MEDICAL INTELLIGENCE UNIT 17 Richard R. Keen and Philip B. Dobrin Development of Aneurysms M EDICAL I NTELLIGENCE U 17 NIT Development of Aneurysms Richard R. Keen, M.D. Cook County Hospital Rush University Chicago, Illinois, U.S.A. Philip B. Dobrin, M.D., Ph.D. Harry S. Truman Memorial Veterans' Hospital University of Missouri Columbia, Missouri, U.S.A. LANDES BIOSCIENCE EUREKAH.COM GEORGETOWN, TEXAS AUSTIN, TEXAS U.S.A. U.S.A. D A EVELOPMENT OF NEURYSMS Medical Intelligence Unit Eurekah.com Landes Bioscience Designed by Judith Kemper Georgetown, Texas, U.S.A. Copyright ©2000 Eurekah.com All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Printed in the U.S.A. Please address all inquiries to the Publishers: Eurekah.com / Landes Bioscience, 810 South Church Street Georgetown, Texas, U.S.A. 78626 Phone: 512/ 863 7762; FAX: 512/ 863 0081 www.Eurekah.com www.landesbioscience.com ISBN: 1-58706-000-0 While the authors, editors and publisher believe that drug selection and dosage and the specifications and usage of equipment and devices, as set forth in this book, are in accord with current recommend- ations and practice at the time of publication, they make no warranty, expressed or implied, with respect to material described in this book. In view of the ongoing research, equipment development, changes in governmental regulations and the rapid accumulation of information relating to the biomedical sciences, the reader is urged to carefully review and evaluate the information provided herein. Library of Congress Cataloging-in-Publication Data Development of Aneurysms / [edited by] Richard R. Keen, Philip B. Dobrin. p. cm. -- (Medical intelligence unit) Includes bibiographical references and index. ISBN 1-58706-000-0 (alk. paper) 1. Aneurysms--Etiology. 2. Aneurysms--Pathophysiology. I. Keen, Richard R. II. Dobrin, Philip B. III. Series. [DNLM: 1. Aneurysms--etiology. 2. Aneurysm--pathology. 3. Arteries--pathology. 4. Vascular Diseases--complications. WG 580 D489 1999] RC693.D48 1999 616.1´33--dc21 99-36406 DNLM/DLC CIP CONTENTS 1. Epidemiology of Abdominal Aortic Aneurysm (AAA)................. 1 Henrik Bengtsson Definition of AAA.................................................................................1 Prevalence of AAA.................................................................................2 Close Relatives of AAA Patients.............................................................7 Patients with Occlusive Arterial Disease ................................................7 Patients with Hypertension...................................................................8 Patients with Miscellaneous Symptoms.................................................8 Summary...............................................................................................8 2. Epidemiological and Familial Aspects of Nonaortic Lower Extremity Aneurysms.................................................................15 Peter F. Lawrence, Philip B. Dobrin Epidemiology......................................................................................15 Familial Aspects...................................................................................17 3. The Mechanical Properties of the Normal and Aneurysmal Abdominal Aorta In Vivo.......................................................... 24 Björn Sonesson, Toste Länne Background.........................................................................................24 The Biology of the Aortic Wall and the Mechanical Properties............24 Methods of Studying the Mechanical Properties of Arterial Walls In Vivo .................................................................25 Ultrasonic Echo-Tracking ...................................................................25 The Normal Infrarenal Aortic Diameter..............................................28 The Mechanical Properties of the Normal Aorta.................................28 The Diameter and the Mechanical Properties of the Aneurysmal Abdominal Aorta.............................................................................35 4. Elastin, Collagen, and the Pathophysiology of Arterial Aneurysms.................................................................42 Philip B. Dobrin Elastin.................................................................................................42 Collagen..............................................................................................47 In Vitro Simulation of Aneurysms.......................................................48 Factors Determining the Enlargement of Aneurysms...........................55 Stability of Aneurysms.........................................................................57 Aneurysmal Tortuosity........................................................................60 Bioengineering Aspects of Aneurysms..................................................63 5. Matrix Protein Synthesis and Genetic Mutations of Collagen, Elastin and Fibrillin .............................................. 74 Janet J. Grange, B. Timothy Baxter Introduction........................................................................................74 Biochemical and Genetic Features of Matrix Proteins..........................74 Organization of Matrix Proteins in the Vascular Wall.........................76 Matrix Proteins in Aortic Aneurysms...................................................76 Factors Modulating Matrix Synthesis..................................................79 Genetic mutations Associated with Aneurysms....................................80 Summary.............................................................................................82 6. Pathology and Pathogenesis of Degenerative Atherosclerotic Aneurysms ................................................................................ 84 William E. Stehbens Introduction........................................................................................84 Acquired Mural Weakness...................................................................85 Poststenotic Aneurysm........................................................................93 Bioengineering Fatigue........................................................................95 Cerebral Berry Aneurysms...................................................................98 Experimental Aneurysms...................................................................103 Internal Elastic Lamina Tears............................................................106 Aortic Aneurysms..............................................................................109 Miscellaneous Aneurysms..................................................................116 Complications...................................................................................117 Secondary Infection...........................................................................117 General Comments...........................................................................119 7. In Vivo Animal Models of Aneurysms......................................127 Philip B. Dobrin, Richard R. Keen Atherosclerosis and Atherosclerosis Regression ..................................127 Genetic Abnormalities of Metabolism...............................................128 Experimental Alterations of Metabolism: BAPN, Theophylline, Hormonal Manipulations..............................................................128 Mechanical and Chemical Injury.......................................................129 Hemodynamic Factors ......................................................................130 Allografts and Xenografts...................................................................132 Inflammation ....................................................................................132 Elastase Infusion Model.....................................................................133 8. Cytokine-Mediated Inflammation and Aortic Aneurysm Formation................................................................................152 Andy C. Chiou, William H. Pearce Introduction......................................................................................152 Tissue Studies....................................................................................153 In Vitro Studies.................................................................................153 In Situ Studies...................................................................................155 Conclusion........................................................................................156 9. Pharmacologic Treatment of Aneurysms..................................159 Richard R. Keen Introduction......................................................................................159 The Etiology of Aneurysms: Is Prevention Possible?..........................160 Matrix Metalloproteinases and Their Pharmacologic Blockade..........161 Tetracycline Derivatives ....................................................................163 Anti-Inflammatory Agents.................................................................167 Antihypertensive Agents....................................................................170 Conclusion........................................................................................171 10. Is Blood Flow the Cause of Aneurysms?...................................176 Richard R. Keen Introduction......................................................................................176 Pulse and Pressure.............................................................................177 Shear Stress .......................................................................................181 Vibration...........................................................................................189 Conclusion........................................................................................190 11. Infection, Atherosclerosis, and Aneurysmal Disease ................ 196 Michael T. Caps, Philip B. Dobrin Atherosclerosis and Aneurysm...........................................................196 Infection and Atherosclerosis.............................................................197 Infection and Aneurysm....................................................................200 Conclusions.......................................................................................201 12. A Perspective on the Etiology of Abdominal Aortic Aneurysms ..............................................206 David K.W. Chew, James Knoetgen III, M. David Tilson III Introduction......................................................................................206 Normal Structural Support of the Aorta............................................206 The Enzymatic Basis for Matrix Destruction.....................................207 Inflammation—The Machinery of Destruction.................................209 The Search for Aortic Autoantigens...................................................210 The Genetics of AAA Disease............................................................211 Molecular Mimicry—The Shared Epitope Hypothesis......................211 MHC Class II DR Locus as a Candidate for a AAA Susceptibility Gene........................................................................213 13. Search for the Aneurysm Susceptibility Gene(s).......................219 Helena Kuivaniemi, Gerard Tromp Candidate Gene Approach ................................................................221 Search for New Candidate Genes Using Differential Display ............226 DNA Linkage Analyses to Identify Susceptibility Loci.......................226 Genetic Association Studies as Tools to Determine Genetic Components of AAA..........................................................................................229 Concluding Remarks.........................................................................230 Index ............................................................................................... 234 EDITORS Richard R. Keen, M.D. Department of Surgery Cook County Hospital and Assistant Professor of Surgery Rush University Chicago, Illinois, U.S.A. Chapters 7, 9 and 10 Philip B. Dobrin, M.D., Ph.D. Chief of Staff Harry S. Truman Memorial Veterans' Hospital and Professor of Surgery and Associate Dean University of Missouri School of Medicine Columbia, Missouri, U.S.A. Chapters 2, 4, 7 and 11 CONTRIBUTORS B. Timothy Baxter, M.D. VA Puget Sound Health Care Professor of Surgery System University of Nebraska Medical Surgical and Perioperative Care Center Seattle, Washington, U.S.A. Omaha, Nebraska, U.S.A. Chapter 12 Chapter 5 David K.W. Chew, M.D. Henrik Bengtsson, M.D., Ph.D. Department of Surgery Department of Surgery St. Luke's Roosevelt Hospital Central Hospital New York, New York, U.S.A. Kristianstad, Sweden Chapter 12 Chapter 1 Andy C. Chiou, M.D., M.P.H. Michael T. Caps, M.D. Vascular Surgery Fellow Assistant Professor of Surgery Division of Vascular Surgery University of Washington Medical Department of Surgery Center Northwestern University Medical Department of Surgery School Division of Vascular Surgery Chicago, Illinois, U.S.A. and Chapter 8 Janet J. Grange, M.D. William H. Pearce, M.D. Department of Surgery Professor of Surgery University of Nebraska Medical Divsion of Vascular Surgery Center Department of Surgery Omaha, Nebraska, U.S.A. Northwestern University Medical Chapter 5 School Chicago, Illinois, U.S.A. James Knoetgen III, M.D. Chapter 8 Department of Surgery St. Luke's Roosevelt Hospital Björn Sonesson, M.D., Ph.D. New York, New York, U.S.A. Department of Vascular and Renal Chapter 12 Diseases Lund University Malmö University Hospital Helena Kuivaniemi, M.D., Ph.D. Malmö, Sweden Associate Professor Center for Molecular Medicine Chapter 3 Wayne State University School of Medicine William E. Stehbens, M.B., B.S., Detroit, Michigan, U.S.A. M.D., D.Phil, F.R.C.P.A., Chapter 13 F.R.C.Path Professor Emeritus Department of Pathology Toste Länne, M.D., Ph.D. Wellington School of Medicine Department of Vascular and Renal Wellington South, New Zealand Diseases Lund University, Malmö Chapter 6 University Hospital Malmö, Sweden M. David Tilson, M.D. Chapter 3 Professor of Surgery Columbia University and St. Luke's Roosevelt Hospital Peter F. Lawrence, M.D. New York, New York, U.S.A. Associate Dean for Clinical Programs and Professor of Chapter 10 Surgery University of California at Irvine Gerard Tromp, Ph.D. College of Medicine Assistant Professor Irvine Hall Center for Molecular Medicine Irvine, California, U.S.A. Wayne State University Chapter 2 School of Medicine Detroit, Michigan, U.S.A. Chapter 13 PREFACE Approximately five percent of men over the age of 55 have an abdominal aortic aneurysm, and rupture of abdominal aortic aneurysms has up to 90% mortality. This translates into approximately 15,000 deaths per year in the United States. There are many books that describe eh diagnosis and treatment of aortic aneurysms. This book is not one of them. Rather, this text is a compilation of papers devoted to the understanding of the formation and development of aneurysms. This text is divided into six sections. The first is concerned with epidemiology and familial aspects of aneurysms. In the first chapter, Henrik Bengtsson examines the epidemiology of abdominal aortic aneurysms in Sweden. In his Chapter, Dr. Bengtsson considers the strngths and weaknesses of population screening studies and postmortem studies. In the second Chapter, Peter Lawrence and Philip Dobrin examine the epidemiological and familial aspects of peripheral aneurysms of the lower extremity. The second section of this book is devoted to the physiology and pathophysiology of aortic aneurysms. In Chapter 3, Björn Sonesson and Toste Länne describe the mechanical properties of the normal and aneurysmal abdominal aorta as studied by ultrasonic echo-tracking methods. In Chapter 4, Philip Dobrin examines the contributions of elastin and collagen to the physiology and pathophysiology of the arterial wall. In Chapter 5, Janet Grange and Timpothy Baxter describe connective tissue protein synthesis associated with aortic aneurysms. The third section of the book considers the pathologic aspects of aneurysms. In Chapter 6, William Stehbens describes the pathology of aneurysms and proposes mechanisms of pathogenesis of degenerative lesions. This chapter provides the unique perspective of the experimental pathologist. The fourth section of the book describes models of aneurysms. In Chapter 7, Philip Dobrin and Richard Keen assemble the wide variety of animal models used to simulate arterial aneurysms. Sugical, enzymatic and metabolic models are described in some detail. The fifth section of the book examines the role of inflammation. Andy Chiou and William Pearce discuss the role of cytokine-mediated inflammation on the formation of aneurysms. Their work describes molecular studies supporting an inflammatory model. In Chapter 9, Richard Keen examines the possible role for pharmacologic agents and their potential limitations in the prevention and treatment of aneurysms. The sixth and last section of the book considers the etiology of aneurysms. Four related chapters are included. In Chapter 10, Richard Keen discusses the possible roles of pulse pressure, shear stress and vibrations in the formation of aneurysms. In Chapter 11, Michael Caps and Philip Dobrin discuss the possible roles of infectious agents in the etiology of aneurysms. This Chapter focuses particularly on Chlamydia pneumonia and cytomegalovirus. In Chapter 12, David Chew, James Knoetgen III and David Tilson discuss the possible genetic