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Contemporary Cardiology Series Editor: Peter P. Toth Karam Kostner Gerhard M. Kostner Peter P. Toth Editors Lipoprotein(a) Contemporary Cardiology Series Editor Peter P. Toth, Ciccarone Center for the Prevention of Cardiovascular Disease Johns Hopkins University School of Medicine Baltimore, MD, USA For more than a decade, cardiologists have relied on the Contemporary Cardiology series to provide them with forefront medical references on all aspects of cardiology. Each title is carefully crafted by world-renown cardiologists who comprehensively cover the most important topics in this rapidly advancing field. With more than 75 titles in print covering everything from diabetes and cardiovascular disease to the management of acute coronary syndromes, the Contemporary Cardiology series has become the leading reference source for the practice of cardiac care. Karam Kostner • Gerhard M. Kostner Peter P. Toth Editors Lipoprotein(a) Editors Karam Kostner Gerhard M. Kostner Mater Hospital Medical University of Graz University of Queensland Graz, Austria Brisbane, QLD, Australia Peter P. Toth Ciccarone Center for the Prevention of Cardiovascular Disease Johns Hopkins University School of Medicine Baltimore, MD, USA ISSN 2196-8969 ISSN 2196-8977 (electronic) Contemporary Cardiology ISBN 978-3-031-24574-9 ISBN 978-3-031-24575-6 (eBook) https://doi.org/10.1007/978-3-031-24575-6 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Humana imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Preface Lipoprotein metabolism embodies great biochemical complexity and broad- spectrum functionality within serum and tissues. At first glimpse, one assumes that the role of a lipoprotein is to distribute lipids and sterols to systemic tissues and foster intermediary metabolism. Over the past five decades, we have come to learn that lipoproteins are highly active polymolecular supersystems that are extraordi- narily responsive to prevailing metabolic conditions, undergo continuous modification in serum, can undergo chemical alteration when taken up into tissues, and have both beneficial and deleterious roles in health and disease. The functionality of a lipoprotein is impacted not only by its cargo of apoproteins, but also the specific constituents of its lipidome, proteome, and capacity to interact with cell surface receptors, enzymes, and intracellular signaling pathways. Lipoprotein(a) [Lp(a)] was discovered 60 years ago and has been a biochemical and physiological enigma. It is unique among lipoproteins in that it represents a low-density lipoprotein (LDL) particle with a covalently linked apoprotein(a) moi- ety bound to its apoprotein B scaffold. The kringle IV repeats of the apoprotein(a) create a whole family of molecules that are genetically determined and also impact its metabolism, level in serum, and many of its molecular behaviors. A large number of clinical, epidemiological, and basic scientific investigations identify Lp(a) as highly pathogenic. Elevated levels of Lp(a) correlate with increased risk for atherosclerotic disease as well as aortic valve calcification. Like its lipoprotein cousin, LDL, it can induce endothelial cell dysfunction, potentiate adhesion molecule expression, promote the influx of inflammatory white cells into the subendothelial space of arteries, activate pro-inflammatory nuclear transcription factors, promote smooth muscle cell migration, and foam cell formation. Lp(a) activates calcium deposition proteins which can induce both aortic valve and arterial calcification. Lp(a) may also be prothrombotic. Lp(a) is an important transport vehicle of oxi- dized phospholipids, which can be proinflammatory, proatherogenic, and stimulate osteogenesis in various cell types. v vi Preface Somewhat contrapuntal to such a diverse array of potentially injurious activity are the observations that Lp(a) participates in wound healing and angiogenesis, impacts the mortality associated with various types of cancer, participates in immunity and complement activation, is an acute phase reactant, and can modulate systemic inflammatory tone as well as risk for autoimmune disease, among other effects. Unlike other lipoproteins whose clearance from plasma is well understood, our understanding of how Lp(a) is cleared from the systemic circulation is remark- ably incomplete. We do not know which receptors along the hepatocyte surface drive this process. Interestingly, although high levels of Lp(a) are predictive of heightened risk for coronary artery disease and risk of myocardial infarction, multiple longitudinal cohort studies also suggest that elevated Lp(a) levels are protective against the development of diabetes mellitus. The mechanistic basis for this finding also remains to be elucidated. Insight into the genetics of Lp(a) is progress- ing rapidly as is our characterization of the many Kringle IV isoforms and how their functions vary. Lipoprotein(a) is now recognized as an important risk factor for the development of atherosclerotic disease and aortic valve stenosis. It is generally recommended that Lp(a) be measured at least once in one’s lifetime for overall risk assessment. Lp(a) levels are genetically determined and, unlike the levels of other lipoproteins, generally unresponsive to lifestyle modification. Lp(a) levels are also poorly responsive to such drugs as statins, ezetimibe, fibrates, and bile acid-binding resins. Although responsive to high-dose niacin therapy, multiple trials failed to show any clinical benefit from Lp(a) reduction with this drug. Two recent trials with the use of proprotein convertase subtilisin: kexin type 9 antibodies did show that Lp(a) reduction with these molecules contributed to overall risk reduction in patients with established cardiovascular disease. The apheresis of Lp(a) also demonstrates cardiovascular benefit with reduced risk for acute coronary syndromes and death in patients with elevated Lp(a). With the dawn of ribonucleic acid therapeutics, we now have both RNA oligonucleotide and antisense technology directed against hepatic Lp(a) production. These are being tested in large prospective, randomized clinical trials to evaluate their efficacy and safety. We must also resolve how best to measure Lp(a) levels and adopt a uniform means of expressing its measured value. This is important not only for reproducible quantification, but also to make com- parison between studies done in different parts of the world more feasible. Although relatively unimportant for other lipoproteins, the kidney plays a major role in Lp(a) metabolism. In the settings of chronic kidney disease and nephrotic syndrome, Lp(a) can become markedly elevated. In this volume, these issues are discussed in considerable detail. Given all that we know and do not know about Lp(a), we thought it was time to produce a book which synthesizes what we do know about this still highly enig- matic lipoprotein, both positive and negative. We also explore unanswered Preface vii questions. While the book is highly scientific throughout, we emphasize clinical aspects whenever possible. Chapters were prepared by leading experts in the field of Lp(a) research. We anticipate that Lp(a) will emerge as a treatment target in the clinical arena and hope that this volume provides both context and knowledge that helps to ensure that clinicians will evaluate patients for Lp(a), incorporate it into cardiovascular risk stratification, and treat it as appropriate. Brisbane, Australia Karam Kostner Graz, Austria Gerhard M. Kostner Baltimore, MD, USA Peter P. Toth Contents 1 60 Years of Lp(a) Research: From Ouchterlonys Double Diffusion to Copy Number Variation and a Significant Risk Factor for CHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Gerd Utermann 2 Lp(a) Biochemistry, Composition, and Structure . . . . . . . . . . . . . . . . 39 Gerhard M. Kostner 3 Genetics of Lipoprotein(a) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 Gerd Utermann 4 Lp(a) Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 John S. Millar and Daniel J. Rader 5 Contemporary Aspects of Lp(a) Metabolism and Therapies Based on Tracer Kinetic Studies in Humans . . . . . . . . . . . 91 Dick C Chan, Jing Pang, and Gerald F Watts 6 Role of Proprotein Convertase Subtilisin Kexin Type 9 in Lipoprotein(a) Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 Antonio Gallo, Kévin Chemello, Romuald Techer, Ali Jaafar, and Gilles Lambert 7 The Role of Cell Surface Receptors in Lp(a) Catabolism . . . . . . . . . . 125 Lamia Ismail, Déanna Shea, and Sally McCormick 8 Physiological Roles and Functions of Lipoprotein(a) . . . . . . . . . . . . . 135 Zaid N. Safiullah, Thorsten Leucker, Steven R. Jones, and Peter P. Toth 9 The Role of Lp(a) in Atherosclerosis: An Overview . . . . . . . . . . . . . . 159 Anastasiya Matveyenko, Marianna Pavlyha, and Gissette Reyes-Soffer ix x Contents 10 Molecular Mechanisms of Lipoprotein(a) Pathogenicity: Tantalizing Clues and Unanswered Questions . . . . . . . . . . . . . . . . . . . 173 Michael B. Boffa and Marlys L. Koschinsky 11 Thrombosis, Inflammation, and Lipoprotein(a): Clinical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 Maya S. Safarova and Patrick M. Moriarty 12 The Kidney Is the Heart of the Organs: Its Role in Lp(a) Physiology and Pathophysiology . . . . . . . . . . . . . . . 207 Hans Dieplinger 13 Lp(a) as a Cardiovascular Risk Factor . . . . . . . . . . . . . . . . . . . . . . . . . 231 Angela Pirillo and Alberico Luigi Catapano 14 Lp(a) and Aortic Valve Stenosis, Stroke, and Other Noncoronary Cardiovascular Diseases . . . . . . . . . . . . . . . . . . . . . . . . . 241 Anne Langsted and Pia R. Kamstrup 15 Lipoprotein(a) in Cardiovascular Disease: Evidence from Large Epidemiological Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 Peter Engel Thomas, Signe Vedel-Krogh, and Børge G. Nordestgaard 16 Lipoprotein(a) and Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 O. I. Afanasieva, T. I. Arefieva, M. V. Ezhov, and S. N. Pokrovsky 17 When Should We Measure Lipoprotein(a)? . . . . . . . . . . . . . . . . . . . . . 275 Karam Kostner 18 Measurement of Lipoprotein(a) in the Clinical Laboratory . . . . . . . . 281 David Sullivan, Catherine Woolnough, Nimalie Perera, Jay Ramanathan, and Tony Badrick 19 Standardization of Analytical Methods for the Measurement of Lipoprotein(a): Bridging Past and Future Initiatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 Noemie Clouet-Foraison, Tomas Vaisar, and Santica M. Marcovina 20 On the Way to a Next-Generation Lp(a) Reference Measurement System Based on Quantitative Protein Mass Spectrometry and Molar Units . . . . . . . . . . . . . . . . . . . . . . . . . . 325 Christa Cobbaert, Liesbet Deprez, and Renee Ruhaak 21 Therapy of Elevated Lipoprotein(a) . . . . . . . . . . . . . . . . . . . . . . . . . . . 347 S. Ibrahim and Erik S. G. Stroes 22 Antisense Oligonucleotide Therapy to Treat Elevated Lipoprotein(a) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 Sotirios Tsimikas