Table Of ContentC O N T E M P O R A R Y C A R D I O L O G Y
Vascular
Disease
and Injury
Preclinical Research
Edited by
Daniel I. Simon,
MD
Campbell Rogers,
MD
HUMANA PRESS
V D I
ASCULAR ISEASE AND NJURY
CC CC
OONNTTEEMMPPOORRAARRYY AARRDDIIOOLLOOGGYY
CCCHHHRRRIIISSSTTTOOOPPPHHHEEERRR PPP... CCCAAANNNNNNOOONNN
SSSEEERRRIIIEEESSS EEEDDDIIITTTOOORRR
Vascular Disease and Injury: Preclinical Research, edited by
Daniel I. Simon and Campbell Rogers, 2001
Blood Pressure Monitoring in Cardiovascular Medicine
and Therapeutics,edited by William B. White, 2001
Preventive Cardiology: Strategies for the Prevention and Treatment
of Coronary Artery Disease, edited by JoAnne Micale Foody,
2001
Nitric Oxide and the Cardiovascular System,edited by Joseph
Loscalzo and Joseph A. Vita, 2000
Management of Acute Coronary Syndromes, edited by
Christopher P. Cannon, 1999
Minimally Invasive Cardiac Surgery,edited by Mehmet C. Oz
and Daniel J. Goldstein, 1999
Annotated Atlas of Electrocardiography: A Guide to Confident
Interpretation, edited by Thomas M. Blake, 1999
Platelet Glycoprotein IIb/IIIa Inhibitors in Cardiovascular
Disease, edited by A. Michael Lincoff and Eric J. Topol, 1999
V D
ASCULAR ISEASE
I
AND NJURY
P R
RECLINICAL ESEARCH
Edited by
D I. S ,
ANIEL IMON MD
C R ,
AMPBELL OGERS MD
Brigham and Women's Hospital
Boston, MA
Foreword by
V J. D ,
ICTOR ZAU MD
Brigham and Women's Hospital
Boston, MA
H P
UMANA RESS
T , N J
OTOWA EW ERSEY
© 2001 Humana Press Inc.
999 Riverview Drive, Suite 208
Totowa, New Jersey 07512
For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact
Humana at the above address or at any of the following numbers: Tel.: 973-256-1699; Fax: 973-256-
8341; E-mail: [email protected] or visit our Website:
http://humanapress.com
All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in
any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise
without written permission from the Publisher.
Due diligence has been taken by the publishers, editors, and authors of this book to assure the accuracy of the information
published and to describe generally accepted practices. The contributors herein have carefully checked to ensure that the drug
selections and dosages set forth in this text are accurate and in accord with the standards accepted at the time of publication.
Notwithstanding, as new research, changes in government regulations, and knowledge from clinical experience relating to drug
therapy and drug reactions constantly occurs, the reader is advised to check the product information provided by the manu-
facturer of each drug for any change in dosages or for additional warnings and contraindications. This is of utmost importance
when the recommended drug herein is a new or infrequently used drug. It is the responsibility of the treating physician to
determine dosages and treatment strategies for individual patients. Further it is the responsibility of the health care provider
to ascertain the Food and Drug Administration status of each drug or device used in their clinical practice. The publisher,
editors, and authors are not responsible for errors or omissions or for any consequences from the application of the information
presented in this book and make no warranty, express or implied, with respect to the contents in this publication.
This publication is printed on acid-free paper. (cid:39)
ANSI Z39.48-1984 (American National Standards Institute) Permanence of Paper for Printed Library Ma-
terials.
Cover design by Patricia F. Cleary.
Photocopy Authorization Policy:
Authorization to photocopy items for internal or personal use, or the internal or personal use of specific
clients, is granted by Humana Press Inc., provided that the base fee of US $10.00 per copy, plus US $00.25
per page, is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923.
For those organizations that have been granted a photocopy license from the CCC, a separate system of
payment has been arranged and is acceptable to Humana Press Inc. The fee code for users of the Transactional
Reporting Service is: [0-89603-753-3/01 $10.00 + $00.25].
Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1
Library of Congress Cataloging-in-Publication Data
Vascular disease and injury: preclinical research/edited by Daniel I. Simon, Campbell Rogers.
p.;cm.—(Contemporary cardiology)
Includes bibliographical references and index.
ISBN 0-89603-753-3 (alk. paper)
1. Blood-vessels—Diseases—Animal models. I. Simon, Daniel I. II. Rogers, Campbell.
III. Contemporary cardiology (Totowa, N.J. : unnnumbered)
[DNLM: 1. Vascular Diseases. 2. Blood Vessels—injuries. 3. Blood
Vessels—transplantation. 4. Disease Models, Animal. WG 500 V331265 2000]
RC691.4. V35 2000
616.1'3—dc21
00-039603
F
OREWORD
We have entered an era of biomedicine marked by an explosion of new data
and information and an impressively rapid translation of basic science discov-
eries to clinical applications. Nowhere is this more apparent than in the field of
cardiovascular medicine, where in recent years significant advances have been
made in our understanding of the etiology, pathophysiology, diagnosis, and
therapy of coronary heart disease, atherosclerosis, hypertension, and congestive
heart failure, among other diseases. New molecules, genes, and signaling path-
ways are being discovered at an unprecedented rate, and new drugs, devices, and
surgical innovations are being developed that transform medical practice.
The most common cause of cardiovascular disorders is vascular disease.
Central to the pathobiology of vascular disease is injury to the blood vessel. Data
derived from experimental studies and human investigations have suggested
that the major forms of vascular disease, i.e., atherosclerosis, restenosis, graft
stenosis, and transplant vasculopathy, are the result of the body’s response to
various forms of biochemical, mechanical, infectious, and immunological inju-
ries. The elucidation of the biological processes of response to injury (such as
endothelial dysfunction, oxidation stress, inflammation, proliferation, and
apoptosis) and the mediators of these processes (including nitric oxide, reactive
oxygen species, cytokines, chemokines, and growth factors) have not only im-
proved our understanding of vascular diseases, but have resulted in novel therapies.
Discoveries in this area have been highly dependent on in vitro investigation,
experimental animal models, and other preclinical studies. Accordingly, there
is much demand for a book that brings together the voluminous preclinical
information on this diverse subject: for a single source that can provide access
to all the important data on vascular injury, compare and contrast the different
models and conditions, provide insights into common themes and mechanisms
unifying these diseases, and also identify differential processes that are specific
to the various conditions. Such analysis will be of great use to students and
researchers interested in vascular disease and therapy.
The rapid advances in vascular research have also created a significant chal-
lenge for researchers, especially those new to the field. Despite recent achieve-
ments in information technology, obtaining access to data that are properly
linked, annotated, and interpreted is still a major difficulty. Furthermore, with
the proliferation of ideas, resources, and technologies, the task of locating and
v
vi Foreword
then selecting sources for equipment, reagents, and animals has often become
quite complicated.
For all these reasons, Vascular Disease and Injury: Preclinical Researchis
important and timely. The book is a tour de force, assembling leading experts to
review the essential topics of vascular diseases under a single cover. Impor-
tantly, the book provides a “how-to” guide, paying attention to the practicality
of the content by including equipment lists and sources for animals, diet, and
reagents. In my opinion, this book is the most comprehensive available on this
subject and will undoubtedly become a classic in the field. Simon and Rogers,
through their meticulous attention and innovative efforts in developing this
book, have set high standards for the definition of translational research.
Victor J. Dzau, MD
Hersey Professor of the Theory and Practice of Medicine,
Harvard Medical School
Chairman, Department of Medicine,
Brigham and Women’s Hospital
Boston, MA
P
REFACE
Issues related to arterial vascular injury are central to the cardiovascular
practitioner and research scientist alike. Whether acute (i.e., mechanically induced)
or chronic (i.e., hypertension, atherosclerosis, and immune-mediated), vascular
injury and the responses it elicits are leading causes of disease today, producing
such acute ischemic syndromes as transient ischemic attacks, stroke, unstable
angina pectoris, and acute myocardial infarction, as well as restenosis following
percutaneous angioplasty or revascularization surgeries. The development of
effective cardiovascular therapeutics to treat or prevent atherosclerosis and
restenosis relies on preclinical research—both cell biological studies and obser-
vations and findings from animal models.
We have found that no one resource is available for a comprehensive presentation
of animal models related to vascular disease. We hope thatVascular Disease and
Injury: Preclinical Researchwill provide such a medium by presenting topics
related to vascular injury in an organized and comprehensive fashion. Our
approach is to present issues related to vascular disease and injury in five major
areas: acute mechanical injury and vascular repair, models of arterial thrombosis,
chronic atherosclerotic models, vascular disease in transplanted vessels,and vas-
cular disease in models of systemic and pulmonary arterial hypertension. We
have aimed to provide a “how-to” guide and have, therefore, worked to ensure
that each chapter is highly practical by including equipment lists, current sources
for animals, diet and reagents, schematic diagrams and, when pertinent, photo-
micrographs of sample histology.
In Part I of the book,Acute Mechanical Injury and Vascular Repair,Drs. Welt
and Rogers review the widely used rabbit iliac artery models of balloon- and
stent-induced angioplasty. Dr. Schwartz follows with a comprehensive presenta-
tion of the classic porcine overstretch stent model, emphasizing the relationship
he has characterized between the degree of vascular injury and resultant neointimal
thickening that follows. Dr. Carter extends this model into an atherosclerotic
milieu. Drs. Nedelman and Rogers then apply central elements of these lower
animal models to nonhuman primate experimental angioplasty and stenting, a
burgeoning field suited to evaluation of human-targeted biologics. Since venous
conduits are used extensively with high failure rates in coronary and peripheral
bypass procedures, Dr. Dzau’s group provides a chapter on pathologic responses
in experimental models of arterial-venous grafting. Murine systems allow cardio-
vascular researchers to take advantage of key transgenic and knockout strains.
Therefore, we have provided extensive material on recently described models of
vii
viii Preface
acute and chronic vascular injury in mice. Dr. Lindner, who pioneered the use
of mice in this field, discusses wire denudation and ligation models of neointimal
thickening. Drs. Chen, Rogers, and Simon then describe a recently published
model of arterial dilation and endothelial denudation that is accompanied by
inflammatory cell recruitment and neointimal thickening. Drs. Eitzman and
Westrick present a very interesting vascular photochemical model that has com-
ponents of thrombosis, as well as neointimal thickening. Finally, Dr. Coller’s
group discusses their approach using a femoral wire injury model, a modifica-
tion of the carotid wire denudation resulting in increased neointimal thickening.
In Part II, two chapters will focus on Models of Arterial Thrombosis. In the
first, Drs. Fay, Parker, and Zhu use perivascular ferric chloride to induce arterial
injury and thrombosis in the mouse carotid. These investigators have exploited
this model to investigate the importance of plasminogen activator inhibitor-1 in
modulating endogenous fibrinolysis. Finally, Dr. Folts provides a comprehensive
overview of his animal preparation for studying in vivo platelet activity and platelet
interactions with damaged arterial walls. This model has been instrumental in the
clinical development of therapeutics for acute ischemic syndromes and percu-
taneous coronary interventions.
Part III focuses on Chronic Atherosclerotic Models. Drs. Palinski, Napoli, and
Reaven provide an in-depth overview of mouse models of atherosclerosis, in
particular the apolipoprotein E (ApoE) and low density lipoprotein (LDL) receptor
knockouts. Drs. Aikawa and Libby then present their work regarding progression
and regression of atherosclerosis using the classic hypercholesterolemic rabbit
model. Finally, Drs. Nicolosi and Kritchevsky present the use of higher animals,
including nonhuman primates, for preclinical research in atherosclerosis.
Part IV of the book concentrates on Vascular Disease in Transplanted
Vessels. Drs. Shi and Hoover discuss the use of a murine carotid loop model of
transplant disease that has been helpful in elucidating the important role of
proteases, such as plasminogen, in transplant-related vascular disease. Dr.
Mitchell then follows with an overview of heterotopic heart transplantation in
the mouse. His group has used this model to study the role of cytokines and
immune co-stimulatory molecules in parenchymal rejection and accelerated
graft arteriosclerosis. The concluding chapter in this section by Drs. Chen and
Adams presents exciting material regarding hyperacute vascular rejection in pig-
to-primate xenotransplantation.
The next set of chapters in Part V concentrates on Vascular Disease in Models
of Arterial Hypertension. Dr. Baumbach examines methods for investigating
cerebrovascular disease in experimental systemic hypertension. Two chapters
are devoted to pulmonary hypertension. In the first, Dr. Rabinovitch provides an
in-depth discussion of monocrotaline-induced pulmonary hypertension. She focuses
on the cellular and molecular biology of pulmonary vasculopathy, integrating
dynamic interactions between smooth muscle cells, extracellular matrix, and the
Preface ix
endothelium. This leads into the chapter by Drs. Meyrick and Tchekneva on
chronic pulmonary hypertension in the hypoxic rat and in the sheep following
continuous air embolization.
The final section, Part VI, provides an essential foundation in Animal Care
and Tissue Processing and analysis. Dr. Marini discusses veterinary issues and
anesthesia options, addressing all species covered elsewhere in the book, from mice
to nonhuman primates. Key points regarding survival surgery, choice of anes-
thetic, and analgesia are included. Histopathologic methods are then discussed
by Drs. Seifert, Rogers, and Edelman. This chapter provides the “basics” for
tissue harvesting and fixation, and histology methods for routine immunology
and electron microscopy.
The topics we have chosen to include in Vascular Disease and Injury: Pre-
clinical Researchare not meant to be all inclusive and, undoubtedly, a few areas
have not been covered. We have simply tried to show the range and breadth of
animal models that have been useful in translational cardiovascular research. It
is important to end this discussion on a cautionary note. The track record of
animal models of vascular repair after injury, as predictors of human responses,
is poor. Myriad agents have been proven effective in one or another model, only
to fail clinical scrutiny. This fact means that for each experimental approach, by
any of the models described in this book, the purpose of research must be to
further mechanistic understanding, not to recapitulate human disease in an
experimental animal.
In closing, we must acknowledge the tremendous efforts of our administrative
assistant, Paula McColgan, the series editor, Dr. Christopher Cannon, and the staff
of Humana Press. We are indebted to Drs. Eugene Braunwald, Victor J. Dzau,
Thomas W. Smith, and Peter Libby for encouraging and supporting our clinician-
scientist careers. Dr. Rogers would like to thank most deeply his mentors in the
study of vascular injury and repair, Drs. Morris Karnovsky and Elazer Edelman,
and to dedicate this book to his wife Nathalie and three children, Camille,
Genevieve, and Charles. Dr. Simon would like to honor his mentor in life and
medicine, Dr. Norman M. Simon, and to dedicate this book to his wife Dr. Marcy
Schwartz and three children Benjamin, Maxwell, and Aaron.
Daniel I. Simon, MD
Campbell Rogers, MD
