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

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Lipoprotein(a)

Part of the book series: Contemporary Cardiology ((CONCARD))

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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.

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Acknowledgement

JP was supported by the National Health and Medical Research Council (HMRC) Investigator Grant.

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Authors and Affiliations

  1. Medical School, University of Western Australia, Perth, WA, Australia

    Dick C Chan, Jing Pang & Gerald F Watts

  2. Lipid Disorders Clinic, Department of Cardiology and Internal Medicine, Royal Perth Hospital, Perth, WA, Australia

    Gerald F Watts

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  1. Dick C Chan
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  2. Jing Pang
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  3. Gerald F Watts
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Correspondence to Gerald F Watts .

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Editors and Affiliations

  1. Mater Hospital, University of Queensland, Brisbane, QLD, Australia

    Karam Kostner

  2. Medical University of Graz, Graz, Austria

    Gerhard M. Kostner

  3. Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Peter P. Toth

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Chan, D.C., Pang, J., Watts, G.F. (2023). Contemporary Aspects of Lp(a) Metabolism and Therapies Based on Tracer Kinetic Studies in Humans. In: Kostner, K., Kostner, G.M., Toth, P.P. (eds) Lipoprotein(a). Contemporary Cardiology. Humana, Cham. https://doi.org/10.1007/978-3-031-24575-6_5

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