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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.

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.

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.

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.

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 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.

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.

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.

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

C-reactive protein (CRP) is a non-specific but sensitive marker of underlying systemic inflammation. High CRP plasma levels correlate with risk for future cardiovascular events. The present study evaluated the effects of atorvastatin (10–40 mg) and bezafibrate (400 mg) on CRP concentrations after 6 and 12 months of treatment in 103 patients with combined (mixed) hyperlipidemia. The number of cardiovascular risk factors present in a given patient was associated with baseline CRP levels. After 6 months and 1 year, atorvastatin treatment was associated with significant (P 0.001) decreases from baseline of CRP concentrations by 29 and 43%, respectively, while bezafibrate-treated patients showed non-significant reductions of 2.3 and 14.6%, respectively (P=0.056 and 0.005 for the respective differences between the two treatment arms at 6 months and 1 year). The magnitude of change in CRP after 1 year was directly related to baseline CRP levels. Covariance analysis showed that CRP decreases in the atorvastatin group were unrelated to total cholesterol and LDL cholesterol reductions; however, they were directly related to triglyceride changes (r=0.28, P = 0.047) and inversely related to HDL cholesterol changes (r =− 0.28, P=0.045). A model including baseline CRP values and treatment effect showed that atorvastatin use was a significant predictor of change in CRP levels over time (=0.82, P =0.023). These results suggest a potential anti-atherosclerotic additional benefit of atorvastatin in patients at a risk of cardiovascular disease. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

THERE IS A HIGH prevalence of cardiovascular disease among long-term renal transplant recipients. Its etiology is multifactorial, though hyperlipidemia has been identified as one of the most important risk factors. The atherogenic capacity of the lipoproteins is conditioned by the fatty acid composition of their lipid component. The balance in the concentration of polyunsaturated and monounsaturated fatty acids in low-density lipoproteins (LDL) influences the susceptibility of the LDL particles to oxidation. The fatty acid content of the various lipid fractions has not been extensively studied in renal transplant recipients. The aim of the study was to analyze the fatty acid distribution in the LDL fraction of renal transplantation patients treated with cyclosporine-neoral.

Cardiovascular disease (CVD) is the main cause of mortality among long-term renal transplant recipients (RTR). On the other hand, allograft chronic nephropathy is the primary cause of graft loss among long-term RTR. Hyperlipidemia is a predisposing factor for both conditions. Polymorphisms of the apolipoproteins modulate lipid metabolism. The aim of the study was to evaluate the effect of apo A-I, apo A-IV and apo C-III genotypes on the long-term results of renal transplantation. Clinical assessment (renal allograft and patient survival) and genotyping for apo A-I (+83C/T), apo C-III (Sst I), and apo A-IV (Thr347Ser and Gln360His) polymorphisms were evaluated in 516 kidney transplant patients and correlated with the clinical evolution over 12 months. The distribution of the apo A-I (+83C/T) polymorphisms was: CC 91.9%, CT 7.9%, and TT 0.2%. The apo C-III genotype showed: S1S1 84.4%, S1S2 15.2%, and S2S2 0.4%. The apo A-IV (Pvu II) polymorphism was: GG 82%, GT 18%, and 0% TT. Finally, the frequency of apo A-IV (Hinf I) polymorphism was: AA 69%, AT 27%, and TT 4%. The frequency of polymorphisms was similar between men and women. In conclusion, there was no significant influence of apolipoprotein polymorphisms on renal and patient survival.

Objective— The purpose of this study was to assess femoral atherosclerosis by ultrasound in patients with molecularly defined heterozygous familial hypercholesterolemia (FH) in comparison with matched control subjects and in relation to mutational class in the LDL receptor and apolipoprotein B (APOB) genes. Methods and Results— Femoral intima-media thickness (IMT) and plaque were evaluated in 146 FH patients carrying null alleles (n=48), defective-receptor alleles (n=62), undetermined-function alleles (n=25), or APOB defects (n=11) and in 193 healthy subjects. Twenty-three patients had coronary heart disease (CHD). The frequency of both tendon xanthomas and CHD was ≈2-fold higher and average LDL cholesterol was 30 mg/dL higher in null-allele genotype compared with receptor-defective mutations. All femoral measurements were increased in FH patients versus controls ( P P for trend, 0.001). By multivariate analysis, independent associations of mean IMT, a measure of early atherosclerosis, were age, LDL cholesterol, sex, and systolic blood pressure. Age, null-allele genotype, sex, and smoking explained 42% of the variability of maximum IMT, a measure of advanced atherosclerosis. Conclusions— FH patients have increased femoral IMT in relation to mutational class. The findings support the usefulness of genetic testing in FH beyond securing the diagnosis.