Lipoprotein(a) [Lp(a)] is a unique lipoprotein that has emerged as an independent risk factor for cardiovascular vascular disease. Data from case control, epigenetic and mendelian randomization studies indicate that people with elevated Lp(a) have a two-fold to four-fold increased risk of cardiovascular events compared to people with low Lp(a) levels. Despite this risk, awareness of Lp(a) is still very low among health care providers. Even cardiologists often overlook Lp(a), in part because Lp(a) is not as well-understood as other risk factors and treatment options are still very limited.
This book offers an authoritative and comprehensive overview of Lipoprotein(a). It provides an in-depth review of all aspects of Lp(a), from pathophysiology to metabolism. Chapters offer the reader a contemporary view of the important roles of Lp(a) as a risk factor for cardiovascular disease. In addition, this volume discusses the clinical implications of elevated Lp(a) and current and future therapies. Lipoprotein(a) is an essential resource for physicians, medical students, residents, fellows, and allied health professionals in lipidology, cardiology, endocrinology, pharmacotherapy, and health promotion and disease prevention.
Author(s): Karam Kostner, Gerhard M. Kostner, Peter P. Toth
Series: Contemporary Cardiology
Publisher: Humana Press
Year: 2023
Language: English
Pages: 445
City: New York
Preface
Contents
Contributors
Chapter 1: 60 Years of Lp(a) Research: From Ouchterlonys Double Diffusion to Copy Number Variation and a Significant Risk Factor for CHD
A Historical Review
The Discovery of Lp(a)
Isolation and Characterization of Lp(a)
Metabolism
The LPA Gene and Apolipoprotein(a)
Functional Studies
Animal Studies and the Era of Transgenics
Unraveling the Genetics of Lp(a)
Lp(a), CHD, and Mendelian Randomization
Non-Genetic Effects, Renal Disease, and Type 2 Diabetes
The Road to Therapy
Outlook
References
Chapter 2: Lp(a) Biochemistry, Composition, and Structure
Historical Developments
Purification and Composition of Lp(a)
Preparation of Pure Lp(a)
Chemical Composition of Purified Lp(a)
The Protein Structures of Lp(a) and Apo(a)
The Carbohydrate Moiety of Apo(a)
The Role of Structural Apo(a) Features for the Lp(a) Metabolism
Impact of Gene Variants on the Apo(a) Structure
Impact of the Assembly on Plasma Concentrations of Lp(a)
Impact of Apo(a) Mutations on Coronary Artery Disease (CAD)
Impact of the LDL Structure on the Lp(a) Assembly
References
Chapter 3: Genetics of Lipoprotein(a)
Introduction
Structure of Lp(a) and LPA Gene
LPA KIV-2 VNTR and Lp(a) Concentration
Causal Effect of the KIV-2 VNTR on Lp(a) Concentration
Simple Repeats, RSPs, and SNPs in LPA and Their Effects on Lp(a) Levels
Summary
References
Chapter 4: Lp(a) Metabolism
Introduction
Lp(a) Metabolism
Studies Addressing Potential for VLDL, LDL, and Lp(a) Interconversion
Studies Examining the Determinants of Lp(a) Concentration
The Role of the LDL Receptor in Lp(a) Clearance
The Role of Other Receptors in Lp(a) Clearance
Drug Effects on Lp(a) Metabolism
Statins
PCSK9 Inhibitors
Niacin
Inhibitors of apoB Synthesis/Secretion
Other Drugs on Lp(a) Metabolism
Targeting Apo(a) Production to Lower Lp(a)
Conclusion
References
Chapter 5: Contemporary Aspects of Lp(a) Metabolism and Therapies Based on Tracer Kinetic Studies in Humans
Introduction
Structure and Genetics of Lipoprotein(a) in Brief
Stable Isotopic Tracer Methodologies
Metabolism of Lipoprotein(a)
Synthesis, Assembly and Secretion
Clearance and Catabolism
Kinetic Determinants of Plasma Lipoprotein(a) Concentrations
Production Rate vs. Fractional Catabolic Rate
Apo(a) Isoform Size
Mechanisms of Action of Lipid-Regulating Agents on Lipoprotein(a) Metabolism
Statins
Niacin
PCSK9 Inhibitors
CETP Inhibitors
ApoB Antisense Oligonucleotides
Other Therapies
Conclusions and Future Perspectives
References
Chapter 6: Role of Proprotein Convertase Subtilisin Kexin Type 9 in Lipoprotein(a) Metabolism
PCSK9, a Key Player in Lipoprotein Metabolism
PCSK9, an Ideal LDL Cholesterol-Lowering Drug Target
Lipoprotein(a) Plasma Levels Are Chiefly Governed by Production
The PCSK9-LDLR-Lp(a) Axis
Conclusion
References
Chapter 7: The Role of Cell Surface Receptors in Lp(a) Catabolism
Introduction
Lp(a) Structure and Assembly
Lp(a) Catabolism
Liver Receptors
Kidney Receptors
Macrophage Receptors
Summary
References
Chapter 8: Physiological Roles and Functions of Lipoprotein(a)
Delivery Platform of Oxidized Phospholipids
Promoter of Inflammation
Impact on Malignancies
Lp(a) in Thrombosis
Lp(a) in Diabetes
Lp(a) in Wound Healing
Lp(a) in Autoimmune Disease
Lp(a) in Calcific Aortic Stenosis
Lp(a) in Acute Coronary Syndromes
Evolution of Lp(a)
Lp(a) and COVID-19
Conclusions
References
Chapter 9: The Role of Lp(a) in Atherosclerosis: An Overview
Introduction
Lipoprotein(a) and Atherosclerotic Cardiovascular Disease
Lipoprotein(a) and Links to Inflammation
Lipoprotein(a) and Atherosclerosis: Brief Review of Clinical Outcomes
Myocardial Infarction
Aortic Stenosis
Stroke
Peripheral Artery Disease (PAD)
Lp(a): Cardiovascular Mortality
Lipoprotein(a): Genetics and Atherosclerosis
Effects of Available Treatments on Lp(a) and Risk of Atherosclerosis
Conclusions
References
Chapter 10: Molecular Mechanisms of Lipoprotein(a) Pathogenicity: Tantalizing Clues and Unanswered Questions
Introduction
Effect of Lp(a) on Vascular and Immune Cell Phenotype
Effects of Lp(a) on Vascular Endothelium
Effects of Lp(a) on Vascular Smooth Muscle Cells
Lp(a) and Monocyte/Macrophage Phenotype
Lp(a) and Valve Interstitial Cell Phenotype
Effect of Lp(a) on Thrombosis and Thrombolysis
Is There Direct Evidence That Lp(a) Inhibits Fibrinolysis?
Could Lp(a) Promote Thrombosis Indirectly?
Concluding Remarks
References
Chapter 11: Thrombosis, Inflammation, and Lipoprotein(a): Clinical Implications
Introduction
Lp(a) and Thrombosis
Lp(a), Platelets, and Coagulation
Lp(a) and Inflammation
Future Directions, Relevance, and Conclusions
Antiplatelet Agents and Anticoagulation
Apo-B Lowering
References
Chapter 12: The Kidney Is the Heart of the Organs: Its Role in Lp(a) Physiology and Pathophysiology
Introduction
Definition of Lipoprotein(a)
Metabolism of Lipoprotein(a)
Synthesis, Assembly, and Secretion
Clearance and Catabolism
Immune-Histochemical Studies
Role of LDL Receptor and Other Receptors for Lp(a) Clearance
In Vivo Studies
Lp(a) in Kidney Disease
Proteinuria and Nephrotic Syndrome
Early Stages of Kidney Disease
Chronic Kidney Disease Treated by Hemodialysis or Peritoneal Dialysis
Kidney Transplantation
Lipoprotein(a) and Cardiovascular Outcome in CKD
Metabolic Relation Between Kidney and Lipoprotein(a): Conclusions and Gaps in Knowledge
References
Chapter 13: Lp(a) as a Cardiovascular Risk Factor
Introduction
Lp(a) and CVD: A Causal Relationship
The Prevalence of Elevated Lp(a) Levels in Individuals with Coronary Artery Disease
Lp(a) in Familial Hypercholesterolemia
The Impact of Race and Ethnicity on Lp(a) Levels and Cardiovascular Risk
Conclusions
References
Chapter 14: Lp(a) and Aortic Valve Stenosis, Stroke, and Other Noncoronary Cardiovascular Diseases
Introduction
Aortic Valve Stenosis
Stroke
Ischemic Stroke
Hemorrhagic Stroke
Arterial Ischemic Stroke in the Young
Other Noncoronary Cardiovascular Diseases
Heart Failure
Peripheral Arterial Disease
Summary
References
Chapter 15: Lipoprotein(a) in Cardiovascular Disease: Evidence from Large Epidemiological Studies
Introduction
Lipoprotein(a) in Contemporary Primary Prevention Studies
Lipoprotein(a) in Contemporary Secondary Prevention Studies
Future Perspectives
References
Chapter 16: Lipoprotein(a) and Immunity
Introduction
Lipoprotein(a) and IgG and IgM Autoantibodies (AAbs)
Lipoprotein(a) and Innate Immunity Cells
The Role of Lipoprotein(a) and Proinflammatory Status in ASCVD Pathogenesis
Lipoprotein(a) as a Carrier of Inflammatory Mediators
References
Chapter 17: When Should We Measure Lipoprotein(a)?
Introduction
Lp(a) and ASCVD Risk Assessment
Recommendations from International Guidelines
Synopsis (Authors’ Recommendations)
References
Chapter 18: Measurement of Lipoprotein(a) in the Clinical Laboratory
Background to Lipoprotein(a) Measurement for Clinical Purposes
Method Selection
Safety and Quality
Clinical Application
Interpretation
Healthcare Systems
Conclusion
References
Chapter 19: Standardization of Analytical Methods for the Measurement of Lipoprotein(a): Bridging Past and Future Initiatives
Standardization: What, Why, and How?
Importance of Standardization in Clinical Laboratory Medicine
Metrological Traceability, Standardization, and Harmonization
What Does “Establishing Standardization” Mean?
The Specific Case of Lp(a)
Measuring Lp(a): A Major Challenge
A History of Standardization Initiatives for Lp(a)
The Current Harmonization System
Development of a New Approach to Measure Lp(a): LC-MS/MS
Potential for Standardization Using a Higher-Order LC-MS/MS Method
LC-MS/MS for the Measurement of Lp(a) in Clinical Laboratories
What Is the Clinical Relevance of Standardizing Lp(a)?
Conclusions
References
Chapter 20: On the Way to a Next-Generation Lp(a) Reference Measurement System Based on Quantitative Protein Mass Spectrometry and Molar Units
Introduction
Metrological Traceability of Lp(a) Test Results
Evolution in Science and Metrology
Current Lp(a) Measurement Procedures
Structural Properties of Lp(a) in the Continuum of apoB-Containing Lipoprotein Classes
Characteristics and Design of Conventional Lp(a) Tests
Effect of Lp(a) Test Inaccuracy on Clinical Utility
Lp(a): The Most Misunderstood Metric and the No(n)-sense of Lp(a) Mass Results
The Degree of Lp(a) Test Harmonization and Its Impact on Cardiovascular Risk Management
Development of a Next-Generation SI-Traceable apo(a)/Lp(a) Reference Measurement System
cRMP in a Network of Calibration Labs
Development of Primary and Secondary Reference Materials
How Do Current Immunoassay-Based Lp(a) Tests Compare to the Next-Generation Reference Measurement Procedure?
Transitioning from the WHO-IFCC RMS to an SI-Traceable Reference Measurement System
Background and Current WHO Reference Material for Lp(a)
New JRC-IFCC/LNE Reference Materials
Interim Solutions
Transitioning from Old to New Lp(a) Reference Measurement System: Recommendations to Cardiologists and Other Stakeholders
Relevance of Accurate Test Results Within Allowable Total Error
What Were the Determinants of Inaccuracy in Case of Lp(a) Testing in the Twentieth Century?
Concordance and Discordance of Contemporary Immunoassay-Based Methods Compared to a Higher-Order Mass Spectrometry-Based Method, Being a Predecessor of the SI-Traceable cRMP
Transitioning from Old to New Lp(a)/apo(a) Reference Measurement System: Recommendations for Stakeholders and End-Users
References
Chapter 21: Therapy of Elevated Lipoprotein(a)
Expected Benefit of Lp(a) Lowering
Effect of Current Therapies on Lp(a)
Statins
Ezetimibe
PCSK9 Inhibitors
Other Lipid-Modifying Agents
Apheresis
Non-apoB-Directed Therapies
Future Perspectives: Experimental Drugs
Antisense Oligonucleotides
Small Interfering RNA
Conclusion
References
Chapter 22: Antisense Oligonucleotide Therapy to Treat Elevated Lipoprotein(a)
Preclinical Proof of Concept in Lowering Plasma Lp(a) Levels
Evolution of Various Generations of Antisense Technology
Development of a Human Candidate to Lower Lp(a) Plasma Levels
Mechanisms of Antisense Oligonucleotide Pharmaceutical Activity
Completed Clinical Trials with ISIS-APO(a)Rx/IONIS-APO(a)Rx
Completed Clinical Trials with IONIS-APO(a)LRx/AKCEA-APO(a)LRx,/TQJ230/Pelacarsen
Lp(a) Horizon Cardiovascular Outcomes Trial and Testing of the “Lp(a) Hypothesis”
References
Chapter 23: Lipoprotein Apheresis for Reduction of Lipoprotein(a)
Introduction
History of Lipoprotein Apheresis (LA) Regarding the Indication of High Lipoprotein(a) [Lp(a)]
Efficiency of LA with Respect to Lowering of Lp(a) Concentrations
Oxidized Phospholipids
Adverse Effects and Contraindications of LA
Efficiency of LA on Cardiovascular Events (CVEs) in Patients with High Lp(a) Concentrations
Observational Studies
Observational Studies
Our Own (Dresden) Experience
Italian Retrospective Multicenter LA Study in Patients with Elevated Lp(a) and Coronary Artery Disease
Study in Patients with Elevated Lp(a) and Peripheral Artery Disease (PAD)
American Single-Center, Retrospective Cohort Study in Patients with High Lp(a) Levels
German Lipoprotein Apheresis Registry
Russian-Specific Columns Against Lp(a) [Lp(a) Lipopak® Adsorption Columns]
MultiSELECt Study
Other Effects of LA in Patients with High Lp(a): A Study with Sham Control
Selected Case Reports
Actions Which Should Be Taken in Patients Who Develop Cardiovascular Events (CVEs) Despite Being Treated with LA
Unresolved Problems
Which LA Method Is the Best?
How Low Should Lp(a) Be to Effectively Prevent New CVEs During LA Therapy
Should We Calculate “True” LDL-C?
LA in Children with Ischemic Stroke and Patients on Hemodialysis with High Lp(a) Levels
Future of LA in Patients with High Lp(a) Levels
Pros and Cons of LA
Diet, Statins, Ezetimibe, Bempedoic Acid, PCSK9 Inhibitors, and Evinacumab
Inhibitors of Apo(a) Synthesis
Conclusions
References
Chapter 24: Elevated Lp(a): Why Should I Test For It, If I Cannot Treat It? A Patient’s Perspective
“How Can I Have Normal LDL-Cholesterol and Almost Die of a Heart Attack?”
Reveal Lp(a): “You Must Have Had Some Really Bad Habits When You Were Younger”
TEST Lp(a): “Why Test for It If You Cannot Treat It?”
Educate, Empower, and Save Lives: “I Wish All My Patients Were Like You and Engaged in Their Care”
What We Know: The Facts
What We Know: The Clinical Evidence
Conclusion
Awareness
Women’s Heart Disease Data
Access to Latest Top-Quality Evidenced-Based Data
Clinical Centers of Excellence for High Lp(a)
Lack of Standard of Care for High Lp(a)
Rapid Deployment of a Globally Standardized Assay for High Lp(a)
Improved Risk Calculators
Precision Medicine
Aspirin for Event Prevention for Patients with High Lp(a)
National Database for Cardiovascular Disease
Measurable Impact But Still More Work to Be Done
References
Chapter 25: Unresolved Questions
Is There a Function of Lp(a) in Longevity and Suppression of Malignant Growth?
Metabolism
Pathophysiology: What Are the Most Important Determinants of Lp(a) Pathogenicity?
Lp(a) Analysis in Clinical Laboratories
Does Lp(a) Lowering Reduce Hard CV Endpoints?
How Much Should Lp(a) Be Lowered?
Which Is the Most Effective Therapy to Lower Lp(a)?
The Effect of Statins on Plasma Lp(a) Levels
Who Should We Screen for Lp(a) and How?
References
Index
