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We wished to determine whether apolipoprotein C-IIToronto, a mutant form of apolipoprotein C-II that contains a C-terminal cysteine residue, exists as a monomeric species or as multiple disulfide-linked species in plasma lipoproteins. The plasma lipoproteins from a heterozygous carrier and two homozygous carriers of apoC-IIToronto were investigated. The mutant apolipoprotein was found in homodimeric form and as heterodimers with apolipoprotein A-II, apolipoprotein B-100, and apolipoprotein E. Of particular interest was the demonstration of the existence of the disulfide-linked species apolipoprotein B-100:A-II and B-100:C-IIToronto in the very low density and low density lipoproteins in subjects who were carriers of apoC-IIToronto. We also observed that apoE3:C-IIToronto and apoE3:A-II dimers were present in the chylomicrons and very low density lipoproteins of these subjects. The observation of the existence of apolipoprotein B-100:A-II was extended to other hypercholesterolemic and hypertriglyceridemic subjects. The highest proportion of apolipoprotein B-100:A-II was observed in the very low density lipoproteins of hypertriglyceridemic subjects. The concentration of this species was significantly higher in hyperlipidemic subjects than in normolipidemic controls. These results demonstrate that the molecular species of cysteine-containing apolipoproteins are complex and should be considered in studies of human lipoprotein composition and function.

Competing Interests: LRB has served on advisory boards Amgen, HLS Therapeutics, Novartis, and UltraGenyx, and has received honoraria for continuing medical education talks from Amgen, HLS Therapeutics, Novartis, and UltraGenyx. RAH has served on advisory boards for Acasti, Akcea-Ionis, Amgen, Arrowhead, HLS Therapeutics, Medison, Novartis, Pfizer, Sanofi, Regeneron, and UltraGenyx, and has received honoraria for continuing medical education talks from Amgen, HLS Therapeutics, Novartis, and Pfizer.

Background: Apathy in patients with Alzheimer's disease (AD) is associated with significant morbidity and is often one of the first neuropsychiatric symptoms to present in mild cognitive impairment (MCI). Apathy is associated with accelerated cognitive decline and atrophy in fronto-striatal regions of the brain. Previous work has shown a link between apathy and the APOE gene in the context of AD, as the APOE ε 4 allele is already known to be associated with the onset of AD. However, other genetic associations with apathy are largely unexplored., Objective: To examine whether interactions between genetic variants related to neurotransmitter systems and regional brain atrophy are associated with apathy in patients with MCI and AD., Methods: In a sample of individuals with AD (n = 266), MCI (n = 518), and cognitively normal controls (n = 378), a partial least squares correspondence analysis modeled interactions between single nucleotide polymorphisms, structural whole-brain imaging variables, and apathy., Results: An interaction was found between apathy, the possession of an APOE ε4 allele combined with minor homozygosity for the DAT1 (dopamine transporter 1) gene, and regional brain atrophy. This interaction was closely linked to the MCI and AD groups., Conclusions: The results point to an association of a dopaminergic genetic marker and apathy in the AD continuum and may inform future design of clinical trials of apathy, as well as new treatment targets., Competing Interests: Declaration of conflicting interestsDr Saykin receives support from multiple NIH grants (P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U19 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, U01 AG068057, U01 AG072177, and U19 AG074879). He has also received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor) and participated in Scientific Advisory Boards (Bayer Oncology, Eisai, Novo Nordisk, and Siemens Medical Solutions USA, Inc) and an Observational Study Monitoring Board (MESA, NIH NHLBI. He also serves as Editor-in-Chief, Brain Imaging and Behavior, a Springer-Nature Journal and serves on four other NIA External Advisory Committees. Dr Saykin is an Editorial Board Member of this journal but was not involved in the peer-review process of this article nor had access to any information regarding its peer-review.The remaining authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Elevated plasma homocysteine (Hcy) is associated with an increased risk of developing neurodegenerative diseases; however, its relationship with the apolipoprotein E (APOE) ε4 allele has not been well characterized., Methods: Participants clinically diagnosed with Alzheimer's disease or mild cognitive impairment (AD/MCI), frontotemporal dementia, Parkinson's disease, or cerebrovascular disease were stratified by the presence of the APOE ε4 allele. Volumetric magnetic resonance imaging, plasma amyloid/tau/neurodegeneration biomarkers, and cognitive performance were quantified., Results: Across all diagnostic groups, Hcy was associated with lower brain parenchymal fraction and greater neurofilament light chain in APOE ε4 non-carriers only. In AD/MCI, Hcy was associated with phosphorylated tau 217 in APOE ε4 non-carriers, but not in carriers. Exploratory analyses revealed interactions between Hcy and APOE ε4 on memory and visuospatial function., Discussion: Hcy may contribute to neurodegeneration depending on the presence of the APOE ε4 allele and specific disease processes. Trials on vitamin B12 supplementation may consider stratifying by APOE genotype. Highlights Homocysteine (Hcy) was associated with neurodegenerative biomarkers across disease groups. Relationships with Hcy were predominantly found in apolipoprotein E (APOE) ε4 non-carriers. In Alzheimer's disease, associations between Hcy and phosphorylated tau 217 were found in APOE ε4 non-carriers only. Significant interactions existed between Hcy and APOE ε4 status on cognition., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Vascular calcification is prevalent in chronic kidney disease (CKD). Genetic causes of CKD account for 10-20% of adult-onset disease. Vascular calcification is thought to be one of the most important risk factors for increased cardiovascular morbidity and mortality in CKD patients and is detectable in 80% of patients with end stage kidney disease (ESKD). Despite the high prevalence of vascular calcification in CKD, no single gene cause has been described. We hypothesized that variants in vascular calcification genes may contribute to disease pathogenesis in CKD, particularly in families who exhibit a predominant vascular calcification phenotype. We developed a list of eight genes that are hypothesized to play a role in vascular calcification due to their involvement in the ectopic calcification pathway: ABCC6, ALPL, ANK1, ENPP1, NT5E, SLC29A1, SLC20A2, and S100A12. With this, we assessed exome data from 77 CKD patients, who remained unsolved following evaluation for all known monogenic causes of CKD. We also analyzed an independent cohort (Ontario Neurodegenerative Disease Research Initiative (ONDRI), n = 520) who were screened for variants in ABCC6 and compared this to a control cohort of healthy adults (n = 52). We identified two CKD families with heterozygous pathogenic variants (R1141X and A667fs) in ABCC6. We identified 10 participants from the ONDRI cohort with heterozygous pathogenic or likely pathogenic variant in ABCC6. Replication in a healthy control cohort did not reveal any variants. Our study provides preliminary data supporting the hypothesis that ABCC6 may play a role in vascular calcification in CKD. By screening CKD patients for genetic causes early in the diagnostic pathway, patients with genetic causes associated with vascular calcification can potentially be preventatively treated with new therapeutics with aims to decrease mortality., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Purpose of Review: Multiple agents are being developed that inhibit apolipoprotein (apo) C-III. This state-of-the-art review examines their potential for atherosclerotic cardiovascular disease (ASCVD) risk reduction., Recent Findings: Apo C-III, an apolipoprotein on the surface of triglyceride-rich lipoproteins (TRLs), impairs clearance of TRLs through both lipoprotein lipase dependent and independent pathways, thereby resulting in increased concentrations of triglycerides. Apo C-III has also been shown to have pro-atherogenic effects when bound to high-density lipoprotein (HDL) particles. Classical and genetic epidemiology studies provide support for the concept that apo C-III is associated with an increased risk of ASCVD events. Drug efficacy of agents that silence APOC3 mRNA has been studied in populations with varying hypertriglyceridemia severity, including those with familial chylomicronemia syndrome, multifactorial chylomicronemia syndrome/severe hypertriglyceridemia, and mixed hyperlipidemia. Randomized controlled trials have reported significant reductions in TG and non-HDL cholesterol levels among these patients treated with APOC3 inhibitors. Upcoming clinical outcomes trials seek to establish a role for APOC3 inhibitors to reduce risk of ASCVD., Competing Interests: Declarations Human and Animal Rights and Informed Consent No animal or human subjects by the authors were used for the purposes of the submitted work. Disclosures Dr. Maidman has no relationships to disclose. Dr. Hegele reports consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, Arrowhead, HLS Therapeutics, Pfizer, Novartis, Regeneron, Sanofi and UltraGenyx. Dr. Rosenson reports research funding to his institution from Amgen, Arrowhead, Eli Lilly, Merck, NIH, Novartis, Novo Nordisk, and 89Bio​, consulting fees from Amgen, Avilar, CRISPER Therapeutics, Eli Lilly, Lipigon, New Amsterdam, Novartis, Precision Biosciences, Regeneron, UltraGenyx, Verve Therapeutics​, non-promotional honoraria from Meda Pharma, royalties from Wolters Kluwer (UpToDate)​, and stock holding in MediMergent, LLC.​ He reports patent applications on: Methods and systems for biocellular marker detection and diagnosis using a microfluidic profiling device. EFS ID: 32278349. Application No. (PCT/US2019/026364) (provisional); Compositions and methods relating to the identification and treatment of immunothrombotic conditions. New International Application No. (PCT/US2021/63104926); and quantification of Lp(a) vs. non-Lp(a) apoB concentration: development of a novel validated equation. (PCT/US2021/63248837). Competing Interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Familial chylomicronemia syndrome (FCS) is an ultrarare inherited disorder. Genetic testing is not always feasible or conclusive. European clinicians developed a "FCS score" to differentiate between FCS and multifactorial chylomicronemia syndrome (MCS), a more common condition with overlapping features. A diagnostic score has not been developed for use in the North American context., Objective: To develop and validate a diagnostic score for North American patients based on signs, symptoms and biochemical traits of FCS., Methods: Using the RAND/UCLA modified Delphi process, we convened ten US/Canadian physicians with experience recognizing and treating FCS and one adult patient with FCS. The panel developed and rated 296 scenarios describing patients with FCS. Linear regression analyses used median post-meeting ratings to develop score parameters. We tested the score's sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) in patients with classical FCS, functional FCS, and MCS from Western University's Lipid Genetics Clinic's registry., Results: Numerical scores were attributed based upon the following: age, hypertriglyceridemia onset, body mass index, history of abdominal pain/pancreatitis, presence of secondary factors, triglyceride (TG) levels, ratio of TG/total cholesterol, and apolipoprotein B level. Scores ≥60 indicate definite classical FCS; the score distinguished patients with FCS from MCS in a real-world registry (100.0 % specificity, 66.7 % sensitivity, 100.0 % PPV, 95.5 % NPV). Scores ≥45 were "very likely" to have classical FCS (96.9 % specificity, 88.9 % sensitivity)., Conclusion: Given its simplicity and high specificity for distinguishing patients with FCS from MCS, the NAFCS Score could be used in lieu of - or while awaiting - genetic testing to optimize treatment., Competing Interests: Declaration of competing interest RAH reports grants or contracts from Ionis, Arrowhead, Novartis, Amryt; consulting fees from Arrowhead, Amgen, Acasti Pharma, Aegerion Pharmaceuticals, Akcea Therapeutics/Ionis Pharmaceuticals, HLS Therapeutics, Medison, Novartis, Pfizer, Regeneron, Sanofi, and Ultragenyx; honoraria from Amgen, Sanofi, HLS Therapeutics, and Ionis; and participation on a data safety monitoring board or advisory board for Novartis. ZA reports institutional grants or contracts from the U.S. Department of Defense, the NIH, Ionis; honorarium from Ionis. AA reports grants or contracts from Aegerion, BioMarin, and NIDDK, and honorarium from Ionis. AB (Western University) reports honorarium from Ionis. ABaldassarra reports no conflicts of interest. ABrown reports consulting fees from Pfizer, Amgen, Novartis, Ionis, Esperion, and Amarin; payment or honoraria from Amgen, Regeneron, Esperion, Amarin, Zoll/Itamar. AC reports honoraria from CME Outfitters and Ionis, consulting fees LIB therapeutics. SF reports honorarium from Ionis. BK reports honorarium from Ionis. MM reports consulting fees from Amarin Corporation, 89bio, Ionis. BK reports honoraria from Ionis. MM reports consulting fees from Amarin Corporation, 89bio, and Ionis. NP reports consulting fees from Amryt Pharmaceuticals Inc. for advisory board and from Ionis; honoraria from Amryt Pharmaceuticals Inc. DES reports consulting fees from Amryt, Akcea, Ionis, Novartis, Regeneron, GenInCode; participation on a data safety monitoring board of advisory board for Amgen; contracted research with Amgen, Amryt, Ionis, Novartis, Verve, Heartflow, PCORI, NIH; leadership or fiduciary role as President, National Lipid Association and Director, Philadelphia Lipid Atherosclerosis Club. JW has no disclosures to report. MSB, EC, IY, CC, SNG are employees of PHAR, which was paid by Ionis Pharmaceuticals to conduct the research described in this article. PHAR also discloses financial relationships with the following entities outside of the submitted work: AbbVie, Akcea, Amgen, AstraZeneca, BioMarin Pharmaceuticals, Bristol-Myers Squibb, Boston Scientific Corporation, Eisai, Ethicon, Genentech, Gilead, Novartis, Otsuka, Pfizer, Recordati, Regeneron, Sanofi US Services, Sunovion, Takeda Pharmaceuticals USA., (Copyright © 2024. Published by Elsevier Inc.)

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease of low-density lipoprotein cholesterol (LDL-C) metabolism. Despite the devastating effect of this disease on atherosclerotic cardiovascular health, the disease phenotype and severity are more heterogeneous than previously thought. The predictors of atherosclerotic cardiovascular disease (ASCVD) in HoFH patients have never been systematically studied., Objective: To investigate the univariate and multivariate predictors of ASCVD in HoFH patients., Methods: Patients from the Canadian HoFH Registry were included in the present retrospective longitudinal study. Data for these patients were collected using a standardized questionnaire between 2019 and 2022 in 19 academic sites across Canada. Predictors of ASCVD were evaluated using Cox proportional hazards models., Results: Among 48 HoFH patients, 26 (54 %) of them had at least one ASCVD event. The average age at baseline was 19 ± 15 years and women represented 56 % of the cohort. The independent predictors of ASCVD events were male sex (HR 2.57 (1.13-5.84)), diabetes (HR 16.22 (3.38-77.97)), and LDL-C above the median of 14.45 mmol/L [559 mg/dL] (HR 3.10 (1.24-7.76)). When performing subgroup analysis according to sex, the presence of LDL-C above median was associated with a significantly higher probability of ASCVD (88 % vs. 43 %, p = 0.005) in women, but not in men (100 % at age 40 in both groups, p = 0.98)., Conclusion: This study reported for the first time the univariate and multivariate predictors of ASCVD in HoFH patients. We demonstrate that predictors of ASCVD in HoFH differ in males and females with respect to LDL-C levels., (Copyright © 2024. Published by Elsevier Inc.)

Background: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder. This study aimed to study the genotype distribution of FCS-causing genes in the United Kingdom, genotype-phenotype correlation, and clinical differences between FCS and multifactorial chylomicronemia syndrome (MCS)., Methods: The study included 154 patients (FCS, 74; MCS, 80) from the UK FCS national registry and the UK arm of the FCS International Quality Improvement and Service Evaluation Project., Results: FCS was relatively common in non-Europeans and those with parental consanguinity ( P <0.001 for both). LPL variants were more common in European patients with FCS (European, 64%; non-European, 46%), while the genotype was more diverse in non-European patients with FCS. Patients with FCS had a higher incidence compared with patients with MCS of acute pancreatitis (84% versus 60%; P =0.001), recurrent pancreatitis (92% versus 63%; P <0.001), unexplained abdominal pain (84% versus 52%; P <0.001), earlier age of onset (median [interquartile range]) of symptoms (15.0 [5.5-26.5] versus 34.0 [25.2-41.7] years; P <0.001), and of acute pancreatitis (24.0 [10.7-31.0] versus 33.5 [26.0-42.5] years; P <0.001). Adverse cardiometabolic features and their co-occurrence was more common in individuals with MCS compared with those with FCS ( P <0.001 for each). Atherosclerotic cardiovascular disease was more prevalent in individuals with MCS than those with FCS ( P =0.04). However, this association became nonsignificant after adjusting for age, sex, and body mass index. The prevalence of pancreatic complications and cardiometabolic profile of variant-positive MCS was intermediate between FCS and variant-negative MCS., Conclusions: The frequency of gene variant distribution varies based on the ethnic origin of patients with FCS. Patients with FCS are at a higher risk of pancreatic complications while the prevalence of atherosclerotic cardiovascular disease is lower in FCS compared with MCS. Carriers of heterozygous pathogenic variants have an intermediate phenotype between FCS and variant-negative MCS., Competing Interests: H. Soran received personal fees from Amgen, Akcea, Synageva, Napp, Novartis, Takeda, Sanofi, Pfizer, and Kowa and research grants and donations from Akcea, Pfizer, Merck Sharp & Dohme, Amgen, Genzyme-Sanofi, Synageva, Amryt, Synageva, and Alexion. A.S. Wierzbicki is a site investigator on trials from Akcea and Regeneron; received royalties from Elsevier for a book on familial chylomicronemia syndrome; and is a board member for the Familial Hyperlipidaemia group, Europe. D. Datta received honoraria for advisory board from Swedish Orphan Biovitrum. N. Forrester received honoraria for presentations from SOBI. Y. Teoh received speakers fee from Daiichi Sankyo and Amarin. P. Downie received honoraria from SOBI, Novartis, Amgen, and Daiichi Sankyo. R.A. Hegele received consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, Arrowhead, HLS Therapeutics, Pfizer, Novartis, Regeneron, Sanofi, and UltraGenyx. The other authors report no conflicts.

Hepatic lipase deficiency is a rare genetic condition caused by biallelic loss-of-function variants in the LIPC gene encoding hepatic lipase. These variants reduce or abolish the protein's lipolytic activity, resulting in elevated plasma lipids. The condition is classified as autosomal recessive, since dyslipidemia is inconsistently observed in heterozygous patients with only one LIPC variant. However, this has been concluded from historical studies encompassing a few families and having very small sample sizes. Here, we conduct a retrospective chart review of 46 heterozygous subjects, each harboring one rare pathogenic LIPC variant. We compare plasma levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, and apolipoprotein B to those of matched controls without LIPC variants. Variant pathogenicity is classified according to the guidelines of the American College of Medical Genetics and Genomics. We observe that levels of total cholesterol, LDL-C, and triglycerides are significantly elevated in the LIPC variant heterozygotes, but HDL-C and apolipoprotein B are not. When filtering solely with respect to pathogenic or likely pathogenic variants, all lipid variables emerge as significantly elevated compared to controls. Thus, hepatic lipase deficiency may not necessarily be a recessive condition, but perhaps semi-dominant since individuals with one variant are phenotypically distinct from the controls. These hypothesis-generating findings regarding LIPC genetic variations observed in a clinical cohort should be evaluated in larger populations and databases.

Purpose of Review: Since its discovery, most research on fibroblast growth factor 21 (FGF21) has focused on its antihyperglycemia properties. However, attention has recently shifted towards elucidating the ability of FGF21 to lower circulating lipid levels and ameliorate liver inflammation and steatosis. We here discuss the physiology of FGF21 and its role in lipid metabolism, with a focus on genetics, which has up until now not been fully appreciated., Recent Findings: New developments have uncovered associations of common small-effect variants of the FGF21 gene, such as the single nucleotide polymorphisms rs2548957 and rs838133, with numerous physiological, biochemical and behavioural phenotypes linked to energy metabolism and liver function. In addition, rare loss-of-function variants of the cellular receptors for FGF21 have been recently associated with severe endocrine and metabolic phenotypes. These associations corroborate the findings from basic studies and preliminary clinical investigations into the therapeutic potential of FGF21 for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) and hypertriglyceridemia. Furthermore, recent breakthrough research has begun to dissect mechanisms of a potential FGF21 brain-adipose axis. Such inter-organ communication would be comparable to that seen with other potent metabolic hormones. A deeper understanding of FGF21 could prove to be further beneficial for drug development., Summary: FGF21 is a potent regulator of lipid and energy homeostasis and its physiology is currently at the centre of investigative efforts to develop agents targeting hypertriglyceridemia and MASLD., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To investigate the relationship between plasma lipoprotein (a) (Lp[a]) and lipid profiles in patients with severe hypertriglyceridaemia (HTG)., Methods: This case-control study undertook a retrospective chart review of patients from the Lipid Genetics Clinic at London Health Sciences Centre in Ontario, Canada. Plasma Lp(a) was compared between patients with severe HTG and healthy normolipidaemic control subjects. Severe HTG was defined by plasma triglycerides (TG) ≥ 10 mmol/l. Pairwise correlations between Lp(a), TG, apolipoprotein B (apo B) and non-high-density lipoprotein cholesterol (non-HDL-C) were evaluated., Results: This study reviewed 4400 patients and identified 154 patients with severe HTG, which were compared with 272 control subjects. The median Lp(a) was significantly lower in patients with severe HTG compared with control subjects (5.0 versus 10.2 mg/dl, respectively). No correlation was observed between Lp(a) and TG or non-HDL-C. Lp(a) and apo B were modestly correlated in patients with severe HTG ( r  = 0.235) and control subjects ( r  = 0.175). There were no significant differences between the genetic subgroups of patients with severe HTG., Conclusions: Patients with severe HTG have lower plasma Lp(a) than normolipidaemic control subjects. The basis for this relationship is not immediately apparent but is hypothesis-generating and warrants further investigation., Competing Interests: Declaration of conflicting interestR.A.H. reports consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, Arrowhead, Boston Heart, HLS Therapeutics, Pfizer, Novartis, Regeneron, Sanofi and Ultragenyx. The other authors have no conflicts to disclose.

Background: Angiopoietin-like 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases and hepatic uptake of triglyceride-rich lipoprotein remnants. ANGPTL3 loss-of-function carriers have lower levels of triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol and a lower risk of atherosclerotic cardiovascular disease than noncarriers. Zodasiran is an RNA interference (RNAi) therapy targeting expression of ANGPTL3 in the liver., Methods: We conducted a double-blind, placebo-controlled, dose-ranging phase 2b trial to evaluate the safety and efficacy of zodasiran in adults with mixed hyperlipidemia (fasting triglyceride level of 150 to 499 mg per deciliter and either an LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). Eligible patients were randomly assigned in a 3:1 ratio to receive subcutaneous injections of zodasiran (50, 100, or 200 mg) or placebo on day 1 and week 12 and were followed through week 36. The primary end point was the percent change in the triglyceride level from baseline to week 24., Results: A total of 204 patients underwent randomization. At week 24, substantial mean dose-dependent decreases from baseline in ANGPTL3 levels were observed with zodasiran (difference in change vs. placebo, -54 percentage points with 50 mg, -70 percentage points with 100 mg, and -74 percentage points with 200 mg), and significant dose-dependent decreases in triglyceride levels were observed (difference in change vs. placebo, -51 percentage points, -57 percentage points, and -63 percentage points, respectively) (P<0.001 for all comparisons). Other differences in change from baseline as compared with placebo included the following: for non-HDL cholesterol level, -29 percentage points with 50 mg, -29 percentage points with 100 mg, and -36 percentage points with 200 mg; for apolipoprotein B level, -19 percentage points, -15 percentage points, and -22 percentage points, respectively; and for LDL cholesterol level, -16 percentage points, -14 percentage points, and -20 percentage points, respectively. We observed a transient elevation in glycated hemoglobin levels in patients with preexisting diabetes who received the highest dose of zodasiran., Conclusions: In patients with mixed hyperlipidemia, zodasiran was associated with significant decreases in triglyceride levels at 24 weeks. (Funded by Arrowhead Pharmaceuticals; ARCHES-2 ClinicalTrials.gov number, NCT04832971.)., (Copyright © 2024 Massachusetts Medical Society.)

Context: Patients with rare familial chylomicronemia syndrome (FCS) and relatively common multifactorial chylomicronemia syndrome (MCS) both express severe hypertriglyceridemia, defined as plasma triglyceride concentration ≥10 mmol/L (≥885 mg/dL). Clinically there can be confusion between the two conditions., Objective: To compare clinical and biochemical phenotypes in patients with genotypically characterized FCS and MCS., Methods: We performed targeted sequencing of DNA from 193 patients with severe hypertriglyceridemia, classified them as having either FCS or MCS and compared clinical and biochemical characteristics., Results: FCS compared to MCS patients were significantly younger (31.4 ± 16.7 vs. 51.0 ± 11.3 years; P =0.003), with earlier age at symptom onset (15.0 ± 15.8 vs. 37.8 ± 8.8 years; P =0.00066), lower body mass index (23.3 ± 3.1 vs. 30.7 ± 5.0 kg/m2; P =0.000016), and higher prevalence of pancreatitis events (81.8% vs. 35.2%; P=0.003). Furthermore, FCS compared to MCS patients had a higher ratio of triglyceride to total cholesterol, i.e. 4.18 ± 0.92 vs 1.08 ± 0.51 (P <0.0001) and lower plasma apolipoprotein B, i.e. 0.56 ± 0.15 vs 1.02 ± 0.43 g/L (P <0.0001). MCS patients with heterozygous pathogenic variants had a relatively more severe clinical presentation than other MCS genetic subgroups., Conclusions: FCS patients have notable phenotypic differences from MCS patients, although there is overlap. While genetic analysis of patients with persistent severe hypertriglyceridemia can definitively diagnose FCS, 8.2% of MCS patients with sustained refractory hypertriglyceridemia behave functionally as if they have FCS, which should influence their eligibility for novel therapies for severe hypertriglyceridemia., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Persistent chylomicronemia is a genetic recessive disorder that is classically caused by familial chylomicronemia syndrome (FCS), but it also has multifactorial causes. The disorder is associated with the risk of recurrent acute pancreatitis. Plozasiran is a small interfering RNA that reduces hepatic production of apolipoprotein C-III and circulating triglycerides., Methods: In a phase 3 trial, we randomly assigned 75 patients with persistent chylomicronemia (with or without a genetic diagnosis) to receive subcutaneous plozasiran (25 mg or 50 mg) or placebo every 3 months for 12 months. The primary end point was the median percent change from baseline in the fasting triglyceride level at 10 months. Key secondary end points were the percent change in the fasting triglyceride level from baseline to the mean of values at 10 months and 12 months, changes in the fasting apolipoprotein C-III level from baseline to 10 months and 12 months, and the incidence of acute pancreatitis., Results: At baseline, the median triglyceride level was 2044 mg per deciliter. At 10 months, the median change from baseline in the fasting triglyceride level (the primary end point) was -80% in the 25-mg plozasiran group, -78% in the 50-mg plozasiran group, and -17% in the placebo group (P<0.001). The key secondary end points showed better results in the plozasiran groups than in the placebo group, including the incidence of acute pancreatitis (odds ratio, 0.17; 95% confidence interval, 0.03 to 0.94; P = 0.03). The risk of adverse events was similar across groups; the most common adverse events were abdominal pain, nasopharyngitis, headache, and nausea. Severe and serious adverse events were less common with plozasiran than with placebo. Hyperglycemia with plozasiran occurred in some patients with prediabetes or diabetes at baseline., Conclusions: Patients with persistent chylomicronemia who received plozasiran had significantly lower triglyceride levels and a lower incidence of pancreatitis than those who received placebo. (Funded by Arrowhead Pharmaceuticals; PALISADE ClinicalTrials.gov number, NCT05089084.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Familial hypercholesterolemia (FH) is a common genetic disorder, yet it remains largely underdiagnosed in Canada. Multiple national and international guidelines recommend the use of clinical genetic testing for FH. However, the level of its accessibility and use within Canada is unclear. This study aims to describe the current state of clinical FH genetic testing in Canada and barriers to its implementation., Methods: We conducted a cross-sectional survey of 23 genetic counsellors across 8 provinces, through the Canadian Association of Genetic Counsellors Cardiac Communities of Practice, to obtain information about the accessibility of genetic testing for FH and the use of genetic-counselling services., Results: Responses were obtained from 12 genetic counsellors (52%). Of the 8 provinces surveyed, clinical FH genetic testing is available in 7, with British Columbia being the exception. The Simplified Canadian Definition for FH is the diagnostic criterion most commonly utilized to determine genetic-testing eligibility, and it is used in 5 of the 8 provinces. Notably, the referral rate to genetic counsellors typically is low, with most genetic-counselling programs receiving ≤ three referrals per site per month. Quebec is the only province to report a higher rate of genetic-counsellor referrals for FH., Conclusions: Clinical FH genetic testing is not available widely in Canada and its implementation varies significantly by province; this includes the eligibility criteria to qualify for testing as well as the utilization of genetic counsellors. A harmonized national approach to FH diagnosis could improve the rates of diagnosis and treatment., (© 2024 The Authors.)

Lipoprotein(a) (Lp(a)) is an atherogenic low-density lipoprotein (LDL)-like particle that is currently regarded as a non-modifiable risk factor for atherosclerotic cardiovascular disease. The number of patients detected with elevated Lp(a) concentrations has been increasing in recent years, although the implication of this finding is unclear for patients and physicians. We screened our lipid clinic database for patients aged >65 years with very high Lp(a) concentrations, which were defined as >230 nmol/L, and cardiovascular outcomes were assessed. The patients' (n = 16) mean (±standard deviation) age was 72.2 ± 7.1 years and the mean Lp(a) concentration was 313 ± 68 nmol/L. After a cumulative 129.0 patient-year follow-up (mean: 8.1 ± 4.2 years), the mean age was 80.3 ± 7.0 years. We observed a low baseline prevalence of cardiovascular events, with only two patients having a history of cardiovascular events. Furthermore, zero incident adverse cardiovascular events were recorded over the follow-up. Therefore, very high Lp(a) concentrations and disease-free old age are not mutually exclusive. Our aggregated clinical experience is that there is only a modest association between elevated Lp(a) concentrations and adverse outcomes. Nonetheless, we still advise treating modifiable risk factors in these patients., Competing Interests: Declaration of conflicting interestR.A.H. reports consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, Arrowhead, HLS Therapeutics, Pfizer, Novartis, Regeneron, Sanofi, and UltraGenyx. S.H. declares that there is no conflict of interest.

Atherosclerotic cardiovascular disease (ASCVD) is a significant health challenge, and apolipoprotein B (ApoB)-containing lipoproteins are increasingly recognized as central to its progression. Initially labelled as the "low-density lipoprotein hypothesis," our understanding of the etiology of ASCVD has evolved into the "ApoB principle," which highlights the causal and consistent role of all ApoB lipoproteins in ASCVD development. We review the large body of data from genetic studies, to epidemiologic studies, to clinical trials that support this foundational principle. We also provide an overview of the recommendations from guideline committees across the globe on dyslipidemia management and compare these with recent Canadian guidelines. With a few key differences, recent guidelines worldwide provide largely concordant recommendations for diagnosing and managing dyslipidemia with general consensus regarding the need for optimal control of low-density lipoprotein cholesterol and ApoB-containing lipoproteins to prevent cardiovascular events and improve patient care., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: We investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial fibrillary acidic protein (GFAP) in neurodegenerative diseases., Methods: A mediation analysis was performed to assess the relationship between neuroimaging markers and plasma biomarkers on sEF in 333 participants clinically diagnosed with Alzheimer's disease/mild cognitive impairment, frontotemporal dementia, or cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative., Results: PVS was significantly associated with sEF (c = -0.125 ± 0.054, 95% bootstrap confidence interval [CI] [-0.2309, -0.0189], p = 0.021). This effect was mediated by both GFAP and WMH., Discussion: In this unique clinical cohort of neurodegenerative diseases, we demonstrated that the effect of PVS on sEF was mediated by the presence of elevated plasma GFAP and white matter disease. These findings highlight the potential utility of imaging and plasma biomarkers in the current landscape of therapeutics targeting dementia., Highlights: Perivascular spaces (PVS) and white matter hyperintensities (WMH) are imaging markers of small vessel disease. Plasma glial fibrillary protein acidic protein (GFAP) is a biomarker of astroglial injury. PVS, WMH, and GFAP are relevant in executive dysfunction from neurodegeneration. PVS's effect on executive function was mediated by GFAP and white matter disease., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Competing Interests: R.A. Hegele reports consulting fees from Akcea/Ionis, Amgen, Arrowhead, HLS Therapeutics, Medison, Novartis, Pfizer, Regeneron, Sanofi, and UltraGenyx.

Introduction: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive condition. Effective treatment is important as patients are at risk for severe and potentially fatal acute pancreatitis. We review recent developments in pharmacologic treatment for FCS, namely biological inhibitors of apolipoprotein (apo) C-III and angiopoietin-like protein 3 (ANGPTL3)., Areas Covered: FCS follows a biallelic inheritance pattern in which an individual inherits two pathogenic loss-of-function alleles of one of the five causal genes - LPL (in 60-80% of patients), GPIHBP1 , APOA5 , APOC2 , and LMF1 - leading to the absence of lipolytic activity. Patients present from childhood with severely elevated triglyceride (TG) levels >10 mmol/L. Most patients with severe hypertriglyceridemia do not have FCS. A strict low-fat diet is the current first-line treatment, and existing lipid-lowering therapies are minimally effective in FCS. Apo C-III inhibitors are emerging TG-lowering therapies shown to be efficacious and safe in clinical trials. ANGPTL3 inhibitors, another class of emerging TG-lowering therapies, have been found to require at least partial lipoprotein lipase activity to lower plasma TG in clinical trials. ANGPTL3 inhibitors reduce plasma TG in patients with multifactorial chylomicronemia but not in patients with FCS who completely lack lipoprotein lipase activity., Expert Opinion: Apo C-III inhibitors currently in development are promising treatments for FCS.

Background: Heterozygous familial hypercholesterolemia (FH) is among the most common genetic conditions worldwide that affects ≈ 1 in 300 individuals. FH is characterized by increased levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of coronary artery disease (CAD), but there is a wide spectrum of severity within the FH population. This variability in expression is incompletely explained by known risk factors. We hypothesized that genome-wide genetic influences, as represented by polygenic risk scores (PRSs) for cardiometabolic traits, would influence the phenotypic severity of FH., Methods: We studied individuals with clinically diagnosed FH (n=1123) from the FH Canada National Registry, as well as individuals with genetically identified FH from the UK Biobank (n=723). For all individuals, we used genome-wide gene array data to calculate PRSs for CAD, LDL-C, lipoprotein(a), and other cardiometabolic traits. We compared the distribution of PRSs in individuals with clinically diagnosed FH, genetically diagnosed FH, and non-FH controls and examined the association of the PRSs with the risk of atherosclerotic cardiovascular disease., Results: Individuals with clinically diagnosed FH had higher levels of LDL-C, and the incidence of atherosclerotic cardiovascular disease was higher in individuals with clinically diagnosed compared with genetically identified FH. Individuals with clinically diagnosed FH displayed enrichment for higher PRSs for CAD, LDL-C, and lipoprotein(a) but not for other cardiometabolic risk factors. The CAD PRS was associated with a risk of atherosclerotic cardiovascular disease among individuals with an FH-causing genetic variant., Conclusions: Genetic background, as expressed by genome-wide PRSs for CAD, LDL-C, and lipoprotein(a), influences the phenotypic severity of FH, expanding our understanding of the determinants that contribute to the variable expressivity of FH. A PRS for CAD may aid in risk prediction among individuals with FH., Competing Interests: Disclosures L.R. Brunham reports advisory fees from Amgen, HLS Therapeutics, Novartis, Novo Nordisk, and Ultragenyx. A. Baass reports advisory fees from Akcea, Amgen, and Sanofi. R.A. Hegele reports advisory fees from Akcea, Amgen, HLS Therapeutics, Novartis, Pfizer, Regeneron, Sanofi, and Ultragenyx. J. Genest reports advisory fees from Amgen, Novartis, Sanofi, and Ultragenyx. The other authors report no conflicts.

Background: Computational variant effect predictors offer a scalable and increasingly reliable means of interpreting human genetic variation, but concerns of circularity and bias have limited previous methods for evaluating and comparing predictors. Population-level cohorts of genotyped and phenotyped participants that have not been used in predictor training can facilitate an unbiased benchmarking of available methods. Using a curated set of human gene-trait associations with a reported rare-variant burden association, we evaluate the correlations of 24 computational variant effect predictors with associated human traits in the UK Biobank and All of Us cohorts., Results: AlphaMissense outperformed all other predictors in inferring human traits based on rare missense variants in UK Biobank and All of Us participants. The overall rankings of computational variant effect predictors in these two cohorts showed a significant positive correlation., Conclusion: We describe a method to assess computational variant effect predictors that sidesteps the limitations of previous evaluations. This approach is generalizable to future predictors and could continue to inform predictor choice for personal and clinical genetics., (© 2024. The Author(s).)

Background: In Canada, 2 guidelines provide guidance for the management of dyslipidemia. The Patients, Experience, Evidence, Research simplified lipid guidelines, intended for primary care practitioners, and the Canadian Cardiovascular Society guidelines, intended for all practitioners, are based on differing methodologies with distinct priorities and preferences. The disparate approaches may contribute to confusion among family practitioners and their co-managed patients, with the potential for compromised care, differing standards for training in the fundamentals of lipidology, and differing criteria that might be used in practice audits to evaluate quality of care., Methods: The Patients, Experience, Evidence, Research (PEER) recommendations were considered by primary authors of the Canadian Cardiovascular Society guideline to identify areas of concordance, discordance, or agreement with qualifications., Results: Discordance between the guidelines is greatest with respect to interpretation of the cholesterol profile, the implications of elevated triglyceride, the utility of apolipoprotein B and non-high-density lipoprotein-cholesterol measurements, the role of nonstatin medications, and the importance of assuring adherence and avoiding undertreatment through follow-up measurement of lipid profiles. The disparate importance attached to identification of patients with enhanced risk due to an elevated lipoprotein (a) level is also apparent., Conclusions: This comparison attempts to reconcile key principles of practice, to foster both high quality of care and fully informed patient-centred decision-making., (© 2024 The Authors.)

Elevated low-density lipoprotein cholesterol (LDL-C) is a major causal factor for atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality worldwide. Statins are the recommended first-line lipid-lowering therapy (LLT) for patients with primary hypercholesterolemia and established ASCVD, with LLT intensification recommended in the substantial proportion of patients who do not achieve levels below guideline-recommended LDL-C thresholds with statin treatment alone. The proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibody evolocumab has demonstrated significant LDL-C reductions of > 60% in the clinical trial and open-label extension settings, with LDL-C reductions observed early post-evolocumab initiation and maintained long term, during up to 8.4 years of follow-up. Evolocumab therapy, when added to a statin, also conferred a significant reduction in major cardiovascular (CV) events, including a 20% reduction in the composite of CV death, myocardial infarction (MI), or stroke. The absolute benefits were enhanced among various patient types at high and very high risk for secondary ASCVD (e.g., with recent MI, multiple events or peripheral artery disease). Importantly, evolocumab treatment resulted in incremental CV risk reductions during the extended follow-up, including a 23% reduction in CV mortality and no apparent LDL-C level below which there is no further CV risk reduction. Hence, the evolocumab clinical data support the need for early and significant LDL-C lowering, especially in vulnerable ASCVD patients, in order to derive the greatest benefit in the long term. Importantly, evolocumab had no impact on any treatment emergent adverse events apart from a small increase in local injection site reactions. A growing body of real-world evidence (RWE) for evolocumab in heterogeneous populations is consistent with the trial data, including robust LDL-C reductions below guideline-recommended thresholds, a favourable safety profile even at the lowest levels of LDL-C achieved, and a high treatment persistence rate of > 90%. Altogether, this review highlights findings from 50 clinical trials and RWE studies in > 51,000 patients treated with evolocumab, to demonstrate the potential of evolocumab to address the healthcare gap in LDL-C reduction and secondary prevention of ASCVD in a variety of high- and very high-risk patients., Competing Interests: The authors report the following potential conflicts of interest for grants, contracts, consulting fees, honoraria, support for attending meetings, and/or participation on a data safety monitoring board or advisory board. LAL: Amarin, Amgen, AstraZeneca, Esperion, HLS Therapeutics, Kowa, Merck, Novartis, Pfizer, Sanofi; RAH: Acasti, Akcea/Ionis, Amgen, Amryt, Arrowhead, HLS Therapeutics, Medison, Novartis, Pfizer, Regeneron, Ultragenyx; VB: AbbVie, Amgen, BioSyent, Eisai, GSK, Merck, Moderna, Pfizer, Novartis, Novo Nordisk, Sanofi, Seqirus, Sunovion; JB: Amarin, Amgen, Amryt, Arrowhead, Eli Lilly, HLS Therapeutics, Ionis Pharmaceuticals Inc., Kowa, LIB Therapeutics, Medison, New Amsterdam Pharma, Novartis, Novo Nordisk, Regeneron, Sanofi, Ultragenyx; ESM is an employee of and owns stock in Amgen Canada Inc.; GBJM: Amgen, Esperion, HLS Therapeutics, Novartis, Pfizer, Sanofi. The authors declare no conflict of interest., (Copyright: © 2024 The Author(s). Published by IMR Press.)

Background: Familial chylomicronemia syndrome is a genetic disorder associated with severe hypertriglyceridemia and severe acute pancreatitis. Olezarsen reduces the plasma triglyceride level by reducing hepatic synthesis of apolipoprotein C-III., Methods: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with genetically identified familial chylomicronemia syndrome to receive olezarsen at a dose of 80 mg or 50 mg or placebo subcutaneously every 4 weeks for 49 weeks. There were two primary end points: the difference between the 80-mg olezarsen group and the placebo group in the percent change in the fasting triglyceride level from baseline to 6 months, and (to be assessed if the first was significant) the difference between the 50-mg olezarsen group and the placebo group. Secondary end points included the mean percent change from baseline in the apolipoprotein C-III level and an independently adjudicated episode of acute pancreatitis., Results: A total of 66 patients underwent randomization; 22 were assigned to the 80-mg olezarsen group, 21 to the 50-mg olezarsen group, and 23 to the placebo group. At baseline, the mean (±SD) triglyceride level among the patients was 2630±1315 mg per deciliter, and 71% had a history of acute pancreatitis within the previous 10 years. Triglyceride levels at 6 months were significantly reduced with the 80-mg dose of olezarsen as compared with placebo (-43.5 percentage points; 95% confidence interval [CI], -69.1 to -17.9; P<0.001) but not with the 50-mg dose (-22.4 percentage points; 95% CI, -47.2 to 2.5; P = 0.08). The difference in the mean percent change in the apolipoprotein C-III level from baseline to 6 months in the 80-mg group as compared with the placebo group was -73.7 percentage points (95% CI, -94.6 to -52.8) and between the 50-mg group as compared with the placebo group was -65.5 percentage points (95% CI, -82.6 to -48.3). By 53 weeks, 11 episodes of acute pancreatitis had occurred in the placebo group, and 1 episode had occurred in each olezarsen group (rate ratio [pooled olezarsen groups vs. placebo], 0.12; 95% CI, 0.02 to 0.66). Adverse events of moderate severity that were considered by a trial investigator at the site to be related to the trial drug or placebo occurred in 4 patients in the 80-mg olezarsen group., Conclusions: In patients with familial chylomicronemia syndrome, olezarsen may represent a new therapy to reduce plasma triglyceride levels. (Funded by Ionis Pharmaceuticals; Balance ClinicalTrials.gov number, NCT04568434.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: This study aims to show the clinical and biochemical features in patients with severe hypertriglyceridemia (HTG) associated with rare variants in the apolipoprotein A-V (APOA5) gene., Materials and Methods: Demographics, blood lipid levels, body mass index (BMI) and APOA5 mutation subtypes were collected from the endocrinology clinic registry and analyzed for a retrospective cohort study of ten patients with severe HTG and APOA5 gene variants., Results: Of the 10 cases, four were female, and six were male. The median age was 45.0 years (min-max: 21-60 years), the median triglyceride was 2429.5 mg/dL (27.5 mmol/L) (min-max: 1351-4087 mg/dL, 15.3-46.2 mmol/L), and the mean BMI was calculated as 30.4 ± 4.4 kg/m 2 (min-max: 24.9-41.0 kg/m 2 ). Four cases had diabetes mellitus (DM); two were on intensive insulin therapy, and two were on basal insulin therapy. The mean hemoglobin A1c was 9.2 ± 1.2 % (min-max: 8.3-11.0 %). Among the study group, eight different APOA5 gene mutations were detected. These variants were heterozygous in 2 patients and homozygous (bi-allelic) in 8 patients. One patient was homozygous for APOA5 p.Ser19Trp, a relatively common polymorphism that is a risk variant for HTG., Conclusion: We report a cohort of patients with biallelic and single copy APOA5 variants, who were diagnosed later in life. Most had secondary factors, such as DM or obesity with increased BMI. Most rare APOA5 variants found in our patients were of uncertain significance. Our results add to the growing evidence that rare variants in certain candidate genes may predispose to developing HTG, together with secondary factors such as obesity. The genetic basis of HTG in many other patients is still unknown and remains the subject of further investigation., Competing Interests: Declaration of Competing Interest The authors declare there is no conflict of interests., (Copyright © 2023. Published by Elsevier Inc.)

Background: Pediatric patients with homozygous familial hypercholesterolemia (HoFH) have an increased risk of atherosclerotic cardiovascular disease and difficulty meeting low-density lipoprotein cholesterol (LDL-C) goals. In this post hoc analysis, we evaluated pooled safety and efficacy data from 3 studies in pediatric patients with HoFH treated with the PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibody inhibitor evolocumab., Methods: Patients with HoFH aged 10 to 17 years received treatment with open-label evolocumab 420 mg subcutaneously monthly or biweekly in the TAUSSIG, RAMAN, or HAUSER-OLE clinical studies. All patients received background statins with or without ezetimibe. Study duration ranged from 12 to 260 weeks. The primary end point was treatment-emergent adverse events per 100 patient-years. Efficacy end points were changes from baseline to week 12 in lipids and PCSK9., Results: Of the 39 patients in the pooled analysis, 69.2% were males, median age was 13.0 years, and 79.5% (31/39) had genotyped HoFH with LDLR pathogenic variants. Overall, median exposure to evolocumab was 18.2 (Q1, Q3: 3.0, 18.5) months. Treatment-emergent adverse events with an exposure-adjusted patient incidence rate of ≥5% were upper respiratory tract infection (6.6%), influenza (5.2%), and acne (5.0%) per 100 patient-years. Exposure-adjusted patient incidence of serious treatment-emergent adverse events was 13.3% per 100 patient-years. Excluding 4 patients receiving lipoprotein apheresis, week 12 median percentage change from baseline in LDL-C was -2.9% (Q1, Q3: -21.7, 1.5); however, 42.9% (15/35) of patients achieved ≥15% reduction in LDL-C from baseline. Residual LDLR (LDL receptor) activity was not associated with a reduction in LDL-C., Conclusions: In this pooled data analysis from 3 studies in pediatric patients with HoFH, evolocumab was well tolerated, with no new safety signals reported. These safety findings are consistent with findings from previous studies of evolocumab. Patients showed marked variability in LDL-C reduction. Results from this pooled analysis support guidelines suggesting a trial of PCSK9 inhibitor therapy regardless of estimated residual LDLR function., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01624142, NCT03403374, and NCT02624869., Competing Interests: Disclosures F.J. Raal has received research grants, honoraria, or consulting fees for professional input and lectures from Sanofi, Regeneron, Amgen, and Novartis; and travel support to attend the 2023 European Atherosclerosis Society (EAS) Congress from EAS. R.A. Hegele reports receiving consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, Boston Heart, HLS Therapeutics, Novartis, Pfizer, Regeneron, Sanofi, and Ultragenyx; and lecture fees from Amgen, HLS Therapeutics, and Novartis. A. Ruzza is a former employee and a stockholder of Amgen. He is a current employee and a stockholder of GlaxoSmithKline. He holds a pending patent application PCT/US2021/034489 on PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors and methods of use thereof to treat cholesterol-related disorders. J.A.G. López, A.K. Bhatia, H. Wang, and J. Wu are employees and stockholders of Amgen. D. Gaudet reports receiving research grants, honoraria, or consulting fees for professional input and lectures from Alnylam, Amgen, Applied Therapeutics, Arrowhead, Boehringer Ingelhein, Chiesi (Amryt), CRISPR Therapeutics, Eli Lilly, Esperion, Ionis, Kowa, New Amsterdam Pharma, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi, Ultragenyx, Uniqure, and Verve Therapeutics. A. Wiegman reports research support for pharmaceutical trials of lipid-lowering agents from Amgen, Sanofi-Regeneron Pharmaceuticals, Novartis, Silence Therapeutics, Esperion, and Ultragenyx; and is member of a safety board for Amryt. R.D. Santos reports receiving consulting fees and lecture fees from Abbott, Amgen, Amryt, AstraZeneca, Aché, Biolab, Getz Pharma, Eli Lilly, Libbs, Merck, PTC Therapeutics, Novo Nordisk, Novartis, and Sanofi-Regeneron Pharmaceuticals; and grant support from Amgen, Kowa, Esperion, Novartis, and Sanofi-Regeneron Pharmaceuticals. The other author reports no conflicts.

Background and Aims: Severe hypertriglyceridemia (HTG), defined as plasma triglyceride (TG) concentration > 10 mmol/L, is relatively uncommon, and its implications for atherosclerotic cardiovascular disease (ASCVD) risk remain somewhat unclear. We evaluated the association between severe HTG and carotid intima-media thickness (IMT), a marker for ASCVD., Methods: We studied three clinical cohorts: 88 patients with severe HTG (mean TG level 20.6 mmol/L), 271 patients with familial hypercholesterolemia (FH) as a contrast group, and 70 normolipidemic controls. Carotid IMT was measured using standardized ultrasound imaging. Statistical analysis was conducted using one-way analysis of variance (ANOVA) to compare mean IMT values, analysis of covariance (ANCOVA) to adjust for confounding variables, specifically age and sex, as well as Spearman pairwise correlation analysis between variables., Results: Unadjusted mean carotid IMT was greater in severe HTG and FH groups compared to controls, however, this was no longer significant for severe HTG after adjustment for age and sex. In contrast, adjusted carotid IMT remained significantly different between the FH and control groups., Conclusions: Our findings suggest that extreme TG elevations in severe HTG patients are not significantly associated with carotid IMT, in contrast to the increased IMT seen in FH patients. These findings add perspective to the complex relationship between severe HTG and ASCVD risk., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Robert A. Hegele reports a relationship with 10.13039/100010875Amgen Canada Inc that includes: consulting or advisory and speaking and lecture fees. Robert A. Hegele reports a relationship with HLS Therapeutics Inc that includes: consulting or advisory and speaking and lecture fees. Robert A. Hegele reports a relationship with 10.13039/100009009Novartis Pharmaceuticals Canada Inc that includes: consulting or advisory and speaking and lecture fees. Robert A. Hegele reports a relationship with 10.13039/100013739Pfizer Canada ULC that includes: consulting or advisory and speaking and lecture fees. Robert A. Hegele reports a relationship with Sanofi-Aventis Canada Inc that includes: consulting or advisory and speaking and lecture fees. Robert A. Hegele reports a relationship with Ionis Pharmaceuticals Inc that includes: consulting or advisory. Robert A. Hegele reports a relationship with Arrowhead Pharmaceuticals Inc that includes: consulting or advisory. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Purpose of Review: While biallelic rare APOA5 pathogenic loss-of-function (LOF) variants cause familial chylomicronemia syndrome, heterozygosity for such variants is associated with highly variable triglyceride phenotypes ranging from normal to severe hypertriglyceridemia, often in the same individual at different time points. Here we provide an updated overview of rare APOA5 variants in hypertriglyceridemia., Recent Findings: Currently, most variants in APOA5 that are considered to be pathogenic according to guidelines of the American College of Medical Genetics and Genomics are those resulting in premature termination codons. There are minimal high quality functional data on the impact of most rare APOA5 missense variants; many are considered as variants of unknown or uncertain significance. Furthermore, particular common polymorphisms of APOA5 , such as p.Ser19Trp and p.Gly185Cys in Caucasian and Asian populations, respectively, are statistically overrepresented in hypertriglyceridemia cohorts and are sometimes misattributed as being causal for chylomicronemia, when they are merely risk alleles for hypertriglyceridemia., Summary: Both biallelic and monoallelic LOF variants in APOA5 are associated with severe hypertriglyceridemia, although the biochemical phenotype in the monoallelic state is highly variable and is often exacerbated by secondary factors. Currently, with few exceptions, the principal definitive mechanism for APOA5 pathogenicity is through premature truncation. The pathogenic mechanisms of most missense variants in APOA5 remain unclear and require additional functional experiments or family studies., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Apolipoprotein E E4 allele (APOE E4) and slow gait are independently associated with cognitive impairment and dementia. However, it is unknown whether their coexistence is associated with poorer cognitive performance and its underlying mechanism in neurodegenerative diseases., Methods: Gait speed, APOE E4, cognition, and neuroimaging were assessed in 480 older adults with neurodegeneration. Participants were grouped by APOE E4 presence and slow gait. Mediation analyses were conducted to determine if brain structures could explain the link between these factors and cognitive performance., Results: APOE E4 carriers with slow gait had the lowest global cognitive performance and smaller gray matter volumes compared to non-APOE E4 carriers with normal gait. Coexistence of APOE E4 and slow gait best predicted global and domain-specific poorer cognitive performances, mediated by smaller gray matter volume., Discussion: Gait slowness in APOE E4 carriers with neurodegenerative diseases may indicate extensive gray matter changes associated with poor cognition., Highlights: APOE E4 and slow gait are risk factors for cognitive decline in neurodegenerative diseases. Slow gait and smaller gray matter volumes are associated, independently of APOE E4. Worse cognition in APOE E4 carriers with slow gait is explained by smaller GM volume. Gait slowness in APOE E4 carriers indicates poorer cognition-related brain changes., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare, autosomal semi-dominant lipid metabolism disorder characterized by extremely high low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease. The objective of this study was to investigate sex-differences in the treatment and outcomes of patients with HoFH., Methods: We examined clinical characteristics, lipid-lowering therapy (LLT), and cardiovascular events using descriptive statistics of patients in the Canadian HoFH registry. Major adverse cardiovascular events (MACE) were defined as the composite of cardiovascular death, non-fatal myocardial infarction, and stroke. Sex differences between continuous and categorical variables were analyzed using Mann-Whitney U test and Fisher's Exact test, respectively., Results: This study included 48 patients (27 (56%) female). The median age at diagnosis in females was 14.0 (interquartile range (IQR) 9.0-30.0) and in males was 8.0 (IQR 2.0-23.0) (p = 0.07). Baseline clinical characteristics were comparable between both sexes. The median baseline LDL-C was 12.7 mmol/L (10.0-18.3) in females and 15.3 (10.5-20.0) in males (p = 0.51). Follow up LDL-C levels were 7.6 mmol/L (IQR 4.8-11.0) in females and 6.3 (IQR 4.6-7.5) in males (p = 0.1). Most patients were taking 3 or more LLTs, with comparable proportions in both sexes (p = 0.26). Apheresis was similar in both sexes, 14 (51.8%) vs. 10 (47.6%) (p = 0.2). Over a mean of 10 years of follow-up, MACE occurred in 3 females (11.1%) and 4 males (19.1%) (p = 0.2)., Conclusion: Lipid levels and treatment were similar between sexes. MACE occurred in similar proportions between sexes, indicating that HoFH offsets the inherently lower cardiovascular risk in pre-menopausal females. Further investigation into sex-differences in HoFH in larger sample sizes is warranted., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases., Methods: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aβ) 42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD)., Results: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aβ 42/40 ., Discussion: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Familial hypercholesterolemia (FH) is a genetic condition causing premature atherosclerotic cardiovascular disease (ASCVD). It is well established that patients with FH should be treated with statin therapy. However, there exists discordance concerning low-density lipoprotein cholesterol-lowering goals in the management of these patients between different guidelines worldwide. The objective was to compare the 10-year ASCVD risk of different subgroups of patients with and without FH including those with diabetes or a history of ASCVD and patients with FH within different FH-Risk-Score categories., Methods: This multinational observational study used data from 3 different prospective cohorts. A total of 3383 FH and 6917 non-FH controls matched for age and sex were included (104 363 person-years of follow-up). The 10-year incident ASCVD risk was assessed using Kaplan-Meier estimates, whereas the relative risk was estimated using Cox proportional hazards regression models., Results: FH patients with a high (score >20%) FH-Risk-Score (hazard ratio, 8.45 [95% CI, 6.69-10.67]; P <0.0001), FH patients with diabetes (hazard ratio, 7.67 [95% CI, 4.82-12.21]; P <0.0001), and non-FH patients with ASCVD (hazard ratio, 6.78 [95% CI, 5.45-8.42]; P <0.0001) had a significantly higher incident ASCVD risk over 10 years than the reference group (non-FH without ASCVD or diabetes). The observed 10-year risks in these groups were 32.1%, 30.8%, 30.0%, and 5.1%, respectively. The 10-year ASCVD risk associated with both FH and ASCVD was extremely high (observed risk of 50.7%; hazard ratio, 14.53 [95% CI, 12.14-17.38]; P <0.0001)., Conclusions: This study strongly suggests that the observed risk of FH patients with diabetes, history of ASCVD, and FH-Risk-Score >20% is as high or higher than non-FH individuals with a history of ASCVD. More aggressive management should be recommended for these patients., Competing Interests: Disclosures A. Baass received research grants from Akcea, Amgen, AstraZeneca, Fondation Leducq, Fondation Yvan Morin, Merck Frosst, and Sanofi. He has participated in clinical research protocols from Acasti Pharma, Inc, Akcea, Amgen, AstraZeneca, Ionis Pharmaceuticals, Inc, The Medicines Company, Merck Frosst, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc, and Sanofi. He has served on advisory boards and received honoraria for symposia from Akcea, Amgen, and Sanofi. S. Bernard received research grants from Akcea, Fondation Leducq, and Fondation Yvan Morin. She has participated in clinical research protocols from Akcea, Amgen, Ionis Pharmaceuticals, Inc, The Medicines Company, Novartis, Pfizer, and Sanofi. She has served on advisory boards for Akcea, Amgen, HLS Therapeutics, Novartis, Novo Nordisk, and Sanofi and received honoraria for symposia from Akcea, Amgen, Novo Nordisk, and Sanofi. S. Béliard has received honoraria for board, conferences, clinical trial, or congress from Aegerion, Akcea, Elivie, Sanofi, Ultragenyx, Novartis, or Amgen. B. Cariou has received research funding and personal fees from Sanofi and Regeneron Pharmaceuticals, Inc; research funding from Amgen and Pfizer; and honoraria from Abbott, Amgen, Akcea, AstraZeneca, Gilead, Eli Lilly and Company, MSD (Merck & Co.), Novartis, Novo Nordisk, Pfizer, and Sanofi. A. Gallo has received grants and personal fees from Amgen, Sanofi and Regeneron Pharmaceuticals, Inc, Mylan Viatris, MSD, Akcea Therapeutics, Amryt, Novartis, and Ultragenyx. J. Genest chairs FHCanada (FHCanada.net), a registry of patients with FH across Canada. He has received funding from the Canadian Institutes of Health Research for research related to familial hypercholesterolemia. R.A. Hegele reports consulting fees and honoraria from Acasti Pharma, Inc, Aegerion, Akcea/Ionis Pharmaceuticals, Inc, Amgen, Arrowhead, Boston Heart Diagnostics, Pfizer, Regeneron Pharmaceuticals, Inc, Sanofi, and Ultragenyx. L.R. Brunham is a Michael Smith Foundation for Health Research Scholar and is a Canada Research Chair in Precision Cardiovascular Disease Prevention and reports receiving honoraria from Amgen, Sanofi, Novartis, and HLS Therapeutics. The other authors report no conflicts.

Background and Aims: Statin recommendations in primary prevention depend upon risk algorithms. Moreover, with intermediate risk, risk enhancers and de-enhancers are advocated to aid decisions. The aim of this study was to compare algorithms used in North America and Europe for the identification of patients warranting statin or consideration of risk enhancers and de-enhancers., Methods: A simulated population (n = 7680) equal in males and females, with/without smoking, aged 45-70 years, total cholesterol 3.5-7.0 mmol/L, high-density lipoprotein cholesterol 0.6-2.2 mmol/L, and systolic blood pressure 100-170 mmHg, was evaluated. High, intermediate, and low risks were determined using the Framingham Risk Score (FRS), Pooled Cohort Equation (PCE), four versions of Systematic Coronary Risk Evaluation 2 (SCORE2), and Multi-Ethnic Study of Atherosclerosis (MESA) algorithm (0-1000 Agatston Units)., Results: Concordance for the three levels of risk varied from 19% to 85%. Both sexes might be considered to have low, intermediate, or high risk depending on the algorithm applied, even with the same burden of risk factors. Only SCORE2 (High Risk and Very High Risk versions) identified equal proportions of males and females with high risk. Excluding MESA, the proportion with moderate risk was 25% (SCORE2, Very High Risk Region), 32% (FRS), 39% (PCE), and 45% (SCORE2, Low Risk Region)., Conclusion: Risk algorithms differ substantially in their estimation of risk, recommendations for statin treatment, and use of ancillary testing, even in identical patients. These results highlight the limitations of currently used risk-based approaches for addressing lipid-specific risk in primary prevention., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Competing Interests: Disclosures R.A. Hegele reports consulting fees from Akcea/Ionis, Amgen, HLS Therapeutics, Novartis, Pfizer, Regeneron, Sanofi, and Ultragenyx. The other authors report no conflicts.