Contribution of APOE Genetic Variants to Dyslipidemia.

BACKGROUND: apo (apolipoprotein) E has crucial role in lipid metabolism. The genetic variation in APOE gene is associated with monogenic disorders and contributes to polygenic hypercholesterolemia and to interindividual variability in cholesterol. APOE rare variants may be involved in the phenotype of genetic hyperlipidemias. METHODS: Exon 4 of APOE were sequenced in all consecutive unrelated subjects with primary hyperlipidemia from a Lipid Unit (n=3667) and 822 random subjects from the Aragon Workers Health Study. Binding affinity of VLDL (very low-density lipoprotein) to LDL receptor of pathogenic predicted apoE variants was analyzed in vitro. Lipoprotein particle number, size, and composition were studied by nuclear magnetic resonance. RESULTS: In addition to common polymorphisms giving rise to APOE2 and APOE4, 14 gene variants were found in exon 4 of APOE in 65 subjects. p.(Leu167del) in 8 patients with isolated hypercholesterolemia and in 8 patients with combined hyperlipidemia. Subjects with p.(Arg121Trp), p.(Gly145Asp), p.(Arg154Ser), p.(Arg163Cys), p.(Arg165Trp), and p.(Arg168His) variants met dysbetalipoproteinemia lipid criteria and were confirmed by nuclear magnetic resonance. VLDL affinity for the LDL receptor of p.(Arg163Cys) and p.(Arg165Trp) heterozygous carriers had intermedium affinity between APOE2/2 and APOE3/3. p.(Gly145Asp) and p.(Pro220Leu) variants had higher affinity than APOE3/3. CONCLUSIONS: APOE genetic variation contributes to the development of combined hyperlipidemia, usually dysbetalipoproteinemia, and familial hypercholesterolemia. The lipid phenotype in heterozygous for dysbetalipoproteinemia-associated mutations is milder than the homozygous APOE2/2-associated phenotype. Subjects with dysbetalipoproteinemia and absence of APOE2/2 are good candidates for the study of pathogenic variants in APOE. However, more investigation is required to elucidate the significance of rarer variants of apoE.

Diagnosis of Familial Dysbetalipoproteinemia Based on the Lipid Abnormalities Driven by APOE2/E2 Genotype.

BACKGROUND: Familial dysbetalipoproteinemia (FDBL) is a monogenic disease due to variants in APOE with a highly variable phenotype. Current diagnostic lipid-based methods have important limitations. The objective is twofold: to define characteristics of dysbetalipoproteinemia (DBL) based on the analysis of APOE in patients from a lipid unit and in a sample from the general population, and to propose a screening algorithm for FDBL. METHODS: Lipids and APOE genotype from consecutive unrelated subjects from Miguel Servet University Hospital (MSUH) (n 3603), subjects from the general population participants of the Aragon Workers Health Study (AWHS) (n 4981), and selected subjects from external lipid units (Ext) (n 390) were used to define DBL criteria and to train and validate a screening tool. RESULTS: Thirty-five subjects from MSUH, 21 subjects from AWHS, and 31 subjects from Ext were APOE2/2 homozygous. The combination of non high-density lipoprotein cholesterol (non-HDLc)/apoB 1.7 plus triglycerides/apoB 1.35, in mg/dL (non-HDLc [mmol/L]/apolipoprotein B (apoB) [g/L] 4.4 and triglycerides [mmol/L]/apoB [g/L] 3.5), provided the best diagnostic performance for the identification of subjects with hyperlipidemia and APOE2/2 genotype (sensitivity 100 in the 3 cohorts, and specificity 92.8 [MSUH], 80.9 [AWHS], and 77.6 [Ext]). This improves the performance of previous algorithms. Similar sensitivity and specificity were observed in APOE2/2 subjects receiving lipid-lowering drugs. CONCLUSIONS: The combination of non-HDLc/apoB and triglycerides/apoB ratios is a valuable tool to diagnose DBL in patients with hyperlipidemia with or without lipid-lowering drugs. FDBL diagnosis requires DBL and the presence of a compatible APOE genotype. Most adult APOE2/2 subjects express DBL, making FDBL as common as familial hypercholesterolemia in the population.

Applicability of Diagnostic Criteria and High Prevalence of Familial Dysbetalipoproteinemia in Russia: A Pilot Study.

Familial dysbetalipoproteinemia (FD) is a highly atherogenic genetically based lipid disorder with an underestimated actual prevalence. In recent years, several biochemical algorithms have been developed to diagnose FD using available laboratory tests. The practical applicability of FD diagnostic criteria and the prevalence of FD in Russia have not been previously assessed. We demonstrated that the diagnostic algorithms of FD, including the diagnostic apoB levels, require correction, taking into account the distribution of apoB levels in the population. At the same time, a triglycerides cutoff ≥ 1.5 mmol/L may be a useful tool in identifying subjects with FD. In this study, a high prevalence of FD was detected: 0.67% (one in 150) based on the ε2ε2 haplotype and triglycerides levels ≥ 1.5 mmol/L. We also analyzed the presence and pathogenicity of APOE variants associated with autosomal dominant FD in a large research sample.

Diagnosis of remnant hyperlipidaemia.

PURPOSE OF REVIEW: In recent years, there has been interest for the development of simplified diagnosis algorithms of dysbetalipoproteinemia (DBL) in order to avoid the complex testing associated with the Fredrickson criteria (reference method). The purpose of this review is to present recent advances in the field of DBL with a focus on screening and diagnosis. RECENT FINDINGS: Recently, two different multi-step algorithms for the diagnosis of DBL have been published and their performance has been compared to the Fredrickson criteria. Furthermore, a recent large study demonstrated that only a minority (38%) of DBL patients are carriers of the E2/E2 genotype and that these individuals presented a more severe phenotype. SUMMARY: The current literature supports the fact that the DBL phenotype is more heterogeneous and complex than previously thought. Indeed, DBL patients can present with either mild or more severe phenotypes that can be distinguished as multifactorial remnant cholesterol disease and genetic apolipoprotein B deficiency. Measurement of apolipoprotein B as well as APOE gene testing are both essential elements in the diagnosis of DBL.

Establishing the relationship between familial dysbetalipoproteinemia and genetic variants in the APOE gene.

Familial Dysbetalipoproteinemia (FD) is the second most common monogenic dyslipidemia and is associated with a very high cardiovascular risk due to cholesterol-enriched remnant lipoproteins. FD is usually caused by a recessively inherited variant in the APOE gene (ε2ε2), but variants with dominant inheritance have also been described. The typical dysbetalipoproteinemia phenotype has a delayed onset and requires a metabolic hit. Therefore, the diagnosis of FD should be made by demonstrating both the genotype and dysbetalipoproteinemia phenotype. Next Generation Sequencing is becoming more widely available and can reveal variants in the APOE gene for which the relation with FD is unknown or uncertain. In this article, two approaches are presented to ascertain the relationship of a new variant in the APOE gene with FD. The comprehensive approach consists of determining the pathogenicity of the variant and its causal relationship with FD by confirming a dysbetalipoproteinemia phenotype, and performing in vitro functional tests and, optionally, in vivo postprandial clearance studies. When this is not feasible, a second, pragmatic approach within reach of clinical practice can be followed for individual patients to make decisions on treatment, follow-up, and family counseling.

Genetic and Mechanistic Insights into the Modulation of Circulating Lipoprotein (a) Concentration by Apolipoprotein E Isoforms.

PURPOSE OF REVIEW: Lipoprotein (a) [Lp(a)] is a highly atherogenic lipoprotein species. A unique feature of Lp(a) is the strong genetic determination of its concentration. The LPA gene is responsible for up to 90% of the variance in Lp(a), but other genes also have an impact. RECENT FINDINGS: Genome-wide associations studies indicate that the APOE gene, encoding apolipoprotein E (apoE), is the second most important locus modulating Lp(a) concentrations. Population studies clearly show that carriers of the apoE2 variant (ε2) display reduced Lp(a) levels, the lowest concentrations being observed in ε2/ε2 homozygotes. This genotype can lead predisposed adults to develop dysbetalipoproteinemia, a lipid disorder characterized by sharp elevations in cholesterol and triglycerides. However, dysbetalipoproteinemia does not significantly modulate circulating Lp(a). Mechanistically, apoE appears to impair the production but not the catabolism of Lp(a). These observations underline the complexity of Lp(a) metabolism and provide key insights into the pathways governing Lp(a) synthesis and secretion.

Apolipoprotein E and Atherosclerosis.

PURPOSE OF REVIEW: The functions, genetic variations and impact of apolipoprotein E on lipoprotein metabolism in general are placed in the context of clinical practice dealing with moderate dyslipidaemia as well as dysbetalipoproteinemia, a highly atherogenic disorder and lipoprotein glomerulopathy. RECENT FINDINGS: Additional variants of apolipoprotein E and participation of apolipoprotein E in inflammation are of interest. The mostly favourable effects of apolipoprotein E2 as well as the atherogenic nature of apolipoproteinE4, which has an association with cognitive impairment, are confirmed. The contribution of remnant lipoproteins of triglyceride-rich lipoproteins, of which dysbetalipoproteinemia represents an extreme, is explored in atherosclerosis. Mimetic peptides may present new therapeutic approaches. Apolipoprotein E is an important determinant of the lipid profile and cardiovascular health in the population at large and can precipitate dysbetalipoproteinemia and glomerulopathy. Awareness of apolipoprotein E polymorphisms should improve medical care.

Autosomal recessive hypercholesterolemia: update for 2020.

PURPOSE OF REVIEW: This review summarizes the current knowledge regarding autosomal recessive hypercholesterolemia (ARH) and provides new insight into the natural history and therapeutic management of this lipid disorder. RECENT FINDINGS: Novel homozygous and compound heterozygous ARH-causing mutations have been reported in the literature, to date. The long-term follow-up of a cohort of ARH patients demonstrated that, despite intensive treatment with conventional lipid-lowering therapies, their low-density lipoprotein (LDL) cholesterol levels remain far from target and this translates into a poor cardiovascular prognosis. ARH is also associated with increased risk of developing aortic valve stenosis. However, lomitapide, a microsomal triglyceride transfers protein inhibitor, may represent a new opportunity for the effective treatment of ARH. SUMMARY: ARH is an ultrarare disorder of LDL metabolism caused by mutations in the LDLRAP1 gene. It is inherited as a recessive trait and causative mutations, though heterogeneous, are all predicted to be loss-of-function. Recent investigations have demonstrated that ARH can be considered a phenocopy of homozygous familial hypercholesterolemia, where the risk of atherosclerotic cardiovascular diseases and aortic valve stenosis remains elevated despite conventional therapies. The combination of lomitapide with the conventional LDL-C-lowering medications appears to be a promising approach to treat this condition.

The clinical and laboratory investigation of dysbetalipoproteinemia.

Familial dysbetalipoproteinemia (type III hyperlipoproteinemia) is a potentially underdiagnosed inherited dyslipidemia associated with greatly increased risk of coronary and peripheral vascular disease. The mixed hyperlipidemia observed in this disorder usually responds well to appropriate medical therapy and lifestyle modification. Although there are characteristic clinical features such as palmar and tuberous xanthomata, associated with dysbetalipoproteinemia, they are not always present, and their absence cannot be used to exclude the disorder. The routine lipid profile cannot distinguish dysbetalipoproteinemia from other causes of mixed hyperlipidemia and so additional investigations are required for confident diagnosis or exclusion. A range of investigations that have been proposed as potential diagnostic tests are discussed in this review, but the definitive biochemical test for dysbetalipoproteinemia is widely considered to be beta quantification. Beta quantification can determine the presence of "ß-VLDL" in the supernatant following ultracentrifugation and whether the VLDL cholesterol to triglyceride ratio is elevated. Both features are considered hallmarks of the disease. However, beta quantification and other specialist tests are not widely available and are not high-throughput tests that can practically be applied to all patients with mixed hyperlipidemia. Using apolipoprotein B (as a ratio either to total or non-HDL cholesterol or as part of a multi-step algorithm) as an initial test to select patients for further investigation is a promising approach. Several studies have demonstrated a high degree of diagnostic sensitivity and specificity using these approaches and apolipoprotein B is a relatively low-cost test that is widely available on high-throughput platforms. Genetic testing is also important in the diagnosis, but it should be noted that most individuals with an E2/2 genotype do not suffer from remnant hyperlipidemia and around 10% of familial dysbetalipoproteinemia cases are caused by rarer, autosomal dominant mutations in APOE that will only be detected if the gene is fully sequenced. Wider implementation of diagnostic pathways utilizing apo B could lead to more rational use of specialist investigations and more consistent detection of patients with dysbetalipoproteinemia. Without the application of a consistent evidence-based approach to identifying dysbetalipoproteinemia, many cases are likely to remain undiagnosed.

Evaluation of the Non-HDL Cholesterol to Apolipoprotein B Ratio as a Screening Test for Dysbetalipoproteinemia.

BACKGROUND: Familial dysbetalipoproteinemia is associated with the accumulation of remnant lipoproteins and premature cardiovascular disease. Identification of dysbetalipoproteinemia is important because family members may be affected. Diagnostic testing involves demonstration of ß-lipoprotein in the VLDL fraction or characterization of apo E3. These investigations are complex and relatively expensive. The ratios of apo B to total cholesterol and triglycerides have been proposed as screening tests. However, the ratio of non-HDL cholesterol to apo B (NHDLC/apoB) could offer improved performance as the confounding effect of variations in HDL cholesterol is removed. METHODS: We evaluated NHDLC/apoB as a screening test for dysbetalipoproteinemia, using ß-quantification analysis as a reference standard. Data from 1637 patients referred over a 16-year period for ß quantification were reviewed retrospectively. In 63 patients, diagnostic criteria for dysbetalipoproteinemia (VLDL cholesterol/triglyceride ratio ≥0.69 and presence of ß-VLDL) were fulfilled, and 1574 patients had dysbetalipoproteinemia excluded. RESULTS: Mean NHDLC/apoB in patients with dysbetalipoproteinemia was 7.3 mmol/g (SD, 1.5 mmol/g) and with dysbetalipoproteinemia excluded was 4.0 mmol/g (SD, 0.5 mmol/g). The optimum cutoff of >4.91 mmol/g achieved a diagnostic sensitivity of 96.8% (95% CI, 89.0-99.6) and specificity of 95.0% (95% CI, 93.8-96.0). NHDLC/apoB offered improved performance compared to total cholesterol/apoB [diagnostic sensitivity 92.1% (95% CI, 82.4-97.4) and specificity 94.5% (95% CI, 93.2-95.6) with a cutoff of >6.55 mmol/g]. NHDL/apoB reference ranges were not sex-dependent, although there was a significant difference between men and women for total cholesterol/apoB. CONCLUSIONS: NHDLC/apoB offers a simple first-line test for dysbetalipoproteinemia in selecting patients with mixed hyperlipidemia for more complex investigations.

Remnant Cholesterol Elicits Arterial Wall Inflammation and a Multilevel Cellular Immune Response in Humans.

OBJECTIVE: Mendelian randomization studies revealed a causal role for remnant cholesterol in cardiovascular disease. Remnant particles accumulate in the arterial wall, potentially propagating local and systemic inflammation. We evaluated the impact of remnant cholesterol on arterial wall inflammation, circulating monocytes, and bone marrow in patients with familial dysbetalipoproteinemia (FD). APPROACH AND RESULTS: Arterial wall inflammation and bone marrow activity were measured using 18F-FDG PET/CT. Monocyte phenotype was assessed with flow cytometry. The correlation between remnant levels and hematopoietic activity was validated in the CGPS (Copenhagen General Population Study). We found a 1.2-fold increase of 18F-FDG uptake in the arterial wall in patients with FD (n=17, age 60±8 years, remnant cholesterol: 3.26 [2.07-5.71]) compared with controls (n=17, age 61±8 years, remnant cholesterol 0.29 [0.27-0.40]; P<0.001). Monocytes from patients with FD showed increased lipid accumulation (lipid-positive monocytes: Patients with FD 92% [86-95], controls 76% [66-81], P=0.001, with an increase in lipid droplets per monocyte), and a higher expression of surface integrins (CD11b, CD11c, and CD18). Patients with FD also exhibited monocytosis and leukocytosis, accompanied by a 1.2-fold increase of 18F-FDG uptake in bone marrow. In addition, we found a strong correlation between remnant levels and leukocyte counts in the CGPS (n=103 953, P for trend 5×10-276). In vitro experiments substantiated that remnant cholesterol accumulates in human hematopoietic stem and progenitor cells coinciding with myeloid skewing. CONCLUSIONS: Patients with FD have increased arterial wall and cellular inflammation. These findings imply an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to the increased cardiovascular disease risk in patients with FD.

Effect of adding bezafibrate to standard lipid-lowering therapy on post-fat load lipid levels in patients with familial dysbetalipoproteinemia. A randomized placebo-controlled crossover trial.

Familial dysbetalipoproteinemia (FD) is a genetic disorder associated with impaired postprandial lipid clearance. The effect of adding bezafibrate to standard lipid-lowering therapy on postprandial and fasting lipid levels in patients with FD is unknown. In this randomized placebo-controlled double-blind crossover trial, 15 patients with FD received bezafibrate and placebo for 6 weeks in randomized order in addition to standard lipid-lowering therapy (statin, ezetimibe, and/or lifestyle). We assessed post-fat load lipids, expressed as incremental area under the curve (iAUC) and area under the curve (AUC), as well as fasting levels and safety, and found that adding bezafibrate did not reduce post-fat load non-HDL-cholesterol (non-HDL-C) iAUC (1.78 ± 4.49 mmol·h/l vs. 1.03 ± 2.13 mmol·h/l, P = 0.57), but did reduce post-fat load triglyceride (TG) iAUC (8.05 ± 3.32 mmol·h/l vs. 10.61 ± 5.92 mmol·h/l, P = 0.03) and apoB (0.64 ± 0.62 g·h/l vs. 0.93 ± 0.71 g·h/l, P = 0.01). Furthermore, bezafibrate significantly improved AUC and fasting levels of non-HDL-C, TG, total cholesterol, HDL-C, and apoB. Bezafibrate was associated with lower estimated glomerular filtration rate (78.4 ± 11.4 ml/min/1.73 m2 vs. 86.1 ± 5.85 ml/min/1.73 m2, P = 0.002). In conclusion, in patients with FD, the addition of bezafibrate to standard lipid-lowering therapy resulted in improved post-fat load and fasting plasma lipids. Combination therapy of statin/fibrate could be considered as standard lipid-lowering treatment in FD.

Proprotein Convertase Subtilisin Kexin Type 9 Inhibition for Autosomal Recessive Hypercholesterolemia-Brief Report.

OBJECTIVE: Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors lower low-density lipoprotein (LDL) cholesterol in the vast majority of patients with autosomal dominant familial hypercholesterolemia. Will PCSK9 inhibition with monoclonal antibodies, in particular alirocumab, be of therapeutic value for patients with autosomal recessive hypercholesterolemia (ARH)? APPROACH AND RESULTS: Primary lymphocytes were obtained from 28 genetically characterized ARH patients and 11 controls. ARH lymphocytes treated with mevastatin were incubated with increasing doses of recombinant PCSK9 with or without saturating concentrations of alirocumab. Cell surface LDL receptor expression measured by flow cytometry and confocal microscopy was higher in ARH than in control lymphocytes. PCSK9 significantly reduced LDL receptor expression in ARH lymphocytes albeit to a lower extent than in control lymphocytes (25% versus 76%, respectively), an effect reversed by alirocumab. Fluorescent LDL cellular uptake, also measured by flow cytometry, was reduced in ARH lymphocytes compared with control lymphocytes. PCSK9 significantly lowered LDL cellular uptake in ARH lymphocytes, on average by 18%, compared with a 46% reduction observed in control lymphocytes, an effect also reversed by alirocumab. Overall, the effects of recombinant PCSK9, and hence of alirocumab, on LDL receptor expression and function were significantly less pronounced in ARH than in control cells. CONCLUSIONS: PCSK9 inhibition with alirocumab on top of statin treatment has the potential to lower LDL cholesterol in some autosomal recessive hypercholesterolemia patients.

[Hyperlipoproteinemia and dyslipidemia as rare diseases. Diagnostics and treatment]. / Hyperlipoproteinemie a dyslipidemie jako vzácná onemocnení: diagnostika a lécba.

Hyperlipoproteinemia (HLP) and dyslipidemia (DLP) are of course mainly perceived as diseases of common incidence and are typically seen as the greatest risk factors (RF) in the context of the pandemic of cardiovascular diseases. This is certainly true and HLP or DLP overall affect tens of percents of adults. However we cannot overlook the fact that disorders (mostly congenital) of lipid metabolism exist which, though not formally defined as such, amply satisfy the conditions for classification as rare diseases. Our account only includes a brief overview of the rare HLPs based on the dominant disorder of lipid metabolism, i.e. we shall mention the rare primary forms of hypercholesterolemia, primary forms of hypertriglyceridemia and the rare primary combined forms of HLP. In recent years an amazing progress has been reached relating to these diseases, in particular in the area of exact identification of the genetic defect and the mechanism of defect formation, however each of these diseases would require a separate article, though outside the field of clinical internal medicine. Therefore we shall discuss homozygous familial hypercholesterolemia (FH) in greater depth, partially also the "severe" form of heterozygous FH and in the following part the lipoprotein lipase deficiency; that means, diseases which present an extreme and even fatal risk for their carriers at a young age, but on the other hand, new therapeutic possibilities are offered within their treatment. An internist then should be alert to the suspicion that the described diseases may be involved, know about their main symptoms, where to refer the patient and how to treat them. Also dysbetalipoproteinemia (or type III HLP) will be briefly mentioned. Homozygous FH occurs with the frequency of 1 : 1 000 000 (maybe even more frequently, 1 : 160 000), it is characterized by severe isolated hypercholesterolemia (overall cholesterol typically equal to 15 mmol/l or more), xanthomatosis and first of all by a very early manifestation of a cardiovascular disease. Myocardial infarction is not an exception even in childhood. The therapy is based on high-dose statins, statins in combination with ezetimib and now also newly on PCSK9 inhibitors. Lomitapid and partly also mipomersen hold great promise for patients. LDL apheresis then represents an aggressive form of treatment. Lipoprotein lipase deficiency (type I HLP) is mainly characterized by severe hypertriglyceridemia, serum milky in colour, and xanthomatosis. A fatal complication is acute recurrent pancreatitis. A critical part of the treatment is diet, however it alone is not enough to control a genetic disorder. The only approved treatment is gene therapy. Experimentally, as an "off label" therapy, it is used in case studies with a lomitapid effect. We have our own experience with this experimental therapy. Dysbetalipoproteinemia is a congenital disorder of lipoprotein metabolism, characterized by high cholesterol (CH) and triglyceride (TG) levels. The underlying cause of this disease is the defect of the gene providing for apolipoprotein E. It is clinically manifested by xanthomatosis, however primarily by an early manifestation of atherosclerosis (rather peripheral than coronary).Key words: Lipoprotein lipase deficiency - dysbetalipoproteinemia - familial hypercholesterolemia - gene therapy - homozygous FH - LDL apheresis - lomitapid - mipomersen - PCSK9 inhibitors - rare diseases.

Dysbetalipoproteinemia: an extreme disorder of remnant metabolism.

PURPOSE OF REVIEW: Lipoprotein metabolism and the role of apolipoprotein E in the pathogenesis of dysbetalipoproteinemia. RECENT FINDINGS: Remnant lipoproteins, modulated by lifestyle and genetic factors, are atherogenic. Dysbetalipoproteinemia could be viewed as a monogenic disorder of remnant metabolism. SUMMARY: Elevated plasma triglyceride and cholesterol concentrations (mixed hyperlipidemias) are commonly encountered and dysbetaliproteinemia should be considered in this setting. Dysbetalipoproteinemia (remnant clearance disease, Fredrickson type III hyperlipidemia) is an uncommon dyslipoproteinemia related to mutations in apolipoprotein E that disrupt the clearance of remnants of triglyceride-rich lipoproteins; it may be overlooked because xanthomata of the skin and/or tendons occur in a minority of patients. The diagnosis ideally requires the demonstration of remnant lipoprotein accumulation and a genetic cause. Genotyping for apolipoprotein E2 may not prove the diagnosis as it may be associated with low plasma lipid values. The recent association of remnant lipoproteins with atherosclerosis along with many factors that modulate remnant lipoprotein metabolism underscores the importance of recognising dysbetalipoproteinemia as an extreme state of remnant lipoprotein accumulation. Although there may be some differences between remnants in the general population and dysbetalipoproteinemia, it is clear that remnants promote atherosclerosis. Current treatment strategies are adequate but new strategies could also be of benefit in dysbetalipoproteinemia.

Influence of APOE-2 genotype on the relation between adiposity and plasma lipid levels in patients with vascular disease.

BACKGROUND: Apolipoprotein E (APOE) genotypes are associated with different plasma lipid levels. People with the APO ɛ2 genotype can develop a disorder called dysbetalipoproteinemia (DBL). A possible predisposing factor for DBL is adiposity. We evaluated whether and to what extent the APOE genotype modifies the relation between adiposity and lipids in patients with manifest arterial disease and we looked at possible determinants of DBL in ɛ2 homo- and heterozygote patients. METHODS: This prospective cohort study was performed in 5450 patients with manifest arterial disease from the Secondary Manifestations of ARTerial disease (SMART) study. The APOE genotype was measured in all patients and revealed 58 ɛ2 homozygotes, 663 ɛ2 heterozygotes, 3181 ɛ3 homozygotes and 1548 ɛ4 carriers. The main dependent variable was non-high-density lipoprotein cholesterol (non-HDL-c). The relation between adiposity (including body mass index (BMI), waist circumference (waist), visceral adipose tissue (VAT) and metabolic syndrome (MetS)) and lipids was evaluated with linear regression analyses. Determinants of DBL were evaluated using logistic regression. RESULTS: There was significant effect modification by the APOE genotype on the relation between non-HDL-c and BMI, waist, VAT and MetS. There was an association between BMI and non-HDL-c in ɛ2 homozygotes (ß 0.173, 95% confidence interval (CI) 0.031-0.314, P=0.018) and ɛ4 carriers (ß 0.033, 95% CI 0.020-0.046, P<0.001). In all genotypes, there was an effect of waist, VAT and MetS on non-HDL-c, but these effects were most distinct in ɛ2 homozygotes (waist ß 0.063, 95% CI 0.015-0.110, P=0.011; VAT ß 0.580, 95% CI 0.270-0.889, P=0.001; MetS ß 1.760, 95% CI 0.668-2.852, P=0.002). Determinants of DBL in ɛ2 homo- and heterozygotes were VAT and MetS. CONCLUSION: The APOE genotype modifies the relation between adiposity and plasma lipid levels in patients with vascular disease. The relation between adiposity and lipids is present in all patients, but it is most distinct in ɛ2 homozygote patients. Abdominal fat and MetS are determinants of DBL.

Therapeutic Potential and Critical Analysis of the PCSK9 Monoclonal Antibodies Evolocumab and Alirocumab.

OBJECTIVE: To review the mechanism of action for PCSK9 monoclonal antibodies and critically evaluate the therapeutic potential of evolocumab and alirocumab in the treatment of hypercholesterolemia. DATA SOURCES: Ovid MEDLINE search from 1980 to August 2015 using the terms PCSK9, evolocumab, and alirocumab with forward and backward citation tracking. STUDY SELECTION AND DATA EXTRACTION: English-language trials and studies assessing the mechanism, efficacy, or safety of PCSK9 monoclonal antibodies were included. DATA SYNTHESIS: PCSK9 monoclonal antibodies have a potent ability to reduce low-density lipoprotein (LDL) by almost 50% in controlled trials: -47.49% (95% CI = -69.6% to -25.4%). They have an acceptable safety profile with no significant elevations in Creatine Kinase (CK) (odds ratio [OR] = 0.72; 95% CI = 0.54 to 0.96) or serious adverse events (OR = 1.01; 95% CI = 0.87 to 1.18), and preliminary evidence suggests reductions in myocardial infarction (OR = 0.49; 95% CI = 0.26 to 0.93). Although it is effective in several familial hypercholesterolemia (FH) patient types, it does not work in homozygous patients with dual allele LDL receptor negative polymorphisms or those who are homozygous for autosomal recessive hypercholesterolemia. CONCLUSIONS: Although not preferred over statins because of limited clinical trial evidence of cardiovascular event reductions, dosing convenience, and expense, PCSK9 monoclonal antibodies will have a prominent role to play in the treatment of hypercholesterolemia, especially in patients needing large LDL reductions, including patients with many types of FH.

Dysbetalipoproteinaemia: a mixed hyperlipidaemia of remnant lipoproteins due to mutations in apolipoprotein E.

Atherosclerosis is strongly associated with dyslipoproteinaemia, and especially with increasing concentrations of low-density lipoprotein and decreasing concentrations of high-density lipoproteins. Its association with increasing concentrations of plasma triglyceride is less clear but, within the mixed hyperlipidaemias, dysbetalipoproteinaemia (Fredrickson type III hyperlipidaemia) has been identified as a very atherogenic entity associated with both premature ischaemic heart disease and peripheral arterial disease. Dysbetalipoproteinaemia is characterized by the accumulation of remnants of chylomicrons and of very low-density lipoproteins. The onset occurs after childhood and usually requires an additional metabolic stressor. In women, onset is typically delayed until menopause. Clinical manifestations may vary from no physical signs to severe cutaneous and tendinous xanthomata, atherosclerosis of coronary and peripheral arteries, and pancreatitis when severe hypertriglyceridaemia is present. Rarely, mutations in apolipoprotein E are associated with lipoprotein glomerulopathy, a condition characterized by progressive proteinuria and renal failure with varying degrees of plasma remnant accumulation. Interestingly, predisposing genetic causes paradoxically result in lower than average cholesterol concentration for most affected persons, but severe dyslipidaemia develops in a minority of patients. The disorder stems from dysfunctional apolipoprotein E in which mutations result in impaired binding to low-density lipoprotein (LDL) receptors and/or heparin sulphate proteoglycans. Apolipoprotein E deficiency may cause a similar phenotype. Making a diagnosis of dysbetalipoproteinaemia aids in assessing cardiovascular risk correctly and allows for genetic counseling. However, the diagnostic work-up may present some challenges. Diagnosis of dysbetalipoproteinaemia should be considered in mixed hyperlipidaemias for which the apolipoprotein B concentration is relatively low in relation to the total cholesterol concentration or when there is significant disparity between the calculated LDL and directly measured LDL cholesterol concentrations. Genetic tests are informative in predicting the risk of developing the disease phenotype and are diagnostic only in the context of hyperlipidaemia. Specialised lipoprotein studies in reference laboratory centres can also assist in diagnosis. Fibrates and statins, or even combination treatment, may be required to control the dyslipidaemia.