Pathobiology of the Human Atherosclerotic Plaque

932 Pages·1990·26.95 MB·English

by  Henry C. McGill Jr (auth.)

Pathobiology of the
Human Atherosclerotic Plaque
Seymour Glagov William P. Newman, III
Sheldon A. Schaffer
Editors
Pathobiology of the
HUlllan Atherosclerotic
Plaque
With 273 Figures, 16 in Full Color
Springer-Verlag
New York Berlin Heidelberg
London Paris Tokyo Hong Kong
Seymour Glagov, MD
Professor of Pathology, The University of Chicago Hospital
Chicago, Illinois 60637, USA
William P. Newman III, MD
Department of Pathology, Louisiana State University
New Orleans, Louisiana 70112-1393, USA
Sheldon A. Schaffer, PhD
Colestech Corporation, Hayward, California 94545, USA
Library of Congress Cataloging-in-Publication Data
Pathobiology of the human atherosclerotic plaque / [edited by] Seymour
Glagov, William P. Newman III, Sheldon A. Schaffer.
p. cm.
Contains nearly all the papers which were presented at a workshop
held in Rockville, Md., Sept. 20-23, 1986.
Includes bibliographical references.
ISBN-13: 978-1-4612-7968-6 e-ISBN-13: 978-1-4612-3326-8
DOl: 10.1 007/978-1-4612-3326-8
1. Atherosclerosis-Pathophysiology-Congresses.
2. Atherosclerosis-Etiology-Congresses. I. Glagov, Seymour.
II. Newman, William P. III. Schaffer, Sheldon A.
[DNLM: I. Arteriosclerosis-pathology-congresses. 2. Ultrasonic
Diagnosis-congresses. WG 550 P297 1986]
RC692.P353 1989
616.1 '3607-dc20
DNLMIDLC
for Library of Congress 89-21674
© 1990 Springer-Verlag New York Inc.
Softcover reprint of the hardcover 1st edition 1990
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987654321
Dedication
Colin B. Schwartz and Robert W. Wissler, for the Committee
Although the present volume is dedicated to those
investigators who have made the study of the human athero
sclerotic plaque their central focus of interest, two
scientists whose efforts have been particularly noteworthy
in this regard w.ere honored during the deliberations which
form the basis of this volume. They are Drs. M. Daria Haust
and Elspeth Smith.
The following appreciations of their contributions were
delivered during a special session of the workshop.
M. DARIA HAUST
About 60 years ago, I dare not be more specific,
Dr. Haust made her debut in Central Europe. Her early years
were disrupted by the turmoil of the second world war, but
with rare determination, and an early sense of destiny, she
made her way to Heidelberg where she graduated in 1951 with
the Degree of Doctor of Medicine. Some of you may not know
that she has an excellent voice, doubtless trained in the
cellars of roten Ochsen in Heidelberg, the legendary inn of
the student prince. There she met and married her prince, a
charming friend of many of us, Dr. Heinz Haust, and together
they settled in Kingston, Ontario, Canada, where her career
both as an outstanding pathologist and biomedical scientist
had its beginnings.
In the years 1955-1959 she was a resident in Pathology
at Queens University, and in these years her work in
VI
atherosclerosis commenced, in association with Robert H.
More and Henry Movat. Bob More was one of Daria's outstand
ing mentors, and remains a lifelong friend and colleague. Dr.
Haust progressed rapidly up the rungs of the academic ladder,
and in 1968 was appointed Professor of Pathology at the
University of Western Ontario, where the late Jim Paterson,
one of the founding fathers of the American Society for the
Study of Atherosclerosis, later to become the AHA Council on
Arteriosclerosis, was a close friend and colleague.
Her early papers were landmarks in the field, and
emphasized the role of thrombosis in atherogenesis, and
later provided the first definitive report on the participa
tion of smooth muscle cells in the human plaque. It is fair
to say that Dr. Haust was and is a first class Electronmicro
scopist, and that she pioneered the application of this research
tool to the atherosclerosis arena. Other outstanding scien
tific contributions have included the early application of
fluorescent antibody techniques to the study of atherosclero
sis, and in later years, the characterization of the roles
of connective tissue elements in the pathogenic sequence.
Her scientific productivity has never wained, and she has
over 200 publications to her credit.
She has played a key role in numerous professional and
scientific societies, including the Council on Arteriosclerosis,
the International Academy of Pathology, the International
Atherosclerosis Society, and the Canadian Atherosclerosis
Society, which was founded because of her efforts, and in
which she has held the honored position of President. In 1982
she was the recipient of the Alexander von Humboldt award for
Distinguished Service, in "Recognition of her dedicated
leadership, counsel, and service in the field of Atherosclero
sis". It has been a personal pleasure and honor for me to
have this opportunity, on your behalf, to review only too
briefly a few of the many highlights of her outstanding
scientific career. Dr. Haust has truly dedicated her
scientific life to the study of arteriosclerosis, and also
to helping her colleagues and associates in their endeavors.
We wish you, Daria, good health, and continuing success and
fulfillment in the years ahead. This award is presented to
Vll
you on behalf of your colleagues, and in recognition of
your outstanding achievements. May you continue to inspire
us to probe the nature of the human manifestations of this
complex disease process.
CBS
ELSPETH B. SMITH
We now honor a pioneering, innovative and highly
productive contributor to our knowledge about the chemical
components of the atherosclerotic process in humans. Elspeth
Smith received most of her higher education, including her
biochemical training, in London and Cambridge. Her first
attention-demanding discoveries about human atherosclerosis
were made in London during the decade or more when she worked
at the Courtauld Institute of Biochemistry, under the sponsor
ship and in close association with Sir Charles Dodds.
In 1967 she published what has become a very famous
paper in the Biochemical Journal on the immunological assay
of beta-lipoproteins from human aortic tissue. In 1973, after
she moved to Aberdeen, her highly useful contribution to the
Ciba Foundation Symposium, with the title "Lipids and Low
Density Lipoproteins in the Intima in Relation to its
Morphological Characteristics", appeared, and in 1977 her
most comprehensive overview in the American Journal of
Pathology entitled "Molecular Interactions in Human Athero
sclerotic Plaques" was published. She has recently completed
two outstanding chapters on lipoproteins and atherosclerosis
and the relationship between lipids and atherosclerosis. In
between she has provided over 80 data filled publications,
almost all on macromolecules and their involvement in human
atherosclerotic lesions.
Although several of us were using immunological approaches
to study the human disease in the early 1960's, she recognized
the value of quantitating a number of the lipid, apo-protein
and other blood protein components and relating these results
in an enlightened way to each other, to the different types
of lesions and to various parts of the larger lesions. From
this work came some remarkable insights into the human
viii
atherosclerotic process. These include the recognition that:
1. Substantial amounts of Apo B are localized in the
human atherosclerosis lesion.
2. The lipid in the fatty streak is rich in oleic acid
and poor in Apo B, which she interpreted as indicating that
LDL had probably been altered by the lipid filled cells to
convert it to cholesteryl esters with a predominance of oleic
acid.
3. The lipid in the atheromatous core and that in fibrous
caps and the shoulder regions of the advanced plaque is likely
to be especially rich in polyunsaturated fatty acids, and rich
in Apo B--probably indicating that the lipoproteins had not
been metabolically altered by cells.
As she continued her investigations in Aberdeen she
carried out and shared many other quantitative studies of
arteries. These included some challenging concepts that the
progressive atherosclerotic plaques are derived from gela
tinous streaks, and that fibrinogen as well as albumin are
noteworthy plasma protein components found in the developing
atheromatous lesion. She also produced evidence that we need
to search further for the true explanation for atherosclerotic
plaque initiation and plaque progression.
I have had the honor and privilege of being involved in
many meetings where Elspeth was a star participant and I have
never failed to gain immensely from her stimulating findings
and concepts. It gives me great pleasure to be the one chosen
to present her with this richly deserved honor, a special
award from the American Heart Association through its Council
on Atherosclerosis and its Committee on Lesions.
RWW
Preface
Seymour Glagov
The last meeting, devoted exclusively to an examination
of the atherosclerotic plaque, took place in Chicago 25 years
ago under the joint auspices of the Council on Arteriosclerosis
of the American Heart Association and the Chicago Heart
Association. The proceedings were published subsequently in
a volume entitled "Evolution of the Atherosclerotic Plaque",
edited by Richard J. Jones (1). Both experimental and human
lesions were considered and several provocative new approaches
to the disorder were discussed.
The electron microscope was being applied systematically
to the study of blood vessels at that time, so that details
of the infrastructure and cellular composition of the artery
wall and of atherosclerotic lesions were presented in some
detail. There was, as one result of these explorations,
considerable discussion of morphologic evidence suggesting
that the principal cell involved in the atherogenic process
was neither the fibroblast nor the macrophage, as had been
supposed, but the smooth muscle cell. In particular, the
findings indicated that this cell could incorporate lipid
and become a foam cell.
A session devoted to plaque constituents included
presentations dealing with fatty acids, phospholipids,
lipoproteins, mucopolysaccharides and enzymes. Consideration
of factors modifying plaque development included the roles of
mechanical stress, platelet accretion and thrombosis, lipid
x
deposition, mesenchymal activation and mural collagen
metabolism. The fate of the plaque and the consequences of
plaque formation were addressed in papers on artery wall
vascularization, calcium deposition, thrombotic occlusion,
plaque ulceration and embolization. It is especially note
worthy that one of the presentations, from the laboratories
of Drs. Louis Katz and Ruth Pick, dealt with the potential
reversibility of lesions and emphasized, largely on the basis
of clinical findings associated with wartime undernutrition
and data from animal experiments, that one could no longer
consider atherosclerosis to be an inexorably progressive
disease but was instead a process which might be slowed,
arrested or reversed by modification of such factors as diet
and hormones. Arterial catheterization and angiography were
on the scene by then, but no papers were presented which
dealt with lesion visualization, ~n v~vo lesion quantitation,
or the relationship between lesion localization and hemo
dynamic conditions.
In his preface to the published proceedings, Dr. Jones
wrote, "This symposium was dedicated to an evaluation of the
current concepts of the origin, growth and focal morbid
disposition of the atherosclerotic plaque. The reader needs
no reminder that it is this lesion of arteriosclerosis which,
at the same time that it provides the greatest threat to life,
allow~ the most hope for its reversal. Knowledge of the cause
of this pathological entity is essential to its rational
treatment or prevention".
Since the 1963 meeting, there has been a marked accelera
tion in the use of animal models designed to identify and
reproduce the clinical risk factors and to probe the patho
biologic processes by which these lead to plaque formation.
Tissue culture methods are now widely used to characterize
the metabolic responses and molecular biology of the cells
which comprise both the artery wall and the atherosclerotic
plaque. The smooth muscle cell, still presumed to be a
principal actor in the atherogenic sequence of events continues
to receive a great deal of attention, particularly with respect
to the modulation of its proliferative, biosynthetic and con
tractile responses. The macroohage has however reentered the
xi
scene and has to some degree upstaged the smooth muscle cell,
at least in some of the scenes of the atherogenic drama.
The factors which regulate intimal ingress and egress of
these cells, modify their state of activity with regard to
lipid metabolism and matrix composition and determine their
interactions with smooth muscle cells have become major fields
of study. The latest cell to receive detailed and concentrated
critical scrutiny in relation to atherogenesis is the endo
thelial cell. Previously relegated to relatively passive
roles as a diffusional and convective barrier and as an anti
thrombotic lining, it has now moved to center stage as a major
participant with prominent interactive, metabolic, biosynthetic
and selective transport functions. It seemed at first that
endothelial injury to the point of detachment was required
to permit mitogens to gain access to the media and in so
doing to induce a primary, focal, smooth muscle proliferative
response. Depending on associated conditions, such a focal
initial reaction could conceivably resolve, stabilize or
evolve into a manifest plaque. Recent findings have however
indicated that the integrity and continuity of the endothelial
monolayer is conserved during the initiating phase of lesion
induction. Current approaches tend therefore to focus upon
humoral, cellular and hemodynamic mediators which result in
modified endothelial function rather than in necrosis or
sloughing. Such disturbances, affecting one or more of the
complex of metabolic, biosynthetic or transport functions,
are thought to contribute significantly to the conditions
necessary for induction and progression of atherosclerosis.
Although much of this work has been experimental, the
relevance to human atherosclerotic disease of some of the
findings can now be tested directly. Several of the partici
pants in the present workshop have studied the human plaque
for some time and continue to provide valuable information
on plaque composition and morphology, while others are
applying recently developed experimental techniques of cell
and molecular biology to human lesions. In addition, methods
for detection and characterization of human plaques ~n h~~U
in the living subject have developed rapidly in conjunction
with quantitative methods for assessing the effects of plaques
on flow and of flow on plaques. These findings are being