Ana M. Bea

Effect of Nicotinic acid/Laropiprant in the lipoprotein(a) concentration with regard to baseline lipoprotein(a) concentration and LPA genotype

BACKGROUNDnLipoprotein(a) [Lp(a)] is a lipoprotein in which apolipoproteinB-100 is linked to apolipoprotein(a) [apo(a)]. Significant variation in Lp(a) concentration is specific to LPA gene, which codes for apo(a). Nicotinic acid (NA) is used for treatment of dyslipidemias, and the lowering effect of NA on Lp(a) has been previously reported.nnnOBJECTIVEnTo evaluate the Lp(a) lowering effect of 1g/20mg and 2g/40mgday of Nicotinic acid/Laropiprant in subjects with different baseline Lp(a) concentrations and depending on the LPA genotype.nnnMETHODSnIn an open-label, 10-week study, 1g/20mgday of NA/Laropiprant for 4weeks followed by 6weeks of 2g/40mgday conducted at 3 centers in Spain, 82 subjects were enrolled. Patients were studied at baseline and at the end of both treatment periods and were enrolled in three groups: normal Lp(a) (<50mg/dL), high Lp(a) (50-120mg/dL) and very high Lp(a) (>120mg/dL). The LPA genetic polymorphism was analyzed by a real-time PCR.nnnRESULTSnThere was a significant difference in LPA genotypes among Lp(a) concentration groups and an inverse and significant correlation between baseline Lp(a) concentration and LPA genotype was found (R=-0.372, p<0.001). There were a significant decrease in total cholesterol, triglycerides, LDL cholesterol, apo B and Lp(a), and a significant increase in HDL cholesterol after NA/Laropiprant treatment, without changes in BMI. However, there were no statistical differences in percentage variation of analyzed variables depending on LPA genotype.nnnCONCLUSIONnLPA genotype is a major determinant of Lp(a) baseline concentration. However, the lipid lowering effect of NA is not related to LPA genotype.

ABCG5/G8 gene is associated with hypercholesterolemias without mutation in candidate genes and noncholesterol sterols

CONTEXTnApproximately 20% to 40% of clinically defined familial hypercholesterolemia (FH) cases do not show a causative mutation in candidate genes (mutation-negative FH), and some of them may have a polygenic origin.nnnOBJECTIVEnThe aim of this work was to study the prevalence of ABCG5/G8 genetic variants in mutation-negative FH, as defects in these genes relate to intestinal hyperabsorption of cholesterol and thus ABCG5/G8 variants could explain in part the mechanism of hypercholesterolemia.nnnDESIGN, SETTING, AND PATIENTSnWe sequenced the ABCG5/G8 genes in 214 mutation-negative FH and 97 controls. Surrogate markers of cholesterol absorption (5α-cholestanol, β-sitosterol, campesterol, stigmasterol, and sitostanol) were quantified by high-performance liquid chromatography-tandem mass spectrometry in both studied groups.nnnRESULTSnWe found 8 mutation-negative FH patients (3.73%) with a pathogenic mutation in ABCG5/G8 genes. We observed significantly higher concentration of surrogate markers of cholesterol absorption in mutation-negative FH than in controls. In addition, we found significantly higher concentrations of cholesterol absorption markers in mutation-negative FH with ABCG5/G8 defects than in mutation-negative, ABCG5/G8-negative FH. A gene score reflecting the number of common single nucleotide variants associated with hypercholesterolemia was significantly higher in cases than in controls (Pxa0=xa0.032). Subjects with a gene score above the mean had significantly higher 5α-cholestanol and stigmasterol than those with a lower gene score.nnnCONCLUSIONSnMutation-negative FH subjects accumulate an excess of rare and common gene variations in ABCG5/G8 genes. This variation is associated with increased intestinal absorption of cholesterol, as determined by surrogate makers, suggesting that these loci contribute to hypercholesterolemia by enhancing intestinal cholesterol absorption.

La lipoproteína(a) se asocia a la presencia de arteriosclerosis en pacientes con hipercolesterolemia primaria

INTRODUCTIONnSeveral studies have suggested that Lp(a) could be a risk factor mainly in hypercholesterolemic patients.nnnMETHODSnA total of 909 individuals were selected for this study. 307 were diagnosed of familiar hypercholesterolemia with a pathogenic mutation in LDLR or APOB genes (FH+), 291 of familiar combined hyperlipidemia (FCH) and 311 of familial hypercholesterolemia without a pathogenic mutation in LDLR nor APOB genes (FH-). Main risk factor were studied, included statin treatment. Plasma lipids, Lp(a), HbA1c and C-reactive protein. Intima-media thickness (IMT) of common and bulb carotid in both sides were measured in all subjects.nnnRESULTSnLp(a) values (median, interquartile range) were 21.9mg/dL (9.24-50.5) in FH+, 22.4mg/dL (6.56-51.6) in FCH and 32.7 (14.6-71.5) in FH- (P<.001). Regression analysis including age, gender, HDL cholesterol, LDL cholesterol corrected for Lp(a), Lp(a), C-reactive protein, packs of cigarettes/day per year, systolic blood pressure and glucose as independent variables, demonstrate that Lp(a) was associated with carotid IMT in FH- subjects. Cardiovascular disease was more frequent in subjects with Lp(a) >50mg/dL (17.9%) than in subjects with Lp(a) <15mg/dL (9.6%), and between 15-50mg/dL (10.1%), and it was concentrated mostly in FH-group (6.7, 11.3, and 23.4% for the groups of Lp(a) <15mg/dL 15-50mg/dL, and >50mg/dL, respectively).nnnCONCLUSIONSnOur results indicate that Lp(a) is associated with atherosclerosis burden especially in subjects with FH- and concentrations of Lp(a)>50mg/dL.

Effect of intensive LDL cholesterol lowering with PCSK9 monoclonal antibodies on tendon xanthoma regression in familial hypercholesterolemia

BACKGROUND AND AIMSnThe effect of LDLc lowering with PCSK9 antibodies on tendon xanthomas (TX) is unknown.nnnMETHODSnTX was measured in 24 heterozygous familial hypercholesterolemia (HeFH) cases and in 24 HeFH controls with or without PCSK9 inhibitors for at least one year.nnnRESULTSnExposure to PCSK9 inhibitors in cases was 2.96xa0±xa01.33 years. LDLc decreased 80.8xa0±xa07.66% in cases and 56.9xa0±xa011.1% in controls. There was a decrease in maximum (-5.03%) and mean (-5.32%) TX in cases but not in controls (+3.97%,xa0+3.16, respectively, pxa0=xa00.01). PCSK9 inhibitor treatment was independently associated with TX reduction.nnnCONCLUSIONnAddition of a PCSK9 inhibitor to statin and ezetimibe resulted in a greater decrease in LDLc and TX after 3 years of treatment.

Single Nucleotide Variants Associated With Polygenic Hypercholesterolemia in Families Diagnosed Clinically With Familial Hypercholesterolemia

INTRODUCTION AND OBJECTIVESnApproximately 20% to 40% of clinically defined familial hypercholesterolemia cases do not show a causative mutation in candidate genes, and some of them may have a polygenic origin. A cholesterol gene risk score for the diagnosis of polygenic hypercholesterolemia has been demonstrated to be valuable to differentiate polygenic and monogenic hypercholesterolemia. The aim of this study was to determine the contribution to low-density lipoprotein cholesterol (LDL-C) of the single nucleotide variants associated with polygenic hypercholesterolemia in probands with genetic hypercholesterolemia without mutations in candidate genes (nonfamilial hypercholesterolemia genetic hypercholesterolemia) and the genetic score in cascade screening in their family members.nnnMETHODSnWe recruited 49 nonfamilial hypercholesterolemia genetic hypercholesterolemia families (294 participants) and calculated cholesterol gene scores, derived from single nucleotide variants in SORT1, APOB, ABCG8, APOE and LDLR and lipoprotein(a) plasma concentration.nnnRESULTSnRisk alleles in SORT1, ABCG8, APOE, and LDLR showed a statistically significantly higher frequency in blood relatives than in the 1000 Genomes Project. However, there were no differences between affected and nonaffected members. The contribution of the cholesterol gene score to LDL-C was significantly higher in affected than in nonaffected participants (P = .048). The percentage of the LDL-C variation explained by the score was 3.1%, and this percentage increased to 6.9% in those families with the highest genetic score in the proband.nnnCONCLUSIONSnNonfamilial hypercholesterolemia genetic hypercholesterolemia families concentrate risk alleles for high LDL-C. Their contribution varies greatly among families, indicating the complexity and heterogeneity of these forms of hypercholesterolemias. The gene score explains a small percentage of LDL-C, which limits its use in diagnosis.

Association between non-cholesterol sterol concentrations and Achilles tendon thickness in patients with genetic familial hypercholesterolemia

BackgroundFamilial hypercholesterolemia (FH) is a genetic disorder that result in abnormally high low-density lipoprotein cholesterol levels, markedly increased risk of coronary heart disease (CHD) and tendon xanthomas (TX). However, the clinical expression is highly variable. TX are present in other metabolic diseases that associate increased sterol concentration. If non-cholesterol sterols are involved in the development of TX in FH has not been analyzed.MethodsClinical and biochemical characteristics, non-cholesterol sterols concentrations and Aquilles tendon thickness were determined in subjects with genetic FH with (nxa0=xa063) and without (nxa0=xa040) TX. Student-t test o Mann–Whitney test were used accordingly. Categorical variables were compared using a Chi square test. ANOVA and Kruskal–Wallis tests were performed to multiple independent variables comparison. Post hoc adjusted comparisons were performed with Bonferroni correction when applicable. Correlations of parameters in selected groups were calculated applying the non-parametric Spearman correlation procedure. To identify variables associated with Achilles tendon thickness changes, multiple linear regression were applied.ResultsPatients with TX presented higher concentrations of non-cholesterol sterols in plasma than patients without xanthomas (Pxa0=xa00.006 and 0.034, respectively). Furthermore, there was a significant association between 5α-cholestanol, β-sitosterol, desmosterol, 24S-hydroxycholesterol and 27-hydroxycholesterol concentrations and Achilles tendon thickness (pxa0=xa00.002, 0.012, 0.020, 0.045 and 0.040, respectively).ConclusionsOur results indicate that non-cholesterol sterol concentrations are associated with the presence of TX. Since cholesterol and non-cholesterol sterols are present in the same lipoproteins, further studies would be needed to elucidate their potential role in the development of TX.

Cholesterol oversynthesis markers define familial combined hyperlipidemia versus other genetic hypercholesterolemias independently of body weight

Primary hypercholesterolemia of genetic origin, negative for mutations in LDLR, APOB, PCSK9 and APOE genes (non-FH GH), and familial combined hyperlipidemia (FCHL) are polygenic genetic diseases that occur with hypercholesterolemia, and both share a very high cardiovascular risk. In order to better characterize the metabolic abnormalities associated with these primary hypercholesterolemias, we used noncholesterol sterols, as markers of cholesterol metabolism, to determine their potential differences. Hepatic cholesterol synthesis markers (desmosterol and lanosterol) and intestinal cholesterol absorption markers (sitosterol and campesterol) were determined in non-FH GH (n=200), FCHL (n=100) and genetically defined heterozygous familial hypercholesterolemia subjects (FH) (n=100) and in normolipidemic controls (n=100). FCHL subjects had lower cholesterol absorption and higher cholesterol synthesis than non-FH GH, FH and controls (P<.001). When noncholesterol sterols were adjusted by body mass index (BMI), FCHL subjects had higher cholesterol synthesis than non-FG GH, FH and controls (P<.001). An increase in BMI was accompanied by increased cholesterol synthesis and decreased cholesterol absorption in non-FH GH, FH and controls. However, this association between BMI and cholesterol synthesis was not observed in FCHL. Non-high-density-lipoprotein cholesterol showed a positive correlation with cholesterol synthesis markers similar to that of BMI in non-FH GH, FH and normolipemic controls, but there was no correlation in FCHL. These results suggest that FCHL and non-FH GH have different mechanisms of production. Cholesterol synthesis and absorption are dependent of BMI in non-FH GH, but cholesterol synthesis is increased as a pathogenic mechanism in FCHL independently of age, gender, APOE and BMI.

Different protein composition of low-calorie diet differently impacts adipokine profile irrespective of weight loss in overweight and obese women

BACKGROUND AND AIMSnHigh-protein (HP) diets have shown benefits in cardiometabolic markers such as insulin or triglycerides but the responsible mechanisms are not known. We aimed to assess the effect of three energy-restricted diets with different protein contents (20%, 27%, and 35%; ∼80% coming from animal source) on plasma adipokine concentration and its association with changes in cardiometabolic markers.nnnMETHODSnSeventy-six women (BMI 32.8xa0±xa02.93) were randomized to one of three calorie-reduced diets, with protein, 20%, 27%, or 35%; carbohydrates, 50%, 43%, or 35%; and fat, 30%, for 3 months. Plasma adipokine (leptin, resistin, adiponectin, and retinol-binding protein 4; RBP4) levels were assessed.nnnRESULTSnAfter 3 months, leptin concentration decreased in all groups without differences among them, while resistin levels remained unchanged. Adiponectin concentration heterogeneously changed in all groups (P for trendxa0=xa00.165) and resistin concentration did not significantly change. RPB4 significantly decreased by -17.5% (-31.7, -3.22) in 35%-protein diet (P for trendxa0=xa00.024 among diets). Triglycerides improved in women following the 35%-protein diet regardless of weight loss; RBP4 variation significantly influenced triglyceride concentration change by 24.9% and 25.9% when comparing 27%- and 35%- with 20%-protein diet, respectively.nnnCONCLUSIONSnA 35%-protein diet induced a decrease in RBP4 regardless of weight loss, which was directly associated with triglyceride concentration improvement. These findings suggest that HP diets improve the cardiometabolic profile, at least in part, through changes in adipokine secretion. Whether this beneficial effect of HP diet is due to improvements in hepatic or adipose tissue functionality should be elucidated.nnnCLINICAL TRIAL REGISTRATIONnThe clinical trial has been registered in ClinicalTrials.gov (Identifier: NCT02160496).