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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 byWe 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 byAt 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.The concentrations of serum glycoproteins as assessed by

Resumen Introduccion La Hipercolesterolemia Familiar (HF) es una enfermedad autosomica dominante con una prevalencia estimada entre 1/200-250. Se encuentra infra-tratada e infra-diagnosticada. El rastreo masivo de datos puede incrementar la deteccion de pacientes con HF. Metodos Poblacion a estudio: Residentes en la zona sanitaria de cobertura (N: 195.000 habitantes) y con al menos una determinacion de colesterol ligado a lipoproteinas de baja densidad (C-LDL) realizada entre el 1 de Enero de 2010 y el 30 de Diciembre de 2019. Se seleccionaron los valores mas altos de C-LDL. Criterios de exclusion: sindrome nefrotico, hipotiroidismo, tratamiento hipotiroideo o trigliceridos > 400 mg/dL. Se analizaron 7 algoritmos sugestivos de fenotipo de Hipercolesterolemia Familiar (F-HF).Se selecciono el algoritmo mas eficaz y de facil traslacion a la practica clinica Resultados Partiendo de 6.264.877 asistencias y 288.475 pacientes tras aplicar los criterios de inclusion-exclusion se incluyeron 504.316 analiticas correspondiendo a 106.382 adultos y 10.509 130 mg/dL y el 83% en prevencion secundaria valores >70mg/dL. Se obtuvo una ratio de 7.64 (1-18) pacientes con HF-P por medico solicitante de analitica Conclusiones El rastreo masivo de datos y el perfilado de pacientes son herramientas eficaces y facilmente aplicables en practica clinica para la deteccion de pacientes con HF.

Bempedoic acid acts by inhibiting adenosine triphosphate-citrate lyase (ACL) and consequently cholesterol biosynthesis, leading to increased expression of LDL receptors and increasing low-density lipoproteins (LDL-C) plasma clearence. It is a prodrug for oral administration with intracellular activation. It is activatedin liver cells and to a lesser extent in kidney cells, being absent in adipose tissue and muscle cells. Therefore, unlike statins, its potential myotoxic effect is very limited. It has recently been approved as a lipid-lowering drug in combination with diet, with statins, or with other lipid-lowering drugs in patients with hypercholesterolaemia, mixed dyslipidaemia, statin intolerance, or when these are contraindicated. The marketing of bempedoic acid implies, in clinical practice, having a new family of lipid-lowering drugs.

Cardiovascular risk in heterozygous familial hypercholesterolaemia (HeFH) is driven by LDL cholesterol levels. Since lipid response to statin therapy presents individual variation, this study aimed to compare mean LDL and non-HDL cholesterol reductions and their variability achieved with different types and doses of the most frequently prescribed statins.Among primary hypercholesterolaemia cases on the Spanish Arteriosclerosis Society registry, 2894 with probable/definite HeFH and complete information on drug therapy and lipid profile were included. LDL cholesterol reduction ranged from 30.2 ± 17.0% with simvastatin 10 mg to 48.2 ± 14.7% with rosuvastatin 40 mg. After the addition of ezetimibe, an additional 26, 24, 21 and 24% reduction in LDL cholesterol levels was obtained for rosuvastatin, 5, 10, 20 and 40 mg, respectively. Subjects with definite HeFH and a confirmed genetic mutation had a more discrete LDL cholesterol reduction compared to definite HeFH subjects with no genetic mutation. A suboptimal response (15% or30% reduction in LDL cholesterol levels, respectively with low-/moderate-intensity and high-intensity statin therapy) was observed in 13.5% and, respectively, 20.3% of the subjects.According to the LDL cholesterol reduction in HeFH patients, the ranking for more to less potent statins was rosuvastatin, atorvastatin and simvastatin; however, at maximum dosage, atorvastatin and rosuvastatin were nearly equivalent. HeFH subjects with positive genetic diagnosis had a lower lipid-lowering response. Approximately 1 in 5 patients on high-intensity statin therapy presented a suboptimal response.

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.

Purpose of Review The aim of this report is to review the scientific evidence supporting that lipid lowering therapy (LLT), beyond statins, reduces cardiovascular risk; therefore, treatment strategies based on lipid-lowering drug combination should be implemented. Recent Findings A strong scientific body of evidence supports the effect of statins on cardiovascular risk reduction. Recent trials using non-statin LLT, ezetimibe, and PCSK9 inhibitors have provide scientific evidence about their impact on cardiovascular prevention. Current clinical guidelines still recommend using high-intensity statin monotherapy before considering combination therapy. Summary The causal effect of LDL-C on atherosclerosis is well established. Moreover, new RCT, meta-analysis, and Mendelian randomization data, support that the main determinant of risk reduction is the absolute LDL reduction regardless of LLT. Accordingly, the “high-intensity statin therapy” concept should be substituted by “high-intensity lipid lowering therapy.” Combination therapy must become the standard of care of hypercholesterolemia treatment.

Hipercolesterolèmia familiar; Aterosclerosi; Puntuació de risc genètic Familial hypercholesterolemia; Atherosclerosis; Genetic risk scores Hipercolesterolemia familiar; Aterosclerosis; Puntuaciones de riesgo genético Familial hypercholesterolemia (FH) is associated with mutations in the low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) genes. A pathological variant has not been identified in 30–70% of clinically diagnosed FH patients, and a burden of LDL cholesterol (LDL-c)-raising alleles has been hypothesized as a potential cause of hypercholesterolemia in these patients. Our aim was to study the distribution of weighted LDL-c-raising single-nucleotide polymorphism (SNP) scores (weighted gene scores or wGS) in a population recruited in a clinical setting in Catalonia. The study included 670 consecutive patients with a clinical diagnosis of FH and a prior genetic study involving 250 mutation-positive (FH/M+) and 420 mutation-negative (FH/M−) patients. Three wGSs based on LDL-c-raising variants were calculated to evaluate their distribution among FH patients and compared with 503 European samples from the 1000 Genomes Project. The FH/M− patients had significantly higher wGSs than the FH/M+ and control populations, with sensitivities ranging from 42% to 47%. A wGS based only on the SNPs significantly associated with FH (wGS8) showed a higher area under the receiver operating characteristic curve, and higher diagnostic specificity and sensitivity, with 46.4% of the subjects in the top quartile. wGS8 would allow for the assignment of a genetic cause to 66.4% of the patients if those with polygenic FH are added to the 37.3% of patients with monogenic FH. Our data indicate that a score based on 8 SNPs and the75th percentile cutoff point may identify patients with polygenic FH in Catalonia, although with limited diagnostic sensitivity and specificity This research was funded by the Instituto de Salud Carlos III (ISCIII), and Fondo Europeo de DesarrolloRegional (FEDER) “Una manera de hacer Europa”, grants PI14/01648 (to F.B.-V. and J.M.M.-C.) and PI18/00164(to F.B.-V.), as well as by Fundacióla Maratóde TV3 grant 20152431 (to F.B.-V.), Centro de Investigación Biomédicaen Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), and Centro de Investigación Biomédicaen Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN). CIBERDEM and CIBEROBN are ISCIII projects

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.

Resumen Objetivos Determinar el grado de consecucion del objetivo terapeutico del colesterol de las lipoproteinas de baja densidad (cLDL) en pacientes de alto y muy alto riesgo vascular atendidos en las unidades de lipidos, asi como las causas de no consecucion. Pacientes y metodo Estudio observacional retrospectivo multicentrico. Se incluyo a los pacientes mayores de 18 anos con alto o muy alto riesgo vascular, segun los criterios de la Guia europea de prevencion cardiovascular de 2012, remitidos de forma consecutiva a las unidades de lipidos entre enero y junio del 2012 y con seguimiento a los 2 anos de la primera visita. Resultados Se incluyo a 243 pacientes procedentes de 16 unidades de lipidos. La edad media fue de 52,2 anos (DE 13,7) con un 62,6% de varones. Un 40,3% eran de muy alto riesgo. En la primera visita seguian tratamiento hipolipidemiante el 86,8% (en combinacion 25,1%) y en la segunda visita el 95,0% (en combinacion 47,3%) (p Conclusiones Se consiguieron los objetivos de cLDL en cerca de un tercio de los pacientes. La baja adherencia del paciente, seguida de la inercia medica, son las causas mas frecuentes que pueden explicar estos resultados.

Objectives To determine the extent to which low-density lipoprotein cholesterol (LDL-C) therapeutic targets are achieved in patients with high and very high vascular risk treated in lipid units, and the reasons why these targets are not met. Patients and method Observational and retrospective multi-centre study. Patients over the age of 18 with high or very high vascular risk according to the criteria set forth by the 2012 European guidelines on cardiovascular disease prevention who were consecutively referred to lipid units between January and June 2012 and with follow-up two years after the first visit were included. Results 243 patients from 16 lipid units were enrolled. The mean age was 52.2 years (SD 13.7) and 62.6% of the patients were male. 40.3% were classified as very high risk. At the first visit, 86.8% were on lipid-lowering treatment (25.1% on combination therapy), which rose to 95.0% at the second visit (47.3% on combination therapy) (p Conclusions LDL-C therapeutic targets were achieved in around one third of patients. Patient non-adherence, followed by clinical inertia, are the primary causes that could explain these results.

Resumen Introduccion Los registros clinicos son una herramienta muy eficaz para comprobar la practica clinica habitual, comparar estrategias y mejorar el conocimiento de diferentes procedimientos diagnosticos y terapeuticos. Metodos El Registro Nacional de Dislipemias de la Sociedad Espanola de Arteriosclerosis (SEA) es una base de datos on-line, retrospectiva y prospectiva, donde las diferentes unidades de lipidos espanolas acreditadas por la SEA introducen datos de pacientes con trastornos del metabolismo lipidico. Resultados El registro fue creado en 2013, y desde entonces datos clinicos, analiticos, geneticos y evolutivos de 4.449 pacientes han sido introducidos hasta junio de 2017. En el ultimo ano el registro ha dado pie a un numero considerable de publicaciones internacionales y existen varias mas en desarrollo. Se ha iniciado un ambicioso plan de incentivacion de inclusion de pacientes para conseguir que el registro de la SEA sea un referente mundial que ayude a mejorar el conocimiento y el manejo clinico de estos pacientes. Conclusion Desde el grupo coordinador del registro animamos a todos los socios de la SEA a colaborar en el mismo en las multiples formas que el registro permite, y conseguir que sea una referencia cientifica internacional.

Familial hypercholesterolemia (FH) is the most common genetic disorder in childhood, but in most cases is not detected. High levels of low-density lipoprotein cholesterol are present since the child's birth and this fact will suppose silent development of early atherosclerosis. In cases of homozygous FH, the coronary disease will appear before 20s and in cases of heterozygous FH will occur in middle age. Despite published data, there is not agreement about how and when perform the screening. Familial history of early cardiovascular disease plus presence of hypercholesterolemia in parents is crucial for detection and diagnosis. Actually, it is topic of discussion that it is necessary to achieve therapeutic goals from an early age to improve prognosis. Lifestyle changes are the first line therapy. Statins are the lipid-lowering drugs of choice but the optimal age to start therapy it is still controversial. In this article, current recommendations of expert consensus guidelines about the management and new line therapies of child and adolescents are reviewed.

Familial hypercholesterolemia (FH) is characterized by high low-density lipoprotein (LDL) cholesterol with co-dominant transmission and high risk of cardiovascular disease (CVD), although with high variability among subjects. Currently, CVD stratification tools for heterozygous FH (HeFH) are not available. A definition of severe HeFH has been recently proposed by the International Atherosclerosis Society (IAS), but it has not been validated. Our study aims to see clinical characteristics and prevalence of CVD in subjects defined as severe HeFH by IAS criteria. Probable or definite HeFH introduced in the Dyslipidemia Registry of Spanish Arteriosclerosis Society were analyzed by the IAS criteria. Univariate and multivariate analysis was used to assess the association of CVD with the IAS criteria. About 1,732 HeFH cases were analyzed. Severe HeFH had higher prevalence of familial history of CVD, personal history of tendon xanthomas, LDL cholesterol, and CVD than nonsevere HeFH. A total of 656 (77.1%) and 441 (50.1%) of men and women, respectively, fulfilled the IAS criteria of severe HeFH. In the univariate analysis, subjects defined as severe HeFH showed odds ratio 3.016 (95% CI 3.136 to 4.257, p0.001) for CVD. However, when traditional risk factors were included in the multivariate analysis, only the presence of cholesterol400 mg/dl had a statistically significant association with CVD odds ratio 8.76 (95% CI 3.90 to 19.69, p0.001). In conclusion, the IAS definition of severe HeFH is not significantly associated with CVD when adjusted for classic risk factors. Risk stratification in HeFH is an important issue, but the proposed criteria do not seem to solve this problem.

Current research is focused on improving high-density lipoprotein (HDL) function rather than simply targeting an increase in high-density lipoprotein-cholesterol (HDL-C) levels [(1)][1]. The results of several recent studies indicate that stimulation of the HDL-dependent cholesterol efflux from

Objetivo Describir las características clínicas, las razones del inicio de la terapia y los efectos del tratamiento en la fase inicial de disponibilidad de evolocumab en las unidades de lípidos/medicina interna de España. Métodos Estudio retrospectivo, observacional, a partir de las historias clínicas de pacientes consecutivos que iniciaron tratamiento con evolocumab (de febrero de 2016 a julio de 2017) en 20 unidades de medicina interna en España. Se revisaron las características demográficas y clínicas de los pacientes, el tratamiento hipolipemiante y la evolución de los perfiles lipídicos entre 12 semanas antes y 12 ± 4 semanas después del inicio de evolocumab. Resultados Se analizaron 136 pacientes: el 64,0% eran hombres, con edad media (desviación estándar, DE) de 56,6 (11,5) años. El 75,0% tenían hipercolesterolemia familiar (4 homocigotos), de los que el 51,0% habían sufrido al menos un evento cardiovascular. El 61,0% del total de pacientes presentaban enfermedad cardiovascular aterosclerótica (ECVA). Al inicio de evolocumab, el 61,0% de los pacientes tomaban estatinas de alta intensidad y el 60,3% estaban recibiendo ezetimiba. La media (DE) de los niveles de cLDL al inicio de evolocumab fue de 169,1 (56,6) mg/dl. En 46,4% de los pacientes el cLDL fue superior a 160 mg/dl y en el 26,5% ? 190 mg/dl. Durante el período de observación, evolocumab produjo reducciones significativas de cLDL del 55,7% (p < 0,0001), alcanzando unos valores medios de 74,3 mg/dl. En la semana 12 el 53,8% de los pacientes alcanzaron niveles de cLDL < 70 mg/dl y el 26,9% < 50 mg/dl. Conclusiones En las unidades de lípidos/medicina interna evolocumab se prescribió predominantemente en pacientes con hipercolesterolemia familiar con o sin ECVA. El uso inicial de evolocumab se ajustó a las pautas de la Sociedad Española de Arteriosclerosis (SEA) de 2016, estando las concentraciones de cLDL claramente por encima de los umbrales recomendados para inicio de tratamiento. El tratamiento con evolocumab en la práctica clínica redujo los niveles de cLDL en torno al 55%, cifra comparable a los ensayos clínicos, lo que permitió alcanzar los objetivos terapéuticos en la mayoría de los casos. Objective To describe the clinical characteristics, the reasons for initiating therapy, and the effects of treatment in the initial phase of evolocumab availability in lipid/internal medicine units in Spain. Methods Retrospective, observational study, based on the medical records of consecutive patients initiating treatment with evolocumab (from February 2016 to July 2017) in 20 internal medicine units in Spain. A review was made of the demographic and clinical characteristics of the patients, the lipid lowering treatment, and the evolution of the lipid profiles between 12 weeks pre-initiation and 12 ± 4 weeks post-initiation of evolocumab. Results A total of 136 patients were analysed, of whom 64.0% were men, and the mean age (standard deviation, SD) was 56.6 (11.5) years. The large majority (75%) had familial hypercholesterolaemia (4 homozygous), and 51.0% of them had suffered at least one cardiovascular event. Atherosclerotic cardiovascular disease (ASCVD) was present in 61% of all patients. At initiation of evolocumab, 61.0% of the patients were taking high-intensity statins, and 60.3% were receiving ezetimibe. The mean (and SD) of LDL-C levels at initiation of evolocumab was 169.1 (56.6) mg/dL. The LDL-C was greater than 160 mg/dL in 46.4% of patients, and ? 190 mg/dL in 26.5%. During the observation period, evolocumab produced significant reductions in LDL-C of 55.7% (P < .0001), achieving mean values of 74.3 mg/dL. At week 12, more than half (53.8%) of patients achieved LDL-C levels < 70 mg/dL, and 26.9% < 50 mg/dL. Conclusions In the lipid/internal medicine units, evolocumab was mainly prescribed in patients with familial hypercholesterolaemia, with or without ASCVD. The initial use of evolocumab was in accordance with the guidelines of the Spanish Society of Arteriosclerosis (SEA) of 2016, with LDL-C levels being well above the recommended thresholds for treatment initiation. Evolocumab treatment in clinical practice reduced LDL-C levels by about 55%, a similar reduction to that reported in clinical trials. Most patients achieved LDL-C goals.

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.

In the statin era, the incidence of atherosclerotic cardiovascular diseases (ASCVD) in patients with familial hypercholesterolemia (FH) has not been updated. We aimed to determine the incidence of ASCVD in patients with FH-phenotype (FH-P) and to compare it with that of normal low-density lipoprotein cholesterol (LDL-C) patients. We performed a retrospective cohort study using the Database of the Catalan primary care system, including &ge, 18-year-old patients with an LDL-C measurement. From 1,589,264 patients available before 2009, 12,823 fulfilled FH-P criteria and 514,176 patients were normolipidemic (LDL-C &lt, 115 mg/dL). In primary prevention, patients with FH-P had incidences of ASCVD and coronary heart disease (CHD) of 14.9/1000 and 5.8/1000 person-years, respectively, compared to 7.1/1000 and 2.1/1000 person-years in the normolipidemic group. FH-P showed hazard ratio (HR) of 7.1 and 16.7 for ASCVD and CHD, respectively, in patients younger than 35 years. In secondary prevention, patients with FH-P had incidences of ASCVD and CHD of 89.7/1000 and 34.5/1000 person-years, respectively, compared to 90.9/1000 and 28.2/1000 person-years in the normolipidemic group (HR in patients younger than 35 years: 2.4 and 6.0). In the statin era, FH-P remains associated with high cardiovascular risk, compared with the normolipidemic population. This excess of risk is markedly high in young individuals.

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.

Apolipoprotein A5 gene (APOA5) variability explains part of the individual's predisposition to hypertriacylglycerolaemia (HTG). Such predisposition has an inherited component (polymorphisms) and an acquired component regulated by the environment (epigenetic modifications). We hypothesize that the integrated analysis of both components will improve our capacity to estimate APOA5 contribution to HTG. We followed a recruit-by-genotype strategy to study a population composed of 44 individuals with high cardiovascular disease risk selected as being carriers of at least one APOA5 SNP (-1131T>C and/or, S19W and/or 724C>G) compared against 34 individuals wild-type (WT) for these SNPs. DNA methylation patterns of three APOA5 regions [promoter, exon 2 and CpG island (CGI) in exon 3] were evaluated using pyrosequencing technology. Carriers of APOA5 SNPs had an average of 57.5% higher circulating triacylglycerol (TG) levels (P=0.039). APOA5 promoter and exon 3 were hypermethylated whereas exon 2 was hypomethylated. Exon 3 methylation positively correlated with TG concentration (r=0.359, P=0.003) and with a lipoprotein profile associated with atherogenic dyslipidaemia. The highest TG concentrations were found in carriers of at least one SNP and with a methylation percentage in exon 3 ≥82% (P=0.009). In conclusion, CGI methylation in exon 3 of APOA5 acts, in combination with -1131T>C, S19W and 724C>G polymorphisms, in the individual's predisposition to high circulating TG levels. This serves as an example that combined analysis of SNPs and methylation applied to a larger set of genes would improve our understanding of predisposition to HTG.

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.

Background Autosomal dominant hypercholesterolemia (ADH) is associated with mutations in the low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) genes, and it is estimated to be greatly underdiagnosed. The most cost-effective strategy for increasing ADH diagnosis is a cascade screening from mutation-positive probands. Objective The objective of this study was to evaluate the results from 2008 to 2016 of ADH genetic analysis performed in our clinical laboratory, serving most lipid units of Catalonia, a Spanish region with approximately 7.5 million inhabitants. Methods After the application of the Dutch Lipid Clinic Network (DLCN) clinical diagnostic score for ADH, this information and blood or saliva from 23 different lipid clinic units were investigated in our laboratory. DNA was screened for mutations in LDLR, APOB, and PCSK9, using the DNA-array LIPOchip, the next-generation sequencing SEQPRO LIPO RS platform, and multiplex ligation-dependent probe amplification (MLPA). The Simon Broome Register Group (SBRG) criteria was calculated and analyzed for comparative purposes. Results A total of 967 unrelated samples were analyzed. From this, 158 pathogenic variants were detected in 356 patients. The main components of the DLCN criteria associated with the presence of mutation were plasma LDL cholesterol (LDLc), age, and the presence of tendinous xanthomata. The contribution of family history to the diagnosis was lower than in other studies. DLCN and SBRG were similarly useful for predicting the presence of mutation. Conclusion In a real clinical practice, multicenter setting in Catalonia, the percentage of positive genetic diagnosis in patients potentially affected by ADH was 38.6%. The DLCN showed a relatively low capacity to predict mutation detection but a higher one for ruling out mutation.

Triglycerides (TG) are the initiators of the metabolic changes leading to the atherogenic dyslipidemia, which is a major inducer of atherosclerosis as a result of quantitative and qualitative changes in lipoprotein subclass distributions. We hypothesized that variation at the of APOA5 gene locus, encoding apoAV, a key regulator of TG levels, significantly affect lipoprotein subclass distributions toward a more atherogenic pattern in both hyperTG patients and dyslipemic patients.We recruited four hundred and twenty-two subjects attending a Lipid Clinic, prior to lipid-lowering treatment. We genotyped two APOA5 variants, rs662799 (-1131TC) and rs3135506 (S19W). Circulating lipoproteins were determined by nuclear magnetic resonance (NMR). Intima-media thickness (IMT) was evaluated using B-mode ultrasound.Carriers of the rare alleles of rs662799 and rs3135506 compared to common allele homozygotes, had a significantly proatherogenic profile of the VLDL and LDL subclasses, resulting in increased concentrations of the proatherogenic subclasses, large VLDLs (+133%, p0.001) and small LDLs (+34%, p=0.014). Significant changes in smaller HDL (+71%, p=0.032), as well as an 18% decrease in large HDL (p=0.046), were also been observed. This atherogenic NMR subclass distribution was significantly associated with increased carotid IMT. The observed effects were significantly stronger in patients with a BMI≥25 kg/m2 and in male and female patients with a waist circumference≥90 cm or ≥85 cm, respectively.In a dyslipemic population, genetic variants of APOA5 modulate lipoprotein subclass distributions, inducing an atherogenic profile associated with IMT defined subclinical atherosclerosis.

This is the third update of a planning-table for use in cholesterol-lowering therapy, so as to obtain LDLc objectives. This is an easy to use laptop tool to help choose the best statin or combination therapy (statin plus ezetimibe) depending on the current LDL concentration of the patient, and the LDLc objective to achieve. It is based on a colour code that indicates the drugs that are efficient enough to help patients to achieve their LDL goal. Along with the table, recommendations are given for the best strategy in order to implement the optimal therapy in a maximum of two clinical encounters.

Determination of lipoprotein particle size and number using advanced lipoprotein tests (ALTs) is of particular importance to improve cardiovascular risk prediction. Here we present the Liposcale test, a novel ALT based on 2D diffusion-ordered 1H NMR spectroscopy. Our method uses diffusion coefficients to provide a direct measure of the mean particle sizes and numbers. Using 177 plasma samples from healthy individuals and the concentration of ApoB and ApoA from isolated lipoprotein fractions, our test showed a stronger correlation between the NMR-derived lipoprotein particle numbers and apolipoprotein concentrations than the LipoProfile ® test commercialized by Liposcience. We also converted LDL particle numbers to ApoB equivalents (milligrams per deciliter) and our test yielded similar values of LDL-ApoB to the LipoProfile ® test (absolute mean bias of 8.5 and 7.4 mg/dl, respectively). In addition, our HDL particle number values were more concordant with the calibrated values determined recently using ion mobility. Finally, principal component analysis distinguished type 2 diabetic patients with and without atherogenic dyslipidemia (AD) on a second cohort of 307 subjects characterized using the Liposcale test (area under the curve = 0.88) and showed concordant relationships between variables explaining AD. Altogether, our method provides reproducible and reliable characterization of lipoprotein particles and it is applicable to pathological states such as AD. Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.

HDL-increasing drugs such as fenofibrate and niacin have failed to decrease the cardiovascular risk in patients with type 2 diabetes. Drug-mediated quantitative and qualitative HDL modifications could be involved in these negative results. To evaluate the quantitative and qualitative effects of niacin and fenofibrate on HDL in patients with type 2 diabetes, a prospective, randomised controlled intervention trial was conducted. Thirty type 2 diabetic patients with low HDL were randomised to receive either fenofibrate (FFB) or niacin + laropiprant (ERN/LPR) as an add-on to simvastatin treatment for 12 weeks according to a crossover design. At the basal point and after each intervention period, physical examinations and comprehensive standard biochemical determinations and HDL metabolomics were performed. Thirty nondiabetic patients with normal HDL were used as a basal control group. ERN/LRP, but not FFB, significantly increased HDL cholesterol. Neither ERN/LRP nor FFB reversed the HDL particle size or particle number to normal. ERN/LRP increased apoA-I but not apoA-II, whereas FFB produced the opposite effect. FFB significantly increased Preβ1-HDL, whereas ERN/LRP tended to lower Preβ1-HDL. CETP and LCAT activities were significantly decreased only by ERN/LRP. PAF-AH activity in HDL and plasma decreased with the use of both agents. Despite their different actions on antioxidant parameters, none of the treatments induced detectable antioxidant improvements. ERN/LRP and FFB had strikingly different effects on HDL quantity and quality, as well as on HDL cholesterol concentrations. When prescribing HDL cholesterol increasing drugs, this differential action should be considered.

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.

Introduction Clinical registries are a very effective tool to verify the usual clinical practice, to compare clinical strategies and to improve the knowledge of diagnostic and therapeutic new procedures. Methods The National Registry of Dyslipemias of the Spanish Society of Arteriosclerosis (SEA) is an on-line, retrospective and prospective database where the different Spanish lipid units accredited by the SEA introduce data from patients with disorders of lipid metabolism. Results The registry was created in 2013, and since then clinical, analytical, genetic and evolutionary data of 4449 patients have been introduced until June 2017. In the last year the registry has given rise to a considerable number of international publications and there are several more in progress. An ambitious incentive plan for inclusion of patients has been initiated to get the SEA registry as a global reference that helps to improve the knowledge and clinical management of these patients. Conclusions From the coordinating group of the registry we encourage all SEA partners to collaborate in the multiple forms that the registry allows, and to make it an international scientific reference.

Determination of the level of achievement of the low density lipoprotein cholesterol (LDL-C) therapeutic target in patients with high and very high vascular risk treated in Lipid Units, as well as the causes of non-achievement.Multicentre retrospective observational study that included patients over 18 years with high and very high vascular risk, according to the criteria of the 2012 European Guidelines on Cardiovascular Disease Prevention, referred consecutively to Lipid Units between January and June 2012 and with follow-up two years after the first visit.The study included a total of 243 patients from 16 lipid units. The mean age was 52.2 years (SD 13.7), of whom 62.6% were males, and 40.3% of them were very high risk. At the first visit, 86.8% (25.1% in combination) and 95.0% (47.3% in combination) in the second visit (P.001) were treated with lipid-lowering treatment. The therapeutic target was achieved by 28% (95 CI: 22.4-34.1). As regards the causes of non-achievement, 24.6% were related to the medication (10.3% maximum tolerated dose and 10.9% due to the appearance of adverse effects), 43.4% due to the physician (19.4% by inertia, 13.7% considering that target already reached), and 46.9% due to the patient, highlighting the therapeutic non-compliance (31,4%).LDL-C targets were achieved in about one-third of patients. The low adherence of the patient, followed by medical inertia are the most frequent causes that can explain these results.

Background and aims Familial hypercholesterolemia (FH) is a high cardiovascular risk condition. Less than 20% of patients achieve the LDL targets. Although PCSK9 inhibitors improve control and reduce cardiovascular events, official recommendations for their use are restrictive. We aim to assess the number of FH patients suitable for PCSK9 inhibition according to the European guidelines. Methods A total of 2685 FH patients, with a minimum follow-up of 6 months, included in the Dyslipidemia Registry of the Spanish Arteriosclerosis Society, were sorted according to the intensity of their lipid-lowering therapy (LLT) and LDL cholesterol levels achieved. The number of patients who met the recommendations for PCSK9 inhibition treatment according to the European Atherosclerosis Society (ESC/EAS), Spanish Arteriosclerosis Society and the European Medicines Agency was calculated. Results In total, 1573 patients were on high-intensity LLT; 607 were on moderate-intensity statins; 82 were on low-intensity LLT, and 423 were neither on statins nor on ezetimibe in the last visit registered. The mean LDL reduction among those on high-intensity LLT was 54%. Ninety-one percent of patients on high-intensity LLT had an LDL below 5.2 mmol/L, 53% below 3.4 mmol/L, and 23% below 2.6 mmol/L. Only 12% of FH patients with cardiovascular disease achieved 1.8 mmol/L. Despite this, only 17% of patients qualified for PCSK9 inhibition according to ESC/EAS guidelines. Conclusions For patients with a condition that exposes them to high cardiovascular risk and who have extreme difficulties in achieving LDL targets, wider access to PCSK9 inhibitor therapy is warranted.

Patients with heterozygous familial hypercholesterolemia (HeFH) have been reported to be less vulnerable to type 2 diabetes mellitus (T2DM), although the mechanism is unknown. The aims of the present study were to assess the effects of low density lipoprotein (LDL) cholesterol concentration and the presence of FH-causing mutations on T2DM prevalence in HeFH. Data were collected from the Dyslipidemia Registry of the Spanish Arteriosclerosis Society. Inclusion criteria were definite or probable HeFH in patients aged ≥18 years. T2DM prevalence in HeFH patients was compared with data of the general population. 1732 patients were included. The prevalence of T2DM was lower in patients with HeFH compared with the general population (5.94% vs 9.44%; OR: 0.606, 95% CI 0.486–0.755, p

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.

Background— Homozygous familial hypercholesterolemia (HoFH) is a rare disease characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and extremely high risk of premature atherosclerotic cardiovascular disease. HoFH is caused by mutations in several genes, including LDL receptor ( LDLR ), apolipoprotein B ( APOB ), proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), and LDL protein receptor adaptor 1 ( LDLRAP1 ). No epidemiological studies have assessed HoFH prevalence or the clinical and molecular characteristics of this condition. Here, we aimed to characterize HoFH in Spain. Methods and Results— Data were collected from the Spanish Dyslipidemia Registry of the Spanish Atherosclerosis Society and from all molecular diagnoses performed for familial hypercholesterolemia in Spain between 1996 and 2015 (n=16 751). Clinical data included baseline lipid levels and atherosclerotic cardiovascular disease events. A total of 97 subjects were identified as having HoFH—of whom, 47 were true homozygous (1 for APOB , 5 for LDLRAP1 , and 41 for LDLR ), 45 compound heterozygous for LDLR , 3 double heterozygous for LDLR and PSCK9 , and 2 double heterozygous for LDLR and APOB . No PSCK9 homozygous cases were identified. Two variants in LDLR were identified in 4.8% of the molecular studies. Over 50% of patients did not meet the classical HoFH diagnosis criteria. The estimated HoFH prevalence was 1:450 000. Compared with compound heterozygous cases, true homozygous cases showed more aggressive phenotypes with higher LDL-C and more atherosclerotic cardiovascular disease events. Conclusions— HoFH frequency in Spain was higher than expected. Clinical criteria would underestimate the actual prevalence of individuals with genetic HoFH, highlighting the importance of genetic analysis to improve familial hypercholesterolemia diagnosis accuracy.