👤 Anna Wolska

Familial dysbetalipoproteinemia (FDB) is a genetic lipoprotein disorder that can develop in patients homozygous for the APOE2 genotype (ε2/ε2). It is associated with decreased clearance of remnant lipoproteins and increased atherosclerotic cardiovascular disease (ASCVD) risk disproportionate to their level of LDL-C. A goal of this study was to develop a screening test for the ε2/ε2 genotype based on routinely available lipid tests and to determine those at most risk for ASCVD. After assembly of a primary prevention cohort from the UK Biobank (n= 269,895), gene array and exome data was utilized to classify patients as being ε2/ε2 genotype positive or negative. Lipid profiles and APOB levels were extracted and the number of ASCVD events was tabulated during a 15-year follow-up period. Using a newly developed equation for estimating APOB (eAPOB) with lipid panel test results, the ratio of measured APOB to eAPOB was better than any other individual lipid test or ratio for identifying patients with the ε2/ε2 genotype (AUC: APOB/eAPOB: 0.990 (0.986-0.994), nonHDL-C/APOB: 0.961 (0.952-0.970), APOB: 0.955 (0.949-0.961), VLDL/TG: 0.788 (0.771-0.804)). The majority of ε2/ε2 patients could be identified with the APOB/eAPOB ratio even before they expressed the FDB phenotype with elevated TG and nonHDL-C. The PCE or PREVENT risk equations were the most accurate method for identifying higher risk patients (AUC: PREVENT: 0.690 (0.637-0.742), PCE: 0.697 (0.645-0.749)). The APOB/eAPOB ratio can be used to accurately identify the ε2/ε2 genotype and conventional risk equations are the best method for determining those at risk for ASCVD. Show less

Lipoprotein(a) (Lp(a)) is an independent cardiovascular risk factor, primarily determined by genetic factors. This study assessed Lp(a) concentrations in presumably healthy subjects and evaluated its association with age, sex, and cardiometabolic risk factors. The study included presumably healthy 1046 adults and 276 children. Laboratory parameters: lipid profile, Lp(a), apolipoprotein B (apoB), glucose, HbA1c, C-reactive protein and creatinine were measured. Contributions of Lp(a)-apoB to apoB (%Lp(a)/apoB) and of Lp(a)-cholesterol to LDL-cholesterol (%Lp(a)-C/LDL-C) were calculated. Lipoprotein(a) concentrations were significantly higher in adults than in children (P = 0.014) and in women than in girls (P = 0.003), but showed no overall sex differences. In women, Lp(a) was higher after age 50, while in men a slight rise occurred after age 60. Lipid indices %Lp(a)/apoB and %Lp(a)-C/LDL-C declined in men until their 40s and was higher after 50 in both sexes. In a multivariable logistic regression model increased LDL-C concentration was a significant predictor of Lp(a) ≥ 0.30 g/L in women (odds ratio, OR = 1.77; P = 0.021) and children (OR = 2.83; P = 0.009). Boys had twofold higher probability of Lp(a) ≥ 0.30 g/L than girls (OR = 2.17; P = 0.024). Lipoprotein(a) concentrations increase with age, especially after 50 in women and 60 in men, and are significantly associated with LDL-C. Rising %Lp(a)/apoB and %Lp(a)-C/LDL-C alongside falling apoB and LDL-C suggest greater atherogenicity in older individuals, particularly men. These findings support including Lp(a) in lipid profile for better cardiovascular risk assessment. Show less

A key step in primary prevention is the assessment of atherosclerotic cardiovascular disease (ASCVD) risk. Risk enhancer tests are additional tools used to further improve ASCVD risk assessment over conventional risk markers. Our objective was to determine whether estimated small, dense low-density lipoprotein cholesterol (E-sdLDL-C) can improve risk assessment and serve as a new risk enhancer test. We used a prospective cohort analysis of participants in the UK Biobank study with a median (interquartile range) follow-up of 10 (6.7-12.3) years. We included 271 760 individuals who were not on lipid-lowering medication at baseline and did not have incident ASCVD. The primary study outcome was the incidence of all-cause ASCVD. E-sdLDL-C was strongly associated with ASCVD events with a hazard ratio (HR) of 1.23 (95% CI, 1.22-1.24). After multivariable adjustment for age, sex, systolic blood pressure, hypertension, type 2 diabetes, and blood pressure medications, E-sdLDL-C and ApoB (apolipoprotein B) remained the most significant lipid risk factors (HR, 1.18 [95% CI, 1.16-1.19] and 1.17 [95% CI, 1.16-1.18] per SD, respectively). After further adjustment for ApoB, the association between low-density lipoprotein cholesterol (LDL-C) with all-cause ASCVD was completely reversed with an HR of 0.84 (95% CI, 0.81-0.86), but E-sdLDL-C continued to have a significant positive association with an HR of 1.11 (95% CI, 1.08-1.13). When E-sdLDL-C was discordantly higher than either LDL-C or ApoB, the risk for ASCVD was higher (LDL-C, 31% higher; ApoB, 17% higher). When elevated E-sdLDL-C is coupled with other risk enhancer tests, there is a greater risk for developing ASCVD. In a UK Biobank cohort for primary prevention, the risk of all-cause ASCVD was better captured by E-sdLDL-C than LDL-C. It was also more predictive than LDL-C and ApoB when discordant with these 2 measures. E-sdLDL-C, which can be freely and automatically calculated from a standard lipid panel, can potentially improve ASCVD risk assessment without additional laboratory testing. Show less

Chronic hepatitis C virus (HCV) infection is associated with hypolipidemia. HCV eradication may, therefore, result in hyperlipidemia and increase cardiovascular disease (CVD) risk. We investigated the impact of HCV eradication on serum lipid and lipoprotein profiles and CVD risk during and following direct-acting antiviral (DAA) therapy. We retrospectively analysed stored sera and plasma from 60 DAA-naïve patients, genotypes 1-4, treated with 12 weeks of sofosbuvir-velpatasvir. Serum lipids, apolipoproteins (apo), and a systemic inflammatory marker, GlycA, were measured serially beginning early on treatment and off treatment. Additionally, NMR LipoProfile analysis was performed on plasma samples. Expression of genes regulating lipid metabolism was assessed from paired liver biopsies obtained before and on treatment. Linear mixed models were used to examine changes in lipid and inflammatory markers; Framingham and ASCVD CVD risk scores were assessed before and after treatment. Decline in HCV viremia was associated with a rapid, significant increase in TChol, HDL-C, LDL-C, ApoA-1 and ApoB, and GlycA, improvement in ALT, hepatic inflammation, and steatosis but no change in glycemic control (HOMA-IR and HbA1c). Increase in TChol, LDL-C, and ApoB was associated with an increased SREBP1expression. Both ASCVD and Framingham risk scores were significantly increased at week 24 post treatment after adjusting for age (p < 0.0001). Serum lipids and lipoproteins rapidly increase with inhibition of viral replication during DAA therapy, an effect that may be mediated by genes affecting hepatic de novo lipogenesis. Based on lipid changes, HCV eradication may increase CVD risk, but this needs to be investigated prospectively. Show less

The triglyceride (TG) content of low-density lipoprotein (LDL-TG) has been shown to be more predictive of atherosclerotic cardiovascular disease (ASCVD) events than the cholesterol content of LDL (LDL-C). The goal of our study was to develop an equation for estimating LDL-TG ( Using least-square regression analysis, the following Like LDL-C, LDL-TG can also be calculated from the results of the standard lipid panel. Compared to estimated LDL-C, Show less

Defects in lipolysis can lead to hypertriglyceridemia, which can trigger acute pancreatitis and is also associated with cardiovascular disease. Decreasing plasma triglycerides (TGs) by activating lipoprotein lipase (LPL) with ApoC2 mimetic peptides is a new treatment strategy for hypertriglyceridemia. We recently described a dual ApoC2 mimetic/ApoC3 antagonist peptide called D6PV that effectively lowered TG in several mouse models but has limitations in terms of drug development. The aim of this study was to create the next generation of ApoC2 mimetic peptides. We employed hydrocarbon staples, as well as select amino acid substitutions, to make short single helical mimetic peptides based on the last helix of ApoC2. Peptides were first tested for their ability to activate LPL and then in hypertriglyceridemia mouse models. All-atom simulations of peptides were performed in a lipid-trilayer model of TG-rich lipoproteins to discern their possible mechanism of action. We designed a single stapled peptide called SP1 (21 residues), and a double stapled (stitched) peptide called SP2 (21 residues) and its N-terminal acylated analogue, SP2a. The hydrocarbon staples increased the amphipathicity of the peptides and their ability to bind lipids without interfering with LPL activation. Indeed, from all-atom simulations, the conformations of SP1 and SP2a are restrained by the staples and maintains the proper orientation of the LPL activation motif, while still allowing their deeper insertion into the lipid-trilayer model. Intraperitoneal injection of stapled peptides (1-5 umoles/kg) into ApoC2-hypomorphic mice or human ApoC3-transgenic resulted in an 80%-90% reduction in plasma TG within 3 h, similar to the much longer D6PV peptide (41 residues). Other modifications (replacement L-Glu20, L-Glu21 with their D-isomers, N-methylation of Gly19, Met2NorLeu and Ala1alpha-methylAla substitutions, N-terminal octanoylation) were introduced into the SP2a peptide. These changes made SP2a highly resistant to proteolysis against trypsin, pepsin, and Proteinase K, while maintaining similar efficacy in lowering plasma TG in mice. We describe a new generation of ApoC2 mimetic peptides based on hydron carbon stapling that are at least equally potent to earlier peptides but are much shorter and resistant to proteolysis and could be further developed into a new therapy for hypertriglyceridemia. Show less

Lipodystrophy syndromes cause hypertriglyceridemia that improves with leptin treatment using metreleptin. Mechanisms causing hypertriglyceridemia and improvements after metreleptin are incompletely understood. Determine relationship of circulating lipoprotein lipase (LPL) modulators with hypertriglyceridemia in healthy controls and in patients with lipodystrophy before and after metreleptin. Cross-sectional comparison of patients with lipodystrophy (generalized lipodystrophy n = 3; partial lipodystrophy n = 11) vs age/sex-matched healthy controls (n = 28), and longitudinal analyses in patients before and after 2 weeks and 6 months of metreleptin. The study was carried out at the National Institutes of Health, Bethesda, Maryland. Outcomes were LPL stimulators apolipoprotein (apo) C-II and apoA-V and inhibitors apoC-III and angiopoietin-like proteins (ANGPTLs) 3, 4, and 8; ex vivo activation of LPL by plasma. Patients with lipodystrophy were hypertriglyceridemic and had higher levels of all LPL stimulators and inhibitors vs controls except for ANGPTL4, with >300-fold higher ANGPTL8, 4-fold higher apoC-III, 3.5-fold higher apoC-II, 1.9-fold higher apoA-V, 1.6-fold higher ANGPTL3 ( Elevations in LPL inhibitors apoC-III and ANGPTL8 may contribute to hypertriglyceridemia in lipodystrophy, and may mediate reductions in circulating and hepatic triglycerides after metreleptin. These therefore are strong candidates for therapies to lower triglycerides in these patients. Show less

Among many causes of hypertriglyceridemia (HTG), familial chylomicronemia syndrome (FCS) is a rare monogenic disorder that manifests as severe HTG and acute pancreatitis. Among the known causal genes for FCS, mutations in We present the challenging care of a 43-year-old man with FCS with apoC-II deficiency and the results of two types of TPE and of investigational TG-lowering biologic therapies. The patient's lipid profile was consistent with FCS. A novel homozygous variant was identified in Our case demonstrates the importance of delineating and defining the underlying etiology of a rare disorder to optimize therapy and to minimize unfavorable outcomes. Show less