Lipidology

Are dietary fish oil supplements appropriate for dyslipidemia management? A review of the evidence Purpose of review The purpose of this review is to assess if dietary fish oil supplements are appropriate for patients with elevated triglycerides and cardiovascular risk based on a critical analysis of their composition, quality, and regulatory oversight. Recent findings Approximately 19 million people in the United States take fish oil supplements, many for the purpose of treating or preventing heart disease. Unlike prescription drugs, fish oil supplements are classified as food by the Food and Drug Administration (FDA) and not subject to rigorous clinical testing or manufacturing oversight. Analysis of widely used fish oil supplements show that they may have lower amounts of ω-3 than advertised as well as significant levels of saturated fat and oxidized oils which actually may contribute to dyslipidemia. Clinical outcome trials have failed to show a benefit with fish oil supplements and other low-dose mixed ω-3 fatty acids. Summary Owing to lack of rigorous regulatory oversight and widespread evidence of quality concerns, fish oil supplements are not an appropriate substitute for FDA approved prescription ω-3 fatty acids in the treatment of elevated triglycerides or the prevention of cardiovascular events. Correspondence to R. Preston Mason, PO Box 7100, Beverly, MA 01915, USA. Tel: +1 978 867 2125; fax: +1 978 921 4195; e-mail: rpmason@elucidaresearch.com Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Inborn errors of apolipoprotein A-I metabolism: implications for disease, research and development Purpose of review We review current knowledge regarding naturally occurring mutations in the human apolipoprotein A-I (APOA1) gene with a focus on their clinical complications as well as their exploitation for the elucidation of structure–function–(disease) relationships and therapy. Recent findings Bi-allelic loss-of-function mutations in APOA1 cause HDL deficiency and, in the majority of patients, premature atherosclerotic cardiovascular disease (ASCVD) and corneal opacities. Heterozygous HDL-cholesterol decreasing mutations in APOA1 were associated with increased risk of ASCVD in several but not all studies. Some missense mutations in APOA1 cause familial amyloidosis. Structure–function-reationships underlying the formation of amyloid as well as the manifestion of amyloidosis in specific tissues are better understood. Lessons may also be learnt from the progress in the treatment of amyloidoses induced by transthyretin variants. Infusion of reconstituted HDL (rHDL) containing apoA-I (Milano) did not cause regression of atherosclerosis in coronary arteries of patients with acute coronary syndrome. However, animal experiments indicate that rHDL with apoA-I (Milano) or apoA-I mimetic peptides may be useful for the treatment of heart failure of inflammatory bowel disease. Summary Specific mutations in APOA1 are the cause of premature ASCVD or familial amyloidosis. Synthetic mimetics of apoA-I (mutants) may be useful for the treatment of several diseases beyond ASCVD. Correspondence to Arnold von Eckardstein, MD, Institute of Clinical Chemistry, University Hospital Zurich, Raemistrasse 100, CH 8091 Zurich, Switzerland. Tel: +41 44 255 22 60; e-mail: arnold.voneckardstein@usz.ch Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Tangier disease: update for 2020 Purpose of review To appraise recent advances in our knowledge of the severe genetic HDL deficiency disorder, Tangier disease. Recent findings While Tangier disease can cause premature atherosclerotic cardiovascular disease (ASCVD), new evidence suggests that heterozygous ABCA1 variant carriers are also at increased risk. Advances have been made in the study of the neurological abnormalities observed in Tangier disease, both in their assessment and the identification of potential new therapies. Summary Tangier disease is an extremely rare condition and, as such, the published literature around its range of clinical manifestations, including peripheral neuropathy, premature ASCVD and platelet abnormalities is limited. Patient registries may assist in this regard. Correspondence to John R. Burnett, Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital & Fiona Stanley Hospital Network, Perth, Western Australia, Australia. Tel: +61 8 9224 3121; fax: +61 8 9224 1789; e-mail: john.burnett@health.wa.gov.au Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Familial combined hypolipidemia: angiopoietin-like protein-3 deficiency Purpose of review Angiopoietin-like protein-3 (ANGPTL3) is emerging as a key player in lipoprotein transport with an expanding role on fatty acid and glucose metabolism. Its deficiency is associated with a favorable metabolic profile. The present review will highlight the recent understanding of metabolic and cardiovascular consequences of ANGPTL3 inactivation by considering both genetic and pharmacological investigations. Recent findings Experimental studies have further illustrated the complex interplay between ANGPTL3 and ANGPTL4–8 in orchestrating lipid transport in different nutritional status. Individuals with familial combined hypolipidemia due to homozygous loss-of-function mutations in ANGPTL3 gene showed improved metabolism of triglyceride-rich lipoproteins during fasting and postprandial state and increased fatty acid oxidation and insulin sensitivity. Moreover, mendelian randomizations studies demonstrated that partial ANGPTL3 deficiency associates with reduced risk of atherosclerotic cardiovascular events and, eventually, diabetes mellitus. Finally, inactivation of ANGPTL3, using either a specific mAb or antisense oligonucleotide, was reported to reduce plasma levels of atherogenic lipoprotein in humans and improve hepatic fat infiltration in animal models. Summary Human and animal studies have further dissected the complex role of ANGPTL3 in the regulation of energy substrate metabolism. Moreover, genetic and pharmacological investigations have convincingly indicated that the inactivation of ANGPTL3 may be a very promising strategy to treat atherogenic metabolic disorders. Correspondence to Marcello Arca, MD, Dipartimento di Medicina Traslazionale e di Precisione, Università degli studi di Roma, Sapienza, Viale dell’Università, 35, Roma, Italy. E-mail: marcello.arca@uniroma1.it Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

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. Correspondence to Laura D’Erasmo, Dipartimento di Medicina Interna e Specialità Mediche, Università degli studi di Roma, Sapienza, Viale del Policlinico 155, Roma, Italy. E-mail: laura.derasmo@uniroma1.it Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.