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Cardiovascular diseases (CVD) continue to be the main cause of death in our country. Adequate control of lipid metabolism disorders is a key challenge in cardiovascular prevention that is far from being achieved in real clinical practice. There is a great heterogeneity in the reports of lipid metabolism from Spanish clinical laboratories, which may contribute to its poor control. For this reason, a working group of the main scientific societies involved in the care of patients at vascular risk, has prepared this document with a consensus proposal on the determination of the basic lipid profile in cardiovascular prevention, recommendations for its realization and unification of criteria to incorporate the lipid control goals appropriate to the vascular risk of the patients in the laboratory reports. [ABSTRACT FROM AUTHOR]

Lipoprotein(a) [Lp(a)] concentration in heterozygous familial hypercholesterolemia (heFH) is not well established. Whether the genetic defect responsible for heFH plays a role in Lp(a) concentration is unknown. We aimed to compare Lp(a) in controls from a healthy population, in genetically diagnosed heFH and mutation-negative hypercholesterolemia subjects, and to assess the influence on Lp(a) of the genetic defect responsible for heFH. We conducted a cross-sectional study, performed in a lipid clinic in Spain. We studied adults with suspected heFH and a genetic study of FH genes (LDLR , APOB, APOE and PCSK9) and controls from de Aragon Workers' Health Study. HeFH patients from the Dyslipidemia Registry of the Spanish Atherosclerosis Society (SEA) were used as validation cohort. Adjusted geometric means (95% confidence interval) of Lp(a) in controls (n = 1059), heFH (n = 500), and mutation-negative subjects (n = 860) were 14.9 mg/dL (13.6, 16.4), 21.9 mg/dL (18.1, 25.6) and 37.4 mg/dL (33.3, 42.1), p < 0.001 in all comparisons. Among heFH subjects, APOB -dependent FH showed the highest Lp(a), 36.5 mg/dL (22.0, 60.8), followed by LDLR -dependent FH, 21.7 mg/dL (17.9, 26.4). These differences were also observed in heFH from the SEA cohort. The number of plasminogen-like kringle IV type−2 repeats of LPA , the hypercholesterolemia polygenic score or LDLc concentration did not explain these differences. In LDLR -dependent FH, Lp(a) levels were not different depending on the affected protein domain. Lp(a) is elevated in mutation-negative subjects and in heFH. The concentration of Lp(a) in heFH varies in relation to the responsible gene. Higher Lp(a) in heFH is not explained by their higher LDLc. • Lp(a) concentration is higher in subjects with mutation-negative hypercholesterolemia and heterozygous familial hypercholesterolemia (heFH) than in controls. • Lp(a) concentration in heFH depends on the gene causing FH, and is independent of the type of LDL receptor defect. • Higher Lp(a) in heFH is not explained by the higher LDLc. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia (FH) is a monogenic disease characterized by high levels of low-density lipoprotein cholesterol and premature atherosclerotic cardiovascular disease. FH is caused by loss of function mutations in genes encoding LDL receptor (LDLR), and Apolipoprotein B (APOB) or gain of function (GOF) mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9). In this study, we identified a novel variant in PCSK9 , p.(Arg499His), located in the C-terminal domain , in two unrelated FH patients from Spain and Italy. We studied familial segregation and determined variant activity in vitro. We determined PCSK9 expression, secretion and activity of the variant in transfected HEK293 cells; extracellular activity of the recombinant p.(Arg499His) PCSK9 variant in HEK 293 and HepG2 cells; PCSK9 affinity to the LDL receptor at neutral and acidic pH; the mechanism of action of the p.(Arg499His) PCSK9 variant by co-transfection with a soluble construct of the LDL receptor and by determining total PCSK9 intracellular accumulation when endosomal acidification is impaired and when an excess of soluble LDLr is present in the culture medium. Our results show high LDL-C concentrations and FH phenotype in p.(Arg499His) carriers. In vitro functional characterization shows that p.(Arg499His) PCSK9 variant causes a reduction in LDLr expression and LDL uptake. An intracellular activity for this variant is also shown when blocking the activity of secreted PCSK9 and by inhibiting endosomal acidification. We demonstrated that p.(Arg499His) PCSK9 variant causes a direct intracellular degradation of LDLr therefore causing FH by reducing LDLr availability. Image 1 • We identified a novel PCSK9 GOF variant, p.(Arg499His), in two unrelated FH patients from Spain and Italy. • p.(Arg499His) PCSK9 variant carriers show high LDL-C concentrations and FH phenotype. • In vitro assays revealed reduced LDL receptor expression at membrane surface with p.(Arg499His). • p.(Arg499His) is a GOF mutation that causes FH through an intracellular effect reducing LDLr availability. [ABSTRACT FROM AUTHOR]

Objectives: Research has identified many factors associated with fibromyalgia (FM), but findings have been inconsistent. This study aimed to investigate changes in levels of nitric oxide (NO), inflammatory markers, lipid profile, and cortisol in normaland overweight patients with FM and controls. Since most patients with FM are overweight, we explored possible changes in these markers according to body mass index (BMI). Methods: This preliminary study was performed on serum samples of women with FM and age-matched controls, grouped according to their BMI: 12 normal-weight patients and 12 controls and 13 overweight patients and 8 controls. Ozone-based chemiluminescence assay was used to measure NO. Inflammatory mediators and cortisol were determined by immunoassay. Lipid profile was measured by a spectrophotometric procedure. Functional capacity was assessed by the fibromyalgia impact questionnaire (FIQ). Results: Normal-weight patients showed higher levels of C-reactive protein (CRP) and apolipoprotein B compared to controls (both p < .05). CRP, apolipoprotein B, and triglycerides were higher in overweight patients versus overweight controls (all p < .05) and in overweight versus normal-weight patients (CRP p < .01; apolipoprotein B, triglycerides p < .05). The other markers were unaffected. Apolipoprotein B (r = .762; p < .05) and NO (r = -.921; p < .05) levels correlated with FIQ score in normal-weight patients. CRP level correlated with FIQ (r = .912; p < .05) in overweight patients. Conclusions: CRP and apolipoprotein B, biomarkers linked to cardiovascular events, may be associated with FM-related dysfunction in normal- and overweight women with FM. Their increased levels in these patients may indicate an increased risk of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Abstract: Extremely low LDL-cholesterol concentrations are very unusual and generally related with comorbidities accompanying malnutrition. Less frequently low LDL-cholesterol levels result from mutations in the APOB, PCSK9, ANGPTL3, SAR1B and MTTP genes (primary hypobetalipoproteinemia). We investigated three patients with plasma LDL-cholesterol levels below the fifth percentile of the Spanish population. We recorded data on demographic and anthropometric characteristics, life style habits, physical examination, liver ultrasound and lipid and lipoprotein levels, in the probands and their first-degree relatives. Secondary causes of hypocholesterolemia were ruled out by clinical study, complementary tests and follow-up. The APOB, MTTP and SAR1B genes were sequenced. Patients were found to be heterozygotes for point mutations located in the exon 26 of the APOB gene. One patient, with fatty liver, carried a previously described mutation (c.7600C>T) (Arg2507X), causing the formation of truncated Apo B-55.25. The other two mutations producing truncations are new. One asymptomatic patient carried the Arg3672X (Apo B-80.93) and the other with fatty liver and steatorrhea carried the Ser2184fsVal2193X (Apo B-48.32). Our study reinforces the concept that in the heterozygous carriers of truncated Apo Bs, the clinical manifestations of FHBL are dependent on the size of the truncations. [Copyright &y& Elsevier]

Abstract: Familial hypercholesterolemia (FH), characterized by isolated elevation of plasmatic low-density lipoprotein (LDL) cholesterol and premature coronary heart disease (CHD), is associated with mutations in three major genes: LDL receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin 9 (PCSK9). We have analyzed 5430 Spanish index cases and 2223 relatives since 2004 with LIPOchip® genetic diagnostic platform, a microarray for the detection of Spanish common mutations in these three genes, including copy number variation (CNV) in LDLR, followed by sequencing analysis of the coding regions of LDLR and exon 26 of APOB, when the result is negative. Samples were received from hospitals of all around Spain. The preferred clinical criterion to diagnose FH was Dutch Lipid Clinic Network (DLCN) score. Our results show that there is a broad spectrum of mutations in the LDLR gene in Spain since about 400 different mutations were detected, distributed along almost the whole LDLR gene. Mutations in APOB (mainly p.Arg3527Gln) covered 6.5% of positive cases and only one PCSK9 mutation was detected. We found correlation between more severe mutations and the clinical diagnosis but also that 28% of FH patients harboring mutations do not have a definite clinical diagnosis. This study analyzes the mutation spectrum in Spain, remarks the importance of genetic diagnosis of FH patients, as well as the cascade screening, and shows how it is being carried out in Spain. [Copyright &y& Elsevier]

Abstract: Background: Autosomal dominant hypercholesterolemias (ADHs) are characterised by increased plasma levels of total and LDL cholesterol, predisposing to premature atherosclerosis. ADHs comprise several diseases with undistinguishable phenotype, caused by mutations in different genes: LDLR, APOB and PCSK9. Genetic studies are usually performed in patients with altered cholesterol levels. However, some persons carrying pathogenic mutations are normocholesterolemic and there are no further studies about this subject. We have studied the frequency of families and individuals carrying ADH mutations who do not present the disease in Spanish population. Methods: We have analysed genes known to cause ADH by direct sequencing in 24 ADH families (215 members). Functional effect of some LDLR gene mutations was assessed by transfecting cultured cells with plasmids. Results: Six families with mutations presented 7 mutation carriers who did not show ADH phenotype: 30% of ADH families presented normocholesterolemic individuals, and 7% of carriers of pathogenic mutations did not show ADH phenotype. We have analysed the effect of some of these mutations and they are responsible for impaired LDL receptor function. We have excluded mutations in APOB and PCSK9 genes that could reduce LDLc levels. Conclusions: An important percentage of ADH families presented individuals who do not show an ADH phenotype, but who are able to transmit the pathogenic mutation to their offspring. Genetic study of all subjects in ADH families should be performed in order to identify normocholesterolemic carriers that allow the detection of mutations in their descendants and the prevention of the disease consequences. [Copyright &y& Elsevier]