Lipoprotein(a)

446 Pages·2023·21.56 MB·English

by  Karam Kostner, Gerhard M. Kostner, Peter P. Toth

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
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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 modifica-
tion 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 athero-
sclerotic 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 immu-
nity and complement activation, is an acute phase reactant, and can modulate sys-
temic 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, mul-
tiple longitudinal cohort studies also suggest that elevated Lp(a) levels are protec-
tive 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 respon-
sive 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 car-
diovascular 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