Lipoprotein (a)

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. 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