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AimsMost heterozygous familial hypercholesterolaemia (FH) patients require intensive lipid-lowering therapy (LLT) including PCSK9 inhibitors (PCSK9is) to reach current low-density lipoprotein cholesterol (LDL-C) goals. Persistence with chronic treatment is important to reduce the burden of atherosclerotic cardiovascular disease. We analysed persistence, efficacy, and impact on quality of life (QoL) of PCSK9i in FH patients in clinical practice setting.Methods and resultsSpanish Familial Hypercholesterolaemia Cohort Study (SAFEHEART) is an open, prospective study in genetically defined FH patients in Spain. Patients ≥18 years of age (n = 696, 46% females) on stable LLT treated with PCSK9i were analysed. Median LDL-C at starting PCSK9i was 145 mg/dL [interquartile range (IQR), 123–177], 3.8 mmol/L (IQR 3.2–4.6). After a median follow up of 3.7 years (IQR 2.3–4.8), 27 patients (4%) discontinued PCSK9i treatment: 5 temporarily (0.7%) and 22 permanently (3.2%). Persistence with PCSK9i was 96.1% in the whole period. Median LDL-C levels and % LDL-C reduction attained after 1 year of treatment and in the last follow-up visit were 63 mg/dL (IQR 43–88), 1.6 mmol/L (IQR 1.1–2.23); 61 mg/dL (IQR 44–82), 1.6 mmol/L (IQR 1.1–2.1); 57.6% (IQR 39.5–69); and 58% (IQR 44–68), respectively. 2016 and 2019 ESC/EAS LDL-C goals were attained by 77 and 48% of patients, respectively, at the last follow-up visit (P < 0.001). Mean QoL score increased slightly in the first year and remained stable.ConclusionLong-term persistence with PCSK9i in FH patients is very high, with a good QoL. Effectiveness in LDL-C reduction and LDL-C goal achievement dramatically improved with PCSK9i in this high-risk population in clinical practice setting.Trial registrationClinicalTrials.gov number NCT02693548.

International audience; ObjectivesThis study aimed at investigating the additional contribution of coronary artery calcium (CAC) score to SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study) risk equation (SAFEHEART-RE) for cardiovascular risk prediction in heterozygous familial hypercholesterolemia (HeFH).BackgroundCommon cardiovascular risk equations are imprecise for HeFH. Because of the high phenotype variability of HeFH, CAC score could help to better stratify the risk of atherosclerotic cardiovascular disease (ASCVD).MethodsREFERCHOL (French Registry of Familial Hypercholesterolemia) and SAFEHEART are 2 ongoing national registries on HeFH. We analyzed data from primary prevention HeFH patients undergoing CAC quantification. We used probability-weighted Cox proportional hazards models to estimate HRs. Area under the receiver-operating characteristic curve (AUC) and net reclassification improvement (NRI) were used to compare the incremental contribution of CAC score when added to the SAFEHEART-RE for ASCVD prediction. ASCVD was defined as coronary heart disease, stroke or transient ischemic attack, peripheral artery disease, resuscitated sudden death, and cardiovascular death.ResultsWe included 1,624 patients (mean age: 48.5 ± 12.8 years; men: 45.7%) from both registries. After a median follow-up of 2.7 years (interquartile range: 0.4-5.0 years), ASCVD occurred in 81 subjects. The presence of a CAC score of >100 was associated with an HR of 32.05 (95% CI: 10.08-101.94) of developing ASCVD as compared to a CAC score of 0. Receiving-operating curve analysis showed a good performance of CAC score alone in ASCVD prediction (AUC: 0.860 [95% CI: 0.853-0.869]). The addition of log(CAC + 1) to SAFEHEART-RE resulted in a significantly improved prediction of ASCVD (AUC: 0.884 [95% CI: 0.871-0.894] for SAFEHEART-RE + log(CAC + 1) vs AUC: 0.793 [95% CI: 0.779-0.818] for SAFEHEART-RE; P < 0.001). These results were confirmed also when considering only hard cardiovascular endpoints. The addition of CAC score was associated with an estimated overall net reclassification improvement of 45.4%.ConclusionsCAC score proved its use in improving cardiovascular risk stratification and ASCVD prediction in statin-treated HeFH.

PCSK9 inhibitors are a treatment option for patients with familial hypercholesterolemia not on low-density lipoprotein cholesterol goals despite the use of maximally tolerated high intensity-statins dose.To evaluate the efficacy of alirocumab and evolocumab in LDL-C reduction and targets attainment in patients with heterozygous familial hypercholesterolemia in clinical practice setting.SAFEHEART is an open, long-term prospective study of a cohort of subjects with molecular diagnosis of familial hypercholesterolemia. This study analyze subjects ≥ 20 years of age on stable lipid-lowering therapy, who received PCSK9 inhibitors during the period 2016 to January 2020.433 patients (mean age 55 years, 53% male, 39% with cardiovascular disease) were included and followed-up for a median of 2.5 years (IQR 1.6-3.0). Median LDL-C level prior to PCSK9 inhibitors was 145 mg/dL (IQR 125-173). The addition of PCSK9 inhibitors (211 alirocumab, 222 evolocumab) reduced LDL-C by 58% (IQR 41-70) p0.001, in men and women, achieving a median LDL-C level of 62 mg/dL (IQR 44-87) without differences between both PCSK9 inhibitors. Out of them 67% with and 80% without cardiovascular disease reached 2016 ESC/EAS LDL-C targets, and 46% very high risk and 50% high risk patients achieved 2019 ESC/EAS LDL-C goals. Independent predictor factors for attainment of 2019 ESC/EAS LDL-C goals were to be male, smoking and the use of statins with ezetimibe. Both inhibitors were well tolerated.PCSK9 inhibitors on top of maximum lipid-lowering treatment significantly reduced LDL-C levels in patients with familial hypercholesterolemia and improved the achievement of LDL-C targets.

Heterozygous familial hypercholesterolemia (FH) is associated with premature atherosclerotic cardiovascular disease. Semi-automated plaque characterization (SAPC) by coronary computed tomographic angiography (CTA) provides information regarding coronary plaque burden and plaque characterization. Our aim was to quantify and characterize the coronary plaque burden of patients with FH using SAPC analysis and to identify which factors are related to plaque burden and plaque characteristics. A second aim was to analyse the prognostic implications of these parameters.Two hundred and fifty-nine asymptomatic individuals with molecularly determined FH were enrolled in this follow-up cohort study and underwent a coronary CTA analysed with SAPC.Mean follow-up time after coronary CTA was 3.9 ± 2 years. Mean age was 46.9 (10.7) years (130 women, 50.2%). Median plaque burden was 25.0% (19.0-29.0), non-calcified plaque burden 22.83% (17.94-26.88), calcified plaque-burden 1.12% (0.31-2.86) and CCS 8.9 (0-93). Five-year risk was independently related to plaque burden, non-calcified plaque burden, calcified plaque burden and coronary calcium score (B:3.75, 95%CI:2.92-4.58; p 0.001, B:2.9, 95%CI:2.15-3.66; p 0.001, B:0.75, 95%CI 0.4-1.1; p 0.001 and B:82.2, 95%CI:49.28-115.16; p 0.001 respectively). During follow-up, there were 15 (5.81%) nonfatal events and 1 (0.4%) fatal event. Plaque burden was significantly related to event-free survival during follow-up (HR:1.11; 95%CI:1.05-1.18; p 0.001).Coronary atherosclerosis and its qualitative components may be quantified by means of SAPC in patients with FH. Plaque burden, calcified plaque burden and non-calcified plaque burden were independently related to the estimated cardiovascular risk. Plaque burden was also related to prognosis.

Resumen Introduccion y objetivos El estudio SAFEHEART se diseno para analizar la situacion y mejorar el conocimiento de la hipercolesterolemia familiar heterocigota (HFH) en Espana. Nuestro objetivo es determinar la tasa de incidencia de eventos cardiovasculares, el riesgo estimado de sufrir un evento y su modificacion, el empleo de tratamiento hipolipemiante y la consecucion de objetivos de colesterol unido a lipoproteinas de baja densidad en pacientes con HFH. Metodos El SAFEHEART es un estudio prospectivo de cohorte, abierto, multicentrico, de escala nacional, con seguimiento protocolizado a largo plazo en una poblacion de HFH caracterizada molecularmente. Se analizo a los pacientes mayores de 18 anos con seguimiento completo. Resultados El analisis en este estudio se hizo con 2.648 pacientes con HFH. La mediana de seguimiento fue de 6,6 (4,8-9,7) anos. La tasa de incidencia general de eventos cardiovasculares fue de 1,3 eventos/100 pacientes-ano. El riesgo estimado de sufrir un evento cardiovascular a 10 anos se redujo en el seguimiento, y paso del 1,6 al 1,3% (p Conclusiones En este estudio se muestra la tasa de incidencia de eventos cardiovasculares, el riesgo estimado de sufrir un evento cardiovascular en la mayor poblacion de pacientes con HF en Espana, asi como su modificacion, la consecucion de objetivos en colesterol unido a lipoproteinas de baja densidad y su tratamiento. Aunque el riesgo cardiovascular de la HFH es elevado, un adecuado tratamiento reduce la probabilidad de sufrir un evento. Estudio registrado en ClinicalTrials.gov (Identificador: NCT02693548).

Background and aims Heterozygous familial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of low-density lipoprotein cholesterol (LDL-C). The magnitude of atherosclerotic cardiovascular disease (ASCVD) risk in FH patients is highly variable, and this can result from genetic factors. The aim of our study was to characterize whether polymorphisms in VEGFR2 and OPG genes could influence the expression of ASCVD in FH patients. Methods We studied 318 FH patients from the SAFEHEART registry, without clinical diagnosis of ASCVD. A coronary tomographic angiography (CTA) was performed to determine and evaluate the presence of coronary stenosis and coronary artery calcium, as measured by coronary calcium score (CCS). Genotyping of OPG rs2073618 and VEGFR2 rs2071559 polymorphisms was performed using TaqMan 5′-exonuclease allelic discrimination assays. Results Homozygous GG genotype and G allele of VEGFR2 rs2071559 polymorphism were associated with decreased risk of developing coronary artery stenosis. In the analysis of OPG rs2073618 and VEGFR2 rs2071559 polymorphisms, according to the presence of coronary artery calcium, we found significant differences in both polymorphisms. Homozygous GG genotype and G allele of VEGFR2 rs2071559 polymorphism were associated with decreased risk of accumulation of coronary artery calcium measured by CCS in CTA. Moreover, being a carrier of the GG genotype and G allele of the OPG rs2073618 polymorphism increased the risk of the presence of coronary artery calcium measured by CCS in CTA. Conclusions Polymorphisms in VEGFR2 and OPG genes modify the risk of ASCVD in FH patients.

Secondary hypertriglyceridemia (HTG) are the most common cause of excess triglyceride rich particles in plasma. Faced with HTG, the first thing to do is rule out if there is a secondary cause since it can interact with genetic susceptibility and further aggravate the HTG. The most common causes are diet with high fat and high glycemic index, obesity, diabetes mellitus, alcohol consumption, renal disease like nephrotic syndrome, hepatic disorders and medications. The most important medications that can influence in HTG are oestrogen, isotretinoin, immunosuppressant therapy, L-asparaginase and with less effect thiazides, beta blockers, atypical antipsychotics and glucocorticoids. Other causes less frequent are endocrinological diseases such as Cushing's syndrome, acromegaly, hypothyroidism; pregnancy, lipodystrophies and autoimmune diseases. Lastly, the identifications and treatment or correction of secondary causes is a corner stone in the treatment of this disease.

Aims Familial hypercholesterolaemia (FH) and elevated lipoprotein(a) [Lp(a)] are inherited disorders associated with premature atherosclerotic cardiovascular disease (ASCVD). Aortic valve stenosis (AVS) is the most prevalent valvular heart disease and low-density lipoprotein cholesterol (LDL-C) and Lp(a) may be involved in its pathobiology. We investigated the frequency and predictors of severe AVS requiring aortic valve replacement (AVR) in molecularly defined patients with FH. Methods and results SAFEHEART is a long-term prospective cohort study of a population with FH and non-affected relatives (NAR). We analysed the frequency and predictors of the need for AVR due to AVS in this cohort. Five thousand and twenty-two subjects were enrolled (3712 with FH; 1310 NAR). Fifty patients with FH (1.48%) and 3 NAR (0.27%) required AVR [odds ratio 5.71; 95% confidence interval (CI): 1.78–18.4; P = 0.003] after a mean follow-up of 7.48 (3.75) years. The incidence of AVR was significantly higher in patients with FH (log-rank 5.93; P = 0.015). Cox regression analysis demonstrated an association between FH and AVR (hazard ratio: 3.89; 95% CI: 1.20–12.63; P = 0.024), with older age, previous ASCVD, hypertension, increased LDL-CLp(a)-years, and elevated Lp(a) being independently predictive of an event. Conclusion The need for AVR due to AVS is significantly increased in FH patients, particularly in those who are older and have previous ASCVD, hypertension, increased LDL-CLp(a)-years and elevated Lp(a). Reduction in LDL-C and Lp(a) together with control of hypertension could retard the progression of AVS in FH, but this needs testing in clinical trials. ClinicalTrials.gov number NCT02693548.

Resumen Introduccion y objetivos Poco se conoce acerca de las caracteristicas de los sujetos con hipercolesterolemia familiar (HF) menores de 18 anos, asi como del tratamiento hipolipemiante empleado en estos pacientes y la consecucion de objetivos lipidicos en la vida real. Nuestro objetivo es valorar la consecucion de objetivos de colesterol unido a lipoproteinas de baja densidad (cLDL) en pacientes con HF menores de 18 anos incluidos en un gran registro nacional. Metodos Se analizo a los pacientes menores de 18 anos incluidos en un gran registro en marcha de pacientes con diagnostico genetico de HF en Espana. Se analizo la consecucion de los objetivos recomendados de cLDL en plasma a la inclusion y en el seguimiento en relacion con el uso de terapia hipolipemiante. Resultados Se incluyo a 392 individuos menores de 18 anos, de los que 217 obtuvieron diagnostico genetico de HF y seguimiento completo. El tiempo de seguimiento medio fue 4,69 [intervalo intercuartilico, 2,48-6,38] anos; el 68,2% de los casos con HF tomaban estatinas y el 41,5% de los pacientes tenian el cLDL Conclusiones Este estudio demostro que una alta proporcion de pacientes con HF menores de 18 anos tenia altas concentraciones de cLDL y no lograron alcanzar los objetivos de cLDL recomendados. El uso de estatinas fue el unico predictor independiente asociado a conseguir el objetivo de cLDL recomendado. No se detecto ningun problema de seguridad durante el seguimiento. Estos resultados enfatizan que muchos pacientes con HF no estan suficientemente controlados y aun es posible mejorar del tratamiento.

Introduction and objectives Little is known about the characteristics of persons with familial hypercholesterolemia (FH) younger than 18 years, the lipid-lowering therapy used in these patients, and the lipid goals reached in real life. Our aim was to evaluate the achievement of low-density lipoprotein cholesterol (LDL-C) treatment goals in FH patients younger than 18 years enrolled in a large national registry. Methods We analyzed patients younger than 18 years enrolled in a large ongoing registry of molecularly-defined patients with FH in Spain. The attainment of guideline-recommended plasma LDL-C goals at entry and follow-up was analyzed in relation to the use of lipid-lowering therapy. Results We enrolled 392 individuals younger than 18 years. Of these, 217 were molecularly-diagnosed FH patients and had a complete follow-up. The median follow-up time was 4.69 years (interquartile range, 2.48-6.38 years), 68.2% of FH patients were on statins, and 41.5% patients had LDL-C Conclusions This study shows that a high proportion of FH patients younger than 18 years have high LDL-C levels and fail to achieve recommended LDL-C targets. Statin use was the only independent predictor of LDL-C goal achievement. No safety concerns were detected during follow-up. These results indicate that many FH patients are not adequately controlled and that there is still room for treatment improvement.

Introduction and objectives: The SAFEHEART study was designed to analyze the situation of familial heterozygous hypercholesterolemia (FHH) and improve knowledge of this disease in Spain. Our objective was to determine the incidence rate of cardiovascular events, the estimated risk of developing an event and its modification, the use of lipid-lowering treatment, and the achievement of low-density lipoprotein cholesterol targets in patients with FHH. Methods: SAFEHEART is a prospective, open, multicenter, nationwide cohort study, with long-term protocol-based follow-up in a population of individuals with molecularly-characterized FHH. We analyzed patients older than 18 years with complete follow-up. Results: We included 2648 patients with FHH. The median follow-up was 6.6 (4.8-9.7) years. The overall incidence rate of cardiovascular events was 1.3 events/100 patient-years. After the follow-up, the 10-year estimated risk of developing a cardiovascular event was reduced from 1.6% to 1.3% (P

[Background] Maximal doses of potent statins are the basement of treatment of familial hypercholesterolemia (FH). Little is known about the use of different statin regimens in FH., [Objectives] The objectives of the study were to describe the treatment changes and low-density lipoprotein cholesterol (LDL-C) goal achievement with atorvastatin (ATV) and rosuvastatin (RV) in the SAFEHEART cohort, as well as to analyze the incidence of atherosclerotic cardiovascular events (ACVEs) and changes in the cardiovascular risk., [Methods] SAFEHEART is a prospective follow-up nationwide cohort study in a molecularly defined FH population. The patients were contacted on a yearly basis to obtain relevant changes in life habits, medication, and ACVEs., [Results] A total of 1939 patients were analyzed. Median follow-up was 6.6 years (5–10). The estimated 10-year risk according the SAFEHEART risk equation was 1.61 (0.67–3.39) and 1.22 (0.54–2.93) at enrollment for ATV and RV, respectively (P < .001). There were no significant differences at the follow-up: 1.29 (0.54–2.82) and 1.22 (0.54–2.76) in the ATV and RV groups, respectively (P = .51). Sixteen percent of patients in primary prevention with ATV and 18% with RV achieved an LDL-C, [Conclusion] ATV and RV are 2 high-potency statins widely used in FH. Although the reduction in LDL-C levels was greater with RV than with ATV, the superiority of RV for reducing ACVEs was not demonstrated., This study was supported by Fundación Hipercolesterolemia Familiar; Grant G03/181 and FIS PI12/01289 from Instituto de Salud Carlos III (ISCIII), Grant 08-2008 Centro Nacional de Investigación Cardiovascular (CNIC).

Background Familial hypercholesterolemia (FH) is the most common genetic disorder associated with premature atherosclerotic cardiovascular disease (ASCVD). There are sparse data on attainment of treatment targets; large registries that reflect real-life clinical practice can uniquely provide this information. Objectives We sought to evaluate the achievement of low-density lipoprotein cholesterol (LDL-C) treatment goals in FH patients enrolled in a large national registry. Methods The SAFEHEART study (Spanish Familial Hypercholesterolemia Cohort Study) is a large, ongoing registry of molecularly defined patients with heterozygous FH treated in Spain. The attainment of guideline-recommended plasma LDL-C goals at entry and follow-up was investigated in relation to use of lipid-lowering therapy (LLT). Results The study recruited 4,132 individuals (3,745 of whom were ≥18 years of age); 2,752 of those enrolled were molecularly diagnosed FH cases. Mean follow-up was 5.1 ± 3.1 years; 71.8% of FH cases were on maximal LLT, and an LDL-C treatment target Conclusions Despite the use of intensified LLT, many FH patients continue to experience high plasma LDL-C levels and, consequently, do not achieve recommended treatment targets. Type of LDL-receptor mutation, use of ezetimibe, coexistent diabetes, and ASCVD status can bear significantly on the likelihood of attaining LDL-C treatment goals.

The association of components of a low saturated fat (SFA) and of a Mediterranean diet was tested with atherosclerosis biomarkers in 190 familial hypercholesterolemia adults (FH) from Brazil (BR) and Spain (SP). Median blood LDL-C, Apolipoprotein B (apoB), and C reactive protein (hs-CRP) concentrations were higher in BR than in SP: 179.0 vs.161 mg/dL; 141 vs. 103 mg/dL; and 1.6 vs. 0.8 mg/L respectively (all p, The funding of Sociedade Hospital Samaritano and Ministério da Saúde (PROADI-SUS; SIPAR: 25000.180.672/2011-81) and FAPESP (grant no 2013/17368-0) are gratefully acknowledged.

[Objective] Healthy lifestyle habits are the cornerstone in the management offamilial hypercholesterolaemia (FH). Nevertheless, dietary studies on FH-affectedpopulations are scarce. The present study analyses dietary habits, adherence to aMediterranean diet pattern and physical activity in an adult population with FHand compares them with their non-affected relatives., [Design] Cross-sectional study., [Setting] Data came from SAFEHEART, a nationwide study in Spain., [Participants] Individuals (n 3714) aged ≥18 years with a genetic diagnosis of FH (n2736) and their non-affected relatives (n 978). Food consumption was evaluated using a validated FFQ., [Results] Total energy intake was lower in FH patients v. non-affected relatives (P, [Conclusions] Adult patients with FH report healthier lifestyles than their non-affected family members. They eat a healthier diet, perform more physical activity and smoke less. However, this patient group’s consumption of saturated fats and sugars still exceeds guidelines., This work was supported by Fundación Hipercolesterolemia Familiar; the Instituto de Salud Carlos III (ISCIII; grant numbers G03/181 and FIS PI12/01289); and Centro Nacional de Investigación Cardiovascular (CNIC; grant number 08-2008).

Background Erectile dysfunction affects more than 100 million men worldwide, with a wide variability in prevalence. An overall association of cardiovascular risk factors, lifestyle and diet in the context of ED in a Mediterranean population is lacking. Aim To assess ED prevalence and associated factors in a Mediterranean cohort of non-diabetic patients with cardiovascular risk factors. Methods Observational, cross-sectional study of patients aged over 40 treated at cardiovascular risk units in Catalonia. Anthropometric data, risk factors, lifestyle and diet habits were recorded. ED was assessed using the International Index of Erectile Function. Results Four hundred and forty patients included, 186 (42.3%) with ED (24.8% mild, 6.8% moderate and 10.7% severe). ED presence and severity were associated with age, obesity, waist circumference, hypertension, antihypertensive treatment and ischaemic disease. Patients with ED were more frequently smokers, sedentary and consumed more alcohol. In multivariate analysis, consumption of nuts (> twice a week) (OR 0.41 (95% CI 0.25 to 0.67) and vegetables (≥ once a day) (OR 0.47 (95% CI 0.28–0,77)), were inversely related to ED. Obesity (as BMI ≥ 30 kg/m2) (OR 2.49 (95% CI 1.48–4.17)), ischaemic disease (OR 2.30 (95% CI 1.22 to 4.33), alcohol consumption (alcohol-units a day) (OR 1.14 (95% CI 1.04 to 1.26), and age (year) (OR = 1.07 (95% CI 1.04–1.10) were directly related to ED. Conclusion Erectile dysfunction is a common disorder in patients treated in lipid units in Catalonia for cardiovascular risk factors. This condition is associated with age, obesity, ischaemic disease and unhealthy lifestyle habits.

BACKGROUND: Familial hypercholesterolemia (FH) confers an increased risk of premature atherosclerotic disease. Coronary computed tomographic angiography (CTA) can assess preclinical coronary atherosclerosis. OBJECTIVES: To describe coronary CTA findings in asymptomatic molecularly defined FH individuals, to identify those factors related to its presence and extension, and to assess the impact of these results in patients' care and estimated risk. METHODS: Four hundred and forty individuals with FH, without clinical cardiovascular disease, were consecutively enrolled and underwent a coronary CTA that was used to analyze coronary atherosclerosis based on coronary calcium score (CCS), sum of stenosis severity, and plaque composition sum (PCS). For FH patients, cardiovascular risk was estimated using the specific SAFEHEART risk equation. Follow-up was performed using a standardized protocol. RESULTS: Mean age was 46.4 years (231 women, 52%). Coronary calcium was present in 55%, mean CCS was 130.9, 46% had a plaque with lumen involvement, and mean PCS was 1.1. During follow-up, there were 17 (4%) nonfatal events and 2 (1%) fatal events. CCS was independently associated to the estimated risk and low-density lipoprotein-cholesterol life-years, sum of stenosis severity to the estimated risk, and PCS to the estimated risk and low-density lipoprotein-cholesterol life-years. CTA findings induced a positive change in patients' care and in their estimated risk. CONCLUSION: Coronary artery atherosclerosis is highly prevalent in asymptomatic patients with FH and it is independently associated to cardiovascular risk. More advanced disease on CTA was associated with subsequent intensification of therapy and reduction of estimated risk. Further longitudinal studies are required to know if these findings might improve the risk stratification in patients with FH. (C) 2018 National Lipid Association. All rights reserved.

Resumen Introduccion La hipercolesterolemia familiar es una enfermedad autosomica dominante que cursa con niveles plasmaticos elevados de colesterol unido a lipoproteinas de baja densidad. La presencia de esta alteracion en el metabolismo lipidico se asocia a un aumento del riesgo cardiovascular en los pacientes que la padecen, siendo de gran importancia la realizacion de un diagnostico genetico para ofrecer un tratamiento adecuado y disminuir la morbimortalidad. El objetivo de este trabajo es describir la aplicacion de la secuenciacion de nueva generacion al diagnostico genetico de la hipercolesterolemia familiar, en comparacion con la secuenciacion Sanger, la tecnica convencional usada hasta el momento. Material y metodos Se analizaron 110 muestras de sangre venosa periferica procedente de pacientes que presentaban cuadro clinico de hipercolesterolemia familiar mediante secuenciacion de nueva generacion, utilizando un panel comercial que permite la identificacion de mutaciones en los genes LDLR, APOB, PCSK9 y LDLRAP1 (SEQPRO Lipo, Progenika) con la tecnologia GS JUNIOR 454 (Roche). Resultados Aplicando esta tecnologia fue posible secuenciar los genes asociados a la hipercolesterolemia familiar descritos hasta el momento en grupos de hasta 20 pacientes simultaneamente. Se detectaron un total de 35 mutaciones en las 110 muestras analizadas, localizandose el 94,29% en el gen LDLR. Todas las mutaciones identificadas fueron confirmadas mediante el metodo de secuenciacion Sanger. Conclusiones La utilizacion de la secuenciacion masiva de nueva generacion permite la realizacion de un diagnostico genetico mas rapido y un analisis molecular mas eficiente de los genes implicados en la hipercolesterolemia familiar con una fiabilidad similar a la tecnica convencional Sanger.

Background: Although risk factors for atherosclerotic cardiovascular disease (ASCVD) in familial hypercholesterolemia (FH) have been described, models for predicting incident ASCVD have not been reported. Our aim was to use the SAFEHEART registry (Spanish Familial Hypercholesterolemia Cohort Study) to define key risk factors for predicting incident ASCVD in patients with FH. Methods: SAFEHEART is a multicenter, nationwide, long-term prospective cohort study of a molecularly defined population with FH with or without previous ASCVD. Analyses to define risk factors and to build a risk prediction equation were developed, and the risk prediction equation was tested for its ability to discriminate patients who experience incident ASCVD from those who did not over time. Results: We recruited 2404 adult patients with FH who were followed up for a mean of 5.5 years (SD, 3.2 years), during which 12 (0.5%) and 122 (5.1%) suffered fatal and nonfatal incident ASCVD, respectively. Age, male sex, history of previous ASCVD, high blood pressure, increased body mass index, active smoking, and low-density lipoprotein cholesterol and lipoprotein(a) levels were independent predictors of incident ASCVD from which a risk equation with a Harrell C index of 0.85 was derived. The bootstrap resampling (100 randomized samples) of the original set for internal validation showed a degree of overoptimism of 0.003. Individual risk was estimated for each person without an established diagnosis of ASCVD before enrollment in the registry by use of the SAFEHEART risk equation, the modified Framingham risk equation, and the American College of Cardiology/American Heart Association ASCVD Pooled Cohort Risk Equations. The Harrell C index for these models was 0.81, 0.78, and 0.8, respectively, and differences between the SAFEHEART risk equation and the other 2 were significant ( P =0.023 and P =0.045). Conclusions: The risk of incident ASCVD may be estimated in patients with FH with simple clinical predictors. This finding may improve risk stratification and could be used to guide therapy in patients with FH. Clinical Trial Registration: URL: http://clinicaltrials.gov . Unique identifier: NCT02693548.

Objectives: This study describes health-related quality of life (HRQL) in a large sample of molecularly defined familial hypercholesterolemia (FH) patients compared with unaffected relatives. Study design and setting: Cross-sectional study of cases recruited in the Spanish FH cohort study. A total of 1947 subjects ≥18 years were included—1321 FH and 626 unaffected relatives. HRQL was assessed by 12-Item Short-Form Health Survey questionnaire. Main outcomes were as follows: Self-perceived health, physical summary component, mental summary component and their independent covariates. Results: Mean age was 45.3 years in FH subjects and 40.4 years in control subjects ( P < 0.001). Cardiovascular disease (CVD) was present in 14.1% of FH patients and in 3.2% of control subjects ( P < 0.001). Frequency of optimal self-perceived health, mean physical summary component and mental summary component of FH patients (81.5%, 52.1 and 51.1, respectively), were similar to those of control subjects (83.1%, 53.1 and 51.1, respectively). Factors independently associated with a worse HRQL in FH patients were as follows: CVD, female gender, older age, depression, obesity, lower educational level, lower physical activity and xanthomas. Conclusions: HRQL of FH patients was similar to control subjects, despite their higher burden of premature CVD. The most important factors with a negative impact in quality of life in FH are CVD, female gender and older age.

Objective Hypercholesterolemia is an early risk factor for Alzheimer's disease. Low-density lipoprotein (LDL) receptors might be involved in this disorder. Our objective was to determine the risk of mild cognitive impairment in a population of patients with heterozygous familial hypercholesterolemia, a condition involving LDL receptor dysfunction and lifelong hypercholesterolemia. Methods By using a cohort study design, patients with familial hypercholesterolemia (N=47) meeting inclusion criteria and comparison patients without familial hypercholesterolemia (N=70) were consecutively selected from academic specialty and primary care clinics, respectively. All patients were older than 50 years. Those with disorders that could affect cognition, including history of stroke or transient ischemic attacks, were excluded from both groups. Thirteen standardized neuropsychologic tests were performed in all subjects. Mutational analysis was performed in patients with familial hypercholesterolemia, and brain imaging was obtained in those with familial hypercholesterolemia and mild cognitive impairment. Results Patients with familial hypercholesterolemia showed a high incidence of mild cognitive impairment compared with those without familial hypercholesterolemia (21.3% vs 2.9%; P =.00). This diagnosis was unrelated to structural pathology or white matter disease. There were significant differences, independent of apolipoprotein E4 or E2 status, between those with familial hypercholesterolemia and those with no familial hypercholesterolemia in several cognitive measures, all in the direction of worse performance for those with familial hypercholesterolemia. Conclusion Because prior studies have shown that older patients with sporadic hypercholesterolemia do not show a higher incidence of mild cognitive impairment, the findings presented suggest that early exposure to elevated cholesterol or LDL receptor dysfunction may be risk factors for mild cognitive impairment.

Background and objective High-resolution B-mode ultrasound measurements of intima-media thickness (IMT) and plaque presence are useful to assess preclinical atherosclerosis. Normal carotid IMT values, but not normal femoral IMT values, have been reported in Spanish subjects. Our aim was to define the normality data of femoral ultrasound by sex and age. Subjects and method We studied 192 healthy subjects from a community cohort, 85 men and 107 women (mean age: 49 years; range: 20-81 years). We sonographically determined mean and maximum IMT in the far wall of the common femoral artery, plaque occurrence, and maximum plaque height. Results Reference values for femoral IMT, expressed as 25th, 50th, and 75th percentiles by sex and 5 age groups, were obtained. The 50th percentiles of mean IMT ranged from 0.50 to 1.04 mm in men in the age groups or = 65 years, respectively. For women, corresponding IMT values ranged from 0.40 to 0.53 mm. IMT was positively related to age in both men (r = 0.44; p or = 55 years and women aged > or = 65 years had plaques. Conclusions Both IMT and plaque frequency are associated with age in men and women. Femoral IMT values in a Spanish community cohort are lower than those reported for geographical areas with higher cardiovascular risk, such as the Northern European countries and the US.

Introduccion y objetivo La hiperlipemia familiar combinada (HFC) es la hiperlipemia genetica mas comun, y una causa frecuente de enfermedad cardiovascular prematura. Sin embargo, el origen genetico de esta enfermedad todavia no se conoce totalmente. En el presente estudio, analizamos el perfil de expresion genica en monocitos de sangre periferica en un grupo de individuos control y en un grupo de pacientes con HFC antes y despues del tratamiento con atorvastatina (ATV), con el objetivo de estudiar y profundizar en los mecanismos geneticos asociados a esta enfermedad, e identificar posibles dianas terapeuticas nuevas. Metodos y resultados Se aislaron monocitos de sangre periferica de individuos control y de pacientes con HFC, del mismo sexo y edad, antes y despues del tratamiento con ATV. El perfil de expresion genica se obtuvo usando los microarrays GeneChip Human Genome U133A de Affymetrix, y los cambios en la expresion de los genes seleccionados se validaron posteriormente con la tecnica de retro-transcripcion de la reaccion en cadena de la polimerasa a tiempo real. Nuestros resultados mostraron cambios en la expresion de numerosos genes implicados en funciones clave del macrofago, especialmente en la respuesta inflamatoria (MNDA, IL1R2, ALCAM, LRIG1 y DR3), el control de la composicion de la matriz extracelular (FN1, SDC2 y TFPI2) y el metabolismo lipidico (CD36). Conclusiones Nuestros resultados indican que la HFC afecta de forma directa o indirecta al perfil de expresion genica en monocitos de sangre periferica. Los cambios en la expresion de algunos genes (MNDA, CD36, TFPI2, LRIG1 y DR3) podrian atribuirse al entorno proinflamatorio que rodea los monocitos en la HFC, que es parcialmente revertido por el tratamiento con ATV. Por otra parte, los cambios en la expresion genica que no revierten tras el tratamiento con ATV podrian relacionarse con anomalias metabolicas del tejido adiposo (valores bajos de adiponectina y elevacion de acidos grasos libres y trigliceridos) que no se corrigen con este tratamiento.

Objectives To assess how ultrasound measurements of carotid intima-media thickness (CIMT) and plaque burden compare with the Framingham Risk Score (FRS) in a clinical setting. Methods and results In a cross-sectional study, we determined CIMT and plaque in 409 asymptomatic, non-diabetic hyperlipidemic subjects (242 men, age 49 ± 11 years) who were assessed for risk factors and classified into FRS categories: 10-year risk ≤5% ( n = 191), 6–20% ( n = 176), and >20% ( n = 42). Percentiles of CIMT and plaque height and regression equations of CIMT against age obtained in 250 controls subjects were used to define atherosclerosis and estimate vascular age, respectively. There was a wide dispersion of CIMT for each FRS category. CIMT values were discordant in 242 (59%) subjects, 80% of them showing more atherosclerosis than predicted. Smoking and the metabolic syndrome explained part of the discrepancies in the intermediate-risk group. Triglycerides, homocysteine, and lipoprotein(a) did not predict atherosclerotic burden. Mean vascular age was 14.5 years older than chronological age. Conclusions Carotid atherosclerosis findings readjust FRS categories in many asymptomatic subjects. Both carotid atherosclerotic burden and vascular age may be used to refine CHD risk and tailor preventive treatment beyond the FRS.

Background and aims We aimed to assess whether elevated PCSK9 and lipoprotein (a) [Lp(a)] levels associate with coronary artery calcification (CAC), a good marker of atherosclerosis burden, in asymptomatic familial hypercholesterolemia. Methods We selected 161 molecularly defined FH patients treated with stable doses of statins for more than a year. CAC was measured using the Agatston method and quantified as categorical variable. Fasting plasma samples were collected and analyzed for lipids and lipoproteins. PCSK9 was measured by ELISA, Lp(a) and apolipoprotein (a) concentrations by inmunoturbidimetry and LC-MS/MS, respectively. Results Circulating PCSK9 levels were significantly reduced in patients without CAC (n = 63), compared to those with CAC (n = 99). Patients with the highest CAC scores (above 100) had the highest levels of circulating PCSK9 and Lp(a). In multivariable regression analyses, the main predictors for a positive CAC score was age and sex followed by circulating PCSK9 and Lp(a) levels. Conclusions In statin treated asymptomatic FH patients, elevated PCSK9 and Lp(a) levels are independently associated with the presence and severity of CAC, a good predictor of coronary artery disease.

Autosomal dominant hypercholesterolaemia (ADH) are a heterogeneous group of monogenic lipid disorders. The plasma level of lipoprotein(a) (Lp(a)) is a heritable trait associated with increased coronary heart disease (CHD) risk.To evaluate the frequency of elevated Lp(a) as a cause of ADH and the characteristics of subjects with high Lp(a) (hyperLp(a)).200 healthy subjects and 933 unrelated Spanish subjects with a clinical diagnosis of ADH who were screened for low-density lipoprotein receptor (LDLR) and apolipoprotein B (APOB) gene mutations. Standard cardiovascular risk factors and blood lipid levels, including Lp(a), were evaluated. HyperLp(a) was defined as Lp(a) levelsor=95th centile of control values.Lp(a) was higher in 263 subjects without LDLR or APOB mutations (nonLDLR/nonAPOB group) than in 670 subjects with mutations (FH group): 40.0 mg/dl (interquartile range (IR) 15.0-89.0) versus 31.0 mg/dl (IR 11.0-73.7) respectively, p = 0.002. HyperLp(a) was present in 23% of ADH subjects (odds ratio (OR) 5.6 (95% CI, 2.9 to 10.7) versus controls) and 29% of nonLDLR/nonAPOB subjects (OR 7.7; 3.9 to 15.4). After adjusting for Lp(a), LDL cholesterol levels were95th centile in 28 (10.6%) nonLDLR/nonAPOB subjects and in 9 (1.3%) FH subjects. Lp(a) levels were nonsignificantly higher in ADH subjects with early-onset CHD than in those without (43.5 mg/dl, (IR, 12.0-82.0) versus 31.7 mg/dl (11.8-76.5), respectively).HyperLp(a) is responsible for ADH in approximately 6% of nonLDLR/nonAPOB subjects. HyperLp(a) would not appear to be a risk factor for early-onset CHD in ADH, independently of whether genetic defects have or have not been demonstrated.

Familial hypercholesterolemia (FH) is the most common genetic disorder associated with premature atherosclerotic cardiovascular disease (ASCVD). There are sparse data on attainment of treatment targets; large registries that reflect real-life clinical practice can uniquely provide this information.We sought to evaluate the achievement of low-density lipoprotein cholesterol (LDL-C) treatment goals in FH patients enrolled in a large national registry.The SAFEHEART study (Spanish Familial Hypercholesterolemia Cohort Study) is a large, ongoing registry of molecularly defined patients with heterozygous FH treated in Spain. The attainment of guideline-recommended plasma LDL-C goals at entry and follow-up was investigated in relation to use of lipid-lowering therapy (LLT).The study recruited 4,132 individuals (3,745 of whom were ≥18 years of age); 2,752 of those enrolled were molecularly diagnosed FH cases. Mean follow-up was 5.1 ± 3.1 years; 71.8% of FH cases were on maximal LLT, and an LDL-C treatment target100 mg/dl was reached by only 11.2% of patients. At follow-up, there was a significant increase in the use of ezetimibe, drug combinations with statins, and maximal LLT. The presence of type 2 diabetes mellitus, a defective allele mutation, ezetimibe use, and the absence of previous ASCVD were predictors of the attainment of LDL-C goals.Despite the use of intensified LLT, many FH patients continue to experience high plasma LDL-C levels and, consequently, do not achieve recommended treatment targets. Type of LDL-receptor mutation, use of ezetimibe, coexistent diabetes, and ASCVD status can bear significantly on the likelihood of attaining LDL-C treatment goals.

Objective— The effect of risk factors on carotid atherosclerosis in heterozygous familial hypercholesterolemia (FH) is unclear. We evaluated carotid intima-media thickness (IMT) by sonography in relation to classical and emergent risk factors in a large FH cohort. Methods and Results— Risk factors and carotid IMT were assessed in 196 asymptomatic subjects aged ≥25 years fulfilling strict diagnostic criteria for clinical FH who were either undertreated or treatment-naive. Conventional risk factors, but not lipoprotein(a), homocysteine, or apolipoprotein E (apoE) genotypes were univariately related to IMT. Age-adjusted and gender-adjusted IMT increased with increasing low-density lipoprotein (LDL) cholesterol and decreased with increasing high-density lipoprotein (HDL) cholesterol. Compared with a total cholesterol/HDL ratio >5.0, a ratio ≤5.0 was associated with a lower adjusted IMT, with a mean difference of −0. 09 mm (95% confidence interval, −0.13 to −0.04). By multivariate analysis, age, HDL cholesterol (negatively), physical exercise, family history of early-onset coronary heart disease, LDL cholesterol, and leukocyte count, in this order, were independent associations of IMT (r 2 =0.429, P Conclusions— Traditional risk factors account for a sizeable proportion of variation in carotid IMT in FH. Because the HDL cholesterol level and the total cholesterol/HDL ratio are strong predictors of preclinical carotid atherosclerosis, HDL cholesterol-raising strategies should have an important therapeutic role in FH.

BACKGROUND AND OBJECTIVE: High-resolution B-mode ultrasound measurements of carotid intima-media thickness (IMT) and determination of plaque presence are useful to assess preclinical atherosclerosis. Normal IMT values have not been reported in Spanish subjects. Our aim was to define normality data of carotid ultrasound by sex and age. SUBJECTS AND METHODS: We studied 250 healthy, normolipidemic subjects, 125 men and 125 women, with mean age 49 years (range, 20-81). We assessed cardiovascular risk factors and performed ultrasound determination of mean and maximum IMT in the far wall of the common carotid artery, plaque occurrence, and maximum plaque height. RESULTS: Reference values for carotid IMT, expressed as 25th, 50th, and 75th percentiles by sex and 5 age groups, have been obtained. The 50th percentiles of mean IMT ranged from 0.50 to 0.74 mm in men in the age groups 35 years or younger and 65 years or older, respectively. For women, corresponding IMT values ranged from 0.40 to 0.65 mm. IMT was strongly related (p < 0.001) to age, both in men (r = 0.57) and women (r = 0.61). From the regression equations, the estimated yearly increase in IMT was 0.005 mm in men and 0.007 mm in women. More than 50% of men aged 55 years and older, and of women aged 65 years and older, had carotid plaques. CONCLUSIONS: Both IMT and plaque frequency were associated with age in men and women. Carotid IMT values in a Spanish community cohort were lower than those reported for countries with higher cardiovascular risk, such as Northern European countries and the US.

Objective. To determine the prevalence of preclinical vascular disease and associated risk factors in patients with systemic lupus erythematosus (SLE) or primary antiphospholipid syndrome (APS). Methods. We consecutively studied 70 SLE patients and 25 primary APS patients without clinical coronary artery disease. The control group included 40 healthy women. Carotid ultrasound was performed and the intima-media wall thickness (IMT) and presence of plaque was investigated in all patients and controls. Traditional vascular risk factors and SLE-disease and treatment related factors were also analysed. Results. SLE patients had a higher prevalence of traditional atherosclerosis risk factors: hypertension (P_0.005) and dyslipidaemia (P_0.05) and higher levels of total cholesterol (P^ 0.03), triglycerides (P^ 0.004) and apolipoprotein B (P^ 0.04). The prevalence of carotid plaque was higher and appeared earlier in SLE patients than in the primary APS patients or controls (P_0.001). The IMT was similar in the three groups. SLE patients with secondary APS had a higher prevalence of carotid plaque than patients with primary APS (37.5% vs 8%, P^ 0.03). The presence of plaque in SLE patients was associated with a higher SLICC score (2.40 1.78 vs 1.02 1.18, P^ 0.002), higher ECLAM score (3.10 2.32 vs 1.84 1.59, P^ 0.02) and older age (47.3 8.44 vs 37.38 11.28, P^ 0.003) at the time of carotid ultrasound study. Conclusion. Plaque prevalence in patients with primary APS is similar to that of controls and inferior to that of SLE patients with secondary APS. SLE patients have a high prevalence of early carotid atherosclerosis that is associated with cumulative disease damage and disease activity.

La poblacion envejece y, como consecuencia de ello, en las proximas decadas se producira un incremento espectacular de las enfermedades que se relacionan con la edad. Los procesos neurodegenerativos y la arteriosclerosis seran los fenomenos mas prevalentes en esta poblacion. La conservacion del arbol vascular y un control adecuado de los factores de riesgo preponderantes pueden disminuir la incidencia de estas enfermedades invalidantes. Diversas investigaciones poblacionales, en animales de laboratorio y en humanos, ofrecen datos esperanzadores sobre el papel que desempena el colesterol plasmatico en el deterioro cognitivo. Los farmacos inhibidores de la HMG-CoA reductasa pueden convertirse, en un futuro no muy lejano, en el tratamiento de eleccion en pacientes con factores de riesgo vasculares.

Fundamento y objetivo La hipertrigliceridemia es una causa aceptada de pancreatitis aguda, pero su curso clinico no esta bien definido. Ademas, la presencia de suero lipemico puede interferir en la determinacion de las enzimas pancreaticas y dificultar el diagnostico. El objetivo fue analizar el comportamiento clinico de las pancreatitis agudas por hipertrigliceridemia y el valor diagnostico de la determinacion serica de las enzimas pancreaticas en esta enfermedad. Pacientes y metodo Se analizaron retrospectivamente 31 datos demograficos, clinicos y analiticos de 19 pancreatitis agudas por hipertrigliceridemia y se compararon con los de 19 pancreatitis agudas de etiologia litiasica sin hipertrigliceridemia. El diagnostico de pancreatitis aguda se realizo cuando existian un cuadro clinico y datos radiologicos y/o laparotomicos compatibles. Se considero que habia pancreatitis aguda por hipertrigliceridemia cuando la cifra de trigliceridos era superior a 1.000 mg/dl y se excluian otras etiologias. Se considero que habia pancreatitis aguda litiasica cuando los calculos eran identificados por ultrasonografia, la cifra de trigliceridos era inferior a 200 mg/dl y no existia consumo de alcohol. Resultados Las pancreatitis agudas por hipertrigliceridemia presentaban, respecto a las pan creatitis agudas litiasicas, antecedentes familiares y personales de hipertrigliceridemia (9 frente a 0), mas episodios previos de pancreatitis (13 frente a 2), mayor numero de complicaciones (29 frente a 5) y de pancreatitis graves (13 frente a 5). No hubo mortalidad en ningun grupo. Las cifras de amilasa y lipasa apoyaron el diagnostico en el 26 y el 58% de las pancreatitis agudas por hipertrigliceridemia, frente al 58 y el 79% de las pancreatitis agudas litiasicas, respectivamente. Las pancreatitis agudas por hipertrigliceridemia precisaron de un mayor tiempo de hospitalizacion (24 [45] frente a 7,6 [3,1] dias; p = NS). No se han identificado factores demograficos ni analiticos que permitan predecir la gravedad de las pancreatitis agudas por hipertrigliceridemia. Conclusiones Las pancreatitis agudas por hipertrigliceridemia suelen ser recidivantes y su curso clinico es mas grave que el de las pancreatitis agudas litiasicas. Las cifras de amilasa y lipasa son menos utiles para el diagnostico de pancreatitis agudas hipertrigliceridemicas que en el de las litiasicas.

Fibrate treatment induces adverse changes in biliary-lipid and bile-acid composition. Since the molecular mechanisms underlying these changes are still unclear, we have investigated the effect of fibrate treatment on key factors involved in bile-acid synthesis, biliary-lipid secretion and cholesterol metabolism in gallstone patients.Patients with uncomplicated gallstones and a serum level of low-density lipoprotein (LDL) cholesterol130 mg/dl were randomly assigned to open-label treatment with bezafibrate, fenofibrate, gemfibrozil, or placebo for 8 weeks before elective cholecystectomy. A liver specimen was obtained at operation, and the mRNA relative levels for cholesterol 7alpha-hydroxylase (CYP7A1), hepatocyte nuclear factor-4 (HNF-4), ATP-binding cassette transporters MDR3, ABCG5, and ABCG8, human homologue scavenger receptor BI, sterol response element binding protein-2 (SREBP-2), 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and LDL receptor were determined by means of reverse-transcriptase polymerase chain reaction.Bezafibrate, fenofibrate and gemfibrozil significantly reduced CYP7A1 mRNA levels. The three fibrates tested raised the mRNA levels of ABCG5 and SREBP-2, but only bezafibrate induced significant changes. Although MDR-3 mRNA levels were slightly increased by the three fibrates, no significant differences were obtained.These results show for the first time that fibrate administration to humans downregulates CYP7A1. Although ABCG5 and SREBP-2 mRNA levels were slightly increased by all treatment groups, only bezafibrate induced significant changes.

Introduccion El tratamiento con fibratos provoca cambios tanto en el contenido de lipidos biliares como en la composicion de los acidos biliares, lo que conduce a un incremento de la incidencia de colelitiasis en humanos. Los mecanismos moleculares implicados en estos cambios, observados en pacientes tratados con fibratos durante un largo periodo, todavia no han sido descritos. El objetivo de este estudio ha sido investigar el efecto del tratamiento con fibratos en los factores clave implicados en la sintesis de acidos biliares y en la secrecion biliar de lipidos en pacientes con colelitiasis. Pacientes y metodo Pacientes con colelitiasis y valores de colesterol unido a lipoproteinas de baja densidad (cLDL) elevados (> 130 mg/dl) fueron aleatorizados y asignados al tratamiento con bezafibrato (400 mg/dia), fenofibrato (200 mg/dia), gemfibrozilo (900 mg/dia) o placebo, durante 8 semanas antes de proceder a la intervencion quirurgica (colecistectomia electiva). La obtencion de muestras hepaticas tuvo lugar en el momento de la operacion y mediante RT-PCR se determinaron los valores de ARNm de colesterol 7-α-hidroxilasa (CYP7A1), hepatocyte nuclear factor-4 (HNF-4), transportadores ATP-binding cassette: MDR3, ABCG5, ABCG8 y el homologo humano del receptor scavanger BI (CLA-1). Resultados Fenofibrato, bezafibrato y gemfibrozilo redujeron de forma significativa los valores de cLDL y trigliceridos plasmaticos. Los 3 fibratos ensayados redujeron los valores de ARNm de CYP7A1, pero solo el bezafibrato incremento significativamente los valores de ABCG5. Ninguno de los farmacos por separado produjo cambios importantes en los valores de ARNm de los restantes genes probados, pero los fibratos como grupo incrementaron el ARNm de MDR-3 y ABCG5. Conclusiones Estos resultados muestran por primera vez que la administracion de fibratos a humanos, a dosis similares a las farmacologicas, reduce la expresion de la colesterol 7-α-hidroxilasa e incrementan la expresion de MDR-3 y ABCG5.

Background: Epidemiologic and experimental data suggest that cholesterol may play a role in the pathogenesis of AD. Modulation of cholesterolemia in transgenic animal models of AD strongly alters amyloid pathology. Objective: To determine whether a relationship exists between amyloid deposition and total cholesterolemia (TC) in the human brain. Methods: The authors reviewed autopsy cases of patients older than 40 years and correlated cholesterolemia and presence or absence of amyloid deposition (amyloid positive vs amyloid negative subjects) and cholesterolemia and amyloid load. Amyloid load in human brains was measured by immunohistochemistry and image analysis. To remove the effect of apoE isoforms on cholesterol levels, cases were genotyped and duplicate analyses were performed on apoE3/3 subjects. Results: Cholesterolemia correlates with presence of amyloid deposition in the youngest subjects (40 to 55 years) with early amyloid deposition (diffuse type of senile plaques) (p = 0.000 for all apoE isoforms; p = 0.009 for apoE3/3 subjects). In this group, increases in cholesterolemia from 181 to 200 almost tripled the odds for developing amyloid, independent of apoE isoform. A logistic regression model showed consistent results (McFadden ρ2 = 0.445). The difference in mean TC between subjects with and without amyloid disappeared as the age of the sample increased (>55 years: p = 0.491), possibly reflecting the effect of cardiovascular deaths among other possibilities. TC and amyloid load were not linearly correlated, indicating that there are additional factors involved in amyloid accumulation. Conclusions: Serum hypercholesterolemia may be an early risk factor for the development of AD amyloid pathology.

OBJECTIVE: Combined hyperlipidaemia is a common and highly atherogenic lipid phenotype with multiple lipoprotein abnormalities that are difficult to normalise with single-drug therapy. The ATOMIX multicentre, controlled clinical trial compared the efficacy and safety of atorvastatin and bezafibrate in patients with diet-resistant combined hyperlipidaemia. PATIENTS AND STUDY DESIGN: Following a 6-week placebo run-in period, 138 patients received atorvastatin 10mg or bezafibrate 400mg once daily in a randomised, double-blind, placebo-controlled trial. To meet predefined low-density lipoprotein-cholesterol (LDL-C) target levels, atorvastatin dosages were increased to 20mg or 40mg once daily after 8 and 16 weeks, respectively. RESULTS: After 52 weeks, atorvastatin achieved greater reductions in LDL-C than bezafibrate (percentage decrease 35 vs 5; p < 0.0001), while bezafibrate achieved greater reductions in triglyceride than atorvastatin (percentage decrease 33 vs 21; p < 0.05) and greater increases in high-density lipoprotein-cholesterol (HDL-C) [percentage increase 28 vs 17; p < 0.01 ]. Target LDL-C levels (according to global risk) were attained in 62% of atorvastatin recipients and 6% of bezafibrate recipients, and triglyceride levels

Background and Objectives Fibrates induce hepatic peroxisome proliferation and carcinogenesis in rodents by activating peroxisome proliferator-activated receptor α (PPARα). There is no conclusive evidence that humans are unresponsive to peroxisome proliferation, and concern exists about the long-term safety of fibrate treatment. Methods In a university hospital setting, 48 patients with uncomplicated gallstones and a serum level of low-density lipoprotein cholesterol greater than 130 mg/dL were randomly assigned to open-label treatment with bezafibrate (400 mg/d), fenofibrate (200 mg/d), gemfibrozil (900 mg/d), or placebo for 8 weeks before elective cholecystectomy. Serum samples for lipid determinations were obtained at baseline and before surgery. A liver specimen was obtained at operation, and the relative levels of messenger ribonucleic acid (mRNA) for the wild and truncated forms of PPARα, acyl coenzyme A oxidase, liver carnitine palmitoyltransferase I, apolipoprotein A-I, and stearoyl coenzyme A desaturase were determined. Results Fenofibrate, bezafibrate, and gemfibrozil reduced plasma low-density lipoprotein cholesterol levels by 22% (P = .009), 14% (P = .042), and 11% (not significant), respectively. Plasma triglyceride levels decreased significantly (24%-36%; P < .05), whereas high-density lipoprotein cholesterol levels rose nonsignificantly after treatment with the 3 fibrates. Except for a 35% increase of apolipoprotein A-I mRNA after fenofibrate administration (P < .05), none of the individual fibrates induced significant changes in the mRNAs tested, although as a group they increased the mRNA for liver carnitine palmitoyltransferase I by 40%(P = .08; marginally significant). Conclusions Fibrate administration to humans at pharmacologic doses able to activate PPARα and to induce a hypolipidemic effect does not increase the hepatic expression of acyl coenzyme A oxidase, a well-known marker of peroxisome proliferation in rodents. Clinical Pharmacology & Therapeutics (2002) 72, 692–701; doi: 10.1067/mcp.2002.128605

The most appropriate therapy for combined hyperlipidemia remains to be determined. We compared the lipid-regulating effects of gemfibrozil and lovastatin in 30 patients with familial combined hyperlipidemia (FCHL) in a randomized, double-blind, placebo-controlled crossover study including 8-week courses of one drug followed by a washout period and a crossover phase to the alternate drug. After completion of the trial, open-label combination therapy was given for up to 12 months. Lovastatin was more efficacious than gemfibrozil in the reduction of total cholesterol (23% v. 9%, P

Aims To evaluate the resistance to oxidation of human lipoproteins after hypolipidaemic therapy. Methods VLDL and LDL samples were obtained from patients with Familial Combined Hyperlipidaemia included in a randomized, double-blind, cross-over study, with 8 weeks of active treatment (gemfibrozil, 600 mg twice daily, or lovastatin, 40 mg daily) and a 4-week wash-out period. Oxidation related analytes after Cu-induced oxidation of VLDL and LDL have been investigated. Further, in order to relate possible changes in oxidative behaviour to lipoprotein composition, the proportion of the lipid species transported by lipoproteins (triglycerides, phospholipids, and cholesteryl esters), the molar composition of fatty acids for each lipoprotein lipid, and the content of antioxidant vitamins in plasma (vitamin C) and lipoproteins (vitamin E) have been studied. Results Both drugs reduced the plasma concentration of apo-B lipoproteins (−23% gemfibrozil, −26% lovastatin), but whereas lovastatin affected mainly LDL-cholesterol (−30%), gemfibrozil reduced triglycerides (−49%) and VLDL-cholesterol (−48%). Lovastatin treatment had no effect on the lipid and protein composition, the fatty acid profile, or the vitamin E content of either VLDL or LDL; likewise, lipoprotein oxidation markers (Cu-induced conjugated dienes, thiobarbituric acid reactive substances formation, and lysine residues) were similar before and after lovastatin treatment. Gemfibrozil therapy also had no effect on lipoprotein oxidation; nevertheless, it consistently: a) decreased the proportion of LDL-triglycerides (−32%), and b) increased the proportion (molar%) of 18:3 n-6 in VLDL triglycerides (+140%), phospholipids (+363%) and cholesteryl esters (+53%). Conclusions Based on these results, lovastatin and gemfibrozil do not adversely affect lipoprotein oxidation in patients with mixed dyslipidaemia. In the case of gemfibrozil, this occurs in spite of an increased proportion of some polyunsaturated fatty acids in VLDL. In the context of a fixed dietary intake, such modifications suggest that the drug influences liver enzyme activities involved in fatty acid chain synthesis (elongases and desaturases).

The aim of this study was to determine the relationship between lipoprotein(a) [Lp(a)] and cardiovascular disease (CVD) in a large cohort of patients with heterozygous familial hypercholesterolemia (FH).Lp(a) is considered a cardiovascular risk factor. Nevertheless, the role of Lp(a) as a predictor of CVD in patients with FH has been a controversial issue.A cross-sectional analysis of 1,960 patients with FH and 957 non-FH relatives recruited for SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study), a long-term observational cohort study of a molecularly well-defined FH study group, was performed. Lp(a) concentrations were measured in plasma using an immunoturbidimetric method.Patients with FH, especially those with CVD, had higher Lp(a) plasma levels compared with their unaffected relatives (p 0.001). A significant difference in Lp(a) levels was observed when the most frequent null and defective mutations in LDLR mutations were analyzed (p 0.0016). On multivariate analysis, Lp(a) was an independent predictor of cardiovascular disease. Patients carrying null mutations and Lp(a) levels50 mg/dl showed the highest cardiovascular risk compared with patients carrying the same mutations and Lp(a) levels 50 mg/dl.Lp(a) is an independent predictor of CVD in men and women with FH. The risk of CVD is higher in those patients with an Lp(a) level50 mg/dl and carrying a receptor-negative mutation in the LDLR gene compared with other less severe mutations.

Familial hypercholesterolemia (FH) is the most frequent inherited disorder associated with premature coronary artery disease. Early identification and treatment of patients will reduce cardiovascular outcomes. Identification of index cases and then cascade testing in first-degree relatives using lipid levels and genetic test is the most cost-effective strategy implemented in some countries. FH patients are considered at high cardiovascular risk. Imaging techniques such as coronary computed tomography angiography could identify subjects that will require more intensive treatments. Recent guidelines recommend an LDL-C below 100 mg/dl or at least 50% LDL-C reduction if the first goal is not attained as treatment targets in heterozygous FH. Statins are the first-line agents in almost all patients, and several options exist to obtain larger LDL-C reductions like the addition of ezetimibe and/or colesevelam. Novel agents like microsomal triglyceride transfer protein inhibitors, apolipoprotein B100 antisense or PCSK9-specific monoclonal antibodies, if approved by regulatory agencies, will reduce LDL-C levels and potentially reduce cardiovascular risk in homozygous and severe heterozygous FH patients.