The Lipoprotein Profile Evaluated by 1H-NMR Improves the Performance of Genetic Testing in Familial Hypercholesterolemia.

BACKGROUND: The familial hypercholesterolemia (FH) diagnosis is based on clinical and genetic criteria. A relevant proportion of FH patients fulfilling the criteria for definite FH have negative genetic testing. Increasing the identification of true genetic-based FH is a clinical challenge. Deepening the analysis of lipoprotein alterations could help increase the yield of genetic testing. We evaluated whether the number, size, and composition of lipoproteins assessed by 1H-NMR could increase the identification of FH patients with pathogenic gene variants. METHODS: We studied 294 clinically definite FH patients, 222 (75.5%) with positive genetic testing, as the discovery cohort. As an external validation cohort, we studied 88 children with FH, 72 (81%) with positive genetic testing. The advanced lipoprotein test based on 1H-NMR (Liposcale®) was performed at baseline after a lipid-lowering drug wash-out of at least 6 weeks. The association of variables with genetic variants was evaluated by random forest and logistic regression. Areas under the curve (AUCs) were calculated. A predictive formula was developed and applied to the validation cohort. RESULTS: A formula derived from NMR lipoprotein analyses improved the identification of genetically positive FH patients beyond LDL-C levels (AUC=0.87). The parameters contributing the most to the identification formula were LDL particle number, HDL size and remnant cholesterol. The formula also increases the classification of FH children with a pathogenic genetic variation. CONCLUSIONS: NMR lipoprotein profile analysis identifies differences beyond standard lipid parameters that help identify FH with a positive pathogenic gene variant, increasing the yield of genetic testing in FH patients.

Association between Nordic and Mediterranean diets with lipoprotein phenotype assessed by 1HNMR in children with familial hypercholesterolemia.

BACKGROUND AND AIMS: Both Nordic and Mediterranean diets are considered healthy despite notable regional differences. Although these dietary patterns may lower cardiovascular risk, it is unclear if they improve the lipoprotein phenotype in children with familial hypercholesterolemia (FH). The aim is to determine the impact of Nordic and Mediterranean diets on the advanced lipoprotein profile in children with heterozygous FH (HeFH). METHODS: This was a cross-sectional study performed in children with FH recruited from the Lipid Clinics at Sant Joan University Hospital in Reus (Spain) and Oslo University Hospital (Norway). Two-hundred fifty-six children (mean age 10 y/o; 48% girls): 85 Spanish and 29 Norwegian FH children, and 142 non-FH healthy controls (119 from Spain and 23 from Norway) were included in the study. A pathogenic FH-associated genetic variant was present in 81% of Spanish children with FH and all Norwegian children with FH. An 1H NMR based advanced lipoprotein test (Nightingale®) providing information on the particle number, size and lipid composition of 14 lipoprotein subclasses was performed and correlated to the dietary components. RESULTS: Levels of LDL-C, HDL-C and triglycerides were not significantly different between the Nordic and Mediterranean FH groups. Spanish children with FH had more LDL particles, mainly of the large and medium LDL subclasses, than Norwegian FH children. Spanish FH children also had more HDL particles, mainly medium and small, than Norwegian FH children. The mean LDL size of Spanish FH children was larger, while the HDL size was smaller than that of the Norwegian FH children. The HDL particle number and size were the main determinants of differences between the two groups. In Norwegian children with FH, dietary total fat and MUFAs showed a significant correlation with all apolipoprotein B-containing lipoproteins and LDL size, whereas there was no correlation to SFA. A weaker association pattern was observed in the Spanish children. CONCLUSIONS: The lipoprotein profiles of Spanish and Norwegian children showed differences when studied by 1H NMR. These differences were in part associated with differences in dietary patterns.

Women with familial hypercholesterolemia phenotype are undertreated and poorly controlled compared to men.

Familial hypercholesterolemia (FH) is an autosomal dominant disease that has a prevalence of approximately 1/250 inhabitants and is the most frequent cause of early coronary heart disease (CHD). We included 1.343.973 women and 1.210.671 men with at least one LDL-c measurement from the Catalan primary care database. We identified 14.699 subjects with Familial hypercholesterolemia-Phenotype (FH-P) based on LDL-c cut-off points by age (7.033 and 919 women, and 5.088 and 1659 men in primary and secondary prevention, respectively). Lipid lower therapy (LLT), medication possession ratio (MPR) as an indicator of adherence, and number of patients that reached their goal on lipid levels were compared by sex. In primary and secondary prevention, 69% and 54% of women (P = 0.001) and 64% and 51% of men (P = 0.001) were on low-to-moderate-potency LLT. Adherence to LLT was reduced in women older than 55 years, especially in secondary prevention (P = 0.03), where the percentage of women and men with LDL-c > 1.81 mmol/L were 99.9% and 98.9%, respectively (P = 0.001). Women with FH-P are less often treated with high-intensity LLT, less adherent to LLT, and have a lower probability of meeting their LDL-c goals than men, especially in secondary prevention.

Glycoprotein Serum Concentrations Assessed By 1H-NMR are Increased in Patients With High Blood Pressure.

BACKGROUND: Patients with hypertension present a permanent state of low-grade inflammation, as the disease activates several pro-inflammatory cells and inflammatory pathways. Glycoproteins A, B, and F, determined by proton nuclear magnetic resonance, provide a highly sensitive method for determining a group of liver-derived pro-inflammatory proteins, and their role has not yet been explored in patients with hypertension. In this study, we evaluated the impact of plasma concentrations of these glycoproteins in patients with hypertension. METHODS: This cross-sectional study involved 340 patients attending our vascular and metabolism medicine unit. Of them, 129 were normotensive and 211 were hypertensive. Standard biochemistry and carotid ultrasound measures were performed. Serum concentrations of glycoproteins A, B, and F were determined by proton nuclear magnetic resonance. RESULTS: Hypertensive patients presented a higher prevalence of obesity, metabolic syndrome, and diabetes and higher glycoprotein A, B, and F concentrations. Glycoproteins A, B, and F were positively correlated with systolic and diastolic blood pressure. Multivariate logistic models showed that glycoproteins A, B, and F were associated with higher odds of being hypertensive. Machine learning methods corroborated the relationship between glycoproteins and high blood pressure. The higher prevalence of carotid plaques in patients with high blood pressure was partially mediated by glycoproteins A and F. CONCLUSIONS: Patients with hypertension present systemic, subclinical inflammation as assessed by liver-derived glycoprotein A, B, and F serum levels. These results support the effect of hypertension on the mechanisms of systemic inflammation. Hypertension-associated systemic inflammation plays a role in hypertension-associated vascular injury and probably in hypertension-induced damage to other organs.

Effect of statin therapy on SARS-CoV-2 infection-related mortality in hospitalized patients.

AIM: Assessing the effect of statin therapy (ST) at hospital admission for COVID-19 on in-hospital mortality. METHODS AND RESULTS: Retrospective observational study. Patients taking statins were 11 years older and had significantly more comorbidities than patients who were not taking statins. A genetic matching (GM) procedure was performed prior to analysis of the mortality risk. A Cox proportional hazards model was used for the cause-specific hazard (CSH) function, and a competing-risks Fine and Gray (FG) model was also used to study the direct effects of statins on risk. Data from reverse transcription-polymerase chain reaction-confirmed 2157 SARS-CoV-2-infected patients [1234 men, 923 women; age: 67 y/o (IQR 54-78)] admitted to the hospital were retrieved from the clinical records in anonymized manner. Three hundred and fifty-three deaths occurred. Five hundred and eighty-one patients were taking statins. Univariate test after GM showed a significantly lower mortality rate in patients on ST than the matched non-statin group (19.8% vs. 25.4%, χ2 with Yates continuity correction: P = 0.027). The mortality rate was even lower in patients (n = 336) who maintained their statin treatments during hospitalization compared with the GM non-statin group (17.4%; P = 0.045). The Cox model applied to the CSH function [HR = 0.58(CI: 0.39-0.89); P = 0.01] and the competing-risks FG model [HR = 0.60 (CI: 0.39-0.92); P = 0.02] suggest that statins are associated with reduced COVID-19-related mortality. CONCLUSIONS: A lower SARS-CoV-2 infection-related mortality was observed in patients treated with ST prior to hospitalization. Statin therapy should not be discontinued due to the global concern of the pandemic or in patients hospitalized for COVID-19.

Serum glycoproteins A and B assessed by 1H-NMR in familial hypercholesterolemia.

BACKGROUND AND AIMS: Inflammation is a pathophysiological mechanism of atherosclerosis, and several mediators have been proposed as biomarkers. Acute-phase serum glycoproteins are upregulated in the liver during systemic inflammation. Because of their unique biochemical characteristics, they can be measured by 1H-NMR, and their role as subclinical inflammation markers is under clinical evaluation. We aimed to assess the clinical value of plasma glycoproteins in familial hypercholesterolemia (FH) patients. METHODS: We recruited 295 FH patients (75.6% with FH-associated genetic variants). At baseline, a full glycoprotein profile, glycoprotein A and B (GlycA and B) concentrations and their height and width ratios (H/W) were analysed by 1H-NMR. A carotid artery ultrasound study was performed at baseline and prospectively at the 5-year follow-up in 144 FH patients. RESULTS: At baseline, the GlycA and GlycB concentrations and their H/W ratios were correlated with lipid profile and adiposity parameters, with the correlation between the GlycA and triglyceride concentrations (r = 0.780; p < 0001) being the strongest. Glycoprotein concentrations were also correlated with inflammation markers, mainly hsCRP. Higher glycoprotein concentrations were observed in patients with higher intima media thickness, arterial rigidity and presence of arteriosclerotic plaques. In the multivariate and random forest analyses, the baseline GlycB concentration showed a significant contribution to the detection of FH individuals prone to develop carotid plaques. CONCLUSIONS: The concentrations of serum glycoproteins as assessed by 1H-NMR are robust markers of subclinical inflammation. In FH patients, they are increased in the presence of subclinical vascular damage and could be considered atherosclerosis risk markers in the long term.

El rastreo masivo de datos es una segunda oportunidad para mejorar el manejo de los pacientes con fenotipo de hipercolesterolemia familiar / Massive data screening is a second opportunity to improve the management of patients with familial hypercholesterolemia phenotype

Introducción: La Hipercolesterolemia Familiar (HF) es una enfermedad autósómica dominante con una prevalencia estimada entre 1/200-250. Se encuentra infra-tratada e infra-diagnosticada. El rastreo masivo de datos puede incrementar la detección de pacientes con HF. Métodos: Población a estudio: Residentes en la zona sanitaria de cobertura (N: 195.000 habitantes) y con al menos una determinación de colesterol ligado a lipoproteínas de baja densidad (C-LDL) realizada entre el 1 de Enero de 2010 y el 30 de Diciembre de 2019. Se seleccionaron los valores más altos de C-LDL. Criterios de exclusión: síndrome nefrótico, hipotiroidismo, tratamiento hipotiroideo o triglicéridos > 400 mg/dL. Se analizaron 7 algoritmos sugestivos de fenotipo de Hipercolesterolemia Familiar (F-HF).Se seleccionó el algoritmo más eficaz y de fácil traslación a la práctica clínica. Resultados: Partiendo de 6.264.877 asistencias y 288.475 pacientes tras aplicar los criterios de inclusión-exclusión se incluyeron 504.316 analíticas correspondiendo a 106.382 adultos y 10.509 < 18 años. El algoritmo seleccionado presentó una prevalencia de 0.62%.Se detectaron 840 pacientes con fenotipo de Hipercolestereolemia Familiar (F-HF) siendo el 55.8% mujeres y 178 <18 años, El 9.3% tenían antecedentes de enfermedad cardio-vascular (ECV) y 16.4% habían fallecido. El 65% de los pacientes en prevención primaria presentaron valores de C-LDL >130 mg/dL y el 83% en prevención secundaria valores >70mg/dL. Se obtuvo una ratio de 7.64 (1-18) pacientes con HF-P por médico solicitante de analítica.Conclusiones: El rastreo masivo de datos y el perfilado de pacientes son herramientas eficaces y fácilmente aplicables en práctica clínica para la detección de pacientes con HF.(AU)

Introduction: Familial Hypercholesterolemia (FH) is an autosomal dominant disease with an estimated prevalence between 1/200-250. It is under-treated and underdiagnosed. Massive data screening can increase the detection of patients with FH. Methods: Study population: Residents in the health coverage area (N: 195.000 inhabitants) and with at least one determination of cholesterol linked to low-density lipoproteins (LDL-C) carried out between January 1, 2010 and December 30, 2019. The highest LDL-C values were selected. Exclusion criteria: nephrotic syndrome, hypothyroidism, Hypothyroid treatment or triglycerides> 400 mg / dL. Seven algorithms suggestive of Familial Hypercholesterolemia Phenotype (HF-P) were analyzed, selecting the most efficient algorithm that could easily be translated into clinical practice. Results: Based on 6.264.877 assistances and 288.475 patients, after applying the inclusion-exclusion criteria, 504.316 tests were included, corresponding to 106.382 adults and 10.509 <18 years. The selected algorithm presented a prevalence of 0.62%. 840 patients with HF-P were detected, 55.8% being women and 178 <18 years old, 9.3% had a history of cardiovascular disease (CVD) and 16.4% had died. 65% of the patients in primary prevention had LDL-C values> 130 mg / dL and 83% in secondary prevention values> 70mg / dL. A ratio of 7.64 (1-18) patients with HF-P per analytical requesting physician was obtained. Conclusions. Massive data screening and patient profiling are effective tools and easily applicable in clinical practice for the detection of patients with FH.

Massive data screening is a second opportunity to improve the management of patients with familial hypercholesterolemia phenotype. / El rastreo masivo de datos es una segunda oportunidad para mejorar el manejo de los pacientes con fenotipo de hipercolesterolemia familiar.

INTRODUCTION: Familial Hypercholesterolemia (FH) is an autosomal dominant disease with an estimated prevalence between 1/200-250. It is under-treated and underdiagnosed. Massive data screening can increase the detection of patients with FH. METHODS: Study population: Residents in the health coverage area (N: 195.000 inhabitants) and with at least one determination of cholesterol linked to low-density lipoproteins (LDL-C) carried out between January 1, 2010 and December 30, 2019. The highest LDL-C values were selected. EXCLUSION CRITERIA: nephrotic syndrome, hypothyroidism, Hypothyroid treatment or triglycerides> 400 mg / dL. Seven algorithms suggestive of Familial Hypercholesterolemia Phenotype (HF-P) were analyzed, selecting the most efficient algorithm that could easily be translated into clinical practice. RESULTS: Based on 6.264.877 assistances and 288.475 patients, after applying the inclusion-exclusion criteria, 504.316 tests were included, corresponding to 106.382 adults and 10.509 <18 years. The selected algorithm presented a prevalence of 0.62%. 840 patients with HF-P were detected, 55.8% being women and 178 <18 years old, 9.3% had a history of cardiovascular disease (CVD) and 16.4% had died. 65% of the patients in primary prevention had LDL-C values> 130 mg / dL and 83% in secondary prevention values> 70mg / dL. A ratio of 7.64 (1-18) patients with HF-P per analytical requesting physician was obtained. CONCLUSIONS: Massive data screening and patient profiling are effective tools and easily applicable in clinical practice for the detection of patients with FH.

Dietary intake and lipid levels in Norwegian and Spanish children with familial hypercholesterolemia.

BACKGROUND AND AIMS: Both the Nordic and Mediterranean diets claim to have a beneficial effect on lipid metabolism and cardiovascular prevention. The objective of this study was to compare diets consumed by children with FH at the time of diagnosis in Norway and Spain and to study their relationship with the lipid profile. METHODS AND RESULTS: In this cross-sectional study, we appraised the dietary intake in children (4-18 years old) with (n = 114) and without FH (n = 145) from Norway and Spain. We compared Nordic and Mediterranean diet composition differences and determined the association between food groups and lipid profiles. RESULTS: The Spanish FH group had a higher intake of total fats (mainly monounsaturated fatty acids (MUFAs)), cholesterol and fibre, but a lower intake of polyunsaturated fatty acids (PUFAs) compared to the Norwegian FH group. The Norwegian children consumed more rapeseed oil, low-fat margarine and whole grains and less olive oil, eggs, fatty fish, meat, legumes and nuts. In the Norwegian FH group, fat and MUFAs were directly correlated with total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B and inversely correlated with high-density lipoprotein (HDL-C). In Spanish children with FH, the intake of fats (mainly MUFAs) was directly associated with HDL-C and apolipoprotein A1. CONCLUSIONS: Despite a similar lipid phenotype, diets consumed by children with FH in Norway and Spain have significant differences at time of diagnosis. Nutrition advice should be more adapted to local intake patterns than on specific nutrient composition.

Glycoprotein Profile Assessed by 1H-NMR as a Global Inflammation Marker in Patients with HIV Infection. A Prospective Study.

Plasma glycoproteins are a composite biomarker of inflammation and can be detected by 1H-NMR. The aim of this study was to prospectively appraise the clinical value of plasma glycoproteins assessed by 1H-NMR in people living with HIV (PLWH). A total of 221 patients with HIV infection were recruited and studied at baseline and at 48 and 144 weeks. Patients were distributed into two groups according to baseline CD4+ T-cell number below or above 200 cells/µL. Patients with fewer than 200 cells/µL were distributed into the responders and nonresponders according to antiretroviral therapy (ART) response at 144 weeks. Glycoprotein concentrations were determined by 1H-NMR arising from the protein bond N-acetylglucosamine and N-acetylgalactosamine signals (GlycA); and N-acetylneuraminic acid signal (GlycB) associated with the sugar-protein bond concentration and aggregation state (shapes (height/width)). Basal glycoprotein concentrations were higher in patients with < 200 CD4+ T-cell/µL (Glyc A: 1040(917.9-1199.1) vs. 950.4(845.5-1050.9), p < 0.001, and Glyc B: 521(440.3-610.3) vs. 468.6(417.9-507.0) µ mol/L, p < 0.001) being reduced by ART. The height/width (H/W) ratio was the parameter showing a better association with this clinical status. Baseline glycoproteins predict the condition of responder/nonresponder. In this study, 1H-NMR glycoproteins provide novel insights to assess inflammation status and have prognostic value in PLWH.

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.

Toward a new clinical classification of patients with familial hypercholesterolemia: One perspective from Spain.

The introduction of singular therapies, such as proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), to lower high cholesterol levels requires better classification of patients eligible for intensive lipid lowering therapy. According to the European Medicines Administration, PCSK9i are recommended in primary prevention only in familial hypercholesterolemia (FH) patients. Therefore, an FH diagnosis is not simply an academic issue, because it has many clinical implications. The bases of a diagnosis of FH are not entirely clear. The availability of genetic testing, including large genome-wide association analyses and whole genome studies, has shown that some patients with a clinical diagnosis of definite FH have no mutations in the genes associated with the disease. This fact does not exclude the very high cardiovascular risk of these patients, and an early and intensive lipid lowering therapy is recommended in all FH patients. Because an FH diagnosis is a cornerstone for decisions about therapies, a precise definition of FH is urgently required. This is an expert consensus document from the Spanish Atherosclerosis Society. We propose the following classification: familial hypercholesterolemia syndrome integrated by (1) heterozygous familial hypercholesterolemia: patients with clinically definite FH and a functional mutation in one allele of the LDLR, ApoB:100, and PCSK9 genes; (2) homozygous familial hypercholesterolemia: mutations affect both alleles; (3) polygenic familial hypercholesterolemia: patients with clinically definite FH but no mutations associated with FH are found (to be distinguished from non-familial, multifactorial hypercholesterolemia); (4) familial hypercholesterolemia combined with hypertriglyceridemia: a subgroup of familial combined hyperlipidaemia patients fulfilling clinically definite FH with associated hypertriglyceridemia.

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.

Detecting familial hypercholesterolemia earlier in life by actively searching for affected children:The DECOPIN project.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is underdiagnosed in children. We assessed a combination of two screening methods. The first method was to detect hypercholesteraemic children and then study the parents (Ch-P pathway), and the second one was to study the offspring of FH-affected parents (P-Ch pathway). METHODS: In the Ch-P path, primary care paediatricians were asked to include lipid profiling or, at least, total cholesterol (TC) and then lipid profiling if TC was higher than 5.2 mmol/L in any clinically indicated blood test. Children with LDL-C ≥ 3.5 mmol/L, plus either a family history of early cardiovascular disease or one parent with severe hypercholesterolemia, were referred to the lipid unit where the parents, rather than their children, were studied. In parents with definite, clinical FH, a genetic study was performed. Focused genetic testing was performed on all offspring of genetically positive parents. The P-Ch path consisted of the active study of children from definite FH adults. RESULTS: Fifty-nine paediatricians covering a total population of 63,616 children agreed to participate in the project. Of the 216 children (122 Ch-P and 94 P-Ch) who were ultimately referred to the lipid unit, 87 children with FH (84% genetically positive) were identified. Additionally, 41 parents (from 40 families) were newly diagnosed with FH (63% genetically positive). Forty-nine different mutations were detected: 46 in the LDLR, 2 in the PCSK9 and 1 in APOB gene. CONCLUSIONS: The implementation of active strategies to detect FH in children, in close collaboration with primary care paediatricians, provides a high-performance method for early FH detection.

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.

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.