The Role of Aging in Atherosclerosis: The sequestration hypothesis

272 Pages·2003·6.544 MB·English

by  Richard E. Tracy MD PhD (auth.)

THE ROLE OF AGING IN ATHEROSCLEROSIS
TUE ROLE OF AGING IN
ATUEROSCLEROSIS
The sequestration hypothesis
by
Richard E. Tracy MD PhD
Department of Pathology,
Louisiana State University Health Science Center,
New Orleans, U.S.A.
SPRINGER-SCIENCE+BUSINESS MEDIA, B.V.
A C.I.P. Catalogue record for this book is available from the Library of Congress.
ISBN 978-90-481-6265-9 ISBN 978-94-017-0263-8 (eBook)
DOI 10.1007/978-94-017-0263-8
Printed on acid-free paper
All Rights Reserved
© 2003 Springer Science+Business Media Dordrecht
Originally published by Kluwer Academic Publishers in 2003
Softcover reprint of the hardcover 1s t edition 2003
No part of this work 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, with the exception
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CONTENTS
Chapter One
Introduetion to the sequestration hypothesis
Chapter Two
The sampling theory of fibrotie arterioselerosis 11
Chapter Three
Intrusion of atheroma into the most fibrotieally thiekened intimal sites 19
Chapter Four
Conditions for the intrusion of atheroma in eoronary artery 29
Chapter Five
The size of the SMC realm assessed with the help of sampling theory 37
Chapter Six
Biased eensoring oflow SMC sites by atheroma in eoronary artery 51
Chapter Seven 67
Biased sampling of low SMC sites by atheroma in thoraeie aorta
Chapter Eight 81
SMC numbers at varying depths in intima ofthoraeie aorta
Chapter Nine 97
Histologie appearanees of SMC clusters and realms
Chapter Ten 103
Direet imaging of the hypothetieal quantity, sequestered lipid
Chapter Eleven 119
Loeal sequestration of lipid from plaee to plaee within an artery
Chapter Twelve' 131
Fibroplasia in microseopie renal arteries
Chapter Thirteen 141
Parameters of fibroplasia in renal mierovaseulature
Chapter Fourteen 149
The course of arterial intimal fibroplasia in aging arteries
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Chapter Fifteen 159
The course of fibroplasia per SMC over time in aging arteries
Chapter Sixteen 165
Fibroplasia per SMC in the media of coronary arteries
Chapter Seventeen 183
Influence of arteriolar hyalinization on renovascular fibroplasia
Chapter Eighteen 197
The Hy effect on Ra in widely variable circumstances
Chapter Nineteen 211
Hyalinized renal arterioles and the maleness coronary risk factor
Chapter Twenty 223
Two pathways to atheroma variably linked to renovasculopathies
Chapter Twenty One 233
Age of onset of the sex difference in coronary fibroplasia
Chapter Twenty Two 237
Adrenocortical nodularity in relation to coronary fibroplasia
Chapter Twenty Three 247
Atheroma and intimal fibroplasia in periodontal disease
Chapter Twenty Four 255
Atheroma and intimal fibroplasia in relation to obesity
Chapter Twenty Five 265
Paucity ofliterature relevant to SMC numbers and the aging risk factor
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PREFACE
The cover of this book summarizes the central features of the sequestration hypothesis:
Commonplace appearances seen in human coronary artery, fat stained in paraffin
seetions by a new technique explained in Chapter Eleven, are arranged to suggest
pathways of evolution toward atheroma. The hypothesis formulated and defended in
the pages ofthis book is this: Fibroplasia progresses upward in column "a" from "la"
to "3a" as a characteristic feature of aging. This starts sooner and progresses faster in
men than in wornen. Numbers ofSMC's remain essentially constant so that fibroplasia
per SMC steadily increases. The rise upward conveys an increasing propensity to
sequester atherogenic lipids, causing transition rightward into column "b". Sequestered
extracellular lipid then attracts fatty streak elements, especially foam cells and
lyrnphocytes, to propel the arterial site rightward into column "c". Frame "lc"
corresponds to the AHA Lesions Committee classification type IIb, the progression
resistant fatty streak arising directly without prior lipid sequestration; this can progress
to atheroma, but slowly after much delay, although extreme provocation can accelerate
the process. Such progression is rightward toward atherorna with thin cap, not upward
toward fibroplastic thickening. Frame "2c" corresponds to the AHA classification, type
Ha, progression prone fatty streaks. These readily evolve into atheroma, again by
horizontal progression. Frame "3a" corresponds to the AHA classification "adaptive
thickening", which becomes type III lesions in Frame "3c" after sequestering lipid and
then acquiring fatty streak elements; the deeply situated extracellular lipid is
conspicuous here. These are "intermediate lesions" in the sense of standing between
Frame "3a" and atheroma (not illustrated here). They are not intermediate in the sense
of standing between frames "I a" and "3c", a form of evolution that is thought to happen
only in the fibrous cap of the atheroma, after the intrusion of a necrotic core into the
prepared site. The risk factors age and maleness are thought to act upon arterial intima,
to prepare for atheroma, by propelling fibroplasia upward in column "a"; geography is
also envisioned in this way, as for instance the contrast between New Orleans and
Mexico City. The great statistical power ofa ge, maleness, and geography as risk factors
for atherosclerosis suggest that the upward progression in column "a" is the rate
limiting step in atherogenesis under usual circumstances in most persons. Arrows mark
intima-media boundaries, these arrows are all oflength 20 Ilm.
INTRODUCTION
HOW TO MEASURE AGE
In human experience, the dominant risk factor for atherosclerosis and its
complications is age. Yet age rarely enters the usual experimental models of
atherosclerosis in laboratory animals, and even then only as a peripheral concern. The
present inquiry, therefore, concentrates solely upon human experience, since animal
observations have so litde immediate relevance.
In most studies of aging, the age of an animal is measured not in units of days
or years, but rather in fractions ofthe usuallife span ofthe species [15]. A dog year
is said to be seven man years, and this would point to one rat year as 28 man years, and
one mouse year as 56 man years. This way of measuring is not of great relevance to
the aging of arteries. Rather, we have reason to suspect that the 3-year old rat
resembles the 3-year old human, the 8 year old cow resembles the 8 year old human,
the 20-year old horse resembles the 20-year old human, and so on [3,59]. This idea is
based upon small amounts of data and some limited observations in descriptive
pathology. If it should prove correct, however, then experimental approaches to
explaining the "age" risk factor will be tedious, slow, and expensive.
Investigators seldom pose the question ofwhat does aging do to the arterial
tissue in preparation for later intrusion by atheroma. Perhaps the reason for this
omission is that plausible hypotheses are wanting, leaving a vast gap in our
understanding. Yet that gap is now beginning to fill, because of the observations to be
examined in this treatise.
An especially crucial feature of arterial aging is the time-ordered incremental
thickening ofthe intimallayer, beginning at or before age 20 years around the cessation
of pubertal growth. Concerning this condition, Klotz in 1911 [26] tells us, "In
1885,Thoma set forth his views concerning the fundamental principles underlying
arteriosclerosis. From the first Thoma's attention was concentrated on the intimal
thickening . . . and with the degenerative processes that develop in these intimal
thickenings." This theory later evolved into generalized arteriosclerosis [1 ;Allbutt
1911], and has persisted under such names as inelastic fibrous tissue [17; Duguid
1926], intimal thickening [16; Duff 1935], arterial injury [14; Dock 1946], diffuse
intimal thickenings (DITs) [80; Wilens 1951], eccentric thickenings [48; Stary 1992],
adaptive intimal thickenings [10,11; Comrnittee on Lesions ofthe AHA 1992], and
pathological thickenings [79; Virmani et. al., 2000]. In this discussion the term
"fibroplastic arteriosclerosis" is preferred, bearing in mind that it carries an implication
of generalized affliction of all arteries.
The observations reviewed in future chapters generate two startling
conclusions: (1) The influence of age on the evolution of fibroplastic arteriosclerosis
can be summarized in an amazingly simple formula, F = ßN(l - aA), where F is a
quantitative measure of fibroplastic arteriosclerosis, and A is age in years. The
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-x- INTRODUCTION
ß
coefficients and CX are empirical parameters that serve to transform the effects of
time, A, into their morphological consequences, F. The parameters vary between
groups of subjects such as between men and women and between nations, so that
"aging" is not exactly identical in everyone nor in every group. Aging ofa rteries cannot
be measured in fractions oflife span, but it also cannot be measured by the strict ticking
of an exact atomic clock. (2) The intrusion of atheroma is govemed by another
amazingly simple formula, W = bF - a, where W > 0 marks a high probability of
atheroma and W < 0 marks a low probability, while a and bare empirical parameters.
The parameters a and b can be influenced by fatty deposits (i.e. "fatty streaks"), arterial
size, and some other factors. Current evidence, however, finds remarkable constancy
under most circumstances for the ratio of the parameters aJb, which determines F when
o.
W = This ratio fails to vary among age groups, between demographie groups, and
in other comparisons. This constancy implies that the effect of age upon intrusion of
atheroma is govemed solely by its actions upon F in aB kinds ofhuman subjects.
The way that age acts to prepare the arterial intima for intrusion of atheroma
is now known in broad outline, and the search can now begin for the biological
mechanisms to explain this phenomenon. By knowing what agencies affect the
magnitudes ofwhich parameters in the system, we can devise testable hypotheses. For
ß
instance, data reviewed later indicate a possible strong effect on the parameter by
arteriolar hyalinization in the renal cortex. Subjects with severe hyalinization appear
to grow old more quickly than usual in the particular tissues ofthe arteries. This could
be the starting point for fruitful inquiries.
Chapter One
Introducing the Sequestration Hypothesis
Abstract. Aging ofthe coronary intima sometimes induces SMC's to fabricate excessive collagenous matrix
materials around themselves. Could this fabrication be the usual rate limiting step governing the evolution
toward atheroma?
1.1. Photo Illustrations ofH ypothesis
Figure 1-1 provides examples of features frequently seen in H&E stained paraffin
sections of human coronary arteries. These are arranged to illustrate a proposed
pathogenetic scheme [53-56], as summarized here in five stages: (1) During
adolescence the coronary artery is thought to construct a normal intima which further
matures until about age 25 years (Figure I-lA). (2) During its ongoing maturation, this
intima begins to acquire small regions of fibroplastic thickening, sometimes called
adaptive thickening [10,11,48], which display excessive production of collagenous
matrix by a neady stable population of smooth muscle cells (SMC's) (Figure
I-IB).Such fibroplasia begins at well defined anatomie sites [11,49] and spreads from
there throughout life, often coming to occupy the entire coronary artery [60,61]. (3)
Scattered deposits oflipid arise, as recognized in H&E-stained paraffin sections by the
Fig 1-1. Examples ofprevalent appearanees in eoronary arteries are arranged to suggest a
pathogenetie scheme. Arrows mark intima-media boundaries. Rectangular areas of JOO/Jm
width in A and Bare used to enumerate SMC's. Leuering in Frame Eidentifies the
atheronecrotie lipid eore, A, and itsfibrous cap, C, andfibrous base, B. H&E.
2 CHAPTERONE
presence of foam cell infiltrates accompanied by lymphocytes and other fatty streak
elements [48], these can affect regions ofpreviously normal intima (Figure I-IC) or
variably far advanced fibroplasia ("adaptive thickening", Figure I-1D). (4) When fatty
streak elements collocate with fibroplasia, this produces a progression prone condition
that often quickly evolves into outright atheroma (Figure 1-lE). When deposited into
normal intima, fatty streak elements can initiate an evolution to atheroma, but only with
extreme provocation. (5) Atheroma, i.e. the necrotic core which is the chief hall mark
ofthe "vulnerable plaque", can sometimes precipitate ischemic injury and death.
Step 2 may be the usual rate limiting step in the proposed scheme of
atherogenesis. Advanced degrees of fibroplastic intimal thickening, Step 2, are thought
to act as "lipid traps" [45,78,80,81] to catch and hold atherogenic lipids, and this
concept will be elaborated in later chapters. The intimal fibroplasia at Step 2 can be laid
down by excessively numerous SMC's or through excessive production of fibrous
matrix materials by each of the SMC' s. Previous reports [54] described a dominant
influence by the second kind of fibroplasia, excessive matrix per SMC, in the
promotion of atheroma and cardiac death.
1.2. Atheromatous andjibroplastic intimal thickenings
Figure l-lE illustrates atheromatous thickening and Figure 1-1 B illustratesjibroplastic
intimal thickening of coronary arteries. These two distinct pathological entities call for
careful separation. To help achieve this objective, the term "fibroplasia" is introduced
to emphasize this distinctive type of"thickening". The more frequently encountered
terms "hyperplasia" or "hypertrophy" are avoided, because those terms can hold the
deceptive implication that cells proliferate, which doesn't happen in this setting. The
recently popular term "adaptive thickening" is avoided because it can have the
unwanted implication that the process is confined only to certain anatomic sites. The
collocating of fatty streak elements with fibroplasia, illustrated in Figure 1-lD, is
hypothesized to be a transition stage leading from fibroplasia to atheroma, and
corresponds to the "AHA type III" lesion [11].
A YesA artery is one containing an instance of atheroma (AHA type IV or
greater [11]); all others are NoA arteries.
Measuring the fibroplastic intimal thickness in a specimen of coronary artery
is usually a straight forward operation, but it encounters complications when atheroma
intrudes. Atheromatous intimal thickenings often alter surrounding conditions in several
ways, including calcification, inflammation, hemorrhage, vascularization, erosion, and
wound healing responses related to SMC proliferation. For this reason, the
atheromatous portions of artery are omitted when measuring fibroplasia, and the
measured sampie must therefore be treated statistically as a "censored" data set, as
examined in Chapter Three and later.