Contemporary Aspects of Lp(a) Metabolism and Therapies Based on Tracer Kinetic Studies in Humans

Research output: Chapter in Book/Conference paperChapterpeer-review

Abstract

Lipoprotein(a) [Lp(a)] is an inherited and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis. Use of stable isotope tracers and compartmental modelling has provided deeper understanding of the physiology and pathophysiology of Lp(a) metabolism in humans, and the mode of action of lipid-regulating agents. Kinetic data have demonstrated that newly synthesized Lp(a)-apolipoprotein (apo) B-100 and Lp(a)-apo(a) are secreted as a holoparticle, with tightly coupled apo(a) and apoB-100 residence times in the circulation. In subjects with normal or high Lp(a) concentrations, the plasma Lp(a) concentration is predominantly determined by the rate of production of Lp(a) particles, irrespective of apo(a) isoform size and background therapy with statins. Lp(a) particle catabolism may only play a modest role in determining Lp(a) concentration in subjects with normal Lp(a) concentration or larger apo(a) isoform size. Kinetic studies also show that niacin and cholesteryl ester transfer protein inhibitors lower plasma Lp(a) concentration by increasing the clearance or catabolism of apo(a), whereas apoB antisense oligonucleotides lower plasma Lp(a) concentration by decreasing hepatic production. Proprotein convertase subtilisin kexin type 9 inhibitors can lower plasma Lp(a) concentration by a dual mode of action involving both increased clearance and decreased production of apo(a), depending on background Lp(a) concentration and/or statin use. Further studies of RNA therapeutics targeted at apo(a), angiopoietin-like 3 and apoC-III on the metabolism of Lp(a) and other lipoproteins will further our understanding of these therapies in decreasing the development of ASCVD.
Original languageEnglish
Title of host publicationLipoprotein(a)
EditorsKaram Kostner, Gerhard M. Kostner, Peter P. Toth
Place of PublicationSwitzerland
PublisherHumana Press Inc.
Chapter5
Pages91-111
Number of pages21
ISBN (Electronic)978-3-031-24575-6
ISBN (Print)978-3-031-24574-9
DOIs
Publication statusPublished - 4 Mar 2023

Publication series

NameContemporary Cardiology
PublisherSpringer
ISSN (Print)2196-8969
ISSN (Electronic)2196-8977

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