Principles and Treatment of Lipoprotein Disorders

Major advances have been made in the understanding of the molecular mechanisms of atherosclerosis, the disease that still affects more than 50 percent of the population in the highly industrialized countries. This volume covers the most recent advances in the treatment of hyperlipidemia. It represents a necessary update because molecular mechanisms of atherogenesis have been discovered in the past few years and their molecular mechanisms of action identified. Extensively treated are the molecular mechanisms of disease etiology of arteriosclerosis in relation to the major risk factor "hyperlipidemia", rationale for more effective treatment of this disease by dietary means, the treatment of associated or causing diseases, and the treatment using hypolipidemic drugs.

Section A: Physiology and Pathophysiology of Lipid Metabolism.- 1 An Introduction to the Biochemistry and Biology of Blood Lipids and Lipoproteins.- A. Introduction.- B. Blood Lipid Transport: Historical Aspects.- C. Blood Lipids, Apolipoproteins, and Lipoproteins.- I. Lipids.- II. Apolipoproteins.- III. Lipoproteins.- D. Enzymes and Transfer Factors Involved in the Biochemistry of Blood Lipid Regulation.- E. Lipoprotein Metabolism.- I. Transport of Exogenous Lipids.- II. Transport of Endogenous Lipids.- F. Cholesterol and Atherosclerosis.- G. High-Density Lipoprotein Cholesterol and Reverse Cholesterol Transport.- H. Triglycerides, High-Density Lipoprotein Cholesterol, and Coronary Artery Disease.- I. Conclusion.- References.- 2 Lipoprotein Metabolism.- A. Introduction.- B. Plasma Apolipoproteins.- C. Cellular Receptors.- I. Low-Density Lipoprotein Receptor.- II. Scavenger Receptor(s).- III. Chylomicron Remnant Receptor.- IV. High-Density Lipoprotein Receptor.- D. Lipoprotein Metabolism.- I. ApoB Metabolic Cascade.- II. High-Density Lipoprotein Metabolism.- III. Lp(a).- E. Major Plasma Atherogenic and Antiatherogenic Lipoproteins.- I. Low-Density Lipoproteins.- II. ? Very Low Density Lipoproteins.- III. Lp(a).- IV. High-Density Lipoproteins.- F. Summary.- References.- 3 Lipoprotein Receptors.- A. Introduction.- B. The Low-Density Lipoprotein Receptor.- I. Functions of the Low-Density Lipoprotein Receptor in the Body.- II. Structure of the Low-Density Lipoprotein Receptor.- 1. Domains.- 2. Evolution.- 3. Low-Density Lipoprotein Receptor Polymorphisms.- III. Low-Density Lipoprotein Receptor Endocytosis, Recycling and Turnover.- IV. Low-Density Lipoprotein Receptor Mutations and Familial Hypercholesterolaemia.- 1. Classes of Low-Density Lipoprotein Receptor Mutations.- a) Class I Mutations (Null Alleles).- b) Class II Mutations (Transport-Defective Alleles).- c) Class III Mutations (Binding-Defective Alleles).- d) Class IV Mutations (Internalization-Defective Alleles).- e) Class V Mutations (Recycling-Defective Alleles).- 2. Clinical Variability in Familial Hypercholesterolaemia.- V. Low-Density Lipoprotein Receptor Regulation.- 1. Low-Density Lipoprotein Receptor Promoter.- 2. Control in the Liver.- VI. Low-Density Lipoprotein Receptor and Therapy.- 1. Drug Therapy.- 2. Liver Transplantation.- 3. Gene Therapy.- C. Chylomicron Remnant Receptor.- I. Receptor-Mediated Clearance of Chylomicron Remnants.- II. Low-Density Lipoprotein Receptor Related Protein: Candidate Chylomicron Remnant Receptor.- III. Structure of Low-Density Lipoprotein Receptor Related Protein.- IV. Properties of Low-Density Lipoprotein Receptor Related Protein.- 1. Binding of Ligands.- 2. Regulation of Ligand Binding.- D. High-Density Lipoprotein Receptor.- I. Cholesterol Efflux.- II. High-Density Lipoprotein Endocytosis.- E. The Scavenger Receptor.- I. The Modified Low-Density Lipoprotein Hypothesis.- II. Scavenger Receptor Structure.- III. Scavenger Receptor Function.- IV. Human Scavenger Receptor Gene.- V. Expression and Regulation.- VI. Scavenger Receptor and Atherogenesis.- F. Conclusion.- References.- 4 Genetic Disorders of Lipoprotein Metabolism.- A. Introduction.- B. Familial Hyperchylomicronemia.- I. Lipoprotein Lipase Deficiency.- II. Apolipoprotein C-II Deficiency.- C. Familial Hypercholesterolemia.- I. Heterozygous Familial Hypercholesterolemia.- 1. Low-Density Lipoprotein.- 2. Pathophysiology and Clinics of Familial Hypercholesterolemia.- 3. Diagnosis of Familial Hypercholesterolemia.- II. Homozygous Familial Hypercholesterolemia.- III. Familial Defective ApoB-100.- 1. Population Genetics of Familial Defective ApoB-100.- 2. Diagnosis of Familial Defective ApoB-100.- 3. The Familial Defective ApoB-100 Phenotype.- D. Lp(a) Hyperlipoproteinemia.- I. Structure and Evolution.- II. Genetics.- III. Genetics of Lp(a) and of Lp(a) Hyperlipoproteinemia.- IV. Lp(a) Hyperlipoproteinemia and Atherosclerotic Vascular Disease.- E. Hyperlipoproteinemia Type III.- I. ApoE Polymorphism.- II. Multifactorial Type III Hyperlipoproteinemia.- III. Dominant Type III Hyperlipoproteinemia.- IV. Pathophysiology of Type III Hyperlipoproteinemia.- F. Familial Combined Hyperlipoproteinemia.- G. Polygenic Hypercholesterolemia.- H. Familial Hypertriglyceridemia.- I. Familial Hyperalphalipoproteinemia and Familial Hypoalphalipoproteinemia.- References.- 5 Interactions Between Lipoproteins and the Arterial Wall.- A. The Molecular Mechanisms of Atherogenesis Are Not Known.- B. The Low-Density Lipoprotein Receptor Pathway and the Pathogenesis of Atherosclerosis.- C. Is Low-Density Lipoprotein Atherogenic?.- D. The Low-Density Lipoprotein Receptor is a Member of a Family of Lipoprotein Receptors: The Low-Density Lipoprotein Receptor Related Proteins, a Very Low-Density Lipoprotein Receptor, and Glycoprotein 330.- E. The Low-Density Lipoprotein Receptor Dependent-Arachidonic Acid Pathway.- F. The Oxidation and Scavenger Receptor Hypotheses.- G. High-Density Lipoproteins and the Reverse Cholesterol Transport Hypothesis.- H. Arterial Wall Cells Form Biologically Active Mediators of Inflammation in Response to Cholesterol Feeding.- I. Adhesion Molecules Are Involved in Leukocyte-Endothelial Cell Interactions.- J. Proto-oncogenes Are Expressed in Atherosclerotic Lesions.- References.- 6 Lipoprotein Lipase and Hepatic Lipase.- A. Introduction.- B. Gene Structures.- C. Molecular Structure.- D. Effects of Apolipoproteins on Lipase Action.- E. Lipoprotein Lipase and Hepatic Lipase ― What Are the Functional Differences?.- F. Actions of Lipoprotein Lipase.- G. Sites of Synthesis.- H. Maturation into Active Lipoprotein Lipase.- I. Transfer to the Endothelium.- J. Transport in Blood.- K. Lipases in Pre- and Postheparin Plasma.- L. Regulation.- M. Lipoprotein Lipase as Ligand for Binding of Lipoproteins to Cells and Receptors.- N. Is Lipoprotein Lipase Rate-Limiting for Catabolism of Triglyceride-Rich Lipoproteins?.- O. Impact on Lipoprotein levels.- References.- 7 Animal Models of Lipoprotein Metabolism.- A. Introduction.- B. Animal Models.- C. Lipoproteins.- I. Rabbit.- II. Monkey.- D. Conclusion.- References.- Section B: Lipid Lowering Therapy.- 8 Rationale to Treat.- A. Introduction.- B. Mortality- and Morbidity-Based Drug Trials.- C. Mortality- and Morbidity-Based Diet Trials.- D. Atherosderotic Regression Trials ― Uncontrolled Case Series and Case Reports.- I. Femoral Artery.- II. Popliteal Artery.- III. Renal Artery.- IV. Carotid Artery.- V. Coronary Artery and Aorta.- E. Controlled Coronary Angiographic Studies of Drug Therapy.- F. Coronary Angiographic Studies of Diet Therapy.- G. Femoral Angiographic Drug Studies.- H. Atherosclerosis Regression in Experimental Animal Models.- I. Summary.- References.- 9 The Dietary Therapy of Hyperlipidemia: Its Important Role in the Prevention of Coronary Heart Disease.- A. Introduction.- B. Dietary Cholesterol.- C. Effects of Dietary Fats Upon the Plasma Lipids and Lipoproteins.- D. The Cholesterol-Saturated Fat Index of Foods.- E. Polyunsaturated Fatty Acids.- F. Carbohydrate.- G. Fiber, Saponins, and Antioxidants.- H. Protein.- I. Calories.- J. Alcohol.- K. Coffee and Tea.- L. The Dietary Design to Achieve Optimal Plasma Lipid-Lipoprotein Levels.- M. A Phased Approach to the Dietary Treatment of Hyperlipidemia.- N. Predicted Plasma Cholesterol Lowering from Three Phases of the Low-Fat, High Complex Carbohydrate Diet.- O. The Applicability of the Low-Cholesterol, Low-Fat, High-Carbohydrate Diet in the Treatment of the Various Phenotypes and Genotypes of Hyperlipidemia.- P. The Use of the Low-Fat, High Complex Carbohydrate Diet in Diabetic Patients, Pregnant Patients, Children, and Hypertensive Patients.- Q. Interrelationship Between Dietary and Pharmaceutical Therapy of Hyperlipidemic States.- R. Summary.- References.- 10 Lipid Apheresis.- A. Introduction.- B. Low-Density Lipoprotein Apheresis Procedures.- C. The Heparin-Induced Extracorporeal Low-Density Lipoprotein Plasmapheresis System.- D. Clinical Experience with the Heparin-Induced Extracorporeal Low-Density Lipoprotein Plasmapheresis System.- E. Experience with Combined Heparin-Induced Extracorporeal Low-Density Lipoprotein Plasmapheresis and 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitor Therapy.- F. Treatment Tolerance and Safety of Heparin-Induced Extracorporeal Low-Density Lipoprotein Plasmapheresis.- G. Typical Case Reports.- I. Case 1.- II. Case 2.- H. The Heparin-Induced Extracorporeal Low-Density Lipoprotein Plasmapheresis Treatment in Heart-Transplant Patients with Severe Hypercholesterolemia: Report of an Ongoing Study.- I. The Heparin-Induced Extracorporeal Low-Density Lipoprotein Plasmapheresis U System for a Simultaneous Hemodialysis: Low-Density Lipoprotein Apheresis.- I. Case Report.- J. Comparison of Techniques to Lower Low-Density Lipoprotein Levels by Apheresis.- K. Indication for Heparin-Induced Extracorporeal Low-Density Lipoprotein Apheresis.- L. Conclusion.- References.- Section C: Lipid Lowering Drugs.- 11 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors.- A. Introduction.- B. Structure and Mechanism of Action of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors.- I. Structure.- II. Pharmacokinetic Properties of Lovastatin, Pravastatin, and Simvastatin.- III. Mechanism of Action.- IV. Effects on Lipoprotein Metabolism.- V. Other Potential Effects of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors.- C. Clinical Efficacy of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors in the Treatment of Hyperlipidemia.- I. Effects in Primary Hypercholesterolemia.- II. Effects in Combined Hyperlipidemia.- III. Effects in Hypertriglyceridemia and Hypoalphalipoproteinemia.- IV. Potential Utility of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors in Patients with Secondary Causes of Hyperlipidemia.- D. Safety and Side-Effect Profile of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors.- E. Contraindications and Inappropriate Uses of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors.- F. Use of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors in Combination Drug Therapy.- G. Conclusions.- References.- 12 Fibrates.- A. Introduction.- I. Clinical Use.- II. History and Development.- III. Helsinki Heart Study.- B. Comparative Pharmacology of the Fibrates.- I. Clofibrate.- II. Bezafibrate.- III. Ciprofibrate.- IV. Fenofibrate.- V. Gemfibrozil.- C. Mechanism of Action.- I. Effects on Very Low-Density Lipoprotein Metabolism.- II. Effects on Chylomicron Metabolism.- III. Effects on Low-Density Lipoprotein Metabolism.- IV. Effects on Low-Density Lipoprotein Composition and Subfraction Profile.- V. Effects on Cholesterol Synthesis.- VI. Effects on High-Density Lipoprotein Metabolism.- D. Toxicology.- I. Hepatomegaly and Carcinogenicity.- II. Bile Lithogenicity.- E. Adverse Clinical Effects.- I. Side Effects.- II. Drug Interactions.- F. Special Uses.- I. Combination Therapy.- II. Paediatric Use of the Fibrates.- G. Conclusions.- References.- 13 Nicotinic Acid and Derivatives.- A. Introduction.- B. The Vitamin.- I. Biochemistry and Requirements.- II. Mechanism of Action.- III. Deficiency.- C. The Drug.- I. Pharmacology.- II. Effects in Lipid Metabolism.- 1. Free Fatty Acid Metabolism.- a) Extracellular Metabolism.- b) Intracellular Metabolism.- 2. Plasma Lipoprotein Metabolism.- a) Very Low-Density Lipoproteins and their Subfractions.- b) Low-Density Lipoprotein Concentrations and Subfractions.- c) Apolipoprotein B, C, and E.- d) Kinetic Studies of Apolipoprotein B-Containing Lipoproteins.- e) High-Density Lipoprotein Concentrations and Subfractions.- f) Lipoprotein Lp(a).- g) Postprandial Lipaemia.- 3. Enzyme Activities and Receptor Functions in Lipid Metabolism.- a) Hormone-Sensitive Lipase.- b) Lipoprotein Lipase and Plasma Triglyceride Removal.- c) Hepatic Lipase.- d) Other Enzymes and Receptors in Lipid Metabolism.- 4. Biliary Lipid Metabolism and Cholesterol Balance.- 5. Summary of the Mechanism of Hypolipidaemic Action of Nicotinic Acid.- 6. Prostanoid Metabolism.- III. Effects on Glucose Metabolism.- 1. Basal Mechanisms.- 2. Non-Insulin-Dependent Diabetes in Man.- a) Short-Term Studies.- b) Long-Term Studies.- 3. Differences Between Nicotinic Acid Derivatives.- 4. Conclusions About Effects on Glucose Metabolism.- D. Clinical Approach.- I. Side Effects.- 1. Flushing.- a) Symptoms.- b) Preventing Flushing.- 2. Gastrointestinal Side Effects.- 3. Hepatic Side Effects.- 4. Cutaneous Side Effects.- 5. Lactacidosis.- 6. Gout.- 7. Retinal Edema.- 8. Time-Release Nicotinic Acid.- II. Laboratory Safety Tests.- III. Start of Treatment.- 1. Fast Dosage Increase.- 2. Slow Dosage Increase.- IV. Treatment Compliance.- V. Combinations with Other Plasma Lipid-Lowering Drugs.- 1. Nicotinic Acid and Bile Acid Sequestrants.- a) Nicotinic Acid and Colestipol.- b) Acipimox and Cholestyramine.- c) Nicotinic Acid and Lovastatin.- VI. Recommendations for Drug Treatment.- 1. Policy Statement of the European Atherosclerosis Society.- 2. The National Cholesterol Education Program.- E. Clinical Effects.- I. Coronary and Femoral Artery Disease.- 1. Mortality and Morbidity.- a) The Coronary Drug Project (CDP).- b) The Stockholm Ischaemic Heart Disease Study.- 2. Regression of Atherosclerosis.- a) Coronary Atherosclerosis.- b) Femoral Atherosclerosis.- 3. Conclusion on the Effect of Nicotinic Acid on Atherosclerosis.- II. Dementia.- F. General Conclusions.- References.- 14 Ion Exchange Resins.- A. Introduction.- B. Chemistry and Pharmacology.- C. Mode of Action.- D. Clinical Experience.- E. Pharmacodynamic and Pharmacokinetic Parameters.- F. Drug Interactions.- G. Adverse Effects of Resins.- H. Other Indications.- I. Children and Adolescents.- J. Combined Drug Treatment with Resins.- I. Bile Acid Sequestrants and Cholesterol Synthesis Enzyme Inhibitors.- II. Bile Acid Sequestrants and Nicotinic Acid or Analog.- III. Bile Acid Sequestrants plus Fibrates.- IV. Bile Acid Sequestrants plus Probucol.- V. Triple Drug Therapy.- References.- 15 Probucol.- A. Introduction.- B. Chemistry, Physical Properties, and Dosage.- C. Absorption, Metabolism, and Excretion.- D. Effects on Plasma Lipids, Lipoproteins, and Apolipoproteins.- I. Cholesterol and Low-Density Lipoproteins.- II. High-Density Lipoproteins and Reverse Cholesterol Transport.- III. Apolipoproteins, Lipoprotein Composition, and Enzymes.- IV. Effect of Combination Therapy with Probucol.- E. Antioxidant Properties and Antiatherogenic Effects.- I. Effect on Low-Density Lipoprotein.- 1. In Vitro Studies.- 2. In Vivo Studies.- a) The Watanabe Heritable Hyperlipidemic Rabbit.- b) Other Animal Models.- 3. Studies in Man.- II. Studies with Lipoprotein (a).- F. Mechanisms of Action.- I. Mechanism of Low-Density Lipoprotein-Lowering Effect.- II. Mechanism of High-Density Lipoprotein-Lowering Effect.- III. Antioxidant Effect.- G. Side Effects, Safety, Tolerance, and Drug Interactions.- H. Other Properties and Use of Probucol in Specific Diseases.- I. Anti-inflammatory Effect.- II. Probucol and Diabetes.- III. Probucol and Renal Disease.- IV. Probucol and the Heart.- I. Conclusions.- References.- 16 Miscellaneous Lipid-Lowering Drugs.- A. Introduction.- B. ?-Sitosterol.- I. Chemistry, Physical Properties, and Dosage Form.- II. Absorption, Metabolism, and Excretion.- III. Effects on Plasma Lipids and Lipoproteins.- 1. Treatment with ?-Sisterol Alone.- 2. Combined Drug Treatment.- IV. Mechanisms of Action.- V. Side Effects, Safety, Tolerance, and Drug Interactions.- VI. Conclusions.- C. Neomycin.- I. Chemistry, Physical Properties, and Dosage Form.- II. Absorption, Metabolism, and Excretion.- III. Effects on Plasma Lipids and Lipoproteins.- 1. Treatment with Neomycin Alone.- 2. Combined Drug Treatment.- a) Neomycin and Niacin.- b) Neomycin and Cholestyramine.- c) Neomycin and Clofibrate.- d) Neomycin and Lovastatin.- IV. Mechanisms of Action.- V. Side Effects, Saf...