Familial Hypercholesterolemia, Familial Combined Hyperlipidemia, and Elevated Lipoprotein(a) in Patients With Premature Coronary Artery Disease.

BACKGROUND: Familial hypercholesterolemia (FH), familial combined hyperlipidemia (FCHL), and elevated lipoprotein (a) (Lp[a]) increase risk of premature coronary artery disease (CAD). The objective of this study was to assess the prevalence of FH, FCHL, elevated Lp(a) and their impact on management in patients with premature CAD. METHODS: We prospectively recruited men ≤ 50 years and women ≤ 55 with obstructive CAD. FH was defined as Dutch Lipid Clinic Network scores ≥ 6. FCHL was defined as apolipoprotein B > 1.2 g/L, triglyceride and total cholesterol > 90th population percentile, and family history of premature cardiovascular disease. Lp(a) ≥ 50 mg/dL was considered to be elevated. RESULTS: Among 263 participants, 9.1% met criteria for FH, 12.5% for FCHL, and 19.4% had elevated Lp(a). Among patients with FH, 37.5% had FH-causing DNA variants. Patients with FH, but not other dyslipidemias, were more likely than nondyslipidemic patients to have received lipid-lowering therapy before presenting with CAD (33.3% vs 12.3%, P = 0.04) and combined lipid-lowering therapy after the presentation (41.7% vs 7.7%, P < 0.001). One year after presentation, 58.3%, 54.5%, and 58.8% of patients with FH, FCHL, and elevated Lp(a) had low-density lipoprotein cholesterol (LDL-C) < 1.8 mmol/L, respectively, compared with 68.0 % in reference group. Patients with FCHL were more likely to have non-high-density lipoprotein (HDL) and apolipoprotein B above recommended lipid goals (70.0% and 87.9%, respectively). CONCLUSIONS: FH, FCHL, and elevated Lp(a) are common in patients with premature CAD and have differing impact on treatment and achievement of lipid targets. Assessment for these conditions in patients with premature CAD provides valuable information for individualized management.

Comparative assessment of LDL-C and VLDL-C estimation in familial combined hyperlipidemia using Sampson's, Martin's and Friedewald's equations.

BACKGROUND: Sampson et al. developed a novel method to estimate very low-density lipoprotein cholesterol (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) in the setting of hypertriglyceridemia. Familial Combined Hyperlipidemia (FCHL) is a common primary dyslipidemia in which lipoprotein composition interferes with LDL-C estimation. This study aimed to evaluate performance of LDL-C using this new method (LDL-S) compared with LDL-C estimated by Friedewald's and Martin eq. (LDL-F, LDL-M) in FCHL. METHODS: Data were collected from 340 subjects with confirmed FCHL. Concordance for VLDL-C measured by ultracentrifugation and LDL-C estimated using these measures compared to Sampson's, Martin's and Friedewald's equations was performed using correlation coefficients, root mean squared error (RMSE) and bias. Also, concordance of misclassified metrics according to LDL-C (< 70 and < 100 mg/dL) and Apo B (< 80 and < 65 mg/dL) thresholds were assessed. RESULTS: Sampson's equation was more accurate (RMSE 11.21 mg/dL; R2 = 0.88) compared to Martin's (RMSE 13.15 mg/dL; R2 = 0.875) and the Friedewald's equation (RMSE 13.7 mg/dL; R2 = 0.869). When assessing performance according to LDL-C, Sampson's had highest correlation and lowest RMSE compared to other equations (RMSE 19.99 mg/dL; R2 = 0.840). Comparing performance strength across triglyceride levels, Sampson's showed consistently improved correlations compared to Martin's and Friedewald's formulas for increasing triglycerides and for the FCHL phenotype of mixed dyslipidemia. Sampson's also had improved concordance with treatment goals. CONCLUSIONS: In FCHL, VLDL-C and LDL-C estimation using Sampson's formula showed higher concordance with lipid targets assessed using VLDL-C obtained by ultracentrifugation compared with Friedewald's and Martin's equations. Implementation of Sampson's formula could improve treatment monitoring in FCHL.

Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on Low-Density Lipoprotein Cholesterol in Patients at High Risk for Cardiovascular Disease: The CLEAR Wisdom Randomized Clinical Trial.

Importance: Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies. Objective: To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy. Interventions: Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks. Main Outcomes and Measures: The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers. Results: Among 779 randomized patients (mean age, 64.3 years; 283 women [36.3%]), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference, -17.4% [95% CI, -21.0% to -13.9%]; P < .001). Significant reductions with bempedoic acid vs placebo were observed at week 12 for non-high-density lipoprotein cholesterol (-10.8% vs 2.3%; difference, -13.0% [95% CI, -16.3% to -9.8%]; P < .001), total cholesterol (-9.9% vs 1.3%; difference, -11.2% [95% CI, -13.6% to -8.8%]; P < .001), apolipoprotein B (-9.3% vs 3.7%; difference, -13.0% [95% CI, -16.1% to -9.9%]; P < .001), and high-sensitivity C-reactive protein (median, -18.7% vs -9.4%; difference, -8.7% [asymptotic confidence limits, -17.2% to -0.4%]; P = .04). Common adverse events included nasopharyngitis (5.2% vs 5.1% with bempedoic acid and placebo, respectively), urinary tract infection (5.0% vs 1.9%), and hyperuricemia (4.2% vs 1.9%). Conclusions and Relevance: Among patients at high risk for cardiovascular disease receiving maximally tolerated statins, the addition of bempedoic acid compared with placebo resulted in a significant lowering of LDL-C level over 12 weeks. Further research is needed to assess the durability and clinical effect as well as long-term safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02991118.

Measurement of the Cellular Hemoglobin Concentration by Laser Scatter Method from Excessive Lipemic Sample: CASE REPORT.

A 33-month old female child presented at a pediatric clinic with acute tonsillitis, and it was subsequently discovered that she had familial hyperlipidemia. Measurement of the patient's whole blood tests was performed by a multiparameter automated hematology analyzer, the CELLDYN Ruby System® (Abbott, Lake Forest, USA) using venous blood extracted from a tube containing 3.0 mL of EDTA. Although her hematocrit levels were within normal limits, the hemoglobin (Hgb) level, mean corpuscular volume (MCH) and mean corpuscular Hgb concentration (MCHC) could not be determined using the spectrophotometric method. The results of these tests could not be measured when repeated using dilution. When the sample was left to rest for several minutes, it was observed to be excessively lipemic. The measurements were repeated using the Alinity HQ Analyzer® (Abbott), which determines Hgb concentration using laser scatter and spectrophotometry. Hgb cellular concentration was incorrectly measured as being 21.9 mg/dL using routine spectrophotometry (denoted by a flag indicating Hgb interference) and correctly found to be 10.8 mg/dL. Thus, in samples of excessive lipemia, Hgb, MCH, and MCHC levels cannot be measured accurately using spectrophotometry. Hematology analyzers that can measure cellular hemoglobin (cHGB) and average erythrocyte hemoglobin concentration (cHCM) by laser scatter method may be recommended when analyzing a blood sample that contains excessive lipemia.

Metabolic disorders and inflammation are associated with familial combined hyperlipemia.

BACKGROUND: Familial Combined Hyperlipidemia (FCH) is related to different metabolic disorders. The objective of this study was to evaluate the presence of alterations of hydrocarbonated metabolism and lipid profile together with inflammatory and adhesion molecules in subjects with FCH compared to controls. METHODS: 75 HFC patients and 75 healthy individuals were studied. Glucose, insulin, HOMA-IR index and lipid parameters, in addition to anti-oxidized LDL antibodies (Anti ox-LDL), small and dense LDL (sdLDL) and HDL subfractions, proinflammatory cytokines and adhesion molecules were measured. RESULTS: FCH patients showed higher levels of hydrocarbonated metabolism parameters, total cholesterol, triglycerides, LDLc, Apolipoprotein B and non-HDLc (p < .001), and lower levels of HDLc (p < .001) and Apolipoprotein AI (p < .05) than controls. In addition, the inflammatory markers hsCRP, IL-6, IL-8, P-selectin, E-selectin and ICAM were all higher with (p < .05) respect to controls. The increase of sdLDL was correlated with the presence of IR and IL-6 levels. Significant differences in diameter and percentage of phenotype B LDL, small HDL subfractions and Anti ox-LDL were also detected between patients and controls. CONCLUSIONS: The lipid characteristics of FCH are confirmed by IR and a low grade inflammatory state in patients, and are associated with the predominance of sdLDL and Anti ox-LDL.

Decreasing the Cholesterol Burden in Heterozygous Familial Hypercholesterolemia Children by Dietary Plant Stanol Esters.

This review covers the current knowledge about plant stanol esters as a dietary treatment option for heterozygous familial hypercholesterolemia (he-FH) children. The current estimation of the prevalence of he-FH is about one out of 200⁻250 persons. In this autosomal dominant disease, the concentration of plasma low-density lipoprotein cholesterol (LDL-C) is strongly elevated since birth. Quantitative coronary angiography among he-FH patients has revealed that stenosing atherosclerotic plaques start to develop in he-FH males in their twenties and in he-FH females in their thirties, and that the magnitude of the plaque burden predicts future coronary events. The cumulative exposure of coronary arteries to the lifelong LDL-C elevation can be estimated by calculating the LDL-C burden (LDL-C level × years), and it can also be used to demonstrate the usefulness of dietary stanol ester treatment. Thus, when compared with untreated he-FH patients, the LDL-C burden of using statin from the age of 10 is 15% less, and if he-FH patients starts to use dietary stanol from six years onwards and a combination of statin and dietary stanol from 10 years onwards, the LDL-C burden is 21% less compared to non-treated he-FH patients. We consider dietary stanol treatment of he-FH children as a part of the LDL-C-lowering treatment package as safe and cost-effective, and particularly applicable for the family-centered care of the entire he-FH families.

Performance of LDL-C calculated with Martin's formula compared to the Friedewald equation in familial combined hyperlipidemia.

BACKGROUND AND AIMS: A novel method to estimate low density lipoprotein cholesterol (LDL-C) has been proposed by Martin et al. This may permit a more accurate estimation of cardiovascular risk, however, external validation is needed. Here, the performance of LDL-C using this new method (LDL-N) is compared with LDL-C estimated with Friedewald equation (LDL-F) in familial combined hyperlipidemia (FCHL), a common primary dyslipidemia in which apolipoprotein B containing particle composition is abnormal and interferes with LDL-C estimation. METHODS: A total of 410 FCHL subjects were included. LDL-C was estimated with both the Friedewald equation (LDL-F) and the novel formula (LDL-N). Apolipoprotein B levels and non- HDL-C were recorded. The correlation and concordance between LDL-F and LDL-N and both Apolipoprotein B and non-HDL-C levels were calculated. Analysis stratifying for triglyceride tertiles and FCHL lipid phenotypes was also carried out. RESULTS: The correlations between LDL-N and Apo B and non-HDL-C were ρ = 0.777 (95%CI 0.718-0.825) and ρ = 0.735 (95%CI 0.648-0.816), respectively. The corresponding correlations for LDL-F were ρ = 0.551(95%CI 0.454-0.637) and ρ = 0.394 (95%CI 0.253-0.537), respectively. In mixed dyslipidemia or isolated hypertriglyceridemia, these correlations were significantly better using LDL-N. With respect to concordance, LDL-N performed significantly better than LDL-F when considering apoB <90 mg/dL (κLDL-N = 0.495 vs. κLDL-F = 0.165) and non-HDL-C <130 (κLDL-N = 0.724 vs. κLDL-F = 0.253). CONCLUSIONS: In FCHL, LDL-C estimation using Martin's formula showed greater correlation and concordance with non-HDL-C and Apo B compared with the Friedewald equation.

PAI-1 levels are related to insulin resistance and carotid atherosclerosis in subjects with familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCH) is a primary atherogenic dyslipidemia with insulin resistance and increased cardiovascular risk. Plasminogen activator inhibitor type 1 (PAI-1) and myeloperoxidase (MPO) activity are associated with proinflammatory and atherothrombotic risk. Our aim was to study the role played by PAI-1 and MPO activity in the carotid atherosclerosis prevalence in FCH subjects. 36 FCH unrelated subjects (17 women) were matched by age and body weight with 36 healthy normolipidemic subjects (19 female). Blood lipids, glucose, insulin, insulin resistance (homeostasis model assessment (HOMA)), MPO, and PAI-1 were determined in both groups. Carotid intima media thickness (IMT) was measured by the same investigator by standardized protocol. No differences in age, body mass index (BMI) or waist circumference were observed between the two groups. HOMA and PAI-1 values were higher in the FCH group, reaching statistical significance in those subjects with insulin resistance. In addition, PAI-1 values correlated significantly with metabolic syndrome components and carotid IMT. It is known that the elevated cardiovascular risk that characterizes FCH is frequently associated with insulin resistance. We have detected that two known proinflammatory and proatherothrombotic factors (MPO and PAI-1) are significantly elevated in FCH subjects with insulin resistance. These results could partly explain the high cardiovascular risk present in FCH subjects.

Relationship Between Total Serum Bilirubin Levels and Carotid and Femoral Atherosclerosis in Familial Dyslipidemia.

OBJECTIVE: Bilirubin is a potent antioxidant that has been inversely related to cardiovascular disease. There is little information on serum total bilirubin (TB) in relation to atherosclerosis in familial dyslipidemia. We assessed the association between TB and carotid and femoral atherosclerosis in this high-risk group. APPROACH AND RESULTS: We evaluated 464 individuals with familial dyslipidemia (56% men; median age, 48 years), 322 with familial hypercholesterolemia, and 142 with familial combined hyperlipidemia. Carotid and femoral arteries were imaged bilaterally with a standardized ultrasonographic protocol. Mean and maximum intima-media thickness and plaque presence (≥1.2 mm) and height were recorded. Cross-sectional associations between TB and atherosclerosis variables were investigated in multivariable-adjusted models, including lipid values and hypolipidemic drug use. Inflammatory markers (C-reactive protein, total leukocyte count, and lipoprotein[a]) were also determined. Increasing TB levels were associated with decreasing intima-media thickness of all carotid segments (P<0.05, all). TB also related to carotid plaque, present in 78% of individuals, and to plaque burden (≥3 plaques), with odds ratios (95% confidence interval) 0.59 (0.36-0.98) and 0.57 (0.34-0.96) for each increase of 0.5 mg in TB, respectively. Findings were confirmed in a validation cohort of 177 subjects with nonfamilial dyslipidemia. Only the familial combined hyperlipidemia group, with higher inflammation-related markers, showed an inverse association between TB and femoral plaque height (ß=-0.183; P=0.030). CONCLUSIONS: TB was inversely and independently associated with carotid plaque burden in familial and nonfamilial dyslipidemia. These findings support the use of TB as a biomarker of atherosclerosis in this high-risk group.

The Contribution of GWAS Loci in Familial Dyslipidemias.

Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 affected FCH individuals across the families, seven (3%) carried Mendelian variants and 83 (35%) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined.

Long-term therapeutic efficacy of lipoprotein apheresis on circulating oxidative stress parameters--A comparison of two different apheresis techniques.

BACKGROUND: A chronic lipoprotein apheresis therapy leads to an expressed reduction in the incidence of cardiovascular events in high-risk patients. In addition to the elimination of atherogenic lipoproteins such as LDL and lipoprotein(a), an antioxidative effect of lipoprotein apheresis has been suspected. OBJECTIVES AND METHODS: We investigated long-term biochemical effects in sixteen patients undergoing lipoprotein apheresis - lipid filtration (LF, n = 7) or dextran sulfate adsorption (DSA, n = 9). Systemic oxidative stress markers (blood phagocyte chemiluminescence, levels of oxidized LDL and antioxLDL antibodies) were examined at the 1st, 40th and 80th apheresis sessions. RESULTS: In DSA patients, the 80th apheresis session was associated with significantly higher LDL cholesterol removal and lower HDL cholesterol deprivation as compared to LF patients. In contrast to LF patients, DSA patients showed a long-term progressive decrease in circulating oxidant generating activity as evaluated by whole blood chemiluminescence (p < 0.05). Moreover, a single LF apheresis session was associated with higher systemic generation of reactive oxygen species over time. CONCLUSION: Compared to LF, long-term DSA apheresis is associated with a gradual reduction of circulating oxidative burden and may be considered a beneficial molecular mechanism of this technique.

Clinical experience of scoring criteria for Familial Hypercholesterolaemia (FH) genetic testing in Wales.

BACKGROUND/OBJECTIVE: Familial Hypercholesterolaemia (FH) is caused by mutations in genes of the Low Density Lipoprotein (LDL) receptor pathway. A definitive diagnosis of FH can be made by the demonstration of a pathogenic mutation. The Wales FH service has developed scoring criteria to guide selection of patients for DNA testing, for those referred to clinics with hypercholesterolaemia. The criteria are based on a modification of the Dutch Lipid Clinic scoring criteria and utilise a combination of lipid values, physical signs, personal and family history of premature cardiovascular disease. They are intended to provide clinical guidance and enable resources to be targeted in a cost effective manner. METHODS: 623 patients who presented to lipid clinics across Wales had DNA testing following application of these criteria. RESULTS: The proportion of patients with a pathogenic mutation ranged from 4% in those scoring 5 or less up to 85% in those scoring 15 or more. LDL-cholesterol was the strongest discriminatory factor. Scores gained from physical signs, family history, coronary heart disease, and triglycerides also showed a gradient in mutation pick-up rate according to the score. CONCLUSION: These criteria provide a useful tool to guide selection of patients for DNA testing when applied by health professionals who have clinical experience of FH.

Association of USF1 and APOA5 polymorphisms with familial combined hyperlipidemia in an Italian population.

BACKGROUND: Familial combined hyperlipidemia (FCH) is a polygenic and multifactorial disease characterized by a variable phenotype showing increased levels of triglycerides and/or cholesterol. The aim of this study was to identify single nucleotides (SNPs) in lipid-related genes associated with FCH. METHODS AND RESULTS: Twenty SNPs in lipid-related genes were studied in 142 control subjects and 165 FCH patients after excluding patients with mutations in the LDLR gene and patients with the E2/E2 genotype of APOE. In particular, we studied the 9996G > A (rs2073658) and 11235C > T (rs3737787) variants in the Upstream Stimulatory Factor 1 gene (USF1), and the -1131T > C (rs662799) and S19W (rs3135506) variants in the Apolipoprotein A-V gene (APOA5). We found that the frequencies of these variants differed between patients and controls and that are associated with different lipid profiles. At multivariate logistic regression SNP S19W in APOA5 remained significantly associated with FCH independently of age, sex, BMI, cholesterol and triglycerides. CONCLUSIONS: Our results show that the USF1 and APOA5 polymorphisms are associated with FCH and that the S19W SNP in the APOA5 gene is associated to the disease independently of total cholesterol, triglycerides and BMI. However, more extensive studies including other SNPs such as rs2516839 in USF1, are required.

Glucose-dependent leukocyte activation in patients with type 2 diabetes mellitus, familial combined hyperlipidemia and healthy controls.

BACKGROUND: Leukocyte activation has been associated with vascular complications in type 2 diabetes mellitus (T2DM). Hyperglycemia may be involved in this leukocyte activation. Our aim was to investigate the role of elevated glucose concentrations on leukocyte activation in patients with a wide range of insulin sensitivity. METHODS: Leukocyte activation was determined after ingestion of 75 gram glucose in subjects with T2DM, familial combined hyperlipidemia (FCH) and healthy controls. Leukocyte activation markers were measured by flow cytometry. Postprandial changes were calculated as the area under the curve (AUC), and the incremental area under the curve corrected for baseline values (dAUC). RESULTS: 51 Subjects (20 T2DM, 17 FCH and 14 controls) were included. Fasting neutrophil CD66b expression and CD66b-AUC were respectively 36% and 39% higher in T2DM patients than in controls (p=0.004 and p=0.003). Fasting neutrophil CD66b expression correlated positively with glucose-AUC (Spearman's rho 0.481, p<0.001) and HbA1c (rho 0.433, p=0.002). Although fasting monocyte CD11b expression was not significantly different between subjects, monocyte CD11b-AUC was 26% higher in T2DM than in controls (p=0.006). Similar trends were observed for FCH patients. Monocyte CD11b-dAUC correlated positively with glucose-AUC (rho 0.322, p=0.022) and HbA1c (rho 0.319, p=0.023). CONCLUSIONS: These data suggest that both acute and chronic hyperglycemia, associated with insulin resistance as seen in T2DM and FCH, are involved in the increased fasting and postprandial leukocyte activation observed in these conditions.

Determinants of VLDL composition and apo B-containing particles in familial combined hyperlipidemia.

BACKGROUND: In familial combined hyperlipidemia (FCHL) the severity of the dyslipidemia is determined by an overproduction of VLDL (very low density lipoprotein) particles and by its abnormal lipid composition. However, few are known regarding the metabolic factors that determine these abnormalities. We investigated the impact of metabolic factors on the number of atherogenic particles (apolipoprotein B level (apoB)) and the triglyceride content of very low-density lipoproteins (VLDLs-TG). METHODS: A cross-sectional study done in FCHL subjects and gender and age-matched healthy subjects. A clinical assessment, lipid profile and plasma concentrations of insulin, apolipoprotein CIII (apo CIII), apolipoprotein AII (apo AII), high sensitive C-reactive protein (HS-CRP), adiponectin and leptin were documented in 147 FCHL patients and 147 age-matched healthy subjects. Multivariate regression models were performed to investigate the independent determinants of VLDL-TG and apo B levels adjusting for confounding factors. RESULTS: The variables that determined the VLDL-triglyceride content as a surrogate of VLDL composition were apo CIII (ß=0.365, p<0.001), insulin (ß=0.281, p<0.001), Apo AII (ß=0.145, p<0.035), and adiponectin levels (ß=-0.255, p<0.001). This model explained 34% of VLDL composition (VLDL-TG) variability. However, none of these variables were independent contributors of apo B-containing particles. CONCLUSIONS: In patients with FCHL apo CIII, apo AII and adiponectin are major novel factors determining the VLDL particle composition. However, such factors do not explain apo B-containing particles.

Factors associated with postprandial lipemia and apolipoprotein A-V levels in individuals with familial combined hyperlipidemia.

BACKGROUND: Alterations in postprandial metabolism have been described in familial combined hyperlipidemia (FCH); however, their underlying mechanisms are not well characterized. We aimed to identify factors related to the magnitude of postprandial lipemia and apolipoprotein (apo) A-V levels in subjects with FCH. METHODS: FCH cases (n = 99) were studied using a standardized meal test. Abdominal obesity was assessed using the waist to hip ratio (WHR). A linear regression model was performed to investigate the variables associated with the triglycerides incremental area under the curve (iAUC). Independent associations between metabolic variables and apo A-V iAUC were also investigated in a randomly selected subgroup (n = 44). The study sample was classified according to the presence of fasting hypertriglyceridemia (≥150 mg/dL) and abdominal obesity (WHR ≥0.92 in men and ≥0.85 in women) to explore differences in parameters. RESULTS: The fasting apo B-48 levels (r = 0.404), and the WHR (r = 0.359) were independent factors contributing to the triglycerides iAUC (r2 = 0.29, P < 0.001). The triglycerides iAUC was independently associated with the apo A-V iAUC (r2 = 0.54, P < 0.01). Patients with both hypertriglyceridemia and abdominal obesity showed the most robust triglycerides and apo A-V postprandial responses. CONCLUSIONS: In patients with FCH the fasting apo B-48 level is the main factor associated with postprandial lipemia. Abdominal obesity also contributes to the magnitude of the postprandial response.The triglycerides postprandial increment is the principal factor associated with the apo A-V postprandial response.

Serum lipid responses to weight loss differ between overweight adults with familial hypercholesterolemia and those with familial combined hyperlipidemia.

The effect of weight loss on lipids differs among individuals, although whether it can modify the management of hereditary hyperlipidemias has not yet been explored. The objective of this study was to examine the effect of weight loss on cholesterol metabolism, assessed by circulating noncholesterol sterols, in overweight adults with familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCHL). We conducted a 6-mo weight loss intervention in untreated individuals (FH: n = 28; FCHL: n = 50) with a body mass index of >25 kg/m(2) and mean age of 46.9 ± 11.3 y, of whom 53.8% were men. A hypocaloric diet was implemented and serum lipid analyses, including noncholesterol sterols, were assessed. Global significant mean weight losses of 5.7 kg (-6.6%) and 6.6 kg (-7.6%) were achieved after 3 and 6 mo, respectively. Mean non-HDL cholesterol and triglyceride (TG) changes at 3 and 6 mo compared with baseline were -5.8% (P = 0.004) and -7.1% (P = 0.014), and -30.1% (P < 0.001) and -31.4% (P < 0.001), respectively. Among participants who lost ≥5% body weight, only significant changes in TGs and non-HDL cholesterol were observed in FCHL participants. Sterol precursors of cholesterol synthesis decreased significantly by 10.4% at 6 mo in FCHL participants, mostly because of a 23.9% lathosterol reduction. Baseline synthesis precursors were associated with TG reduction in FCHL participants (P = 0.039; R(2) = 0.20), and intestinally derived sterols were inversely associated with non-HDL cholesterol changes in FH participants (P = 0.036; R(2) = 0.21). Thus, FCHL participants had a better lipid-lowering response to weight loss than did FH participants. This response was positively associated with baseline cholesterol synthesis, which was reduced by weight loss. Our results confirm the cholesterol overproduction mechanism of FCHL and its interaction with fat mass, while also supporting the differential management of familial hyperlipidemias if obesity coexists. This trial was registered at clinicaltrials.gov as NCT01995149.

Bile acid synthesis precursors in familial combined hyperlipidemia: the oxysterols 24S-hydroxycholesterol and 27-hydroxycholesterol.

Familial combined hyperlipidemia (FCHL), the most common inherited disorder of lipid metabolism is characterized by increasing cholesterol synthesis precursors due to hepatic overproduction of cholesterol. The bile acids synthesis pathway has not been previously studied in FCHL. The aim of this work was to study the oxysterol levels which are involved in the bile acids synthesis from cholesterol in FCHL. Clinical parameters and subclinical atherosclerosis were studied in a total of 107 FCHL patients and 126 normolipidemic controls. Non cholesterol sterols (desmosterol and lanosterol) and oxysterols (27-hydroxycholesterol and 24S-hydroxycholesterol) were measured by high performance liquid chromatography tandem mass spectrometry. Desmosterol and lanosterol, markers of cholesterol synthesis, had a positive correlation with BMI and apo B. However, no correlation was found for 24S-hydroxycholesterol and 27-hydroxycholesterol, precursors of bile acids, with these clinical parameters. Only 27-hydroxycholesterol had a positive correlation with apo B, ρ=0.204 (P=0.037). All oxysterol levels were higher in FHCL as compared to normal controls. A total of 59 FCHL subjects (59%) presented values of 24S-hydroxycholesterol above the 95th percentile of this oxysterol in the control population. All oxysterols showed no association with fat mass in contrast with non-cholesterol sterols. FCHL subjects with oxysterol overproduction had less carotid intima media thickness (cIMT), which suggests less atherosclerosis in these subjects. In summary, our data indicate that high oxysterol levels might be good markers of FCHL, unrelated to fat mass, and may exert a protective mechanism for cholesterol accumulation.

Circulating PCSK9 is a strong determinant of plasma triacylglycerols and total cholesterol in homozygous carriers of apolipoprotein ε2.

Homozygous carriers of the apolipoprotein ε2 allele are at risk of type III hyperlipidaemia, but do not necessarily develop this lipid disorder. In the present study, we have investigated the role of circulating PCSK9 (pro-protein convertase subtilisin kexin type 9), an important regulator of LDL (low-density lipoprotein) receptor expression, in the development of this hyperlipidaemic phenotype. In an observational study, plasma PCSK9 was measured in homozygous carriers of apolipoprotein ε2 (ε2/ε2; n=12), normal controls (n=72) and hypertriglyceridaemic patients with FCHL (familial combined hyperlipidaemia; n=38), who served as a hyperlipidaemic reference group. Cholesterol, triacylglycerols (triglycerides) and apolipoprotein B content in VLDL (very-low-density lipoprotein) and LDL particles was determined by ultracentrifugation in ε2/ε2 and FCHL patients. Median circulating PCSK9 levels did not differ between ε2/ε2 carriers compared with controls and hypertriglyceridaemic FCHL patients (84.5 compared with 82.0 and 84.9 ng/ml; P=0.2 and 0.6 respectively). Circulating PCSK9 was associated with total cholesterol and triacylglycerols levels in ε2/ε2 carriers (P<0.05). These associations were stronger in ε2/ε2 carriers when compared with controls (P values for interaction=0.01 and 0.02 respectively). A direct comparison with FCHL patients demonstrated a similar discrepancy for the association with plasma triacylglycerols and also VLDL-apolipoprotein B, cholesterol and triacylglycerols (P value for interaction=0.01, 0.01, 0.03 and 0.03 respectively). Plasma PCSK9 is associated with type III hyperlipidaemia. Its strong relationship with plasma triacylglycerols and total cholesterol distinguishes ε2/ε2 carriers from controls and another type of dyslipidaemia, which provides valuable information regarding the pathogenesis of this complex dyslipidaemia. Furthermore, these results suggest that patients with type III hyperlipidaemia may benefit from PCSK9-antagonizing therapy.