (FFQ) que incluye 137 ítems. La actividad física (AF) se evaluó mediante el cuestionario de Minnesota. El perfil lipídico se evaluó mediante la prueba 2D-1H-NMR (Liposcale Test). Un total de 127 niños (81 en el grupo HF) participaron en la fase prospectiva y fueron reevaluados después de 1 año de la intervención mediante TLSC, que consistió en educación sobre cambios en el estilo de vida impartida por una nutricionista especializada. Resultados: Los grupos HF y no HF fueron similares en los datos antropométricos y clínicos, excepto que los HF eran ligeramente más jóvenes que los no HF. Los participantes de ambos grupos mostraron una composición de dieta similar caracterizada por un alto consumo de calorías totales y un alto porcentaje de grasas, principalmente grasas saturadas. La AF estuvo por debajo del nivel recomendado en ambos grupos. Después de un año de TLSC, se redujo el porcentaje de grasas totales y saturadas, y la cantidad de fibra aumentó significativamente en ambos grupos. El porcentaje de proteína aumentó ligeramente. El número de niños involucrados en al menos 1 hora/día de AF aumentó en un 56% en el grupo de HF y en un 53% en el grupo sin HF, y ambos aumentos fueron significativos. Los números de partículas LDL totales y pequeñas se redujeron en ambos grupos, aunque el cambio absoluto fue mayor en el grupo HF que en el grupo no HF. Conclusiones: Las estrategias educativas para implementar TLSC en niños conducen al empoderamiento, al aumento de la adherencia y a la mejora metabólica general en niños con colesterol alto en sangre, incluidos aquellos con HF

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.

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.

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.

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.

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.

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.

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

Introducción: La hipercolesterolemia familiar (HF) infantil está infradiagnosticada y su diagnóstico no es fácil en la práctica clínica. El objetivo fue evaluar qué características clínicas, bioquímicas y de imagen vascular pueden ayudarnos a detectar a niños/as y adolescentes con hipercolesterolemia afectados de HF. Métodos: Doscientos veintidós niños y adolescentes de entre 4 y 18 años fueron reclutados para participar en un proyecto de detección precoz de HF (proyecto DECOPIN). La HF se diagnosticó por criterios genéticos o clínicos. Se definió hipercolesterolemia poligénica (HP) cuando el c-LDL >135mg/dl pero sin criterios clínicos ni genéticos de HF. Participantes con c-LDL < 135mg/dl se incluyeron en el grupo control (GC). Se recogieron la historia familiar, los datos antropométricos y las variables clínicas. Se analizaron parámetros bioquímicos y lipídicos. Se determinó el grosor íntima-media carotídeo (GIMc) y los tendones de Aquiles por ecografía. Resultados: Noventa y un niños fueron diagnosticados de HF y 23 de HP, y 108 como GC. El grupo HF presentó mayores concentraciones de CT, c-LDL, índice ApoB/ApoA1 e índice colesterol año. El c-HDL fue menor en grupo HF que en el GC. Si bien el c-LDL fue el parámetro más definitorio de HF, el índice ApoB/ApoA1 > 0,82 fue el que de forma aislada mostró mayor sensibilidad y especificad para predecir la presencia de mutación en el grupo de niños HF. El grosor de los tendones de Aquiles no mostró diferencias entre grupos. El GIMc fue mayor en los niños HF sin diferencias significativas. Conclusiones: Los niveles de c-LDL son el marcador de HF. Un índice ApoB/ApoA1 > 0,82 puede ser una herramienta útil para decidir el estudio genético en niños con sospecha de HF

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

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.

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.

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.

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 / Long-term effects of continuous positive airway pressure treatment on subclinical atherosclerosis in obstructive sleep apnoea syndrome

Antecedentes y objetivo: El síndrome de apnea-hipopnea durante el sueño (SAHS) es un factor de riesgo de arteriosclerosis. Nuestro objetivo fue evaluar la arteriosclerosis subclínica en los pacientes con SAHS y el efecto del tratamiento con continuous positive airway pressure (CPAP, «presión positiva continua de la vía aérea superior») sobre el grosor íntima-media carotídeo (GIMc). Pacientes y método: Se incluyeron 125 pacientes con sospecha de SAHS. Después de la polisomnografía, 107 pacientes fueron diagnosticados de SAHS; 58 cumplían criterios de tratamiento con CPAP. El GIMc se midió mediante ecografía a nivel basal y a los 2 años 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 tenían 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 más 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 permaneció estable durante el seguimiento en el grupo sin CPAP, y en el grupo tratado con CPAP disminuyó significativamente (679 ± 122 frente a 631 ± 117 μm, p < 0,0001). Conclusiones: Los pacientes con SAHS presentan un mayor grado de arteriosclerosis subclínica y no se asocia con su gravedad. La ecografía carotídea en el SAHS es un marcador fiable de arteriosclerosis. El tratamiento con CPAP en el SAHS disminuye el GIMc y el riesgo cardiovascular (AU)

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. ResultsThe 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 < .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 (AU)

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 / Intraabdominal fat redistribution in long-term continuous positive airway pressure treatment in obstructive sleep apnea patients

Fundamento y objetivo: La obesidad es el principal factor de riesgo del síndrome de apneas-hipopneas del sueño (SAHS). El objetivo es evaluar el efecto de la continuous positive airway pressure (CPAP, «presión positiva continua de la vía aérea» a largo plazo en pacientes con SAHS sobre la grasa intraabdominal. Pacientes y métodos: Se incluyeron 50 pacientes SAHS con criterio de CPAP y 35 SAHS no candidatos a CPAP con un seguimiento de 2 años. El visceral adipose tissue (VAT, «tejido adiposo visceral»), el subcutaneous adipose tissue (SAT, «tejido adiposo subcutáneo») y la preaortic intraabdominal fat (PIF, «grasa intraabdominal preaórtica») se midieron mediante ecografía. Resultados: En el grupo SAHS no candidatos a CPAP, la media del SAT y del VAT no cambió durante el seguimiento, pero se observó 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 modificó, pero el SAT disminuyó a los 2 años 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 redistribución de la grasa intraabdominal y se asocia a un perfil antropométrico de menor riesgo cardiovascular (AU)

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 (AU)

[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 / Concentraciones circulantes de PCSK9 en población con diabetes tipo 2 y alteraciones metabólicas asociadas

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

Introducción: PCSK9 es una molécula clave en la regulación del metabolismo lipídico. Estudios previos sugieren que la expresión y función de PCSK9 entorno a la regulación del receptor LDL puede alterarse en la diabetes. El objetivo del estudio fue determinar los niveles circulantes de PCSK9 en pacientes con diabetes tipo 2 (DM) y otras enfermedades metabólicas y su relación con las lipoproteínas estudiadas mediante resonancia magnética nuclear (RMN) y la homeostasis de la glucosa. Métodos: Se estudiaron un total de 457 pacientes, afectos de DM y otras alteraciones metabólicas (síndrome metabólico [SMet], obesidad y dislipidemia aterogénica [DA] y otros). Se realizó anamnesis, antropometría, exploración física y estudio vascular de carótidas y adiposidad abdominal. Se realizó bioquímica incluyendo PCSK9 circulante (tras 6 semanas de lavado en pacientes con hipolipemiantes). Se estudió mediante RMN el perfil de lipoproteínas. Se determinaron las variantes genéticas rs505151 y rs11591147 del gen PCSK9. Resultados: Los niveles circulantes de PCSK9 están aumentados en pacientes con DM y SMet (14 y 13%; p<0.005, respectivamente). Los niveles circulantes de PCSK9 se correlacionaron de forma positiva con el perfil lipídico aterogénico y parámetros de resistencia insulínica. Los niveles circulantes de PCSK9 también se asociaron positivamente a DA, definida mediante el número y el tamaño de lipoproteínas analizado mediante RMN. Los portadores de la variante genética rs11591147 mostraron niveles inferiores de PCSK9 plasmática y cLDL. Conclusiones: Los niveles circulantes de PCSK9 están aumentados en pacientes con DM y SMet junto con parámetros de DA y metabolismo de la glucosa, más allá del cLDL

[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.