Atherosclerosis
1. The Beginnings. A Multicentric Disease
“We cannot identify the unknown aspects of modern life that
lead to atherosclerosis until we know the true nature of the
characteristic atherosclerotic lesion.”
Earl Benditt, [12]
The Injurious Agent
Throughout this comprehensive study the term
“Injurious Agent” (IA) will be used to refer to any
agent or any process, singly or in combination, that
might cause cellular dysfunction or injury to the
artery wall, resulting in atherosclerosis.
Response-to-Injury
The response-to-injury hypothesis states that the
initial event in the pathogenesis of atherosclerosis is
injury to the endothelium [1]. A variety of IAs pro-
duce an inflammatory response in which leucocytes,
primarily monocytes, migrate to the area of injury
[2]. The result is retention and oxidation of lipopro-
teins and transformation of monocytes into
macrophages that ingest lipid, particularly oxidized
low density lipoproteins (LDL). These form the fatty
streak that is an early objective sign of atheroscle-
rosis [2]. Important considerations in this theory are
the precise nature of the IA, and the sequence of
events that lead to the retention of lipid. Several
studies in experimental animals have demonstrated
that lipid retention occurs before the monocytes
migrate into the intima [3], showing that the mono-
cyte is not the cause of the lipid retention [4,5].
What, then, is the cause or the mechanism of the
lipid retention?
The Beginnings
Proteoglycans and the
Extracellular Matrix
Previous studies demonstrated that the initial lesion
in atherosclerosis is asymmetrical intimal thicken-
ing, the result of increased production of sulfate-
containing proteoglycans (PGs) - primarily Chon-
droitin Sulfate Proteoglycans (CSPG) and other
forms of extracellular matrix (ECM) - by resident
intimal smooth muscle cells (SMCs) in a focal area
of the arterial wall [6–9]. The IA, directly or indi-
rectly, enters the arterial wall from the circulating
blood, and then either stimulates or enters the resi-
dent SMC, the principal source of vascular PGs
[10], to produce increased amounts of PGs and
ECM. Walton [8] showed this mucoid thickening of
the intima occurs before lipid infiltration and is com-
posed primarily of collagen, PGs, and ECM. Thus,
although lipid accumulation in the artery wall is con-
sidered an early event in atherosclerosis, lipid
retention is not the initiating event, and the fatty
streak is not the first sign of atherosclerotic injury
[11,12]. This initial intimal thickening is not charac-
terized by hypercellularity or proliferation of SMCs
[13], as is seen in other types of vascular injury [14],
but rather by relative acellularity, apparently due to
the increased amounts of PGs and ECM without
associated SMC proliferation [15]. The relative acel-
lularity noted in these early lesions is not believed to
be due to massive cell death of resident intimal cells
[16]. Increased production of PG and ECM, without
an increase in the number of SMCs, is an unusual
response to injury, suggesting a specific type of IA
and/or a specific type of injury or effect on the SMC
[17,18].
Whether the increase in PGs and ECM is a patho-
logic response and, therefore, to be prevented, or is
a physiologic defensive, protective, or reparative
1-1
Atherosclerosis The Beginnings

response to the IA is not known [6,10]. The fact that Adaptive Intimal Thickening
these intimal thickenings develop very early after
wall injury and before lipid accumulation suggest
Stary, et al. [21], believe many asymmetric intimal
this is a protective, healing, or defensive response
thickenings, termed Adaptive Intimal Thickening,
[1,6]. This view is supported by the knowledge that
reflect a physiologic adaptive response to hemody-
CSPG is required and is the predominant PG in
namic stress. They found this thickening at points of
normal wound repair [9]. However, if this is a physio-
arterial bifurcation in infant human beings and ani-
logic defense, it fails badly because the IA agent is
mals. The authors point out that such physiologic
not halted, proliferation of PGs and ECM continues,
thickenings may also be the site of atherosclerotic
and resolution, healing, and stabilization do not
plaques. It may be difficult to distinguish thickenings
occur. The disease continues to progress. In addi-
that are physiologic adaptations from those that are
tion, if the production of PGs and ECM is a physio-
pathologic, particularly in the early stages of
logic defense, why is lipid retained?
atherosclerosis. These adaptive intimal thickenings
are rich is PGs [21]. Evidence of lipid retention,

The ECM is a visco-elastic material containing pri- then, is a primary feature that distinguishes physio-

marily CSPG, a biochemically active scaffold that logic thickening from pathologic atherosclerosis

regulates arterial permeability, filtration, transport of [21]. The presence of intimal thickening at points of

plasma constituents, and regulation of wall bifurcation supports the view that these lesions are

metabolism and function [10]. The increased an adaptation to hemodynamic stresses, but the

amount of PGs produced by the SMC in response occurrence of the same lesions in areas without

to various growth factors associated with bifurcations, Figure 1, or areas of low or relatively

atherosclerotic injury have much longer side chains low hemodynamic stress, suggests other factors are

and form larger aggregates than do the PGs nor- also involved. These other additional factors may be

mally found in the artery wall [10,13,19]. Thus, there acting independently or in conjunction with hemo-

is not only an increase in the PGs and ECM pro- dynamic stresses to transform adaptive intimal

duced, but a change in the structure of the PGs in thickening into atherosclerotic lesions.

the areas of atherosclerotic injury. This change in

PG structure is believed to alter the metabolic prop-
Whether intimal thickenings are initially physiologic
erties and biochemical function of the PGs and
or pathologic, they reflect tissue proliferation to
ECM, resulting in a disturbance in the transfer of
some sort of IA at any age. The fact that some
substrates through the zone of injury, particularly
adaptive intimal thickenings progress on to
alteration of interactions with lipoproteins
atherosclerotic lesions indicates that all such thick-
[10,13,19,20]. These structural and functional
enings may possess the potential to do so and to
changes in the PGs as well as their turnover rate,
become a vulnerable site for the IA to enter the wall
are directly related to the rate of retention of lipid in
[2,11].
the interstices of the ECM [8,9]. The alteration in
structure and the increased production of PGs sug-
gest a pathologic component of the disease pro-
cess, produced and altered, not as a physiologic
defense [2,8], but for the specific purpose of retain-
ing lipid, particularly LDL.

1-2
Atherosclerosis The Beginnings

Figure 1: A, Dissected left coronary artery from a 31-year-old

male who died of head injuries. The artery shows no radiographic
evidence of atherosclerosis. B-H are contiguous segments of the
main left coronary artery, as labeled in A. B, Normal appearing
intima (thin arrows) and media. C, Same coronary segment as B,
but directly opposite on the other side of the lumen. The intima
here is thicker (bracket), with a small focus of relative acellularity
(open arrows). D, Slightly increased intimal thickening (bracket)
and an increased area of acellularity (open arrows) compared to
C. E, Marked increase in intimal thickness (bracket) with loss of
tissue and cells (open arrows) consistent with focal degeneration.
Lipid-laden SMCs (long arrows) surround this area of
degeneration. F, Further increase in intimal thickness (bracket)
with areas of acellularity and lipid-laden SMCs (long arrows). No
areas of degeneration can be identified. G & H, Intimal thickening
(bracket) is decreasing distally from F, but with more prominent
and more numerous lipid-laden SMCs (long arrows). White
asterisk = lumen, fat arrows = media. Hematoxylin & Eosin (H &
E) stain in all photos.

1-3
Atherosclerosis The Beginnings

Early Atherosclerotic Lesions
Figure 1 shows early changes of atherosclerosis in
a 31-year-old white male who died of non-cardiac
causes. Asymmetric intimal thickening begins near
the left coronary ostia (Figures 1B, 1C), and contin-
ues through all contiguous coronary segments,
ending at Figure 1H. Focal areas of relative acellu-
larity can be identified in Figures 1C–1H, consistent
with increased production of PGs and ECM by resi-
dent intimal cells, presumably in response to wall
injury [21]. Lipid retention in the form of lipid-laden
macrophages or extracellular lipid, or evidence of
tissue injury are not evident in unaffected intima
(Figure 1B) nor in mild intimal thickening (Figure
1C). This finding supports the view that intracellular
or extra-cellular lipid deposition does not occur in
the normal artery wall, but only follows the devel-
opment of intimal thickening [2,8]. The asymmetric
intimal thickening involving only a portion of the
luminal circumference indicates that the injury is
focal and that the IA is present and presumably
active at this particular site. Why the IA enters or
affects the wall at a particular site has not been fully
worked out, but it is probably related to local sus-
ceptibility, increased vulnerability, and/or focal injury
to the endothelium by a various agents [1,2].
because the IA has been present and active for a
longer period of time than in adjacent sections. Fig-
ure 1E shows the most advanced changes in terms
of tissue degeneration, cell loss, and lipid accumula-
tion, located approximately midway between the
first proximal intimal thickening (Figure 1C), and the
distal thickening in Figure 1H. Therefore, Figure 1E
could be the site of initial injury and the develop-
ment of intimal thickening, proximally and distally,
may reflect direct spread of the IA agent in both
directions. A review of Figures 1C–1H confirms that
the amount of intimal hickening and the severity of
the degenerative changes tend to decrease in both
directions from Figure 1E.
The histologic changes observed in Figures 1C and
1H may represent the leading edge of the injury that
is spreading longitudinally from the central site in
Figure 1E. Furthermore, if the IA can spread longi-
tudinally then it may also spread circumferentially,
with the leading edge of the injury expanding in the
direction of the plaque shoulder (Figure 2). If this is
the correct interpretation of these histologic
changes, it means an IA can establish a foothold in
the artery wall in spite of defensive responses. It
then has the potential to spread by direct contiguity
in all directions from this central focus.

The presence of asymmetric thickening to a similar

degree through contiguous coronary segments, as
shown in Figures 1C–1H, suggests these thicken-
ings are part of one continuous area of injury
extending in a longitudinal direction [21,22]. If this
assessment is correct, do these contiguous thicken-
ings reflect injury from a single IA that has spread
from a single focal site in a proximal and distal
direction, or do they represent multiple, separate
foci of injury to the same or different IAs? If we pos-
tulate that one agent caused all these lesions from
one focus, is it possible to identify the initial injury
site histologically? In theory, the initial site of injury
should show the most advanced histologic changes
1-4
Atherosclerosis
Figure 2: Coronary section taken from the same left coronary
artery illustrated in Figure 1, approximately 1 centimeter distal to
Figure 1H. A, Low-power view of a small asymmetric plaque with
a central core (black asterisk). Martius Scarlet Blue (MSB) stain.
White asterisk = lumen. B - E, High-power views of different
parts of the plaque corresponding to the letters shown in A. B,
Focal area of tissue degeneration, cell loss, and lipid retention
(open arrows) near one shoulder of the plaque. H & E stain. C,
Midway between the shoulder and the center of the plaque,
showing the size of the degenerative area (open arrows) is larger
than in B. MSB stain. D, Central area of the plaque showing focal
degeneration (open arrows) and frank necrosis, including the
The Beginnings
presence of cholesterol crystals (long arrow) and calcification
(short arrow). H & E stain. E, Area near the other plaque
shoulder with similar amount of tissue degeneration (open
arrows) as shown in B. H & E stain.
Advanced Degeneration
Figure 2, illustrates, in the same artery of the same
patient, another, more advanced focus of intimal
thickening and plaque formation, but distal to that
shown in Figure 1A. The plaque in Figure 2A is the
largest, most advanced atherosclerotic plaque in
this artery, but it is still insignificant in terms of lumi-
nal stenosis. The central area of this plaque (Figure
2D), shows advanced degeneration with focal
necrosis of tissue, loss of both ECM and cells, lipid-
laden SMCs, lipid infiltration, formation of choles-
terol crystals, and a tiny focus of calcification. The
necrosis and calcification indicate this is an
“advanced” lesion, according to the classification of
the American Heart Association’s Committee on
Vascular Lesions [15]. According to this classifica-
tion, any lesion, regardless of luminal stenosis, that
contains an atheroma and/or a fibrolipid plaque and
calcification is considered to be an advanced lesion.
The advanced degenerative changes in Figure 2D
extend toward each plaque shoulder, where the
plaque meets the normal arterial wall, the area of
degeneration and necrosis becoming progressively
smaller and less severe toward the plaque shoulder,
Figures 2B, 2E. Again, as in Figure 1, the IA
appears to be spreading by direct contiguity, only
this time in a circumferential direction toward the
plaque shoulder. The tissue immediately surround-
ing the central core (Figure 2E) appears devoid of
cells, suggesting that these cells were either
destroyed by substances contained within the
necrotic core, have undergone apoptosis or died of
some other consequence of the disease process
[23,24]. Progressive cell loss is characteristic of
1-5
Atherosclerosis The Beginnings

advanced lesions and, with cell death, degenera- responses, whatever they may be, appear to be
tion, necrosis, and formation of a necrotic core unable to halt, sequester, or neutralize the IA or to
follow [23–26]. effect healing and resolution of the injured area.

The plaque in Figure 2A extends proximally into the
adjacent coronary section and distally into two addi-
tional segments, again suggesting active longitudi-
nal spread of the IA. The remainder of the coronary
artery distal to the segment illustrated in Figure 2
showed two additional focal, widely separated
asymmetric intimal thickenings, similar to, but less
severe than those shown in Figure 1. Altogether
there were four separate lesions separated by nor-
mal arterial wall in this one artery. Wilens [11] noted
that IAs can attack the wall at multiple sites, setting
in motion atherosclerotic disease at multiple points,
emphasizing atherosclerosis is a multicentric dis-
ease.
In Review
Unanswered Questions
What is the IA and what is the mechanism of injury?
What kind of an IA can enter the wall and injure or
stimulate resident SMC to produce excess amounts
of abnormal PGs without stimulating the prolifera-
tion of SMC or attracting other SMC from the
media? Does the IA enter the SMC without injuring
the extracellular matrix? Why does this particular
form of PGs retain lipid, when the normally present
PGs do not? What is the relationship between the
IA and the retained lipid? What is the mechanism by
which the IA spreads throughout the intima? Why
do some mucoid swellings degenerate and become
necrotic very early in plaque development while
others do not? These questions will be explored in
subsequent chapters.

The IA causing atherosclerosis appears to enter at

a focal point in the artery wall. In some way it stimu-
lates the resident intimal SMC to produce increased
amounts of an abnormal form of PGs, resulting in
asymmetric intimal thickening and lipid retention.
Asymmetric intimal thickenings are ubiquitous
throughout the coronary tree because atherosclero-
sis is multicentric in origin and the IA, present in
circulating blood, may enter the wall at any vulnera-
ble point. The production of an abnormal form of
PGs appears to be a pathologic component of the
disease process, produced specifically to retain
lipid. The IA appears to establish a locus or focus of
injury and then spreads in all directions from this
central focus, to contiguous areas within the intimal
layer. Lipid-laden SMC are an early, but not the
earliest sign of atherosclerosis. Degeneration,
necrosis and calcification of plaque tissue can occur
very early in plaque development. The defensive

1-6
Atherosclerosis
2. The Smooth Muscle Cell. The Pivot in
Atherosclerosis
“Whereas the precise nature of the initiating event for
atherosclerosis is not known, it is clear that the failure of the
smooth muscle cell to maintain its normal differentiated
phenotypic state becomes a key contributing factor in the
progression of atherosclerotic disease.”
GK Owens, [17]
The Fibroproliferative Response
Atherosclerosis is generally considered a fibroprolif-
erative (FP) disease because atherosclerotic
plaques contain large amounts of fibrous tissue [2].
This FP response is believed to be a defensive,
protective, physiologic response to injury, designed
to wall off, contain, enclose, or sequester the IA,
and then to assist in resolution of the injury [2].
However there is no evidence to show that the FP
response ever functions in a defensive or protective
fashion.
Continued plaque growth suggests the resident
intimal SMCs and any SMCs migrating from the
media are being stimulated to produce more and
more fibrous tissue, but this continued growth does
not prove that the FP response is a physiologic
defensive response to injury. If the growth and pro-
liferation of fibrous tissue were a defensive
response, then why isn’t the disease process halted
in its very earliest stages, and why does the FP
response progress above and beyond that required
to repair a small area of injury [2,12]?
Plaque tissue is produced primarily by intimal
SMCs, not by fibroblasts, the usual cell type nor-
mally involved in wound repair: it therefore differs
from the normal fibrotic response to injury [12,27].
The FP response may not be a defensive mecha-
The Smooth Muscle Cell
nism gone awry [2], but a pathologic component of
the disease process from the very beginning. There
is no reason to think the FP response is physiologic
in any way because all atherosclerotic plaque tissue
represents diseased tissue, regardless of the cir-
cumstances under which it formed.
This chapter presents evidence supporting the view
that the intimal SMC is specifically targeted, its
intracellular functions altered by an IA, to produce a
specific type of pathologic fibrous tissue. We
hypothesize that inherent SMC functions are altered
to such an extent that the SMC becomes a partici-
pant, mediator, and perpetrator of the disease
process, as illustrated in the following examples.
Atherosclerotic Fibrous Tissue
Typical plaque fibrous tissue, illustrated in Figures
3A and 3B, is found throughout atherosclerotic
plaques. The tissue architecture consists of a
meshwork of collagen bundles embedded in ECM,
with many lacunar-like spaces containing SMCs
staining positive with SMC actin antibody (Figure
3C). The collagen and other components of the
ECM are believed to be produced by these SMCs
(2,4,12,27), forming an unusual and distinctive type
of fibrous tissue. The SMC nucleus is flattened
against one side, suggesting compression or
increased pressure within the lacunar space (Fig-
ures 3A, 3B). These SMCs appear to be identical to
those shown in Figure 1, except that these are
larger and enclosed in a uniform fibrous meshwork.
Other investigators have observed these flattened,
attenuated SMCs [28,29].
2-1
Atherosclerosis The Smooth Muscle Cell

The fibrous tissue shown in Figures 3A, 3B is rela-

tively acellular, similar to the asymmetric intimal
thickening shown in Figure 1, representing a further
developmental stage due to the large amount of
collagen and ECM. The SMCs within these lacunar
spaces appear to be filled with clear material, pre-
sumably lipid, that is compressing the nucleus. The
type of lipid has not been identified, but it appears to
be in a different form than that found in macrophage
foam cells (Figure 3B). Lipid droplets are not obvi-
ous, so the SMC may metabolize ingested lipid
differently from monocyte-derived macrophages
[30,31]. The absence of a typical foam cell configu-
ration may be due to a lack of esterification of lipid
by the SMC. Other investigators, using electron
microscopy, have noted that SMC do contain lipid
droplets, showing that at least some of the lipid
ingested by SMC is esterified, but seldom to the
same extent as monocyte-derived macrophages
[17,31].

Figure 3: A, Typical fibrous plaque in a 65-year-old white male.

Note the spindle-shaped, lipid-laden, SMCs (small arrows).
These cells vary greatly in size, and some appear to be
coalescing with neighboring cells (long arrows). The SMC
nucleus is flattened along one side of the lacunar spaces (open

2-2
Atherosclerosis
arrows). There are relatively few cells present, but a large
amount of fibrous tissue. H & E stain. B, High-power view of the
subendothelial area in the same section as A. There are foam
cells (white arrows) and other lipid- containing cells just beneath
the endothelium. Two very large, lipid-filled spaces, apparently
formed by the joining of adjacent, but dead, SMCs are present
(black arrows). Asterisk = Lumen. H & E stain. C, A small fibrous
plaque in a 50-year-old female, stained with SMC actin, showing
the lipid-laden cells (arrows) within the lacunar spaces are, in
fact, SMCs. Asterisk = Lumen. D, Intimal hyperplasia in a 75-
year-old white female who received PTCA at this site 9 months
earlier. Note the hypercellularity, the disorganization of these
cells, the presence of stellate cells (arrow), and the absence of
any lipid-laden SMCs. H & E stain. E, Intimal hypercellularity in a
6-month-old vein bypass graft in a 53-year-old white male. The
SMCs are oriented parallel to the endothelial surface, and none
appear to be lipid-laden. Note the hypercellularity near the
endothelial surface (arrows). Asterisk = Lumen. H & E stain. F,
Oil Red O stain of a fibrous plaque showing the fibrous tissue
diffusely infiltrated with lipid droplets, giving the fibers a granular
appearance. Note the scattered cholesterol crystals (arrows).
Other Types of Vascular Fibrous
Tissue
Contrast the relatively acellular tissue in Figures 3A
and 3B, with the hypercellular response seen follow-
ing percutaneous transluminal coronary angioplasty
(PTCA), (Figure 3D), or a recently placed saphe-
nous vein bypass graft, Figure 3E. These structural
differences plus the absence of lipid-laden SMCs in
Figures 3D, 3E, indicate that these tissues are not,
or at least not yet, atherosclerotic. Presumably the
FP response following PTCA is related to physical
injury produced by the balloon, and the thickening of
the vein graft wall is a physiologic, hyperplastic
response to increased hemodynamic stress within
the vein graft lumen.
These different cellular and structural responses to
different types of vascular injury suggest different
IAs stimulate the SMC to produce different FP
responses, illustrating the pleuri-potential nature of
the SMC [17]. The monoclonality of the SMC, pro-
posed by Benditt [32], suggests the SMC is altered
in a very specific way to produce a very specific
The Smooth Muscle Cell
type of fibrous tissue [12]. Recent evidence shows
different types of SMCs in plaques, but the histo-
logic picture is the same in all plaques [12] and no
pathognomonic changes distinguish one IA from
another.
The Smooth Muscle Cell
The SMCs found in plaques have an altered pheno-
type compared with normal SMCs, but what controls
these phenotypic changes and whether they are the
cause or the consequence of active atherosclerosis
is unknown [17]. These SMC show altered lipid
metabolism, altered growth factor production,
altered ECM production, smaller size, fewer intercel-
lular junctions, and the presence of fatty vacuoles
[12,32]. In addition there is a decrease in myofila-
ments and various proteins, with an increase in
golgi and rough endoplasmic reticulum [17].
Although this phenotypic change is often considered
a physiologic response to an injurious stimulus, the
possibility that this change is actually a pathologic
alteration in SMC function and a key factor in the
development of plaque lesions cannot be excluded
[17].
The structural meshwork of the tissue shown in Fig-
ures 3A and 3B suggests these lacunar spaces may
be created by the ingestion of lipid by the enclosed
SMC [33]. The flattening of the SMC nucleus and
the variation in size of lacunar spaces suggest over-
ingestion and/ or unregulated uptake of lipid by the
SMC is greater or more advanced in some SMCs
than in others. The inability to regulate the uptake of
lipid is one of the features of monocyte-derived
macrophages found in plaque tissue [31]. The lipid-
laden SMC in Figures 3A, 3B may be SMC
macrophages that have also lost that regulatory
ability [1,21,30,31]. The loss of lipid regulatory
capacity is believed due primarily to the presence of
scavenger receptors on the SMC [34].
2-3
Atherosclerosis
SMCs are reported to transform into macrophages
and to take on the appearance of foam cells, but
they are not as efficient as monocyte-derived
macrophages in the uptake of lipid, possibly
because SMCs do not express scavenger receptors
to the same degree as do monocytes [2,31]. Fur-
ther, some of the larger lipid-laden SMCs appear to
be fusing with adjacent lipid-laden SMCs resulting in
the formation of small lipid lakes, suggesting active
and continuing accumulation of lipid (Figure 3B)
[10,35].
If, in fact, these are SMC macrophages, why have
they formed in this location, what is their purpose,
and why are they ingesting lipid? The general pur-
pose of the macrophage is to neutralize and remove
any IA and/or harmful or toxic compounds and to
participate in the removal of dead and injured tissue
[36,37]. Since this is atherosclerotic plaque tissue,
we can assume that three of these factors, the IA,
cytotoxic compounds, and injured tissue are present
within a plaque.
Figure 3F shows plaque fibrous tissue is heavily
infiltrated with lipid, is extra-cellular [33] and is pre-
sumably the source of lipid ingested by the SMC.
The metabolism or oxidation of this retained lipid, an
expected consequence of lipoprotein trapping [19],
results in the formation of cytotoxic compounds
such as oxidized LDL [35,38]. These compounds
may produce the harmful stimulus necessary to
transform the SMCs into macrophages [31]. We can
assume that one of the reasons these SMC are
taking up lipid is because it is a toxic substance or
compound [30,31].
However, these SMCs do not seem to neutralize or
remove the lipid or toxic compounds, but simply
ingest more and more of them, resulting in fibrous
tissue laced with lipid-laden SMCs of different size
(Figures 3A, 3B). Nor is there any evidence that the
IA and/or the injurious process have been slowed,
The Smooth Muscle Cell
halted, or the injury resolved by the activity of the
SMC macrophages. The inability to remove lipid
from the artery wall, for instance, by reverse trans-
port, may be related to a decrease in mobility of
SMCs related to the thick fibrous network. Or the
SMC, like the monocyte-derived macrophages, may
be partially disabled and have decreased mobility
through the excess intake of lipid [30]. Is it possible
that some or all of these SMC functions are patho-
logic components not physiologic defenses, of the
disease process? Whatever the mechanism, the
SMC appears to be a key player, their normal func-
tions targeted and subverted by the IA, serving to
mediate the subsequent development of atheroscle-
rotic disease.
Degeneration and Necrosis
The fibrous tissue shown in Figures 3A and 3B
appears to be fatally flawed. All such tissue, given
sufficient time, may degenerate and undergo necro-
sis, forming a lipid-laden necrotic core or atheroma.
The SMCs die as result of toxic chemical agents
such as oxidized LDL, from the over-ingestion of
lipids, from hypoxia or from apoptosis [25,37,39–
41]. The uptake of oxidized LDL by SMC
macrophages may promote apoptosis [39]. The
death of the SMC leads to discharge of the ingested
lipids and other cellular elements into the extracellu-
lar space, and to the degeneration of non-viable
fibrous tissue. Degeneration and necrosis of the
lipid-laden fibrous tissue lead to a further increase in
the extracellular lipid content, and eventually to a
lipid-rich necrotic core.
Figure 4 illustrates degeneration and destruction of
tissue surrounding the necrotic core. Figure 4A
shows a relatively small plaque with a necrotic core
and an overlying fibrous cap. A fibrous cap is gen-
erally considered to be a protective layer of fibrous
2-4
Atherosclerosis The Smooth Muscle Cell

tissue separating the core from the lumen, formed quent destruction of this same tissue [39] means the
primarily to contain and prevent communication IA and subsequent atherosclerotic disease are
between the lumen and the necrotic core [4]. basically and ultimately destructive in nature [43].

The necrotic core in Figure 4A appears to be

expanding toward the shoulders of the plaque, illus-
trating the tendency for the plaque and the necrotic
core to grow circumferentially, as in Figure 2A. Ero-
sion through the fibrous cap will probably occur first
at the lower shoulder of the plaque where the
fibrous cap is thinnest. The histologic structure of
the fibrous tissue in this fibrous cap is the same as
that illustrated in Figures 3A, 3B. This fibrous cap,
already diseased and weakened by dysfunctional
SMCs, is destined for eventual destruction because
the SMC in the cap will eventually die, the cap will
degenerate, and the plaque will rupture. In other
words, the IA appears to affect and destroy the
SMCs in the fibrous cap and elsewhere, by creating
a toxic necrotic core that destroys surrounding tis-
sue, including the fibrous cap. Thus, the fibrous cap
has become a pathologic component of the disease
process, not a protective structure designed to
enclose the necrotic core.

In Figure 4B, the fibrous cap adjacent to the lumen

in the upper part of the photo separates the lumen
from the deeper necrotic core. The tissue between
the necrotic core and the fibrous cap is in the pro-
cess of degeneration and destruction and will soon
be part of the core, presumably as a result of the
toxic substances within the necrotic core, the growth
and expansion of the necrotic core, and the result-
ing death of SMCs [25,40–42]. Figure 4: A, Crescent-shaped atherosclerotic plaque in the
proximal LAD coronary artery of a 53-year-old white male. Red
and blue injection mass has mixed in the lumen (asterisk). Note
The expanding destruction of tissue surrounding the the major part of the plaque is composed of whitish material (fat
arrows), and microscopic examination shows this white material
necrotic core is vividly apparent in Figure 4C. These
to be the necrotic core. The fibrous cap is made up of what
photos illustrate gradations and zones of tissue
appears to be clear or transparent tissue (thin arrows) and varies
damage and destruction around the necrotic core in thickness from one side of the plaque to the other. The fibrous
from the center of the core outward. They also show cap is quite thin at the plaque shoulder near the bottom of the
photograph (open arrow). B, High-power view of the plaque
that although there is initial proliferation of fibrous
tissue in atherosclerotic disease [31], the subse-
2-5
Atherosclerosis
shown in A. The necrotic core is identified by a black asterisk,
and the arterial lumen by a white asterisk. The fibrous cap has
structure similar to that shown in Figures 3A and 3B, is adjacent
to the lumen. The fibrous tissue (arrows) between the lumen and
the necrotic core has undergone partial degeneration and
necrosis. MSB stain. C, SMC actin stain of a fibrous plaque
surrounding a necrotic core (asterisk) from another patient. The
tissue adjacent to the necrotic core has undergone degeneration
with loss of SMCs, but the basic fibrous structure remains
(Bracket 1). The next layer outward from the necrotic core
(Bracket 2), shows the SMCs are still apparently viable and stain
appropriately with the SMC actin stain, but many are lipid-laden
(long arrows), of different size, with several small lipid lakes and
with early degeneration of tissue at the right side of the
photograph (open arrows). Beyond this second layer is a layer of
cellular fibrous tissue (Bracket 3) composed of viable-appearing
SMCs, and only occasional small lipid-laden SMCs (short
arrows).
In Review
Atherosclerotic fibrous tissue is diseased, patho-
logic tissue produced by SMC’s that have been
targeted and affected and whose intracellular func-
tions have been altered by the IA to produce a
specific, pathognomonic, type of fibrous tissue.
Plaque fibrous tissue is laced with lipid laden SMCs,
probably SMC macrophages, whose normal func-
tion has been subverted by the IA, leading to the
eventual death of the SMC and degeneration of the
fibrous tissue. The SMC is the key cell affected by
the IA, and it mediates the onset and progression of
atherosclerotic disease. The fibrous cap is not a
specialized protective structure but is a typical
atherosclerotic fibrous tissue formed by phenotypi-
cally altered SMCs. It only appears to be a cap
because the necrotic core tends to form first in the
central part of the plaque. Atherosclerosis, in the
final analysis, is basically and primarily a destructive
disease process.
The Smooth Muscle Cell
Unanswered Questions
How does the IA enter the wall? Why is the SMC
targeted and intracellular functions altered? Why
does the IA first stimulate the proliferation of fibrous
tissue, then proceed to destroy this same tissue? Is
this the nature of the disease process, and if so,
what purpose is served by destroying this tissue?
What is the mechanism of growth and expansion of
the necrotic core? Are the SMCs responsible for the
FP response the same cells that transform into
macrophages and ingest lipid, as Owens suggests
[17]? Can the SMCs that migrate from the media
undergo a phenotypic change from producing con-
tractile fibers to synthesizing fibrous tissue, then
subsequently transform or be transformed into a
SMC macrophage? If so, does this confer a survival
advantage [17], or are these migrating SMCs sub-
verted in the same manner as resident SMCs,
becoming part of the disease process?
Can one type of SMC perform all these various
functions, or are there various subsets of SMCs that
transform along certain cell lines, each performing a
different function [44]? Is failure to regulate SMC
differentiation [17] due to the effects of the IA? How
can a cell that is partially disabled, say with scav-
enger receptors, continue to manufacture and
secrete sophisticated and complicated metabolic
compounds, such as growth factors and pro teolytic
enzymes? Whatever the answers to these ques-
tions, clearly the SMC plays a major role in the
progression and development of atherosclerotic
lesions.
2-6
Atherosclerosis Inflammation

3. Inflammation. A Sign of Active Disease

“The lesions of atherosclerosis represent a series of highly
specific cellular and molecular responses that can best be
described, in aggregate, as an inflammatory disease.”
Russell Ross, [18]

Chronic Inflammation
Atherosclerosis is a chronic inflammatory disease
characterized by migration of monocytes and T
lymphocytes to the area of arterial wall injury
[1,18,45]. Early investigators also noted that the
lipid-rich atherosclerotic plaque may develop sec-
ondary to a primary inflammatory process [46].
Inflammation per se, acute or chronic, is believed to
be primarily defensive or protective in nature, its
principal aims being to neutralize and remove the
IA, and to initiate the process of tissue repair and
healing [18,47]. However, the inflammatory media-
tors associated with inflammatory cells are also
potentially harmful because they can damage tissue
and aggravate injury. The presence of T lympho-
cytes with an atherosclerotic plaque indicates that
the immune system has been activated, that the IA,
or a product thereof, is a foreign agent or antigen,
and that antibodies are being produced against it
[48–50]. We can surmise, based on the migration of
monocytes and T lymphocytes to the area of injury,
that the IA initiating the development of atheroscle-
rosis represents a significant threat to the organism,
and that all appropriate defenses are being mobi-
lized against it. It should be emphasized that
inflammatory cell infiltrates are found only within or
overlying atherosclerotic plaques. They are not
found in relation to a normal intima that has no evi-
dence of atherosclerosis [51,52], (Figure 5, Figures
5A,5B). The migration and infiltration of chronic
inflammatory cells, i.e., monocytes and T cells,
reflect “active” inflammatory atherosclerotic disease
[18,48,53].
3-1
Atherosclerosis Inflammation

the entire circumference (arrows), and this is classified as a

Grade IV inflammatory response. H & E stain. Magnification
x11.7.

“Active” Inflammatory
Atherosclerotic Disease
Active, inflammatory, progressive, expanding
atherosclerotic disease is characterized by plaque
growth and the development of luminal stenosis,
presumably due to continuing and expanding injury
produced by the IA. If atherosclerosis is related to
arterial wall injury and this injury results in a chronic
inflammatory response, then the inflammatory infil-
trate associated with an atherosclerotic plaque is a
marker of active, injurious atherosclerotic disease
[53]. The extent and severity of atherosclerotic
lesions, in terms of plaque size, should reflect the
extent and severity of arterial wall injury. The sever-
ity of this injury, in turn, should be reflected in the
extent, magnitude, and/or number of inflammatory
cells present, as seen histologically in the artery
wall.

Adventitial Inflammation
Figure 5: A, Proximal RCA section from a 32-year-old Asian
Table 1 illustrates, in 83 patients who died of acute
male showing a small asymmetric plaque, with a necrotic core
(black asterisk) and a fibrous cap (black arrows). White asterisk
coronary disease (ACD), the relationship between
= lumen. H & E stain. Magnification x19.5. B, High-power view of adventitial inflammatory infiltrates, primarily T lym-
rectangle in A, of the adventitia showing scattered Tcells (thin phocytes, and the extent and severity of atheroscle-
arrows). This amount of inflammatory response was classified as
rotic involvement of the epicardial coronary tree, in
Grade I. Media = fat arrows. H & E stain. C, Large asymmetric
atheroma (asterisk) in a 51-year-old white female with Grade II
terms of luminal stenosis. In order to assess the
inflammation of the adventitia (arrows). Lumen at top of photo. H severity and extent of underlying arterial wall injury,
& E stain. D, Mid-RCA section from a 72-year-old white male. adventitial inflammation was estimated and graded
The luminal stenosis is estimated to be 80% and the lumen
on the basis of circumferential involvement by T
contains a thrombus. Two foci of T cells can be seen in the
adventitia (arrows) on opposite sides of the lumen. This is
lymphocytes in the adventitia in each coronary
classified as a Grade III inflammatory response. H & E stain. segment. Inflammation or inflammatory cell infil-
Magnification x11.2. E, Distal RCA section from a 59-year-old trates of the intima were not considered in this
white male. This section was taken immediately distal to an
grading system, but adventitial inflammation was
occluding thrombus with fragments of thrombus still present in
the lumen. A thick, heavy band of T cells extends virtually around
believed to reflect intimal injury [54].

3-2
Atherosclerosis Inflammation

Table 1:. Comparison of luminal stenosis and circumferential extent of adventitial inflammatory
involvement of the coronary wall in 83 patients who died of acute coronary disease.

Severity of Inflammation
IC None I–II III–IV
Degree of # of Sections % # % # % # % # %
Stenosis (%)

<50 3221 46 957 30* 2264 70 899 28 58 2a

50–80 2458 35 1623 66 835 34 1453 59 170 7
>80 1377 19 1042 76* 335 24 864 63 178 13a
Totals 7056 3622 51 3434 49 3216 45 406 6

IC = Adventitial inflammatory cell involvement; * = p =<0.001; a = p =<0.001

Adventitial inflammation in patients with atheroscle-
rosis is commonly present as discrete foci of T
lymphocytes that have congregated at a particular
site in the adventitia. They are easily recognized
histologically (Figures 5B–5E), and were graded on
the basis of I to IV according to the following sys-
tem: The circumference of each coronary segment
was divided into three, 120° quadrants, with the
presence or absence of adventitial inflammation in
each quadrant recorded. Grade I, the T cells were
rather diffusely scattered in the adventitia overlying
a plaque without a definite discrete focus (Figures
5A,5B). Grades II, III and IV showed discrete foci in
one, two, or all three of the 120° quadrants (Figures
5C–5E). Segments with Grades I, and II inflamma-
tion were considered a “mild” injury, whereas
Grades III and IV were considered “severe” injury of
the artery wall.
Seventy-six percent of all coronary segments with
>80% luminal stenosis had adventitial inflammation,
compared with 30% of coronary segments with
<50% luminal stenosis, p=<0.001, proving that the
frequency of adventitial inflammation is directly
related to plaque size. Comparing the frequency of
Grades III/IV adventitial inflammation in the 178
coronary segments with >80% luminal stenosis to
the 58 segments with <50% stenosis shows Grades
III/IV inflammation is significantly more common in
those with >80% stenosis, p=<0.001. Both the fre-
quency and severity of adventitial inflammation, in
terms of circumferential extent, are directly related
to plaque size [52,55]. We conclude that the size of
the plaque and the circumferential extent of adventi-
tial inflammation are directly related to the severity
or magnitude of the arterial wall injury.

The Magnitude of Injury

In these 83 patients, 3,835 (54%) of over 7000
coronary segments examined histologically showed
more than 50% luminal stenosis. These patients
had widespread injury and significant plaque devel-
opment throughout the coronary tree. Similarly,
3,622 (51%) of coronary segments showed adventi-
tial inflammatory infiltrates, confirming the presence
of widespread, active, atherosclerotic injury and
resulting disease [54].
What factors related to the IA determine the magni-
tude of wall injury? Since plaques vary in size and
composition, the amount of IA may not only vary
from plaque to plaque but vary in potency, toxicity,
virulence, or antigenicity [56]. The susceptibility of
the individual patient to the IA must also be taken
into account. This variability in the inherent charac-
teristics of the IA could explain why plaques vary in
size, in speed of development, and in the degree to
which the histologic changes become “advanced”
3-3
Atherosclerosis
without narrowing the lumen [15]. For example, Fig-
ure 2A is a very small plaque with “advanced”
changes, including calcification and necrosis, but
without adventitial inflammation or stenosis. The IA
may be sufficiently potent, or present in sufficient
amounts, to cause focal but severe injury. Although
the IA may be potent, toxic, or virulent, because this
is still a small plaque, the IA is not yet present in
sufficie/nt amounts to activate the immune system
or present long enough to cause a large plaque to
form. In considering the pathogenesis of atheroscle-
rotic injury, we may be dealing not only with the
amount, but also the potency, toxicity, virulence, or
antigenic potential of the IA.
Luminal Stenosis and
Inflammation
Figure 5 illustrates the direct relationship between
luminal stenosis and adventitial inflammation. Fig-
ures 5A and 5B show a small asymmetric plaque
causing approximately 20–30% luminal stenosis
along with a Grade I adventitial inflammatory infil-
trate, consistent with a small area of focal injury and
beginning activation of the immune system. The
presence of a necrotic core suggests the presence
of an IA sufficiently potent to cause early destruction
and necrosis of tissue, similar to, but more
advanced than in Figure 2A. Of 23 coronary seg-
ments examined from this artery in Figure 5A, 14
showed various degrees of plaque development
causing <50% luminal stenosis. Seven of the seg-
ments showed Grade I adventitial inflammation, and
one segment showed Grade II inflammation. There
were no ulcerated plaques (UP) or thrombotic
lesions in this artery, nor any coronary calcification.
This artery may have been injured in multiple focal
areas by a potent IA, actively growing and expand-
ing and beginning to cause activation of the immune
system, but not yet causing any plaque ulceration
(PU), erosion, or calcification. However, even
though the plaque is small and produces no signifi-
Inflammation
cant luminal stenosis, it is still a vulnerable plaque
with a relatively thin fibrous cap. Theoretically it
could ulcerate early in plaque development [57].
Figures 5C–5E are examples of Grades III and IV
adventitial inflammatory involvement associated
with increasing luminal stenosis that illustrate the
association between inflammation and luminal
stenosis.
Failure of Inflammatory Defenses
The inflammatory defensive responses detailed
above appear to be no match for the IA. Specifi-
cally, these inflammatory defenses, in spite of what
appears to be a vigorous response, fail to neutral-
ize, contain, or remove the IA and/or to halt the
spread of the disease at an early stage of plaque
development. This observation is similar to those
made in regard to the FP response (Chapter 2) in
that the FP response also failed to halt the spread
of the IA. The failure of these defensive measures
suggests the monocytic and/or T lymphocyte
responses are either inadequate to deal with the
strength or toxicity of the offending agent, or that
these inflammatory responses have been altered
changed, or subverted in some way from performing
their usual protective, reparative functions following
wall injury [47]. Leibovich and Ross [36] noted the
importance of normally functioning macrophages in
wound healing. Therefore, continued plaque growth
may reflect either an overwhelming or resistant IA
and/or a disabled inflammatory response to injury
on the part of macrophages and/or T lymphocytes.
Natural History of Wall Injury
What is the natural history of atherosclerotic wall
injury and the associated inflammatory response
caused by the IA? Is the IA ever completely neutral-
ized and removed, or can it persist indefinitely in a
dormant, inactive state? Table 1 showed 24% of all
coronary segments with stenosis greater than 80%
3-4
Atherosclerosis
were without adventitial inflammation, similar to the
results of other investigators [54]. Some arteries
seem able to heal, and the inflammation may sub-
side. This implies that the IA can, in some circum-
stances, be neutralized, removed, or become
dormant, with the injured area undergoing resolution
and healing. Plaque growth may be phasic with
exacerbations and remissions of the active inflam-
matory disease process, but the factors causing
remission are not known.
Clinical Manifestations of
Atherosclerotic Inflammation
One of the great mysteries surrounding active
atherosclerosis is the absence of clinical manifesta-
tions of inflammation in spite of diffuse inflammatory
involvement of the coronary tree (Table 1). Virtually
all clinical symptoms of active, progressive
atherosclerosis are related to obstruction of coro-
nary blood flow, and to resultant ischemia or infarc-
tion of the myocardium. They are not related directly
to inflammation. Patients with active atherosclerosis
do not exhibit fever, pain, increased sedimentation
rate, or a significant increase in white blood count,
or other signs of an active inflammatory disease.
This suggests that the IA is not exposed to the nor-
mal bodily defenses that recognize and remove
most IAs. The IA may be residing within a cell and
thus escape detection.
In Review
Inflammation, in the form of adventitial T lymphocyte
infiltration, follows and responds to atherosclerotic
injury and subsequent plaque formation. It is a
marker of active, injurious atherosclerotic disease
[54,55]. Adventitial inflammation is found only over-
lying atherosclerotic plaques. It serves to identify
the site of injury and, presumably, the location of the
IA. The frequency and circumferential extent of
adventitial inflammation are directly related to
Inflammation
plaque size, and reflect the magnitude of the injury.
Plaque growth and the development of luminal
stenosis may be due to the continued presence of
an active IA that spreads to adjacent tissue, expand-
ing the area of injury and producing increased
inflammatory responses. Atherosclerosis and
adventitial inflammation are diffuse and widespread
in patients who die of ACD. The magnitude of the
injury and the speed of plaque development appear
to be directly related to the amount, potency, toxic-
ity, or virulence of the IA and/or individual suscepti-
bility to the IA. The inflammatory response to injury
fails to halt the growth and spread of the IA. The IA
may be too powerful or resistant to these inherent
inflammatory defenses, or the macrophage and/or T
lymphocyte functions may have been subverted,
thereby preventing their neutralizing the IA.
Unanswered Questions
What kind of an IA is this that can apparently alter
intracellular mechanisms without killing the cell and
can subvert normal defensive responses? What is
the mechanism of spread and expansion of the IA?
Does the IA replicate and, if so, by what mecha-
nism? Why is the adventitia the site of such heavy
infiltration of T lymphocytes compared with the
intima, the area of injury? Does the IA, or a byprod-
uct thereof, pass to the adventitia via the lymphat-
ics, with the adventitia functioning much like a
regional lymph node? What is the life cycle of the IA
and what is the energy source that drives growth
and expansion of the plaque?
3-5
Atherosclerosis Atheromas Are Caseous Abscesses

4. Atheromas Are Caseous Abscesses

As stated in Chapter 3, plaque size, as reflected by
“This lesion (the atheroma), undoubtedly the most dangerous
the severity of luminal stenosis, is directly related to
of all prethrombotic processes, has often been called an
atheromatous abscess.” the magnitude, severity, and extent of injury caused
Meyer Friedman, [60] by the IA, as shown in the magnitude of the T lym-
phocyte response in the adventitia. The same may
be true of the formation and growth of atheromas. If
The Necrotic Core plaque size is directly related to the magnitude of
the injury caused by the IA, then it follows that the
Atherosclerosis is characterized by the proliferation,
size of the atheroma, also produced as a result of
then destruction of intimal fibrous tissue, resulting in
activity of the IA, is also related to the magnitude of
the formation of an atheroma, as originally proposed
the injury. The formation and growth of an atheroma
by Virchow [39]. The presence of a necrotic core is
may also be directly related to the toxicity, virulence,
objective evidence that atherosclerosis is ultimately
concentration, or dose of the IA causing atheroscle-
a destructive, not an FP disease, and the necrotic
rosis, and/or to the susceptibility of the patient to the
core is a component, not a complication of
ongoing, progressive, destructive activity of the IA.
atherosclerotic disease. The precise mechanism of
atheroma formation has not been fully worked out
[12,37], but apparently the IA, directly or indirectly, Size of Atheroma and Luminal
is responsible for cell death, leading to non-viable Stenosis
degenerative tissue and eventual necrosis [58]. The
Table 2 illustrates the relationship between luminal
overall cell count within a plaque decreases as the
stenosis and the presence of an atheroma in 83
plaque enlarges, indicating that the lost cells are not
patients who died of ACD. Atheromas were present
being replaced, and that plaque enlargement is due
in 2,223 (32%) of 7,056 coronary segments taken
primarily to the growth of the necrotic core rather
from these 83 patients, with 88% in plaques with
than to the growth of fibrous tissue [58]. The mech-
more than 50% luminal stenosis. There was a signif-
anism of cell death is believed to be either coagula-
icant difference in frequency, p=<0.001, of athero-
tion necrosis or apoptosis, possibly related to the
mas in those segments with >80% stenosis
toxic effects of oxidized LDL or pro-apoptotic mech-
compared with segments having <50% stenosis.
anisms [25,37,39,59]. Both of these responses,
These results show that the frequency of atheromas
active tissue proliferation and progressive enlarge-
increases as the plaque enlarges.
ment of the necrotic core, result in increasing lumi-
nal stenosis and ultimately, if unchecked, to
obstruction of coronary flow.

4-1
Atherosclerosis Atheromas Are Caseous Abscesses

Table 2:. Comparison of luminal stenosis and size of atheroma in 83 patients who died of acute
coronary disease.

Size of Atheroma
Antheroma None I–II III–IV
Degree of # of Sections % # % # % # % # %
Stenosis (%)

<50 3221 46 387 12* 2834 88 383 12 4a 0.1

50–80 2458 35 1037 42 1421 58 983 40 54 2.0
>80 1377 19 799 58* 578 42 711 52 88a 6.0
Totals 7056 2223 32 4833 69 2077 29 146 2.0

* = p =<0.001; a = p =<0.001

The circumferential extent of intimal involvement

Atheromas Are Similar to
with an atheroma, also determined by a review of
Bacterial Abscesses
each microscopic section, was graded in the follow-
Atheromas are abscess-like in the sense that they
ing manner: Each artery segment was divided into
are associated with inflammatory infiltrates, grow in
four, 90° quadrants, then graded on how many of
size, are composed of necrotic, amorphous mate-
the four quadrants contained an atheroma. Grade I
rial, are acellular, and contain toxic, irritating, and
indicated one quadrant contained an atheroma;
antigenic material [37,60,61]. Atheromatous degen-
Grades II, III, and IV indicated involvement of two,
eration is similar to caseation observed with tuber-
three, or four additional quadrants contained an
culosis in that both have a high lipid content and
atheroma. Table 2 shows the relationship between
appear “cheesy” on gross appearance. Figures 6A,
luminal stenosis and the severity and extent of
6B, illustrate the gross and microscopic appearance
atheromas in each coronary segment. The relation-
of atheromas, showing a yellow, acellular, lipid-
ship between luminal stenosis and the circumferen-
laden, cheese-like necrotic core with a semi-solid
tial extent of the necrotic core showed Grades III
consistency. These photos show the tendency of
and IV atheromas were significantly more common,
atheromas to grow circumferentially from a central
p=<0.001, in those segments with >80% luminal
focus toward the plaque shoulder, and are fre-
stenosis than in those with <50% stenosis. There-
quently associated with adventitial inflammatory
fore, a direct relationship exists between plaque
infiltrates (Figures 5B-5E).
size, as reflected in the severity of luminal stenosis,
and the circumferential extent to which each coro-
nary segment is involved with an atheroma. Pro- The natural course of events for most bacterial

gressive and expanding injury caused by the IA abscesses is to point and drain spontaneously,

results in a progressive increase in plaque size and removing the offending organism and the toxic core

a progressive increase in the proportion of that material. The spontaneous rupture of a bacterial

plaque that is atheroma. abscess is related to increasing volume and pres-

sure within the necrotic core, plus the action of
digestive, proteolytic enzymes on the surrounding
tissue, particularly on the overlying cap. Resolution
and healing of such abscesses commonly follows
this spontaneous drainage, provided the necrotic
core is sufficiently emptied of necrotic material to
4-2
Atherosclerosis Atheromas Are Caseous Abscesses

allow resolution to take place. The over-all inflam-

matory response associated with localization and
encapsulation of the necrotic tissue and of the
offending agent that characterizes a bacterial
abscess is an important component. This is thought
to be a physiologic defense against the growth and
spread of a necrotizing, destructive organism. The
development of a pathologic condition or disease as
a result of this spontaneous drainage does not
mean these physiologic defenses, per se, are at
fault. For example: Rupture of a bacterial bowel
abscess that results in peritonitis does not mean the
defensive responses leading to spontaneous rup-
ture and drainage of the abscess are pathologic, or
that these defensive responses can or should be
prevented. Proper treatment is to focus on and treat
the IA, not the defensive responses. The same may
be true of atheromas.

Figure 6: A, Large necrotic, yellowish, crescent-shaped,

asymmetric atheroma in the proximal CIRC artery of an 81-year-
old female. Virtually all fibrous tissue in the core area has been
digested, leaving the lipid-laden core (asterisk). Note thin fibrous

4-3
Atherosclerosis Atheromas Are Caseous Abscesses

architecture, and it stains differently from neighbor-

cap (fat arrows) and small embolus in lumen (open arrow).
Magnification x9.25. B, Microscopic section of large necrotic
ing, viable cellular tissue. If these proteolytic
atheroma in the CIRC marginal branch of a 78-year-old male. enzymes are essential to the physiologic resolution
The intima is totally necrotic, and plaque hemorrhage has of injury, then the action of such enzymes in the
occurred (open arrows). The media and adventitia are intact.
formation of atheromas is, in the final analysis, also
Partially digested fibrous tissue is present along the left side of
the photo (long arrows). MSB stain. Magnification x19.5. C,
a physiologic response, not a complication of the
Atheroma in the mid-RCA of a 69-year-old white male. The disease. In other words, these enzymes may pro-
fragment (asterisk) appears to be undergoing digestion (open vide a key defense by promoting the removal of
arrows) with moth-eaten irregular border. Red blood cells (RBCs)
degenerating tissue and toxic agents from the artery
and fibrin (small arrows) suggest communication with the lumen.
MSB stain. D, Abrupt termination of a strand of fibrous tissue
wall.
within an atheroma (open arrow) of a 74-year-old male. The
digestive process appears to be attacking the fibrous tissue, and
portions of undigested fibrous tissue have been separated from
Some of the fibrous fragments are quite large, have
the main fiber (arrows). MSB stain. E, Same patient and section been completely separated from the surrounding
as D, but in a different area. Small fibrous fragment dangling wall, and are free-floating within the lipid core (Fig-
from the wall of the atheroma (thin arrows). The fragment
ure 6F). Should a major PU occur, these tissue
appears to be undergoing digestion with loss of fibrous
architecture and lighter staining amorphous tissue (fat arrows).
fragments would constitute a sizable embolus to the
MSB stain. F, Atheroma with a large free-floating fragment (open distal circulation. Because of their fibrous structure,
arrow) in an UP, located in a empty necrotic core in the proximal they may be difficult to remove by circulating
RCA of a 41-year-old white male. H & E stain.
enzymes and may cause ischemia and/or focal
infarction [64]. The digestion of these fragments by
Proteolytic Enzymes MMPs, while the atheroma is still intact and before
rupture or ulceration, may reduce the pathogenetic
Atheromas contain a number of proteolytic potential of such tissue emboli.
enzymes, particularly matrix metalloproteinases
(MMPs), derived primarily from monocyte-derived
“Exit” Tracts
macrophages present in and around the necrotic
core of atheromas [62,63]. These digestive
Another potential action of MMPs is the creation of
enzymes, because of their ability to digest injured or
communicating channels or tracts between deep-
degenerated tissue, play a major role in the
lying atheromas and the artery lumen. Figures 7A-
enlargement and growth of atheromas, but they are
7C illustrate an example of a tiny, narrow, long,
also necessary for the repair of injury [62]. There-
serpiginous tract that connects the lumen with an
fore, the digestion and destruction of dead or injured
underlying necrotic core. The presence of red blood
tissue by MMPs is a component of active
cells and injection mass within these tracts proves
atherosclerotic disease and constitutes one method
their in-vivo existence and excludes the possibility
of converting dead and damaged tissue to a
that they are cutting or post-mortem artifacts. Fur-
semisolid form, presumably for the purpose of
thermore, the presence of fibrin, red staining mate-
removing it.
rial on Martius Scarlet Blue (MSB) stain, (Figures
7A, 7B), shows pre-mortem communication with the
Figures 6B-6F illustrate digestion of fibrous tissue, lumen, activation of the clotting system, and forma-
taking place within different atheromas in different tion of intraintimal thrombus. These tracts pass
patients. The fibrous tissue undergoing digestion is through acellular, degenerated fibrous tissue (Fig-
acellular with loss of normal tissue substance and ure 7C). They are presumably formed by the action
4-4
Atherosclerosis Atheromas Are Caseous Abscesses

of MMPs secreted by macrophages that line the

tracts, and possibly with other digestive enzymes as
well [63], providing a route for plaque contents to
enter circulating blood. Specifically, these tracts are
NOT formed by the splitting and disruption of nor-
mal, cellular, viable fibrous tissue by external forces,
such as hemodynamic stresses [63], but are due to
actions and metabolic activities taking place within
the core [65]. Such tracts may be called “exit” tracts
because they contribute to core decompression and
reverse lipid transport. These communicating tracts
are similar to the sinus tracts observed in chronic
osteomyelitis and may open and close at recurrent
intervals, depending on factors contained within the
atheroma. Perhaps all plaques, at some time in their
existence, will develop such tracts that serve to
reduce plaque size.

4-5
Atherosclerosis
Figure 7: A - C, Coronary section from the proximal LAD of a 74-
year-old white male. A & B, Low and intermediate power views of
a plaque showing a tiny tract (arrows) traversing the fibrous cap
at the shoulder, communicating with a small necrotic core, rich in
fibrin (open arrow). The deeper, larger core in A (long arrow) also
stains positive for fibrin, suggesting the tract also communicates
with this large core. C, High-power view of rectangle shown in B
at mouth of tract, showing injection mass (solid arrows) and
RBCs (open arrows) within the tract. MSB stain. Fibrous tissue
stains blue, fibrin orange-red, and RBCs yellow with MSB stain.
D, Mid-LAD coronary artery of a 39-year-old male showing an
asymmetric plaque with two lipid cores (asterisks) separated by a
fibrous layer (thin arrow). Note a finger-like extension (open
arrows) of one lipid core in the direction of the shoulder of the
plaque, in the lower part of the photo, and thinning of the fibrous
cap at this point (white arrows). The different tissue
characteristics create a “layering” effect on visual examination.
Magnification x12. E, Cleavage plane (arrows) in a fibrous plaque
in the LAD coronary artery in a 33-year-old male. The cleavage
plane contains no injection mass and is partially closed by fibrous
tissue. MSB stain. F, Microscopic view of mid-LAD of a 53-year-
old white female showing two atheromas (asterisks) separated
by a partially calcified fibrous strand (thin arrows). Note these two
atheromas are oriented toward the shoulder at the upper margin
of the plaque (fat arrows). H & E stain. Magnification x19.75.
Cleavage Planes
Atherosclerotic plaques often present a layered
appearance, both on gross and histologic examina-
tion (Figures 7D–F). Stary, et al, suggest this lay-
ered appearance may be due to repeated disrup-
tions of the lesion surface associated with
hematomas or thrombotic deposits [15]. However,
Atheromas Are Caseous Abscesses
the layered appearance on gross examination to
which we are referring, (Figures 7D–7F), is due to
alternating layers of fibrous tissue and necrotic core
tissue, caused by different light-absorbing proper-
ties of these two major tissue types. Tracing this
layering through subserial sections often shows
these seemingly separate foci of necrosis are actu-
ally caused by extensions of a single necrotic core,
located either proximal or distal to this site. The lay-
ered appearance may be the result of a proximal/
distal expansion or burrowing of an atheroma, prob-
ably facilitated by MMPs, growing and expanding in
a longitudinal direction within the plaque at different
depths [32]. Also, adjacent atheromas may commu-
nicate and fuse with one another to form intercon-
necting necrotic cores that can extend long dis-
tances throughout the intimal layer and be
associated with multiple cleavage planes or tracts
within a given atheroma or between atheromas [66].
The cleavage planes are often oriented parallel to
the fibrous cap, with the necrotic core generally
directed or oriented toward to plaque shoulder (Fig-
ures 7D–7F). Some of these cleavage planes may
represent a previous exit tract, now healed (Figure
7E).
If this is the correct assessment of these cleavage
planes, is the presence or formation of such tracts
an important feature of atherosclerosis? The cleav-
age planes may be important if blood enters the
core at one site, as through an UP, and then
extends along cleavage planes, taking the path of
least resistance through the atheroma, with result-
ing plaque swelling and an increase in luminal
stenosis. The planes may also be important from
the standpoint of drainage of plaque contents in that
an exit tract at one point may serve to drain a
necrotic core some distance away.
4-6
Atherosclerosis Atheromas Are Caseous Abscesses

Plaque Shoulder Ulcerations Incision and drainage followed by resolution and

It is well known that macrophage foam cells and the
MMPs they produce are heavily concentrated at the
plaque shoulder [63], and that there is a propensity
for the plaque to ulcerate at this site. Ridolfi, et al.,
noted a fibrous cap that was eroded on the under
surface over a necrotic core, supporting the view
that the fibrous cap is eroded from within [67].
Figures 8A–8C, illustrate ulcerations involving the
shoulder of the plaque in different patients. The
fibrous cap is thin and attenuated at the point of
ulceration. The free end of the fibrous cap appears
to be valve-like in structure, (Figures 8A–8C), so it
could allow the extrusion of plaque contents in dias-
tole, then close in systole, preventing the ingress of
blood from the lumen. If this is correct, nature may
provide a mechanism for plaque contents to be
extruded, at the same time preventing or reducing
the inflow of large amounts of blood into the core
area. The force of arterial pulsation may pump or
“milk” plaque contents into the lumen in this man-
ner. Thus, the necrotic core may be intermittently
drained or partially drained in this manner.
healing are the proper treatment for all bacterial
abscesses. Incision and drainage may also be the
proper treatment for atheromas. PTCA is basically a
form of incision and drainage because the atheroma
is split, its contents drained by this procedure. Fol-
low-up studies after PTCA show a reduction in
luminal stenosis consistent with resolution and heal-
ing [68]. As long as the PTCA is accomplished
without such complications as thrombosis or
restenosis, this may be the preferred method of
treatment for a large atheroma or a vulnerable
plaque [69]. The use of coronary stents may con-
tribute to the success of the PTCA by assisting in
complete drainage, preventing or reducing post-
PTCA dissection along cleavage planes, and pro-
moting healing and subsequent resolution.

None of these UPs are associated with significant

luminal or occlusive thrombosis. Therefore, sponta-
neous PU and debulking, early in plaque develop-
ment prior to the development of significant luminal
stenosis, may be beneficial. Ulceration and
drainage of the necrotic core early in plaque devel-
opment are rarely associated with thrombosis and
may be beneficial if resolution, reendothelialization,
and fibrotic scarring stabilize the plaque and reduce
luminal stenosis [57]. These observations lead us to
question the prevailing opinion that PU is a patho-
logic event that must be prevented if we are to
prevent acute coronary disease [63].

4-7
Atherosclerosis Atheromas Are Caseous Abscesses

Figure 8: A, RCA section of a 37-year-old white male showing a

large shoulder ulceration (arrows) with the tract penetrating to the
necrotic core (black asterisk). Magnification x15.6. B, UP
(arrows) containing injection mass, involving the proximal CIRC
of a 58-year-old white male who developed cardiogenic shock
following acute inferior myocardial infarction. This was not the
culprit lesion. C, High-power view of the rectangle in B showing
plaque fragments near the mouth of the ulceration (white arrows)
within the artery lumen. D, Mid-RCA of a 62-year-old white male
who died within 24 hours of coronary artery bypass surgery. The
cholesterol crystals are aligned parallel (long arrows) in the exit
tract. The tract also contains many foam cells (short arrows).
Small amount of fibrin (open arrows) is present within the core.
MSB stain. E, UP in the proximal CIRC of an 82-year-old white
male who died of cardiogenic shock in the hospital. The
cholesterol crystals are again aligned parallel, as if being
extruded under pressure from within the core. RBCs and fibrin
surround the cholesterol crystals. H&E stain. F, Proximal RCA
section of an 82-year-old white male who died SCD out-of-
hospital. The cholesterol crystals appear to form a volcano-like
eruption. Note the disruption is through the center of the fibrous
cap and the marked adventitial inflammatory cell infiltrate (fat
black arrows). The eruption is associated with tiny luminal
thrombosis (white arrow), hemorrhage, and fibrin within the core
(thin black arrows). H & E stain. Magnification x12.6. In all
photos, white asterisk = lumen.

Increased Intraplaque Pressure

Evidence for increased pressure within an atheroma

comes from observation of the actions of cholesterol
crystals within the necrotic core. Figures 8D-F, illus-
trate parallel alignment of cholesterol crystals at the
site of PU, suggesting that these crystals are being
4-8
Atherosclerosis
actively and forcibly extruded under pressure from
within the necrotic core. This alignment of choles-
terol crystals may be a marker of impending PU in
the intact atheroma.
Figure 8F illustrates an explosion-like eruption of a
relatively small atheroma, preceded by parallel ori-
entation of cholesterol crystals within an exit tract. If
disruption of the fibrous cap were caused by exter-
nal hemodynamic stress, we would not expect to
see such uniform orientation, but rather a total dis-
organization of the cholesterol crystals. These
findings provide further support for, and are consis-
tent with, increased intraplaque pressure and spon-
taneous rupture or ulceration of the necrotic core
[66,70].
We propose actively growing atheroma result in
increased pressure within the necrotic core. This
increased pressure contributes to spontaneous
ulceration and drainage of plaque contents, similar
to that observed with bacterial abscesses.
The parallel orientation of the cholesterol crystals in
Figures 8D and 8E, raises further questions about
these crystals. Are they actually sharp and needle-
like as they appear, and could they act like a batter-
ing ram to pierce or damage tissue, thereby
facilitating or promoting PU? If so, then this is
another mechanism to consider in the pathogenesis
of PU.
Thermal Heterogeneity
Further evidence that atheromas are actively grow-
ing, inflammatory abscesses is provided by studies
of thermal heterogeneity. These studies show
active, progressive, growing, inflammatory athero-
mas are “hot” compared with adjacent normal
tissue. Increasing vascularity is associated with this
inflammation and is similar to the increased temper-
ature associated with an inflamed and swollen
Atheromas Are Caseous Abscesses
bacterial abscess [65,71]. Although virtually all UP
are associated with inflammation and could there-
fore be considered “hot,” there are many plaques
with associated severe inflammation that have not
ulcerated [57]. Therefore the use of this tool to iden-
tify the vulnerable plaque ready to ulcerate may be
difficult. At present, the determination of thermal
heterogeneity is an invasive technique, but its
potential for identifying the most active plaques
would be a major step forward.
In Review
Atherosclerosis is initially an FP disease, but it
evolves into a destructive process that leads to
luminal stenosis, caused primarily by the growth
and expansion of lipid-laden, necrotic atheromas.
PU and subsequent drainage of plaque contents are
components of and a natural consequence of the
growth of an atheroma, not, per se, a pathologic
event. Attempts to prevent PU may not be appropri-
ate. Atheromas grow primarily by the digestion of
degenerated, lipid-rich, fibrous tissue, through the
action of proteolytic digestive enzymes, particularly
MMPs. The growth and expansion of atheromas
result in increased pressure within the necrotic core,
leading to the formation of cleavage planes that
communicate with adjacent atheromas and to the
formation of exit tracts and/or UP, primarily at the
shoulder of the plaque. Decompression and/or
debulking of atheromas through PU, early in plaque
development, prior to significant luminal stenosis,
may be beneficial in stabilizing the plaque, reducing
luminal stenosis, and halting active progression of
the disease process at that site.
Unanswered Questions
What is the natural history of an UP that is not com-
pletely drained of necrotic contents at the time of
plaque rupture or ulceration? Do such partially
drained atheromas act like an incompletely drained
4-9
Atherosclerosis Atheromas Are Caseous Abscesses

bacterial abscesses? Do they continue to fester as

a chronic, indolent lesion that intermittently drains
and releases plaque contents, as in chronic
osteomyelitis? Do all plaques with a necrotic core
ulcerate and drain, not just once, but repeatedly
during their development? What are the implica-
tions, in terms of potential complications, of a single
necrotic core extending long distances along the
course of the coronary artery? Is PU beneficial if it
can be accomplished without pathologic sequelae?
Could the alignment of cholesterol crystals or
intraintimal fibrin be detected by Magnetic Reso-
nance Imaging (MRI) or other modalities and be
used as a means of identifying the vulnerable
plaque with impending rupture [72,73]? These are
some of the questions that must be considered in
dealing with the pathogenesis of atherosclerosis
and the subsequent sequelae.

4-10
Atherosclerosis Calcification

5. Calcification: A Physiologic Defense

the pathogenesis of injury and calcification. This
“Atherosclerotic calcification is an organized, regulated chapter will show that vascular calcification is a
process similar to bone formation that occurs only when other physiologic defense against active, progressive
aspects of atherosclerosis are present.”
atherosclerotic disease, that it is produced by phys-
L Wexler, et al., American Heart Association Writing Group,
[74] iologic mechanisms similar to those required for
normal bone formation [74,77,78], and that it is
potentially reversible [79,80].
Considerable insight into the nature and character
of the IA causing atherosclerosis can be gained
from the study of coronary calcification. Figure 9
shows postmortem X-rays illustrating different pat-
terns of coronary calcification in intact human hearts
(Figures 9A,B,D) and one case of dissected, unin-
jected coronary arteries (Figure 9C), in four patients
of differing age and sex who died of ACD. Calcific
deposits may be small, discrete, widely separate
foci, measuring only a few mm, or large, confluent
masses measuring several cm in length (Figures
9A-C). Calcification does not occur in a normal ves-
sel wall [74] and, when present, provides objective
evidence of arterial wall injury and the presence,
location, and extent of atherosclerotic plaque forma-
tion within the coronary tree [75]. Widely separate
foci of calcification, as shown in Figure 9, confirms
that atherosclerosis is multi-centric in origin, with the
IA being present and simultaneously active at multi-
ple separate sites within the coronary tree.

Confluent, uninterrupted blocks of calcification (Fig-

ures 9A-C), reflect active longitudinal growth with
fusion of adjacent plaques [76], as reported in
Chapter 2. The most extensive calcification is often
found in the proximal half of the main epicardial
coronary arteries, particularly the Left Anterior
Descending (LAD) artery [75], (Figures 9A,C,D),
suggesting hemodynamic forces contribute to wall
injury and plaque growth. Extensive calcification,
however, is often present in the distal half of a coro-
nary artery as well (Figures 9A-C), implicating
additional factors besides hemodynamic stress in
5-1
Atherosclerosis Calcification

Figure 9: Post-mortem X-rays of 3 hearts before injection of

barium gelatin mass (A, B, D) and the dissected coronaries of
one heart not injected (C). A, 42-year-old white male who died of
cardiogenic shock shows extensive, confluent calcification of the
LAD coronary artery (long arrows) and focal discrete calcium
deposits of the RCA (short arrows). B, 54-year-old white male
who died of SCD outside the hospital. Extensive calcification of
all three coronary arteries, particularly the RCA (white arrows),
with diffuse confluent calcification. Note the circumferential
calcification of the CIRC (black arrow). C, Coronary arteries of a
62-year-old white male who died SCD outside the hospital. The
RCA (short thin arrow)shows focal calcification extending into the
posterior descending artery. Extensive, confluent calcification is
seen in the LAD coronary artery (long arrow), and the intimedius
branch (fat arrow). D, 93-year-old white female who died as a
result of cardiogenic shock secondary to a large anterior
myocardial infarction. Relatively minimal calcification is present in
the RCA (short white arrow), the LAD coronary artery (long black
arrows), and CIRC (short black arrow) in this elderly patient.

Aging and Vascular Calcification

The presence of widely spaced calcified plaques in

a young patient, shown in Figure 9A, indicates
atherosclerotic injury occurred early in life and at
multiple locations, leading to premature, accelerated
atherosclerosis and to early death from ACD. We
5-2
Atherosclerosis Calcification

can assume, based on the multiple foci of calcifica-
tion, that the IA was active at multiple locations
within the coronary tree, spreading proximally, dis-
tally, and circumferentially, with fusion of adjacent
plaques.
Extensive calcification in young persons, Figure 9A,
and less extensive calcification in older persons,
Figure 9D, demonstrate calcification is not, per se,
an aging or age-dependent process [81], even
though the extent and amount of vascular calcifica-
tion tend to increase with age. If calcification were
an aging process, then all older persons would
show calcification, and the amount and extent of
calcification would be directly related to age. Calcifi-
cation reflects and is related to atherosclerotic
injury, caused by an IA that can and does occur at
any age. The increase in extent and severity of cal-
cification that occurs with increasing age is due to
the patient’s harboring and surviving an active,
spreading, IA for a long period of time. Age, per se,
plays no direct role in the pathogenesis of coronary
calcification.
Calcification and Luminal
Stenosis
Table 3 compares the relationship between coro-
nary calcification and luminal stenosis in the same
83 patients who died of ACD, shown in Table 1,
Chapter 3, and Table 2, Chapter 4. The amount of
calcification was determined histologically by view-
ing each microscopic slide and estimating the
circumferential extent of calcification. Each coronary
segment was divided into four 90° quadrants and
graded according to the presence or absence of
calcification in each quadrant. Grade I indicated one
quadrant showed calcification whereas Grades II,
III, and IV indicated the number of additional quad-
rants with calcification.

Table 3:. Comparison between the frequency and circumferential extent of calcification and luminal
stenosis, determined histologically, in 83 patients who died of acute coronary disease.

Amount of Calcification
% Calcification None I–II III–IV
Degree of # of Sections % # % # % # % # %
Stenosis (%)

<50 3221 46 574 18* 2647 82 548 17 26a 1

50–80 2458 35 1196 49 1262 51 1046 43 150 6
>80 1377 19 877 64* 500 36 654 47 223a 16
Totals 7056 2647 38 4409 62 2248 32 399 6

* = p =<0.001; a = p =<0.001

calcification is similar to adventitial inflammation and

The results: 2,647 (38%) of 7,056 coronary seg-
to the presence of a necrotic core in that all three
ments contained calcification. Of these segments,
basically reflect the magnitude, extent, and severity
2,073 (78%) were associated with >50% luminal
of injury caused by the IA. Calcification is a compo-
stenosis. Calcification was significantly more com-
nent and another consequence of active atheroscle-
mon, P=<0.001, in segments with >80% stenosis
rotic disease, not a specific pathologic complication
than in those with <50% stenosis. The frequency of
of the disease process [82,83] that can or should be
calcification is directly related to the severity of
prevented, apart from preventing atherosclerotic
luminal stenosis or to plaque size. Plaque size, as
disease itself.
discussed previously, is directly related to the mag-
nitude of the injury caused by the IA. Therefore,

5-3
Atherosclerosis Calcification

Further examination of Table 3 shows extensive

calcification of a given segment, Grades III/IV, is
significantly more common in those segments with
>80% stenosis than it is in those with <50% steno-
sis, p<0.001. These results confirm our previous
observations, Chapters 1 and 4, that the IA tends to
spread in a circumferential direction, and that calci-
fication of the injured tissue produced by the IA
follows in the wake of this expanding injury [Figure
9B].

Figure 9B, and Figures 10A and 10B, illustrate, in

one patient, the direct relationship between the
magnitude of atherosclerotic injury, the extent of
calcification, and the severity of luminal stenosis.
The entire right coronary artery, Figure 9B, is
involved with what appears to be a confluent block
of calcification, presumably formed by the growth,
enlargement, and fusion of many adjacent plaques.
The calcification is so severe that the lumen, even
though filled with injection mass, cannot be detected
in Figure 10A. In Figure 10B, after decalcification, it
is evident the patient has severe and extensive
obstructive disease throughout the course of this
artery, although the channel itself is not completely
obstructed. The amount and extent of calcification
reflect the plaque burden as well as the extent and
severity of atherosclerotic injury. Further, no acute
lesions such as thrombosis and/or UPs were
present in this artery, so extensive calcification is
not synonymous with nor indicative of acute or
unstable lesions [74].

5-4
Atherosclerosis
Figure 10: Radiographs of dissected coronary arteries in 2
patients, taken before (A, C) and after (B, D) decalcification. A &
B, Themid-RCA of the same patient shown in Figure 9B.
Removing the calcium deposits in A reveals extensive
obstructive disease of the artery in B. C & D, The RCA from a
63-year-old white male who died in hospital of cardiogenic shock,
secondary to a large anterior myocardial infarction. This artery
showed small flecks of calcification,one area located just
proximal to a 90% luminal stenosis (white arrow). The artery
beyond this obstruction shows no significant angiographic
stenosis, but histologic examination showed multiple areas with
70% stenosis.
Luminal Stenosis without
Calcification
Table 3 shows that 51% of all coronary segments
with 50–80% stenosis, and 36% of segments with
>80% stenosis did not show calcification.
Atherosclerotic plaques can become quite large,
significantly occluding the lumen, and still not show
calcification, confirming that not all plaques become
calcified and that the absence of calcification does
not exclude significant stenosis [74]. These obser-
vations limit the usefulness of electron beam com-
puted tomography (EBCT) to predict plaque volume
or the severity of stenosis at a specific site in the
coronary tree based on the amount and location of
calcification [84,85].
Calcification
The primary purpose of EBCT is to identify the
presence and extent of atherosclerotic involvement
of the artery wall and the overall “plaque bur-
den” [86,87]. However, calcific deposits must be >2
mm to be seen by EBCT, and the reproducibility of
the scans is low [88], making it difficult to follow the
progression of the disease at a specific site in the
coronary tree. The identification of coronary calcifi-
cation by EBCT has broad implications for
increased risk (89), but EBCT cannot detect the
current activity of the IA [74]. It is not possible to
distinguish an actively growing, progressive plaque
from an inactive, stable plaque on the basis of coro-
nary calcification. Therefore EBCT is of limited
value in determining or predicting acute events [90].
Figures 10C, 10D, are examples of diffuse, obstruc-
tive atherosclerotic disease of the right coronary
artery, with one tiny fleck of calcium at the point of a
90% stenosis in a 63-year-old, insulin-dependent,
diabetic patient. Multiple, widely separated areas of
70% stenosis were present throughout the length of
this coronary artery without associated calcification,
but no acute lesions, thrombosis, or UPs were
present in the artery. These observations empha-
size the difficulty of predicting the extent and sever-
ity of stenosis on the basis of coronary calcification,
even in high-risk patients.
However, a previous study from this laboratory
showed virtually all acute coronary lesions to be
associated with calcification at the site of the acute
lesion [57]. The absence of calcification, even at
points of significant stenosis, is strong evidence
against the presence of an acute lesion at such
sites [57]. The absence of calcification at the site of
significant stenosis suggests a stable, non-
dangerous, non-vulnerable lesion. At the same time,
the consistent presence of calcification at the site of
UPs, with or without thrombosis [57], means that
5-5
Atherosclerosis Calcification

calcification must play some role, discussed below, as nucleators for vascular calcification and may be
in the pathogenesis of PU and the development of present within degenerating SMCs or be excytosed
ACD. into the extracellular space (Figures 11A, B), the
way matrix vesicles pinch off from chondrocytes in

Calcification Is Similar to Bone bone formation (Figure 13D) [74,93,97]. Matrix vesi-

Formation cles tend to clump and fuse together causing a

breakdown of the matrix vesicle membrane, expos-
ing their contents to intra- or extracellular fluid
Vascular calcification is now recognized as an
containing bone matrix proteins (Figures 11A, B),
active, organized, complex, highly regulated pro-
followed by the formation of HA. Matrix vesicles are
cess that is similar, if not identical, to normal bone
an objective sign of cellular injury, death or apopto-
formation [60,74,77,91]. It is NOT the result of pas-
sis [25,96,98], are an essential element required for
sive precipitation of calcium salts in or on degener-
calcification, and are commonly present in most
ating fibrous tissue [74]. Vascular cells are induced
atherosclerotic plaques.
to calcify by the same set of genes as those
expressed during bone formation [92]. Specifically,
the calcification of atherosclerotic plaques involves
The tiny focus of calcification shown in Figure 11B
virtually the same biologic reactions as normal phys-
is composed of many matrix vesicles that have
iologic bone formation and is not the result of a
fused together in a rather random, disorganized
pathologic biochemical calcification process. The
fashion in an area of tissue degeneration containing
calcium deposits in vascular calcification exist pri-
many other isolated matrix vesicles. In contrast Fig-
marily in the form of hydroxyapatite (HA) that is
ure 11C, the calcification process appears to be
identical to the HA in bone [77,93]. Although the
quite organized with the formation of a relatively
sequence of events leading to normal bone forma-
uniform calcification front [93,94], surrounded by
tion is well known, the sequence of events leading
many matrix vesicles. The calcification front identi-
to vascular calcification is not completely under-
fies the dividing line between viable and nonviable
stood. Various mechanisms may be involved
tissue. Note how the degenerating fibrous tissue in
[74,91,94].
Figure 11C serves as scaffolding for calcium depo-
sition and how the basic fibrous architecture is
Matrix Vesicles maintained after calcification. Why an organized
calcification front develops in some plaques while in
Figures 11, 12 and 13 illustrate the similarity others tiny foci of calcification are scattered
between vascular calcification and normal bone throughout the plaque is not clear.
formation. Vascular calcification is believed to begin
with the formation of matrix vesicles within degen-
erated SMCs [25,82,95], Figures 11A–11C, while in
bone formation matrix vesicles are formed within
degenerating chondrocytes (Figure 13D). Matrix
vesicles are tiny, round structures of variable size
and density, containing microcrystalline calcium
derived from mitochondria, other cell organelles, or
from influx of calcium from the extracellular space
[25,74,95,96]. Matrix vesicles are believed to serve
5-6
Atherosclerosis Calcification

5-7
Atherosclerosis Calcification

Figure 11: A, This section was taken from the proximal LAD
coronary artery and shows “dead” SMCs containing intracellular
matrix vesicles, clumped together and forming tiny foci of
calcification. The cell spaces are of different size, suggesting
adjacent cells have fused together (arrows). H & E stain. B, A
small focus of calcification composed of multiple matrix vesicles
that appear to have fused together (open arrow) in an area of
cellular and tissue degeneration. Cell loss and degeneration of
fibrous structure have occurred with many matrix vesicles in the
area (solid arrows). H & E stain. C, Calcified plaque lying
adjacent to the lumen of a 68-year-old female. Note the relatively
uniform calcification front (thin arrows) and the presence of
numerous matrix vesicles (fat arrows) surrounding the front.
Viable tissue is above the front and calcified tissue below. The
tissue architecture is preserved and serves as a scaffolding for
the advancing front. Asterisk = lumen. H & E stain. D, Low-power
view of a calcified plaque (solid arrows) and an adjacent mass of
amorphous globular material (open arrow), staining red with MSB
stain. E, Higher-power view of the material in D, showing its
“knobby” appearance and attachment to the calcification front
(arrow). F, Monoclonal antibody staining for osteopontin of the
osteoid-like tissue shown in D & E. A brown, positive staining
reaction for osteopontin (arrows), is present throughout this
tissue, suggesting active calcium deposition.

5-8
Atherosclerosis Calcification

Figure 12: A, A calcified plaque stained for osteopontin (brown

reaction product), illustrates positive staining of the calcification
front (open arrows), the surrounding matrix vesicles (thin arrows),
and lipid laden SMCs (fat arrows). B, A focus of calcification
showing a large number of matrix vesicles (arrows) congregating
and fusing along a calcification front. The matrix vesicles stain
red, in the same manner as they do in degenerating cartilage in
Figure 13D, with the MSB stain. A calcified plaque shows
multiple calcification layers (open arrows), suggesting
appositional growth. C (H&E stain) and D (MSB stain). Clumps of
matrix vesicles (thin arrows) along the outer layer suggest an
active, advancing calcification front. E, High-power view of a
calcification front (arrows) with matrix vesicles within SMC
spaces. H & E stain. F, Same area as in E with MSB stain,
demonstrating positive MSB staining material within the
degenerated SMCs (solid arrows), as well as fusion and
enlargement of the lacunar spaces (open arrows).

5-9
Atherosclerosis
Figure 13: All sections in this figure were taken from the bone of
the sheep heart. A, Low-power view showing marrow elements
(short arrows) and bright red staining of cancellous bone (open
arrows). MSB stain. B, High-power view of the periosteal layer of
the bone shown in stained for osteopontin, showing osteoblasts
Calcification
contain large amounts of osteopontin (arrows). C, Interface
between cartilage and bone Note chondrocytes (open arrows)
and surrounding cartilage do not stain red with the MSB stain,
but the encroaching osteoid, cancellous bone, stains deeply red
(solid arrows) similar to the red staining matrix vesicles in SMCs
in Figure 12E & 12F. D, Degenerated chondrocytes (long arrows)
containing matrix vesicles (short arrows) that stain red with the
MSB stain suggest that osteoid and bone matrix proteins (open
arrows) line the margins of the lacunae.
Osteoid
Normal bone formation requires osteoid, the
organic, unmineralized matrix of bone produced by
osteoblasts. Osteoid is composed of matrix vesi-
cles, osteopontin, collagen, and other non-
collagenous bone matrix proteins. It often has a
knobby appearance. The deposition of calcium salts
in both normal bone formation and in vascular calci-
fication is believed to begin and progress under the
influence of osteopontin and other bone matrix pro-
teins, which act as mediators of the calcification
process [74,93,94,99]. Once osteoid is formed, cal-
cification is believed to progress rapidly, within one
or two weeks, with rapid disappearance of the
osteoid [99]. Although osteoblasts involved in bone
formation have not been identified as such in
atherosclerotic plaques, several investigations have
shown pericytelike cells, possibly originating in
SMCs, within the plaque. These function much like
bone osteoblasts [77,78,92,100]. It is reasonable to
believe these pericytelike cells have the ability to
produce osteoid.
Osteoid and Atherosclerotic
Calcification
Calcification begins with the exposure of HA in the
matrix vesicles to osteoid [99] and to bone matrix
proteins that are found in atherosclerotic plaques,
but not in normal vessel wall [93]. Osteopontin is
synthesized by vascular SMCs, macrophages, and
endothelial cells [100], has calcium-binding sites, is
5-10
Atherosclerosis
regulated by cytokines, binds readily to HA, and is
found at the sites of early calcification [74,99,101]. If
atherosclerotic vascular calcification and bone are
similar in formation and composition, then osteoid or
osteoid-like tissue should be present in atheroscle-
rotic plaques. Demer [99] believes some of the
atherosclerotic matrix resembles osteoid, but
osteoid, per se, has not been identified in calcified
atherosclerotic plaques.
Figures 11D–11F, are examples of tissue in the wall
of a calcified coronary artery that has features con-
sistent with osteoid. These deposits consist of an
amorphous, relatively acellular mass of tissue, stain-
ing bright red with MSB stain, knobby in appear-
ance, and located adjacent to a calcified plaque.
Immunohistochemistry staining of this tissue with
osteopontin monoclonal antibodies shows intense
staining, (Figure 11F), suggesting this material may
be osteoid. Connected to the amorphous mass is a
calcification front, also staining bright red with MSB
(Figures 11D, 11E), and also with osteopontin anti-
body, Figure 12A. The amorphous mass and the
calcification front may be related to and composed
of the same tissue. If this amorphous tissue is
osteoid, then it may be a site of active calcification
and of an active expanding, spreading calcification
front.
Figures 12C, 12D illustrate layering, apparently pro-
duced by an advancing calcification front. This
appositional growth of the calcified plaque is similar
to the appositional growth of bone. Note that the
leading edge of the calcification front and associ-
ated matrix vesicles stain red with MSB, but those
residual calcification fronts behind the leading edge,
not surrounded by matrix vesicles, do not stain red
with MSB. Therefore, a calcification front staining
red with MSB and surrounded with similarly staining
matrix vesicles, (Figures 12 B-F), may indicate
active calcification is occurring, and the calcification
front is advancing. If these features are absent,
Calcification
active calcification may have ceased. The MSB
stain may be a convenient method of identifying
osteoid in the artery wall. To further explore the
possibility that this amorphous tissue in the artery
wall may be osteoid, we performed similar stains on
normal bone.
Normal Bone and Cartilage
Figure 13 illustrates the staining features of normal
bone, cartilage, osteoid, and matrix vesicles in the
bone and cartilage found within the sheep heart
[102]. Cancellous bone, Figure 13A, is immature
bone, recently formed from osteoid, that stains
bright red with MSB like the amorphous masses in
Figures 11D, 11E. Figure 13B shows osteoblasts at
the periosteal surface, the site of new bone forma-
tion, stain strongly with osteopontin antibody, con-
sistent with active bone matrix formation. Normal
cartilage, (Figure 13C), does not stain red with the
MSB stain, confirming that normal cartilage does
not contain osteoid. However, osteoid-like tissue
appears to be advancing into and replacing the car-
tilage. Finally, in Figure 13D, the matrix vesicles,
like the matrix vesicles in Figure 11A, are contained
within degenerating chondrocytes, and stain bright
red with MSB. This is strong evidence that the
amorphous mass, staining bright red with MSB stain
in Figures 11D and 11E, is osteoid.
Evolutionary Purpose
What is the significance or evolutionary purpose of
bone or bone-like deposits in the wall of an
atherosclerotic artery?
Why is it necessary that these calcific deposits be
bone, formed by a very complex series of biochemi-
cal reactions, rather than, say, by the passive
precipitation of salts [99]? Is there a larger purpose
here than just the calcification of injured, degenerat-
ing tissue? Is vascular calcification a physiologic
5-11
Atherosclerosis
defense against the action of the IA or is it a patho-
logic process, a complication, of atherosclerosis,
that should be prevented, as theorized by some
investigators [82,83]? If vascular calcification is the
same as normal bone, formed by the same bio-
chemical reactions as normal bone, it is difficult to
understand how this physiologic process suddenly
becomes a pathologic process, a complication that
must be prevented.
Calcification, in general, is often regarded as an
important component of the healing process, gener-
ated as a physiologic defense designed to contain,
wall off and stabilize injured or damaged tissue and/
or foreign agents [99]. Calcification of a ghon com-
plex is an example. Atherosclerotic calcification,
however, appears to have a different purpose
because the IA is not sequestered or walled off. In
fact, calcification appears to have little if any direct
influence on the activity of the IA because the dis-
ease continues to progress. The preservation of the
fibrous tissue architecture behind the calcification
front, as illustrated in Figures 11C and 12A, indi-
cates the injured and degenerated tissue was
calcified quickly, before the onset of necrosis. If
there is prompt formation of pericytes or osteoblast-
like cells and these cells produce osteoid, calcifica-
tion of degenerated fibrous tissue by an advancing
calcification front could occur rapidly, utilizing the
same biochemical mechanisms as normal bone
formation that are already present. The rapid calcifi-
cation of degenerating fibrous tissue may be viewed
as a physiologic defense that can be mobilized rela-
tively quickly and efficiently.
Therefore, one evolutionary purpose of vascular
calcification may be to preserve the fibrous tissue
architecture by rapidly calcifying this tissue to main-
tain wall integrity, delaying the onset of necrosis. It
is important to remember that necrotic tissue, per
se, does not undergo calcification, primarily
because necrotic tissue has no structure or scaffold-
Calcification
ing for the deposition of calcium salts. A second
evolutionary purpose of calcification may be to
delay the longitudinal spread of the IA by creating
barriers between adjacent plaques, preventing or
delaying the formation of cleavage planes between
plaques and adjacent necrotic cores. Atheroscle-
rotic calcification is an abnormality, but that does
not prove it is pathologic in nature. Seen from the
standpoint of a threatening, advancing, destructive,
IA, calcification may be an essential physiologic
defense, in delaying destruction of the artery wall.
Reversibility of Coronary
Calcification
Several histologic observations suggest coronary
calcification is reversible. Patients who died from
malignant disease have a very low frequency of
coronary calcification, indicating that calcification
may be reversed in wasting conditions [75]. Clinical
studies of patients receiving HMG-CoA reductase
inhibitors to lower blood cholesterol show a reduc-
tion in calcium score on serial testing with EBCT
[79,80]. Apparently the activity of the IA can be
slowed or arrested, and calcification can be
reversed. Figures 14A–14D, are typical calcified
plaques from two patients of different ages. In Fig-
ure 14A and B the central portion of the calcified
plaque contains many lacunae, of different size,
apparently formed from dead SMC, that appear to
be fusing or coalescing as a result of degeneration,
destruction, or resorption of the calcified fibrous
septa between them. In Figure 14C and 14D, these
lacunae have fused to form a small lipid lake pre-
sumably formed by the fragmentation, erosion, and
dissolution of the calcified, lipid-rich, fibrous tissue.
Resorption, destruction, or dissolution of the central
portion of calcified plaques may have important
implications for plaque progression.
5-12
Atherosclerosis
What is the mechanism of this apparent resorption?
Several possibilities can be considered. First,
Jeziorska, et al [103], found multinucleated giant
cells in close apposition to carotid calcification that
demonstrated all the normal features of bone forma-
tion and resorption. Vascular calcification may
seemingly undergo resorption in the same manner
as bone. Second, bone undergoes resorption and
avascular necrosis when deprived of its blood sup-
ply. The same may be true of vascular calcification
that has no nutrient blood supply [104]. Third, SMC
produce and contain MMPs. These enzymes may
remain active after the SMC dies and be a signifi-
cant factor in the degradation and resorption of
calcified vascular tissue [94,105], particularly when
resorption originates within the central part of calci-
fied plaque. Vascular calcification may not be a
permanent or inert deposit, but an active, dynamic,
changing structure capable of being reversed,
removed, and/or remodeled [99]. If this is correct,
then all calcified plaques have the potential to
undergo reversal and resorption.
Figure 15A shows a large, circumferential calcified
plaque containing a similar circumferential, struc-
ture-less, necrotic core. Figure 15B, in contrast,
shows a very small, calcified plaque with similar
findings, showing that such a structure-less central
core can develop in calcified plaques of any size.
Figure 15C illustrates a large necrotic core with a
tiny rim of focal calcification that has an irregular,
moth-eaten border facing the necrotic core. This
calcified rim appears to be undergoing digestion or
destruction, presumably by substances contained
within the core. This calcific deposit does not stain
bright red with the MSB stain, suggesting osteoid
formation and active calcification are not taking
place. This rim of calcification may be receding, not
forming.
Calcification
Support for this view is provided in Figure 15D,
another calcific deposit at the rim of a necrotic core,
but stained with osteopontin monoclonal antibody.
Again, we have the irregular moth-eaten border
consistent with degeneration and resorption, and
this degeneration is associated with free-floating
fragments within the necrotic core, also staining
positive for osteopontin. The calcific deposit
appears to be breaking up rather than forming. The
rim of calcification commonly found at the edge of a
necrotic core may be a remnant of a previously cal-
cified plaque and the necrotic core may have origi-
nated and been formed by the resorption and
dissolution of the calcified plaque. If this is correct,
then the chemical agents and biologic compounds
that are by-products of calcification resorption will
be added to all the other compounds present within
the necrotic core. Since HA is very irritating when
injected into joints [96] it is possible that it may also
be very irritating and toxic when present in the
necrotic core.
What role, if any, does plaque calcification play in
the formation of the necrotic core? What is the
sequence of events in the growth and development
of the calcified plaque? What comes first, the
necrotic core or calcification? How can necrosis and
the formation of an atheroma occur before calcifica-
tion, as suggested by Stary, et al. [15], when matrix
vesicles form at the time of SMC death, fuse, form
calcific deposits, and calcify degenerated fibrous
tissue well before the onset of actual necrosis? The
presence of microcrystalline calcium within a
necrotic core [15] suggests calcified tissue was
digested in the formation of the core and that calcifi-
cation preceded the development of necrosis.
Evidence presented shows that calcified plaques
may be reversible. This reversal appears to result in
the destruction and dissolution of the lipid-rich scaf-
folding of fibrous tissue, and leads to the formation
5-13
Atherosclerosis Calcification

of a structureless central core that, in time, may

lead to the formation of a necrotic, atheromatous
core.

Figure 14: A, Low-power view of a calcified plaque (open

arrows) from the CIRC coronary artery of a 51-year-old male.
The calcified fibrous tissue appears to be undergoing
degeneration, and the lipid-laden lacunar spaces fusing together
(solid arrows). B, High-power view of the same plaque as A.

5-14
Atherosclerosis Calcification

Lacunar spaces vary in size, presumably formed by the fusion of

adjacent lacunae formed from dead SMCs. H & E stain. C, A
calcified plaque showing fusion and enlargement of lipid-laden
lacunae (solid arrows) forming a small lipid lake (open arrow). D,
High-power view of rectangle in C showing dissolution of the
calcified fibrous tissue (solid arrows) and fragmentation of tissue
at the edge of the lipid lake (open arrows). H & E stain.

Figure 15: A, Section from the mid-LAD coronary artery in a 58-

year-old male. A large circumferential calcified plaque (arrows)
surrounds a large lipid rich necrotic core (asterisks). H & E stain.
Magnification x11.5. B, Small calcified plaque (arrows) in the
distal RCA of a 58-year-old male, showing a small structureless
central core (asterisk). H & E stain. C, Large necrotic central core
with small rim of calcification (solid arrows). Note the irregular,
moth-eaten border (open arrows) that faces the core. MSB stain.
D, Small calcium deposit at the rim of a necrotic core (solid
arrows), immunostained for osteopontin (brown reaction
product), showing that these calcium deposits stain intensely for
osteopontin. Note that the loose fragment (open arrow) also
stains positive for osteopontin.

Sequence of Events

Insight into the sequence of plaque development

can be gained by reviewing Table 1 in Chapter 3,
Table 2 in Chapter 4 and Table 3 in this chapter.
These tables show 51% of all coronary segments
have inflammatory cell infiltrates, Table 1; 38%
show calcification, Table 3; and 32 % show the
presence of a necrotic core, Table 2. The frequency
of calcification in Table 3 is greater than the fre-
quency of a necrotic core at all levels of stenosis,
whether <50% stenosis, 50—80% stenosis, or
>80% stenosis. Inflammation develops first follow-
ing the injury, followed by calcification and then by
5-15
Atherosclerosis Calcification

the formation of a necrotic core. This evidence sup-
ports our view that many atheromas have their
origins within a calcified plaque. The reversal or
resorption of plaque calcification may explain why
EBCT studies are not reproducible, and why plaque
volume cannot be quantitated from the amount of
calcification present [88].
formation of an atheroma by adding the byproducts
of resorption to the necrotic core. The sequence of
events in plaque development following injury is
inflammation, followed by calcification of the dam-
aged tissue, ending ultimately in the formation of a
necrotic core.

In Review

Calcification of the coronary arteries identifies the

site and extent of atherosclerotic involvement. Calci-
fication is a component not a complication of
atherosclerosis. Uninterupted blocks of calcification
indicates the IA spreads in a longitudinal direction
and adjacent plaques fuse together. Age plays no
direct role in the pathogenesis of calcification. The
amount of calcification reflects the magnitude,
extent and severity of the injury caused by the IA.
The amount of calcification tends to reflect plaque
size, but is not sufficiently accurate to predict the
severity of luminal stenosis. Calcification does not
detect the current activity of the IA or the site of cur-
rently active disease, limiting its clinical usefulness.
The absence of calcification is strong evidence
against the presence of active disease even with
significant luminal stenosis. Calcification plays some
role in PU.

Vascular calcification is believed to utilize the same

biochemical processes and substances as in normal
bone formation, and the composition of both bone
and vascular calcification is similar. Matrix vesicles
derived primarily from degenerating SMCs act as
nucleators for the deposition of calcium salts in
atherosclerotic plaques, with calcification commonly
occurring on a scaffolding of degenerated fibrous
tissue, in the same manner as bone forms on the
scaffolding of degenerating cartilage. Calcification
serves to preserve the integrity of the artery wall,
delaying and/or retarding the spread of the IA. Calci-
fication is reversible and may contribute to the
5-16
Atherosclerosis Adventitia – The Ultimate Defense

6. Adventitia – The Ultimate Defense

plaque, but is distributed uniformly over the entire
“Another feature of importance is the great tensile strength of circumference of the plaque. This diffuse thickening
the adventitia.” suggests that the IA causing intimal injury and
MC Winternitz, et al., [104]
atherosclerosis is also responsible, directly or indi-
rectly, for producing adventitial thickening. The IA
Previous chapters have shown how the IA spreads itself, or a product thereof, may diffuse or pass
in both a longitudinal and circumferential direction through to the adventitia from the plaque by direct
within the intima. The possibility exists, judging by perfusion, convection [106] or via the lymphatics,
intimal destruction and the formation of a necrotic precipitating this thickening. The actual mechanism
core, that the destructive process could also spread of growth may be the release of growth factors,
outward or laterally through the arterial wall, empty- such as Fibroblast Growth Factor, that are released
ing plaque contents into the pericardial space. by intimal macrophages and pass to the adventitia
However, erosion, destruction, necrosis or perfora- [107]. Some stimulus related to plaque formation
tion of the artery wall do not occur in the course of and growth causes the adventitia to respond in a
active atherosclerosis. The elastic lamina, the consistent, uniform, and characteristic way to the
media, and the adventitia appear to be resistant to injurious process occurring in the intima.
the effects of the IA, preventing lateral spread. Win-
ternitz, et al. [104] showed the adventitial layer of
the artery wall to be extremely strong with a very
high tensile strength. It was virtually impossible,
using a balloon, to rupture an artery with an intact
adventitia. These same arteries were easily rup-
tured by removing the adventitia. The media and the
elastic lamina do not compare to the adventitia in
tensile strength. The adventitia may be the structure
that contributes most to preventing outward growth
and expansion of the IA, and may be extremely
important in maintaining the integrity of the artery
wall.

Adventitial Thickening over

Atherosclerotic Plaques
The adventitia often thickens over atherosclerotic
plaques [60], but not over unaffected artery wall,
(Figures A-D). A relationship exists between the
injury occurring in the intima and the resulting
adventitial FP, but the precise relationship is not
clear. The adventitial thickening illustrated in Figure
16 is not localized in just one area overlying the
6-1
Atherosclerosis Adventitia – The Ultimate Defense

Figure 16: A, Proximal CIRC coronary artery from a 43-year-old

white male who died in the hospital of cardiogenic shock
following an AMI. The asymmetric plaque is calcified and
contains two necrotic foci (asterisks), and the adventitia overlying
this plaque is thickened in a rather uniform manner. The
adventitia is not thickened over normal, uninvolved wall. B, High-
power view of rectangle B in A showing heavy Tcell infiltrates in
a thickened adventitia (short fat arrows) and associated with a
similar infiltrate in the intima (long arrows). The intimal fibrous
tissue adjacent to inflammatory infiltrates appears to be
undergoing digestion. The media appear to be intact (open
arrows). A large adventitial arteriole is close by (white asterisk).
MSB stain. C, High-power view of rectangle C in A. The intima
(white arrow) is of normal thickness and is not involved with
atherosclerosis. The media (open arrow) and the adventitia
appear normal without injury, thickening, inflammation, or
increased vascularity. MSB stain. D, High-power view of
rectangle D in A, containing a small portion of the intima
(asterisk), the internal elastic lamina (solid arrows), the media
(open arrows), and the adventitia (bracket). The adventitia is
composed of layers of thick collagen fibers, often wavy in
appearance and oriented in a circumferential direction. Relatively
few cells are present and typical intimal SMCs cannot be
identified in the adventitia. H & E stain.

Evolutionary Purpose of
Adventitial Thickening

Why should the adventitia thicken when the primary

injury involves the intima? Shi, et al. [108] demon-
strated adventitial thickening following balloon injury
6-2
Atherosclerosis
to the coronary arteries in pigs. They noted striking
similarities between ordinary wound healing and the
adventitial response to injury. In circumstances of
traumatic injury, clearly the adventitia plays a key
role in resolution and repair, with fibromyoblasts
migrating to the intima [108]. Perhaps the adventitial
thickening associated with active atherosclerosis is
produced in response to intimal injury, particularly to
progressive and expanding injury by the IA.
What role or what evolutionary purpose does adven-
titial thickening play in atherosclerosis? Is adventitial
thickening a pathologic response that should be
prevented, or is it a physiologic response to injury?
The most logical explanation is that the thickening is
a physiologic, defensive response to outward
spread and expansion of the IA, similar to the FP
response observed in many chronic inflammatory
conditions [109].
Adventitial Resistence to the IA
Fibroblasts, not SMC, are the predominant cells of
the adventitia. They do not succumb to the IA, do
not transform into macrophages, and do not pro-
duce an abnormal form of extracellular matrix that
reacts with and retains lipid. Lipid-laden
macrophages, foam cells, or excessive amounts of
extracellular lipid are not a prominent feature of the
adventitial thickening over plaques, and lipid-laden
SMC are not present in these areas (Figure 16D).
Adventitial cells and tissue do not contribute to the
destructive process and do not undergo degenera-
tion or necrosis as the disease advances. There-
fore, unlike monocyte macrophages and intimal
SMC, the adventitial fibroblast does not become a
component of active atherosclerotic disease. The
failure of atheromas to erode through the adventitia
and ulcerate into the pericardial space, and the fail-
ure of a necrotic core to form in the adventitia
indicate an inherent resistance of the adventi tia to
the aggressive, destructive effects of the IA. The
Adventitia – The Ultimate Defense
adventitia is an extremely strong barrier that, in
essence, serves to restrict the IA to the intima,
where the only outlet for the expanding necrotic
core is into the arterial lumen.
Histologic Features of Adventitial
Thickening
What characteristics of the adventitia combine to
make it resistant to atherosclerotic injury? Typical
features of adventitial thickening, shown in Figures
16A and 16D, are tight, thick layers of sparsely cel-
lular collagen, wavy in appearance and oriented,
band-like fashion, circumferentially around the
artery. These histologic features are markedly dif-
ferent from the intimal FP response shown in Fig-
ures 3A and 3B. There are significant structural
differences between the fibrous tissues of the intima
and the adventitia to support the observed differ-
ences in their physiologic responses.
Adventitial fibrous tissue has been termed “fibrillar
collagen” [10] because of its thick fibers, and
because it has been shown to be relatively stiff,
hard, and rigid compared with the fibrous tissue of
the intima, producing a stiff collar around the artery
[10,108). Some of this stiffness may be related to
differences in the amount and composition of the
ECM. Intimal fibrous tissue has a higher content of
PGs and is more visco-elastic and compressible
than the adventitia where the PG content is quite
low [43]. These different physical characteristics of
tissue may impart tensile strength to the adventitia
and may also contribute to its inherent resistance to
the IA.
Significance
The adventitial FP response and inherent resistance
to the IA may have teleological significance
because preservation of arterial wall integrity is
more important to the organism than preserving the
6-3
Atherosclerosis Adventitia – The Ultimate Defense

luminal diameter of the artery. In other words, loss

of arterial wall integrity by the IA’s eroding through
to the pericardial space means certain death, but
loss of luminal diameter due to the activity of the IA
that is confined to the intima may be tolerated and
be compatible with life. Adventitial thickening, the
infiltration of T lymphs into the adventitia, and the
marked increase in vascularity due to the profuse
development of the vasa vasorum may be physio-
logic responses that limit the growth and expansion
of the IA.

In Review
The adventitia is resistant to the IA causing
atherosclerosis, and it prevents the destructive pro-
cess from eroding outward through the arterial wall
into the pericardial space. The adventitia thickens
and acts to maintain wall integrity as well as to con-
fine the IA to the intima, where the only outlet for the
necrotic core is into the artery lumen. Adventitial
fibroblasts and adventitial collagen are not affected
or subverted by the IA and they do not contribute to
the growth and expansion of the disease process.

6-4
Atherosclerosis
7. Surface Erosions
“Erosion of proteoglycan-rich and smooth muscle cell-rich
plaques lacking a superficial lipid core or plaque rupture is a
frequent finding in sudden death due to coronary thrombosis.”
A Farb, etal., [110]
The IA causing atherosclerosis is believed to enter
the artery wall from the circulating blood through a
breach in endothelial integrity, localizing in the
intima and initiating the injurious, destructive pro-
cess that leads to plaque development [18]. The IA,
however, is not necessarily confined to the depths
of the intima, but may also localize at the endothe-
lial surface overlying the plaque and cause injury,
erosion, and destruction of the endothelium and
subendothelial tissue (Figure 7)[110]. The histologic
features surrounding these surface erosions are
similar if not identical to those found in the deeper
necrotic core, including the presence of
macrophage foam cells, tissue debris, and evidence
of tissue digestion and destruction. Both deep and
superficial lesions may be caused by the same IA.
Surface erosions occur only over atherosclerotic
plaques, not over normal wall. They therefore follow
and are superimposed on an already established
plaque. This means there is a time interval between
initial plaque formation and the subsequent devel-
opment of surface erosions, suggesting that the IA
initially traversed the endothelial barrier without
affecting or injuring the endothelial cell. If both deep
and superficial lesions are caused by the same IA,
but at different time intervals, then the IA must be
present and persist in the circulating blood for long
periods of time. The subsequent development of a
surface erosion results in two active, destructive
processes proceeding simultaneously, but at sepa-
rate locations within a plaque, with surface erosions
arising separately, independent of the deeper injuri-
ous process.
Surface Erosions
Endothelial Vulnerability or
Dysfunction
The observation that surface erosions are limited to
the endothelial surface overlying a plaque suggests
the endothelium in this region has become altered
in some way [18,111] and may be more vulnerable,
dysfunctional, or susceptible to the IA than is the
endothelium over normal wall. Something or some
agent contained or acting within an atherosclerotic
plaque appears to adversely affect the overlying
endothelium, particularly in its ability to withstand
injury by the IA [111]. Endothelial dysfunction or
injury is apparently multifactorial in origin [18], but
this does not mean the IA is also multifactorial.
However, surface erosions are not present over
every plaque so there may be variable responses
by the endothelium overlying atherosclerotic
plaques.
Judging by the histologic changes taking place at
the endothelial surface, an IA, such as a virus, may
actually enter the endothelial cell and alter intracel-
lular mechanisms and functions [112]. For example,
Figure 17A shows a single layer of endothelial cells
distended with lipid, suggesting they have trans-
formed into macrophages, ingested lipid, and sub-
sequently developed into macrophage foam cells.
The plaque tissue underlying this layer of endothe-
lial cells, although diseased and abnormal, does not
contain macrophage foam cells. The IA may have
targeted and entered these endothelial cells directly.
The macrophage foam cell is an afflicted cell that is
unable to migrate within tissue, to regulate the
uptake of lipid or to maintain endothelial integrity
[30]. The protective, defensive responses that char-
acterize a normally functioning macrophage have
apparently been altered in some way by the IA, pre-
7-1
Atherosclerosis Surface Erosions

sumably to its advantage. If the IA enters the

endothelial cell and alters intracellular function to
suit its own purposes, then the endothelial
macrophage becomes a subverted pawn of the IA
and a pathologic component, fostering the progres-
sion of the disease process.

Figure 17B and C, show a surface erosion or a

superficial ulceration involving the endothelial and
subendothelial tissue that is much more extensive
than that in Figure 17A and is associated with many
loosely attached macrophage foam cells. This ero-
sion involves a rather sizable portion of the luminal
circumference. It is also associated with a rather
deep penetrating ulcer near the center of the
plaque. Close examination of the tissue interface at
the base of the erosion shows evidence consistent
with active digestion and destruction of plaque tis-
sue (Figure 17C). This histologic picture is of an
active, expanding, spreading, destructive process
involving the endothelial and subendothelial surface
in an erisipelas-like fashion. In addition, since the
destructive changes are most severe in the central
portion of the erosion, this area may have been the
initial focus of injury. Note also that the depth of the
superficial erosion tends to taper in both directions
from the central area to the lateral extent of the ero-
sion in Figure 17B. The IA seems to have estab
lished a focus of injury in the central part of the ero-
sion, then spread contiguously in a circumferential
direction. The central, penetrating ulceration shows
the IA is also spreading downward toward the cen-
ter of the plaque toward the necrotic core. This
picture of a spreading destructive IA, localized to
the endothelial surface, is similar if not identical to
the spreading destructive process, proposed in
Chapter 1 and 4, involving the center of the plaque
and the formation of a necrotic core.

7-2
Atherosclerosis Surface Erosions

Proteolytic Enzymes

The spread of the IA and the destruction of endothe-

lium and subendothelial tissue may be promoted by
production of proteolytic enzymes, such as MMPs,
by the macrophage foam cell, possibly through
stimulation by oxidized LDL [113]. These proteolytic
enzymes can digest and break down surrounding
tissue, and have been shown to play a key role in
PU and rupture [37,114]. Perhaps they play a simi-
lar role in facilitating the spread of the IA at the
endothelial surface. Perhaps the production of these
proteolytic enzymes is also the result of altered
intracellular mechanisms, produced by the IA to
foster its spread along the endothelial surface.

Longitudinal Spread of the IA

Figures D and E, illustrate an extreme case of sur-

Figure 17: A, Endothelial cells have transformed into foam cells
face erosion involving the proximal 5cm of the right
(short arrows) overlying an atherosclerotic plaque in the mid-
RCA of a 76-year-old white female. Endothelial integrity has coronary artery of a young male who died sudden
been breached, with injection mass visible beneath these foam cardiac death (SCD) outside the hospital.
cells (long arrows). Lipid-laden SMCs are present in the
underlying plaque tissue (open arrows). White asterisk = lumen.
H & E stain. B and C, Same patient as in A, but approximately 1 Eighteen contiguous coronary segments, beginning
cm distal to A, shown in low-power (B) and high-power (C). A at the RC ostia, were involved with this erosive pro-
surface erosion has destroyed a portion of the endothelium
cess which included virtually the entire luminal
(arrows), subendothelial tissue, and, in addition, a deep
ulceration (rectangle) appears to be penetrating into the plaque
surface of each segment. It was almost as if a cor-
in the direction of the necrotic core. Many foam cells and rosive acid had been poured down the artery. The
considerable tissue debris are present. In C, note the irregular, endothelium was eroded and the intima was virtu-
moth-eaten border of the ulceration (arrows), consistent with
ally destroyed down to the internal elastic lamina in
digestion and destruction. D, X-ray of dissected RCA of a 38-
year-old white male who died SCD outside the hospital. There is
a number of places (Figure 17E), but no significant
no evidence of significant luminal obstruction, but the luminal mural thrombi were present at any site. The post-
margins are fuzzy and indistinct in the proximal 1/3 of the artery mortem angiogram, (Figure 17D), shows no signifi-
(arrows). Asterisk = RC ostia with cannula in place. E, A typical
cant luminal stenosis, but there are areas of
section taken from the proximal portion of the artery shown in D.
Large portions of the intima have been destroyed down to the
calcification and considerable evidence of T cell
internal elastic lamina (thin arrows). A small focus of calcification infiltration in the adventitia, consistent with active,
is present (fat arrows) plus marked adventitial inflammatory ongoing injury (Figure 17E). This particular case
response (open arrows). Considerable tissue debris and
shows that the IA is able to spread, not only in a
microemboli fragments are present in the lumen. H & E stain. F,
Superficial erosion and partial destruction of the fibrous cap
circumferential direction, but also longitudinally
(arrows) overlying a large necrotic core (asterisk) of a 86-year- along the endothelial surface. The magnitude and
old white male who died SCD in the hospital. H & E stain. extent of the surface erosion may reflect the inher-
ent pathogenicity of the IA.
7-3
Atherosclerosis
Destruction of the Fibrous Cap
Figure 17, figure F illustrates a surface erosion that
involves the fibrous cap overlying a large necrotic
core. The center of the fibrous cap is undergoing
erosion and destruction from the luminal side, but
this destructive process has not yet penetrated into
the necrotic core - shown by the absence of injec-
tion mass in the core. Destruction of the central
portion of the fibrous cap is potentially more serious
than a shoulder ulceration because the center of the
core will be exposed to flowing blood, increasing the
potential for acute thrombosis and acute coronary
events. Surface erosion, independently or in con-
junction with erosion from beneath the fibrous capm
[67], is another mechanism of PU that can lead to
acute coronary events.
Absence of Resolution
A brief review of the illustrations in Figure 17 shows
that none of these erosions is associated with evi-
dence of resolution or healing. That is, there is no
evidence of mural thrombosis, even though large
amounts of subendothelial collagen are exposed,
nor is there evidence of the hypercellular response
that would be expected in the normal resolution of
injured tissue. Certainly there is no neointimal, FP
response resembling that seen following PTCA. The
IA, directly or indirectly, apparently prevents such
responses. Presumably, there are also inheremt
thrombolytic factors acting at the site of erosion that
prevent thrombosis and other normal healing
responses. Therefore, a surface erosion over an
atherosclerotic plaque is not an ordinary injury in
which the IA comes and leaves quickly, followed by
resolution, but is consistent with an IA that contin-
ues to be present and active on a long-term basis.
Because the natural history of these surface ero-
sions has not been determined, they may exist as
chronic, festering lesions and persist for indefinite
periods invading, expanding, and destroying the
Surface Erosions
fibrous cap. Such chronic lesions could result in
elevation of acute phase reactants, like fibrinogen
and C Reactive Protein, that persist for long periods
of time [115,116].
Frequency of Surface Erosions
A previous study from this laboratory showed that
approximately 25% of all UPs that are present
WITHOUT luminal thrombosis are of the surface
erosion type, often multiple in any given patient [57].
They are consistently associated with infiltration of T
cells into the adventitia, and to calcification of the
artery wall, all indications of active, progressive
atherosclerotic disease. The vast majority of these
superficial erosions are not associated with signifi-
cant luminal stenosis. They may be relatively
asymptomatic. However, in the presence of signifi-
cant luminal stenosis, these surface ulcerations may
form the substrate for occlusive thrombosis and
acute coronary events [110]. Surface erosions are
not benign lesions, even though they may be cur-
rently asymptomatic, not associated with luminal
stenosis.
Significance of These Findings
Surface erosions offer further information on the
nature of the IA, showing it to be capable of attack-
ing, localizing, and destroying the endothelial and
subendothelial tissue overlying an atherosclerotic
plaque. If these findings are correct, it should be
possible to find the IA in the area immediately sur-
rounding a surface erosion. This also means that
any therapeutic agent designed to neutralize, kill, or
remove the IA can readily reach the IA in this super-
ficial location, as opposed to an IA buried deep
within a plaque.
7-4
Atherosclerosis Surface Erosions

In Review
Surface erosions are probably caused by the same
IA responsible for initiation of the plaque and forma-
tion of the necrotic core. The IA, directly or indi-
rectly, appears to alter and subvert intracellular
functions, converting endothelial macrophages into
pathologic components of the disease process. The
evolutionary purpose of these alterations may be to
create intra and extracellular conditions favorable to
the growth and replication of the IA. Replication and
growth of the IA inevitably lead to and result in the
spread of the IA in all directions from a central
focus. This is aided by the production of MMPs by
macrophage foam cells. Surface erosion and asso-
ciated destruction of the fibrous cap by the IA may
contribute to PU, thrombosis and acute coronary
events. Surface erosions may exist as chronic
lesions for long periods of time without resolution or
healing, producing chronic elevations of C Reactive
Protein, Fibrinogen, and other acute phase reac-
tants. Surface erosions are very frequent in patients
with ACD and are a component of active, progres-
sive atherosclerosis. They may serve as a substrate
for acute thrombosis when underlying luminal
stenosis approaches 80% of the cross-sectional
area [57].

7-5
Atherosclerosis Blind Pockets and False Channels

8. Blind Pockets and False Channels

“An unusual variation of this phenomenon was found in even
fewer cases where rupture and subsequent extrusion of plaque
contents occurred, leaving only a shelled out mural plaque.”
RL Ridolfi, et al., [67]
results in the emptying or “wash out” of plaque con-
tents into the distal circulation. The end result is a
“shelled out” appearance to the necrotic core, as
shown in Figure 18, reducing plaque bulk and, pos-
sibly luminal stenosis also [67].

We have previously emphasized (Chapter 4) that

the growth of the necrotic core is associated with
increased intracore pressure leading to sponta-
neous ulceration and drainage of the core itself
[66,117,118]. Spontaneous ulceration represents
the culmination of factors and forces internal or
external to a necrotic core, resulting in the removal
or partial removal of necrotic material from the
artery wall [4]. This chapter will further explore the
mechanism of PU and show that some plaques may
drain by forming false channels that course through
the body of the necrotic core. It will also consider
the role of blind pockets, created by the discharge
of plaque contents, in the pathogenesis of acute
coronary occlusion.

False Channels
Figure 18 illustrates replacement of necrotic core
contents by injection mass in five different patients,
reflecting pre-mortem ulceration and drainage of the
necrotic core. None of these UPs was associated
with an occlusive thrombosis, nor did any of these
patients receive thrombolytic drugs. The tissue sur-
rounding the margins of these empty atheromas
have red blood cells, providing further evidence of
pre-mortem formation. The fibrous cap overlying the
empty core is intact, suggesting these empty
plaques are, in reality, false channels. Histologic
examination, both proximal and distal, showed
these false channels extended anywhere from 4-to-
25mm in length. The formation of a false channel
requires both a proximal entrance point and a distal
exit, and the flow of blood through this channel
8-1
Atherosclerosis Blind Pockets and False Channels

the necrotic core at a proximal site of ulceration may

then exit through a distal ulcerated site without dis-
rupting the overlying fibrous cap, creating a false
channel [119].

Figure 19 is an example of a false channel involving

a long segment of the mid-LAD coronary artery in a
58-year-old man who died of inferior wall cardiac
rupture several hours after receiving streptokinase
for an acute right coronary thrombotic occlusion.
The fibrous cap is beginning to disintegrate in the
mid-portion of the plaque, Figures 19C and 19D, but
the cap is still intact proximally, Figure 19B, and
distally, Figure 19E. The core contents are com-
pletely gone from this plaque except for some
residual remnants at the distal end of the false
channel, Figure 19E. Significant luminal stenosis is
absent in the area of ulceration, and there is no evi-
dence of thrombus formation.

Figure 18: A - E. These figures show empty, “shelled-out,” We hypothesize that before ulceration and
atheromas in 5 different patients. The fibrous cap (thin white
drainage, this was a relatively large plaque with a
arrows) is intact in all figures, but plaque contents are replaced
by colored injection mass. White asterisk = false lumen. long necrotic core that subsequently drained and
Significant stenosis of the true lumen is present in C and E. debulked without human intervention. Presumably,
Thrombus is absent in both true and false lumen in all figures. An with core contents removed, the area will resolve,
embolic fragment of plaque tissue (fat white arrow) is present in
stabilize, and reendothelialize, resulting in an overall
the lumen in E. Adventitial inflammation (black arrows) is present
in C. reduction in luminal stenosis [68,120]. The absence
of thrombus suggests that resolution and reendothe-
lialization take place by in-growth of surrounding
Formation of False Channels
endothelium, probably over a bed of platelets. The
process of resolution of an UP is probably aided by
Chapters 1 and 5 pointed out that plaques grow complete or relatively complete drainage of plaque
both circumferentially and longitudinally, and that contents from the area, similar to a bacterial
adjacent, but separate, plaques often extend and abscess.
fuse together to form larger and longer plaques. A
long plaque with a long necrotic core will have an
extensive shoulder area, extending down both sides
of the plaque. Since PU commonly occurs at the
shoulder of the plaque, the possibility exists that a
long necrotic core may develop one or multiple
shoulder ulcerations along its length. Blood entering
8-2
Atherosclerosis Blind Pockets and False Channels

Figure 19: A, Post-mortem angiogram showing extensive

ulceration (white arrows) without luminal stenosis of the proximal
LAD coronary artery of a 58-year-old white male. A blind pocket
is present at the distal end of the UP (fat white arrow). B-E,
Contiguous coronary sections taken proximal (B) to distal (E)
from the area of ulceration. The ulceration is approximately 25 to
30mm in length. These sections show the presence of a large
false channel (white asterisk) in which the fibrous cap (white
arrows) overlying the false channel has become thin in B, begins
to disintegrate in C and D, and then is again intact in E. Note the
absence of thrombus in all figures and presence of residual
plaque contents (black arrows) in E. Reproduced with permission
[see Ref 57].

8-3
Atherosclerosis
Frequency of False Channels
How often do false channels develop in the course
of active progressive atherosclerotic disease? Is the
development of false channels a rare phenomenon,
or a common occurrence with ulcerating athero-
mas? Are spontaneous coronary dissections or
coronary dissections following PTCA in reality false
channels coursing through a necrotic core along
cleavage planes, as illustrated and discussed in
Chapter 4? A previous report from this laboratory
showed the longitudinal extent of 109 UPs without
associated luminal thrombosis [57]. Fifty-five per-
cent (55%) of these UPs involved two or more
contiguous segments and 32% involved three or
more contiguous segments. Since the coronary
arteries were cut at 2-3mm intervals, this means
that 1/3 of these UPs were, at a minimum, 6-to-9
mm in length. It is relatively common for UPs to
extend long distances within the artery wall, with the
potential to develop a false channel. We hypothe-
size that all UPs have the potential to extend longi-
tudinally and to develop false channels if the
underlying pathologic substrate is suitable or favor-
able for their formation.
Blind Pockets
The majority of plaques that ulcerate do not go on to
develop false channels. It is our theory that this is
due to anatomic and structural features or to “geo-
metric” changes within and adjacent to the ulcerated
plaque [121]. The formation of a false channel
depends upon the development of a distal exit point,
and failure to develop a false channel creates what
is essentially a “blind pocket” or cavity in the wall of
the artery. Blind pockets form in association with
UPs when there are obstructions within the necrotic
core, particularly at the distal end, and/or the sur-
rounding arterial wall, that prevent the formation of a
distal exit point (Figure 19E). These obstructions
include the presence of fibrous septa criss crossing
Blind Pockets and False Channels
or dividing the necrotic core, a very thick and/or
strong fibrous cap covering the distal extent of the
core, calcification of intimal tissue distal to the core,
and the presence of an arterial bifurcation. These
anatomic features will be different in every patient
and every plaque and may help to explain the great
variation among UPs and their associated complica-
tions.
Blind Pockets and Acute
Occlusions
Figure 20 illustrates examples of blind pockets in
two patients who died of ACD. In Figures 20A and
20B an UP is associated with both a proximal and
distal blind pocket. A mural thrombus is located at
the site of the UP and a remnant of fibrous cap is
mixed with the thrombus. The patient received
streptokinase to treat an acute anterior myocardial
infarction, thought to be caused by this lesion, but
died shortly thereafter of anterior wall rupture. This
patient illustrates the association between a blind
pocket, dislodgement of the fibrous cap, and forma-
tion of an occlusive thrombus. Dislodging the moor-
ings of the fibrous cap, especially that portion of the
cap covering the distal end of an UP, may lead to
acute occlusion of the lumen, caused by a flap of
fibrous cap. The thrombus in this patient was par-
tially lysed by the streptokinase, but the pathologic
substrate, consisting of a blind pocket and a flap of
fibrous cap, were not changed by this clot lysis.
Figures 20C-F, shows severe luminal stenosis pro-
duced by swelling and expansion of a blind pocket
at the distal end of the false channel. This example
illustrates how sudden swelling of a blind pocket
can lead to rapid and severe luminal stenosis, with-
out the formation of an acute thrombus. It is easy to
visualize how the pulsating head of pressure that
drives coronary blood flow could act much like a
battering ram, not only in distending the core area,
but also in dislodging the fibrous cap. Acutely
8-4
Atherosclerosis Blind Pockets and False Channels

developing luminal stenosis, caused by either sud-

den swelling of the plaque or by a flap of fibrous
cap, could precipitate acute coronary events in the
absence of occlusive thrombosis.

8-5
Atherosclerosis
Figure 20: Post-mortem angiograms of dissected LAD coronary
arteries of a 71-year-old male (A) and a 62-year-old male (C). B
& D are schematic diagrams of the X-rays in A & C. UP =
ulcerated plaque. Tc = thrombus. In A, the ulceration involves the
central part of a long necrotic core, with injection mass filling the
proximal portion of the atheroma and also a distal blind pocket. A
mural thrombus partially occludes the lumen at the site of the
ulceration and includes a remnant of the fibrous cap (not shown).
E & F show both a true lumen (white asterisk) and a much larger
false lumen (black asterisk), with the false lumen ending in a
blind pocket in the patient shown in C. A small mural thrombus is
present (black arrows) in E.The true lumen is reduced to a tiny
slit, apparently the result of distention and swelling of the necrotic
core. The true lumen and the false lumen both contain thrombus
distal to E (not shown).
Clinical Implications
Some acute coronary occlusions respond to throm-
bolytic drugs, but others do not [122]. If all acute
coronary occlusions were caused by pure thrombus,
then we would expect 100% of thrombi to be lysed
by a thrombolytic drug. But there are different types
and kinds of acute coronary occlusions, and one
treatment is not suitable for all. A thrombus formed
proximal to an occluding fibrous cap may not lyse,
with blood flow restored, because the fibrous cap
does not respond to a thrombolytic drug.
Blind Pockets and False Channels
However, penetration of the obstruction, presum-
ably a fibrous cap flap, with a guide wire allows the
thrombolytic drug to perfuse down the artery and to
lyse the thrombus [123]. Similarly, acute occlusion
caused by distention and swelling of the plaque, as
in Figures 20C-F, will not respond to a thrombolytic
drug because the occlusion is not caused by a
thrombus. This may explain why PTCA is more suc-
cessful than thrombolytic drugs to treat acute coro-
nary occlusion [124]. For example, balloon dilatation
of an obstruction caused by a flap of fibrous cap or
a distended blind pocket, followed by stent place-
ment, will serve, first, to open the channel by break-
ing up any fibrous obstruction, and, second will
produce closure of blind pockets, tacking up loose
ends of fibrous cap [125]. This approach tends to
correct the pathologic substrate of a blind pocket
and a flap of fibrous cap, and to close any potential
dissection planes that were responsible for the
occlusion in the first place [126]. Stent place ment
may also be beneficial in producing more complete
drainage of the necrotic core through squeezing or
compressing the plaque against the artery wall.
Complete drainage of the necrotic core through the
use of a stent tends to stabilize the plaque, facilitate
resolution and healing, and, in the end, to reduce
luminal stenosis. We hypothesize that the patho-
genesis of many occlusive thrombi associated with
an UP develop when blood cannot exit the necrotic
core, or, in essence, are due to the presence of a
blind pocket and the failure to develop a false chan-
nel.
In Review
Spontaneous ulceration and discharge of an
atheroma may result in a diverticulum-like structure
in the artery wall. It contains a mixture of plaque
contents and blood in what is essentially a blind
pocket. Over-distention of this blind pocket by
inflowing blood can lead to increased luminal steno-
sis and obstruction to coronary flow, before throm-
8-6
Atherosclerosis Blind Pockets and False Channels

bus formation. Pulsatile blood flow, acting like a

battering ram within the blind pocket, may promote
the formation of a distal point of reentry, creating a
false channel within the artery wall. Formation of a
false channel with relatively complete drainage of
core contents results in a reduction in luminal
stenosis without human intervention. The formation
of a false channel is another mechanism by which
toxic plaque contents are removed from the wall,
and it may occur without producing occlusive
thrombosis or acute coronary events. All UPs have
the potential to develop a false channel. The pres-
ence of a blind pocket, associated with the failure to
develop a false channel, constitutes a common
pathologic substrate that underlies the development
of acute coronary events. Obstruction of coronary
flow by a fibrous cap flap is one explanation for the
failure of thrombolytic drugs in patients with acute
S-T segment elevation myocardial infarction.

8-7
Atherosclerosis Thrombosis and the Injurious Agent

9. Thrombosis and the Injurious Agent

becomes pathologic only under certain circum-
“Unless proven otherwise, arterial thrombosis as now stances [127,128]. Marcus [129] believes thrombo-
comprehended is primarily a misdirected or amplified form of sis is a misdirected or amplified form of primary
primary hemostasis and is modulated by blood platelets.”
hemostasis and is modulated by blood platelets. If
AJ Marcus, [129]
this is correct, the ongoing and continuing hemo-
static responses surrounding platelet activation,
Platelets, Injury Repair and over and above what is required for injury repair,
Thrombosis are pathologic and may lead to obstructing thombo-
sis [129]. Specifically, thrombus formation reflects
loss, failure, or inability of the thromboregulatory
The adhesion, activation and aggregation of
system to halt or control basic hemostatic
platelets that lead to the formation of intravascular
responses, and can be interpreted as a pathologic
thrombosis are generally considered a pathologic
breakdown of normal defense systems [129]. What
process, rather than a physiologic response to
causes this loss of thromboregulatory control, and
injury. The same hemostatic response, however,
what is the role of the IA in the pathogenesis of
that occurs with injury to tissues outside the vascu-
thrombosis?
lar system, with the platelet response and with the
same structure as intravascular thrombus, is con-
sidered a normal, necessary physiologic response Pathologic Hemostasis and
to injury. Although intravascular thrombosis may Thrombosis
progress to produce pathologic disease states, this
does not mean that the hemostatic responses tak-
Figures 21A-F, is an example of apparently uncon-
ing place inside the vascular tree are pathologic.
trolled hemostatic responses that resulted in the
The basic, initial hemostatic responses of platelet
formation of a large occlusive coronary thrombus.
activation to intravascular injury cannot, per se, be
The thrombus is composed of large amounts of
considered pathologic in nature (127). Fibrin and
mature fibrin, with a superimposed platelet throm-
mural thrombus formation are beneficial and essen-
bus on the luminal surface (Figure 21D). The
tial to the resolution of injury. They provide the
thrombus does not contain plaque contents, so it
scaffolding for in-growing fibroblasts and other ele-
may have formed on a large endothelial surface
ments essential to injury repair. For example, the
erosion rather than on an ulcerated or ruptured
basic hemostatic responses following PTCA injury
plaque. Remnants of the fibrous cap are encased in
are essential elements in the healing, repair, and
the thrombus (Figure 21F). This thrombus could
stabilization of the PTCA site [68]. It is important to
also have formed on the exposed surface of what
distinguish pathologic thrombosis from physiologic
was once a large and extensive false channel. It
hemostasis within the vascular tree.
has continued to grow, presumably because of con-
tinued platelet activation, aggregation, and the
Platelet activation and aggregation are, broadly formation of fibrin. Such a thrombotic response is
speaking, a physiologic defense whose primary far in excess of that needed to repair this injured
purpose is to stop blood loss and to initiate the artery.
repair and resolution of injury. This response
9-1
Atherosclerosis Thrombosis and the Injurious Agent

Figure 21: A–F are sections taken from three contiguous

segments of the proximal LAD coronary artery of a 34-year-old
male who died SCD outside the hospital. A & B are from the
proximal segment, C & D from the middle segment, and E & F
from the distal segment. Gross (A) and microscopic (B) are
views of a large, circumferential, but incompletely organized
mural thrombus (arrows) producing severe luminal stenosis.
Magnification x15. Low- (C) and high-power (D) views of the
mural thrombus showing the surface is covered with a platelet
thrombus, indicating the thrombus (arrows) is actively growing.
Low- (E) and high-power (F) views of the distal end of the
thrombus showing many platelet fibrin microemboli (arrows) and
a great reduction in the size of the thrombus. In F, a remnant of
the fibrous cap has been incorporated into the thrombus (solid
arrows). A marked infiltration of T cells (open arrows) into the
deep area of the intima is also present. B - F, All MSB stain.

Thromboregulatory Control

The failure to modulate and control platelet activa-

tion and pathologic thrombus formation may be due
in part to an imbalance in the concentration of
thrombolytic and thrombogenic factors in circulating
blood. The ratio of active Tissue Plasminogen Acti-
vator (TPA) to active Plasminogen Activator
Inhibitor (PAI-1) is 1:8 in healthy male subjects, but
9-2
Atherosclerosis
in men with atherothrombotic disease, the ratio is
1:50 [130], indicating that these patients suffer from
a systemic abnormality of the thromboregulatory
system, resulting in a prothrombotic state. The
cause of this imbalance is not clear. It appears to be
due, at least in part, to increased production of PAI-
1 by one or more of the following mechanisms:
First, as recent studies show, increased production
of PAI-1 by endothelial cells and vascular SMCs
that have been stimulated by various growth factors,
including fibroblast growth factor and platelet
derived growth factor, are produced by
macrophages or lipid-laden foam cells [131–133].
Second, studies show a marked increase in
Angiotensin Converting Enzyme (ACE) activity in
the endothelium and other intimal vascular cells,
especially lipid-laden macrophages within
atherosclerotic plaques [134]. This increased ACE
activity results in increased conversion of
Angiotensin I into Angiotensin II. Angiotensin II has
been shown to be a strong stimulus of the increased
production of PAI-1 [134,135]. The increase in ACE
activity within the plaque , producing an increased
amount of PAI-I, may disturb the thromboregulatory
balance within the plaque and attenuate inherent
thrombolytic mechanisms [134].
Third, Angiogtensin II is also involved in platelet
activation and aggregation and could contribute to
the continued and excessive platelet responses
involved in thrombus formation, increasing the
thrombogenic potential [134,135].
The increase in PAI-1 and the failure of the
thrombo-regulatory system can be traced to the
lipid-laden macrophages and foam cells within the
atherosclerotic plaque. These are the same SMC
and lipid-laden macrophages formed in response to
the IA that are responsible for many of the
atherosclerotic lesions described in previous chap-
Thrombosis and the Injurious Agent
ters. The creation or development of a prothrom-
botic state in patients with active disease appears to
be another example of subversion of normal regula-
tory and defensive responses by the IA. In other
words, the IA, directly or indirectly, is the cause of
and actively promotes thrombus formation as a
component of active, progressive atherosclerotic
disease (136). What other mechanisms related to
the activity of the IA alter or affect the thromboregu-
latory system and promote thrombus formation?
Luminal Stenosis and
Thrombosis
Chapters 3, 4, and 5 showed the direct relationship
between active atherosclerotic disease, caused by
the IA, and the development of luminal stenosis.
Luminal stenosis is an essential element required
for thrombus formation, primarily by causing shear
forces that activate platelets and thus promote
thrombosis [121,137,138]. However, luminal steno-
sis and associated platelet activation alone do not
necessarily lead to pathologic thrombosis, and
many severely stenotic lesions remain relatively
unchanged and stable for many years [139]. Lumi-
nal stenosis is not synonymous with thrombosis, but
the activation of platelets may have implications for
other acute lesions, such as UPs [57], within the
coronary tree. Although luminal stenosis is essen-
tial, other factors must be present for thrombi to
form.
Wall Injury and Thrombosis
Breach of endothelial integrity will activate platelets
and provide the substrate for thrombus formation.
The IA, by producing active, expanding, atheroscle-
rotic disease that affects the overlying endothelium,
is responsible, directly or indirectly, for producing
the pathologic substrate necessary for thrombus
formation. Data show that virtually all surface ero-
sions or UPs are associated with adventitial inflam-
9-3
Atherosclerosis
matory cell infiltrates, an objective sign of active,
injurious atherosclerotic disease [57]. We believe
that excessive, pathologic thrombosis is caused by
and promoted by the IA by altering hemostatic fac-
tors, producing luminal stenosis and injuring or
eroding the endothelium, Virchow’s Triad [130].
Evolutionary Purpose
If thrombosis is a component, not necessarily a
complication, of active atherosclerotic disease, what
is the evolutionary purpose of thrombus formation?
Why should the IA subvert or alter the thromboregu-
latory system to promote thrombosis? Is thrombosis
just one of many features of active atherosclerosis,
or does thrombus formation benefit the IA in some
way? Does thrombus supply lipid or some other
energy source for the replication, growth, and
expansion of the IA, as we postulated in Chapter 4?
Apolipoprotein (a) (Lp(a)), closely resembles plas-
minogen. It is found in thrombus and may have
evolved to play a role in wound healing by delivering
cholesterol and other lipids to sites of fibrin deposi-
tion where membrane synthesis is required.
Lipoprotein (a),(Lp(a)), due to its similarity to plas-
minogen, may also interfere with plasmin generation
and inhibit thrombolysis [140]. We speculate that
thrombus provides a more readily available supply
of lipids or other elements necessary for the IA to
survive than does plaque tissue.
Clinical Implications
If thrombosis is a component, not a complication, of
active atherosclerotic disease, what difference does
this make in management of the patient with active
coronary disease, and what is gained by making
this distinction? If thrombosis is a component, then
it is an expected development or event, and all
patients with active atherosclerotic disease should
receive antithrombotic, antiplatelet therapy, ACE
inhibitors, or other drugs to reduce or prevent
Thrombosis and the Injurious Agent
thrombus development beyond that required for
tissue repair. Patient management should aim to
reestablish thromboregulatory balance, prevent fur-
ther injury or breach of the endothelium, and pre-
vent the development of luminal stenosis [129].
However, if thrombosis is a complication of active
atherosclerosis, then it is a pathologic event that
must be prevented. As noted above, we do not wish
to prevent thrombosis, per se, we want to prevent
excessive throm bosis that leads to obstruction of
coronary flow. Treating thrombosis as a pathologic
condition or eliminating it may also prevent or elimi-
nate desirable hemostatic responses necessary to
repair the injured artery. Eliminating all hemostatic
responses may lead to further pathologic conditions
and problems, such as cerebrovascular accidents
and acute coronary events [141]. If thrombosis is
approached as a component of active disease that
will eventually happen, then management will be
aimed at preventing excess growth of thrombus
rather than preventing all thrombus formation.
The essence here is to identify the patient with
active disease. Identifying patients with active dis-
ease will aid greatly in risk stratification and will
focus on measures to avoid or prevent excessive
thrombus formation. The use of C Reactive Protein
and Fibrinogen, acute phase reactants, may be use-
ful in identifying the patient with active atheroscle-
rotic disease, but these tests do not identify the
location of the active disease whether intra- or
extra-cardiac [142]. Not only do we need to know
the presence or absence of active disease, we also
need to develop some way to measure the degree
of activity, and to locate the most active sites. Spe-
cific identification of the most active sites would
allow specific treatments or interventions to be
planned under controlled conditions designed to
prevent excessive thrombus formation. For exam-
ple, if it were possible to identify and quantify the
activity of “vulnerable” plaques [143] it might be
9-4
Atherosclerosis Thrombosis and the Injurious Agent

possible to focus treatments, medical or interven-

tional, designed to stabilize or remove such
plaques, particularly if they were causing significant,
>80%, luminal stenosis. Recent studies of thermal
heterogeneity, using infra red technology have been
able to identify “hot” plaques -those with active
inflammatory disease. These studies may be very
useful in the future [65,71].

In Review
Pathologic thrombosis is due to uncontrolled hemo-
static responses, modulated by platelet activation
over and above what is required for injury repair. An
imbalance in TPA/PAI-1 ratio develops as a result of
breakdown of normal defense systems, leading to a
hypercoagulable state in patients with coronary
atherosclerosis. Thrombosis is actively promoted by
the activity of the IA. It is a component, not a com-
plication, of active, inflammatory, atherosclerotic
disease. The recognition that thrombosis is a com-
ponent of active atherosclerotic disease alters our
view of the pathogenesis of thrombosis, and of our
approach to the treatment and prevention of ACD.

9-5
Atherosclerosis Chronic Ulcerated Plaques

10. Chronic Ulcerated Plaques

“It seems certain that many patients do survive plaque
fissuring without developing any symptoms…”
MJ Davies, et al., [120]
[57,148]. If UPs are of a different age, can their age
be determined? If so, what is their natural history?
Do they reseal and progress, forming a larger
plaque with a larger necrotic core, as Davies sug-
gests [120,149,150], or do they persist as chronic

Chronicity of UPs ulcerations (57,148) without resealing and without

Nagatomo [144] showed UPs persisting as chronic
ulcerations for weeks, months, or years before pro-
gressing to luminal stenosis, thrombosis, and acute
events. Other investigators [145–147] showed com-
plex lesions, present in patients with unstable
angina, persisting as chronic lesions, and progress-
ing to stenosis and acute coronary events. Our
results, Table 4, show UPs were ubiquitous, multi-
ple, occurring in the same artery, but at a different
location, or in a different artery from the one contain-
ing the culprit thrombus. These ulcerations did not
develop simultaneously, and are of different ages
growth of the necrotic core? Nakagawa [151] noted
that PUs associated with an occlusive thrombus
were still present one month after thrombolysis, but
the angiographic degree of occlusion had
decreased. Plaques do ulcerate, empty, and
decompress with regression of stenosis, but they
may not quickly resolve and reendothelialize. The
UPs shown in Figure 22, Figures 22A and 22B,
show no evidence of resolution, no platelet aggrega-
tion, mural thrombosis, recanalized thrombus or
other evidence of repair. They do not present a his-
tologic picture of actively resolving injury.

Table 4:. Comparison of the incidence of coronary thrombosis and of ulcerated plaques without
thrombosis with the degree of luminal stenosis in four different acute coronary syndromes.

Degree of Luminal Stenosis (%) Totals (%)

<50 50–59 60–69 70–79 80–89 90–99 100

Cardiogenic Shock UP 5 11 7 10 2 3 38 48
No. 28 Tc 2 4 6 8 21 41* 52
Total 5 11 9 14 8 11 21 79

SCD w/ AMI UP 3 4 6 4 1 1 19 44
No. 18 Tc 2 2 8 12 24* 56
Total 3 4 6 6 3 9 12 43

SCD w/o AMI UP 15 3 8 7 3 36 61

No. 26 Tc 4 4 6 9 23* 39
Total 15 3 8 11 7 6 9 59

Cardiac Rupture UP 4 3 7 1 1 16 53
No. 11 Tc 3 2 3 6 14* 47
Total 4 6 7 3 4 6 30

Totals UP 27 18 24 28 7 5 109 52
No. 83 Tc 5 10 14 25 48 102* 48
Total 27 18 29 38 21 30 48 211

10-1
Atherosclerosis Chronic Ulcerated Plaques
UP = Ulcerated plaque without thrombosis; Tc = Occlusive coronary thrombus; SCD = Sudden cardiac death; AMI = Acute myocardial
infarction; * = p =<0.001 (Reprinted from reference 57 with permission)

We hypothesize that UPs, once the fibrous cap has

been breached, will not permanently reseal, and the
atheroma will not completely resolve until the
necrotic core is completely empty. Without complete
drainage of the necrotic core the factors that caused
the plaque to ulcerate in the first place are still
present including the active, destructive IA, the toxic
core contents, and the various proteases. We fur-
ther hypothesize that many UPs without thrombosis
are, in reality, indolent, festering, inflammatory,
chronically draining lesions that persist indefinitely
until either fibrotic stenosis without associated
atheroma or occlusive thrombosis develops.

Figure 22: A–C are examples of UPs without luminal thrombosis

and without significant luminal stenosis in 3 different patients.
The fibrous cap has been breached (fat white arrows) in all
patients, portions of the necrotic core have been extruded and
replaced by injection mass. Inflammatory cells are scattered in
the adventitia (not shown).These UPs were not considered to be
the culprit lesions. A, Mid-LAD artery of a 53-year-old white
female who died SCD outside the hospital, 6 weeks following an
acute subendocardial infarction. B, Main left coronary artery of a
69-year-old white female who died in hospital of cardiogenic
shock associated with an AMI. C, Proximal CIRC artery of a 67-
year- old white male who died of cardiogenic shock following an
AMI. All stains H & E. D, Section taken from the mid-LAD artery

10-2
Atherosclerosis Chronic Ulcerated Plaques

inner surface of the intima, and was confined to a

just proximal to an occluding thrombus of a 43-year-old white
male who died SCD out of hospital. A portion of the fibrous cap
single coronary segment. A Grade II ulceration was
(short black arrows) is involved with thrombus (long white also confined to a single segment, but penetrated to
arrows), primarily on the luminal surface. Most of the core the depths of the intima. A Grade III ulceration
contents have been extruded. E, High-power view of rectangle in
involved two adjacent segments, and a Grade IV
D, showing no thrombi have formed on the exposed surface. D &
E = PTAH stain.
involved three or more contiguous segments. Deep
and extensive UPs were as frequent in plaques with
<50% stenosis as they are in plaques with 70 to
Depth and Extent of UPs 79% stenosis. The frequency, depth, and extent of
the UPs was not related to the severity of luminal
The relationship between luminal stenosis and the
stenosis. Severe luminal stenosis is not required for
depth and extent of the 109 UPs without thrombo-
PU, and severe luminal stenosis does not necessar-
sis, shown in Table 4, is presented in Table 5. The
ily develop before PU. These findings support other
UPs were graded in the following manner to deter-
investigations that show PU is not related to plaque
mine the extent, depth, and severity of the ulcera-
size or the degree of luminal stenosis [152,153].
tion [57]: A Grade I ulceration involved only the

Table 5:. Comparison of the degree of luminal stenosis with the severity of the plaque ulceration in
109 ulcerated plaques without thrombosis.

Severity of UP Degree of Luminal Stenosis (%) Totals

(Grade) <50 50–59 60–69 70–79 80–89 90–99

I 7 6 4 6 1 1 25
II 9 5 4 7 1 3 29
III 5 2 6 6 1 20
IV 6 5 10 9 4 1 35
Total 27 18 24 28 7 5 109

UP = Ulcerated plaque without thrombosis. (Reprinted from reference 57 with permission)

tion, calcification, and a necrotic core, and all are

Table 6 compares the frequency of atheromas,
objective signs of active atherosclerotic disease
adventitial inflammation, and calcification at the site
(See Chapters 3,4,5) [57]. We conclude inflamma-
of all UPs associated with or without luminal throm-
tion and calcification play some role in ulceration of
bosis in the 83 patients presented in Tables 4 and
the necrotic core (53,63).
5. Virtually all UPs are associated with inflamma-

Table 6:. Comparison of the incidence of inflammatory cell infiltrates, calcification, and necrotic
plaques at the site of ulcerated plaques without thrombosis and with occlusive thrombotic lesions.
The incidence of these three lesions in the entire group and in the control patients is also provided for
comparison.

CATEGORY # of lesions IC % CA % NP %

Ulcerated Plaques
< 50% Stenosis 27 26 96 26 96 25 93
> 50% Stenosis 82 78 95 70 85 82* 100
Total UP 109 104 95 96 88 107 98

Thrombotic Lesions 102 93 91 95 93 94 92

10-3
Atherosclerosis
CATEGORY # of lesions
Entire Group # of Sections
83 patients 7036
22 controls 1789
IC = Inflammatory cell infiltrates; CA = Calcification; NP = Necrotic plaque; UP = Ulcerated plaque without thrombosis; * = (p = <0.02)
(Reprinted from reference 57 with permission)
UPs and Fibrotic Luminal
Stenosis
If UPs without thrombosis persist indefinitely as
chronic lesions, what is the relationship between
chronic UPs and the development of fibrotic, non-
atheromatous, luminal stenosis? Chronic inflamma-
tory diseases, in general, are characterized by
inflammation, tissue destruction, and a FP response
at the site of the inflammation [47]. We postulate
that the bodily response to chronic inflammation in
the coronary artery will be the same or very similar
to the bodily response to chronic inflammation
elsewhere in the body, i.e., fibrous tissue will form
around the lesion. We would expect an FP
response at the site of a chronic, persistent UP to
be manifested by the development of progressive,
fibrotic, luminal stenosis. Chronic UPs and the
associated release of growth factors could account
for rapid progression of insignificant lesions [154].
Luminal stenosis, in this circumstance, would be
directly related to the inflammatory activity surround-
ing the chronic UP. It would be the result of and
would develop after, not before, the plaque ulcer-
ates. The luminal stenosis would then increase, not
because the plaque reseals but because the UP
stimulates a FP response similar to healing by sec-
ondary intention [57,148,150]. The UP does not
resolve, but persists as luminal stenosis increases.
The longer the UP persists, the greater will be the
fibrotic luminal stenosis. More specifically, the
severity of fibrotic luminal stenosis found in associa-
tion with an UP may reflect the age of the UP.
Chronic Ulcerated Plaques
IC % CA % NP %
IC % CA % NP %
3597 51 2654 38 2195 31
295 16 221 12 101 6
To continue this hypothesis, the 28 UPs without
thrombosis in the 70–79% stenosis range (Table 5),
have been present longest and have resulted in the
most severe stenosis. The 27 UPs associated with
<50% stenosis are the most recently formed, with
the least fibrotic stenosis. The age of the 18 UPs
associated with 50–59% stenosis and the 24 asso-
ciated with the 60–69% stenosis would be interme-
diate in age. These UPs without thrombosis may
then persist as chronic UPs until the underlying
stenosis approaches 80% of the cross sectional
area, at which point the conditions and substrate
favoring thrombosis are present.
Sudden development of acute coronary syndromes
as a result of thrombotic occlusion naturally leads to
the assumption that the UP beneath the acute
thrombus is also an acute event. This assumption is
unproved. We know of no way in which the age of
an UP can be accurately determined histologically.
The chronic UP and the chronic FP response may
have been actively brewing for months or years
without overt symptoms, before the acute event.
Component versus Complication
The well known association between UPs, thrombus
formation, and acute coronary events does not
show PU to be a complication of the disease pro-
cess, but only shows that it has the potential to
develop into a complication under certain circum-
stances. A complication, strictly speaking, describes
a secondary disease that aggravates a previous
one. Since there are many UPs not associated with
thrombosis or other pathologic sequelae, and with-
10-4
Atherosclerosis
out apparent clinical effects [63,120], PU, per se,
cannot technically be called a complication. If PU is
a component of active disease, it is not necessarily
a pathologic event that must be, should be, or even
can be prevented [155].
The distinction between PU as a component rather
than a complication gives us insight into the nature
of the IA and the disease process. It also alters our
approach to the prevention and treatment of the
disease. If PU is a component of active atheroscle-
rotic disease, then all inflammatory atheromas may
be expected to ulcerate at some point, the large
vulnerable plaques [150,153] posing the greatest
danger. If such vulnerable plaques could be identi-
fied in vivo, before ulceration, it may be possible to
devise an intervention to control or remove the
plaque before ulceration develops, or devise a
treatment to neutralize the effects of ulceration
when it does occur.
If PU is a complication of active disease, then it is a
random event, possibly affecting only a few
plaques, with many atheromas never undergoing
ulceration. Identifying vulnerable plaques and per-
forming an intervention, may not be appropriate
because not all such plaques may require interven-
tion. Devising treatments to manage plaques that
will spontaneously ulcerate and drain at some point
in the future is decidedly different than devising
treatments for complications that may or may not
develop.
Early PU Is the Norm
We believe that the norm is for plaques to ulcerate
early in their development. It is their failure to do so
that is abnormal and pathologic in nature. Failure of
a plaque to ulcerate early leads to the formation of a
large necrotic core, such as illustrated in Figure 6,
and to the large vulnerable plaque. Early ulceration
of a necrotic core may be quite beneficial in the
Chronic Ulcerated Plaques
sense that it is an efficient method of reverse trans-
port, debulking and decompressing the plaque core
by extruding plaque contents [15,57].
Absence of Thrombus
Table 4 shows that, consistent with previous inves-
tigations [57,120,156,157], many UPs within the
coronary tree of patients who have died of ACD are
not associated with luminal thrombosis. The obser-
vations in this study of 83 patients demonstrate that
PU is not synonymous with thrombosis, and throm-
bosis does not automatically form on exposed
subendothelial tissue [158]. Exposed subendothelial
tissue, including collagen, may not be as thrombo-
genic as previously believed [159].
Figure 22 shows several examples of UPs without
associated thrombosis. They appear to be open,
draining, abscess-like cavities. The fibrous cap has
been breached, exposing plaque contents and
subendothelial collagen to flowing blood, with result-
ing extrusion and partial emptying of the necrotic
core (Figures 22A-C). Why is thrombus absent if
plaque contents or exposed subendothelial tissue
are so thrombogenic [160]?
The absence of thrombus in some UPs may be
explained by the presence of MMPs and other pro-
teases within atheromas. These enzymes dissolve
tissue proteins, play an important role in degrading
and digesting dead or damaged tissue within the
necrotic core, and erode the surrounding fibrous
tissue, including the fibrous cap [114,161]. T cells
trigger macrophages to secrete MMPs, showing
these MMPs also to be a component of active,
atherosclerotic disease [53,162,163]. MMPs are
also capable of digesting fibrin and of preventing
thrombus formation and have also been shown to
negatively affect platelet adhesion and aggregation
[163]. Thus, the pro-teases contained within
atheromas may prevent thrombus formation in UPs,
10-5
Atherosclerosis Chronic Ulcerated Plaques

particularly those associated with insignificant lumi-

nal stenosis, by contributing to inherent thromboly-
sis.

Figures 22D, E illustrates a large UP with a throm-

bus formed on a remnant of a fibrous cap, with no
evidence of thrombus on the exposed surface at the
base of the core. Most plaque contents are gone
from this plaque with only residual degenerative
tissue lining the margins of the core. In this situa-
tion, a thrombus has formed on one portion of an
UP, but not on other exposed areas of the extensive
ulceration, revealing a difference in the thrombo-
genicity of these two adjacent tissues [160]. If the
tissue around the periphery of the necrotic core is
markedly thrombogenic, we would expect histologic
evidence of platelet aggregation and/or mural
thrombosis in the area. The difference in thrombo-
genicity may be related to the MMPs and other
enzymes that continue to be present at the margins
of the necrotic core, even after the core contents
have been removed [63,114].

In Review
PU is a natural component, not a complication, of
active progressive atherosclerotic disease, often
occurring early in plaque development. PU is
related to the activity of the IA, and it results in the
debulking and decompression of atheromas. It is an
efficient form of reverse transport. The UP without
thrombosis provides insight into the nature of the IA
and to the pathogenesis of PU, fundamental to our
understanding of active atherosclerotic disease.
UPs may persist as chronic festering, inflammatory
lesions for indefinite periods, giving rise to fibrotic
luminal stenosis and ultimately to occlusive throm-
bosis.

10-6
Atherosclerosis
11. What Is the Injurious Agent?
“To survive, a virus infects a cell and forces it to replicate; the
virus uses the cell’s replicative machinery to drive its own
replication.”
K Tanaka, et al., [164]
Single versus Multiple IAs
Atherosclerosis is a complex, chronic, inflammatory
disease, characterized by a series of highly specific
cellular and molecular responses, believed to be
caused by multiple IAs [18,165]. Atherosclerotic
lesions, however, are non-specific. There are no
pathognomonic histologic features that distinguish
one IA from another. If atherosclerosis is caused by
multiple agents, then many different agents produce
identical, highly specific, cellular and molecular
responses. The development of identical or similar
lesions in response to multiple different IAs can only
be explained if arterial cells and tissue respond in
the same way, a non-specific way, to all IAs,
whether that be hypoxia, chemical agents, physical
agents, infectious agents, immune responses,
genetic abnormalities, or nutritional injury [47]. This
concept is not only questionable, it is not consistent
with the pathogenesis of a highly specific, complex
disease. We believe atherosclerosis is too complex
to be caused by multiple agents.
Chapter 2 showed marked differences in the histol-
ogy of arteries injured by PTCA compared with
recently placed coronary bypass vein grafts, or to
atherosclerotic fibrous tissue (Figures A-E). The
artery wall does not respond in a non-specific way
to all IAs. Risk factors such as hyperlipidemia,
smoking, and high blood pressure contribute to,
accelerate, or aggravate the growth and expansion
of the primary IA, but they are not the primary IA
itself. These cardiovascular risk factors cannot be
What Is the Injurious Agent?
the primary IA because all patients who have them
do not develop atherosclerosis and many patients
without them do develop atherosclerosis. We must
look beyond cardiovascular risk factors for the pri-
mary IA.
Atherosclerosis may be caused by a single agent, a
single mutation, a family of similar agents, or possi-
bly through molecular mimicry [166,167]. For exam-
ple, Benditt has shown the SMCs of atherosclerotic
plaques to be monoclonal in origin and suggested
that these monoclonal cells arose out of a single
SMC mutation, possibly caused by chemical muta-
gens or viruses [12,168]. Monoclonality of SMC in
atherosclerotic plaques serves to focus attention on
the possibility that atherosclerosis may be caused
by single rather than by multiple IAs.
Mechanism of Progression
An understanding of how the IA spreads, expands,
and progresses is fundamental to characterizing it.
What is the driving force behind the growth and
expansion of atherosclerotic plaques and the accu-
mulation of excessive numbers of SMCs [12]? What
is the source of energy that sustains and/or replen-
ishes the IA? Does the initiating IA continue to be
present and active, increasing in number, amount,
and concentration as the disease progresses? If so,
by what sustaining mechanism? What is the mech-
anism of continuing injury? Is it caused by the same
IA responsible for the initial injury? Is continuing
injury due to the presence of cellular toxins, such as
oxidized LDL, generated by a series of metabolic
and biological reactions set in place by the original
injury, which then become self-perpetuating [169]?
If so, it is akin to a vicious cycle that once set in
motion is difficult or impossible to stop or interrupt
11-1
Atherosclerosis What Is the Injurious Agent?

[18]. Does oxidized LDL beget oxidized LDL, injur- Evolutionary Purpose
ing more and more tissue, and causing growth and
expansion of plaques? What is the evolutionary purpose of lipid retention in
atherosclerosis? In Figures 1–4, Chapters 1 and 2,
we demonstrated the appearance of lipid-laden
Atherosclerosis is a progressive disease, but not
SMC in early atherosclerotic lesions, and also noted
necessarily steadily progressive. It is marked by
lipid-laden SMC are not present in normal, unaf-
exacerbations and remissions that can be greatly
fected intima. Lipid-laden SMCs must have been
influenced by the control of risk factors, particularly
altered or affected in some specific way, presum-
the reduction of blood lipids [170–172]. A disease
ably by the IA, to cause them to take up excessive
subject to exacerbations and remissions is not con-
amounts of lipid. In vitro studies show infectious
sistent with a disease driven in a relentless, self-
agents can alter biological processes in the artery
perpetuating circle. If this reasoning is correct, the
wall and predispose to atherosclerosis [165]. The IA
progression of atherosclerotic lesions is not due to a
has either entered the SMC and altered intracellular
self-perpetuating chemical or metabolic reaction. It
mechanisms concerned with lipid regulation, or fac-
is due to a series of highly specific cellular and
tors external to the cell, associated with the IA, have
molecular responses, caused by an IA that may be
altered these mechanisms and produced a dysfunc-
considerably influenced by external factors.
tional but still viable cell [175,176]. If the IA were an
extracellular toxin, such as oxidized LDL, we would
expect the cell to be destroyed, not to be rendered
Progressive growth and expansion of atheroscle-
partially dysfunctional. The same holds true for cel-
rotic injury can only be explained and can only
lular injury caused by other classes of IAs, including
occur if the causative IA is able to replicate and/or
hypoxia, physical agents, and nutritional injury,
be continually replenished. Lee, et al, notes lipids
which are unlikely to alter intracellular function in
may become “biologically active,” suggesting lipids
such a specific way without killing the cell. Further-
have a life of their own, are capable of replication,
more, there is no reason for chemical or physical
or are self- replenishing [63]. If the IA is not continu-
agents, hypoxia, or nutritional injury to promote the
ally replenished by some metabolic mechanism,
retention of lipid or the uptake of lipid by the SMC
such as occurs in a vicious circle, but expands by
because the retention of lipid has no effect on the
virtue of replication of the IA, then the IA may be an
action of these agents. For these reasons, we do
infectious organism. Furthermore, if the growth and
not believe the IA causing atherosclerosis is an
progression of atherosclerotic lesions are
extra-cellular toxin, chemical, or metabolite, but is
decreased or reduced by reducing circulating lipid,
an intracellular infectious organism that is able to
and if the IA responsible for this growth is an infec-
alter intracellular mechanisms to suit its own
tious organism, then the infectious organism may
intended purposes.
require lipid for survival, growth, expansion, and
replication. Pathogen-infected cells may alter mem-
brane traffic for nutrient acquisition or act as a Herpes simplex virus (HSV), Cytomegalovirus
cofactor to lipids in atherosclerosis [173,174]. (CMV), Chlamydia Pneumoniae (Cp), and Heliobac-
ter Pylori (H. Pylori) are four organisms currently
being considered in the pathogenesis of atheroscle-
rosis. Studies show these four organisms can target
and infect SMC, macrophages, and endothelial
11-2
Atherosclerosis
cells, and can alter intracellular mechanisms
involved in the uptake, metabolism, and degradation
of cholesterol, with resulting lipid-laden cells [177–
179]. The lipid-laden SMCs in Figures 1–4 may all
be infected with an infectious organism that specifi-
cally alters intracellular metabolism concerned with
the uptake of lipid, presumably for some purpose
beneficial to the IA. For example, Cp is an energy
parasite that utilizes host cell mechanisms to supply
adenosine triphosphate [174]. The uptake of lipid by
an SMC infected with Cp may be caused by or pro-
moted by the organism to secure an energy supply
from the ingested lipid [174,177]. Cp may stimulate
the expression of scavenger receptors by the SMC
to take up oxidized LDL, in the same way H. Pylori
stimulates the formation of iron-scavenging systems
[180]. Lipid retention in the ECM, and the excessive
uptake of lipid by the SMCs may be orchestrated by
Cp or other organisms for their own benefit [174].
The driving force behind the growth and expansion
of the atherosclerotic lesion may be a replicating,
expanding, growing, infectious organism. We specu-
late the infectious organism continues to be present,
active, and replicating as long as an adequate sup-
ply of the necessary lipid is available to it. Restric-
tion or lowering of blood lipid may affect lipid
metabolism within the plaque as well as the avail-
ability of the type of lipid required by the organism.
This could explain why lesion growth is retarded
and acute events decreased in those patients
whose serum lipids are reduced [170–172].
Based on the evidence presented, we hypothesize
that atherosclerosis is caused by an infectious
organism that alters intracellular functions and
mechanisms, creating an increase in lipid uptake
and retention by SMCs. The intracellular infectious
organism then utilizes the retained lipid, either
directly or indirectly, as a source of energy to fuel
replication, growth, and expansion of atherosclerotic
lesions. Eventually it infects other SMCs,
What Is the Injurious Agent?
macrophages, and endothelial cells, causing the
same intracellular abnormalities in each infected
cell.
Single versus Multiple Infectious
Agents
If the IA responsible for initiating atherosclerosis is
an infectious organism, is it a single infectious
agent, a single family of agents, or multiple, differ-
ent, infectious agents that are able, through molecu-
lar mimicry, to produce similar types of injury
(166,167)? The objections raised earlier in this
chapter to multiple IAs causing the same series of
complex cellular and molecular changes in the
artery wall also apply to multiple and different infec-
tious agents. It is unlikely that different types of
infectious agents, such as Cp, HSV, CMV, H. Pylori,
or other unknown infectious agents, could all pro-
duce exactly the same cellular changes and lead to
the same atherosclerotic lesions in all patients. The
possibility exists atherosclerosis may be caused not
only by a single injurious agent, but a single infec-
tious organism [181].
A single infectious organism entering the SMC and
altering specific intracellular functions could be
responsible for the highly specific cellular and
molecular re sponses of plaque formation and the
uniformity of atherosclerotic lesions [18]. A single
infectious organism, circulating in the blood, enter-
ing the artery wall at any vulnerable or injured site,
could explain the multicentric origin (Chapters 1 and
5) and the histologic similarity of widely separated
lesions. The growth, contiguous expansion and
spread of a single, replicating, infectious organism
could explain the circumferential and longitudinal
spread of the disease, the findings of infectious
organisms within plaques [182], and the fusion of
adjacent plaques. An infectious cause of atheroscle-
rosis could explain the consistent presence of
inflammatory cells surrounding plaques, and the
11-3
Atherosclerosis
reason why atherosclerosis is a chronic inflamma-
tory disease. A single infectious organism that
infects and alters SMC function to such an extent
that the cell ultimately dies could explain why
plaque tissue degenerates and a necrotic core is
formed. These observations provide insight into the
nature of the IA, and lead us to advance the follow-
ing hypothesis:
Hypothesis
We hypothesize that atherosclerosis is caused by a
single infectious organism, endemic throughout the
world (183–186]. Atherosclerosis is a world-wide
disease, and its lesions are similar in all peoples, as
with tuberculosis. We hypothesize that the infec-
tious organism resides in a dormant state within a
circulating cell, probably the monocyte exemplified
by HSV, CMV, and Cp, as an obligate intracellular
pathogen (187–189]. The organism is activated
when the monocyte, acting as a vector, is attracted
to sites of endothelial injury and carries the infec-
tious organism into the artery intima (187,188,190].
We further hypothesize that the infectious organism,
after entering the artery wall, is released from the
monocyte enters and “infects” resident, intimal
SMCs, and endothelial cells which now become an
additional host cells [187,191]. The activated infec-
tious organism is now present in monocyte derived
macrophages, intimal SMCs, and endothelial cells
[177], causing intracellular injury [183]. Considering
the possibility that the various histologic features of
atherosclerosis are infectious in origin raises ques-
tions about the mechanisms of injury.
Mechanisms of Injury
We postulate that the basic method or mechanism
of injury utilized by the infectious organism is to
enter and infect an intimal cell, injuring the cell and
altering or subverting normal intracellular functions,
What Is the Injurious Agent?
without killing the cell. Intracellular mechanisms are
altered in ways that foster the replication, expan-
sion, and spread of the infectious organism [183].
This particular mechanism of injury appears to be
repeated over and over again, and is similar to the
way a virus utilizes host cell mechanisms for replica-
tion [164,192]. The affected and infected cell then
becomes a tool of the infectious organism, a com-
ponent and participant in the disease process,
rather than a defender against the infectious organ-
ism. These subverted intracellular mechanisms
include, but are not limited to, the following:
1. Subversion of macrophage functions, resulting in
failure of the macrophage to recognize, kill, and
remove the infectious organism at the time of initial
injury when the organism is present in small
amounts and localized to a small area of the artery
wall. The responsible intracellular mechanisms are
not presently known, but defective killing of phago-
cytosed organisms is known to occur in chronic
granulomatous disease [193]. This initial failure of
macrophage function may explain how the infec-
tious organism is able to establish a foothold, and
“set up shop,” and create atherosclerotic lesions in
multiple, separate areas of the artery wall. In con-
junction with the failure to neutralize and kill the
infectious organism, the macrophages also fail to
phagocytose and remove dead and damaged tis-
sue, as well as fail to participate in the repair and
healing of the injured tissue [194]. Subversion of
these 2 basic defensive responses, failure to
phagocytose and kill the infectious organism, and
failure to remove damaged tissue at the time of ini-
tial infection, is pivotal in the initiation of atheroscle-
rosis.
2. Subversion of normal intracellular functions of the
SMC results in the secretion of an abnormal form of
CSPG that reacts with and retains lipid within the
interstices of the extracellular matrix [10]. This sub-
version may explain why lipid is a major component
11-4
Atherosclerosis
of atherosclerotic tissue [35]. The retention of lipid is
a component, not a complication of atherosclerotic
disease, and all plaque tissue containing such lipid
is not normal tissue. It is diseased and pathologic.
Early plaque growth is associated with proliferation
of SMCs, not normal SMCs but SMCs altered in
some way, inhibited from healing the area of injury
[12].
3. The infectious organism subverts the intracellular
mechanisms of the SMC, monocyte-derived
macrophages, and endothelial cells governing the
uptake, metabolism, and degradation of extracellu-
lar lipid, particularly the expression of scavenger
receptors [167,175]. Disturbing, altering, or subvert-
ing these lipid regulatory mechanisms results in
excessive uptake of lipid and results in the forma-
tion of lipid-laden SMC, macrophages, and endothe-
lial cells. The purpose behind this lipid up take may
be to allow the host cell, directly or indirectly, to
metabolize the lipid into a form that can be utilized,
such as oxidation of LDL and/or the esterification of
cholesterol, by the infectious organism (195). Oxi-
dized LDL may be one form of lipid required by the
infectious organism [175].
4. The ingestion of excess lipid by intimal SMCs is
associated with loss of cellular mobility within the
tissue, limiting the ability to migrate and transport
lipid back into the circulation [37]. Continued lipid
ingestion, over and above that required by inherent
cellular metabolism and/or the infectious organism,
ultimately results in over-distention, rupture, and
death of the cell. Death of the cell releases the
retained lipid, and presumably the infectious organ-
ism itself, into the extracellular space. The infectious
organism is now presumably free to infect other
cells, but it is also exposed to the B and T lympho-
cytes of the immune system (192). The release of
the infectious organism upon the death of the inti-
mal cells may be the event that triggers activation of
What Is the Injurious Agent?
the immune system and the proliferation of B and T
lymphocytes, commonly associated with later, more
advanced stages of atherosclerosis.
5. In some way, the infectious organism is able to
subvert or to avoid the killing immune responses
employed by T and B lymphocytes after the immune
system is activated. As evidence in Chapter 3
showed, the number of T cells in the adventitia
increased in direct proportion to plaque size, indicat-
ing active, continuing injury by the IA, along with
generation of more and more antigen. Activation of
the immune system leads to the proliferation of
antigen-specific T lymphocytes, the number of T
and B cells being directly related to the amount of
the antigen produced or presented to the T cells
[192,193].
However, activation of the immune system and the
associated activation of T lymphocytes, although
quite vigorous and progressive to judge by the
number of T cells, is not effective in neutralizing the
IA, or in halting the growth and spread of the dis-
ease. Plaques continue to grow and expand in spite
of a vigorous immune response. If these immune
responses were effective, growth and spread of the
infectious organism would be stopped, plaque
growth would cease, and the number of T cells
would decrease. Although the T cell and other
immune responses appear to be intact and function-
ing normally, the IA is able to avoid, subvert, or
overcome these various defenses and survive,
replicate, grow, and expand.
We gain some insight into this issue from the study
of H. Pylori. H. Pylori is a well-adjusted parasite that
survives in a hostile environment despite vigorous
humoral and cellular immune responses against it
[180]. The enzymatic pathways it needs for survival
are continually switched on, and the presence of
variable regions in gene coding for surface structure
allows organisms to evade immune responses by
11-5
Atherosclerosis
altering their surface antigens. This could be true in
atherosclerosis if the infectious organism is able to
subvert the immune system.
What immune mechanisms are subverted or altered
to allow an infectious organism survive in
atherosclerotic plaques? Insight is gained from stud-
ies of the Acquired Immunodeficiecy Syndrome
(AIDS) virus. The AIDS virus enters, subverts, and
eventually destroys the helper T lymphocytes that
play a key role in presenting viral antigens to the
killer T lymphocytes [192,193,196]. Helper T lym-
phocytes secrete 2 cytokines, Interluken-2 and
Interferon-gamma, essential for the immune system
to function normally and effectively [193,196]. If
these two cytokines are absent, the immune
response is blunted, killer mechanisms are com-
promised, infectious organisms are not killed, and
the infectious organism continues to replicate, grow,
and spread [196]. Something similar may happen in
atherosclerosis, preventing the infectious organism
from being neutralized and eliminated by the
immune system.
6. An infectious organism subverts normal defen-
sive responses by altering the hemostatic response
to injury. Hemostatic abnormalities are produced by
altering the phenotype of the endothelial cells from
anticoagulant to procoagulant, generating the for-
mation of thrombin [181]. SMCs and endothelial
cells infected with Cp express PAI-1, T factors, and
Interlueken-6, all procoagulants [197]. Excessively
high levels of PAI-1 disturb the thrombo-regulatory
balance between TPA and PAI-1, producing a pro-
thrombotic state. The result is an increase in hemo-
static responses to endothelial injury over and
above that required for injury repair. If this action of
the infectious organism does produce a prothrom-
botic state, to what purpose? The most logical
explanation is that thrombus in some way facilitates
What Is the Injurious Agent?
the growth and replication of the organism, possibly
through increased or more readily available lipid
[140].
Autoimmunity
Perhaps atherosclerosis is an autoimmune disease,
and arterial wall injury is caused by immune com-
plexes [166]. We visualize autoimmune disease as
similar to a vicious circle. Once established, it is
very difficult to stop, and it is not subject to the
exacerbations and remissions seen with atheroscle-
rotic disease. We would also visualize an autoim-
mune disease, caused by circulating immune
complexes, to be a diffuse disease, not a multi cen-
tric, focal disease. Further, we would expect an
autoimmune disease to respond to the administra-
tion of corticosteroids, but steroids have not been
shown to affect the course of human atherosclero-
sis. It is possible that autoimmune mechanisms may
play a role in contributing to the cellular injury and
cell death within a plaque and in this way contribute
to the expansion and spread of the IA.
In Review
Based on the evidence presented, we believe the
primary IA causing atherosclerosis is a single infec-
tious organism, an obligate intracellular pathogen
residing in a circulating cell, probably the monocyte.
Whether the organism is a bacterium or a virus is
unknown. Both classes of agents appear to infect
intimal cells and to alter intracellular mechanisms
with the potential to produce atherosclerotic lesions.
The infectious organism is activated after entry into
the artery wall, infects intimal cells, and establishes
a foothold within the wall. The organism proceeds to
replicate, expand, and grow in all directions from a
central focus. We speculate that the organism
requires lipid, probably oxidized LDL, to fuel replica-
tion and growth, and that it subverts normal cellular
functions and defense mechanisms to procure this
11-6
Atherosclerosis What Is the Injurious Agent?

lipid without killing the cell. We believe all of the

abnormal cellular responses, listed above, are
orchestrated by the infectious organism to procure
the energy required for replication and growth.

11-7
Atherosclerosis
12. The Toxic Atheroma
“Fragmentation and embolization of platelet-rich mural thrombi
at the site of vessel injury could cause damage by obstructing
myocardial microcirculation.”
JF Mustard, [128]
The Fundamental Acute Lesion
All acute coronary syndromes (ACS) can be traced,
in one way or another, to UPs and the resulting
sequelae [57,148]. The UP, therefore, is the funda-
mental lesion underlying the development of ACD
and is the initial precipitating event leading to these
syndromes [57]. The many different ACSs that
develop as a result of PU are due to the many inter-
acting factors triggered by this breach in endothelial
integrity, including the size, location, number, and
specific types of PU [57,148,154,198,199].
The primary aim of this chapter is to make clinical-
pathologic correlations in support of our hypothesis
that the initial symptoms and signs associated with
the onset of many ACSs are caused by the dis-
charge of plaque contents, particularly plaque toxins
from UPs, NOT by ischemia. Plaque contents
include any chemical agents, particulate matter, or
tissue fragment microemboli discharged from UPs.
A secondary aim, in Chapter 13, is to discuss the
potential role of plaque toxins in the subsequent
manifestations of the different ACSs.
The Toxic Atheroma
Necrotic tissue stimulates bodily responses to
remove it because it contains chemical agents that
trigger inflammatory mediators, injuring surrounding
viable tissue [18]. Necrotic tissue becomes increas-
ingly acidotic as cells undergo degeneration and
destruction, and as cellular proteins are denatured
The Toxic Atheroma
[200]. A necrotic focus will spontaneously ulcerate
and drain the necrotic material into a body cavity,
onto the body surface, or be resorbed and undergo
fibrotic replacement.
Some of the chemical toxins associated with
atheromas are products of lipid metabolism [61],
acids generated as part of cell necrosis [200],
inflammatory cytokines [18], immune complexes
[201], and other unknown factors. Oxidized LDL,
one of the most well known IAs, is believed to play a
major role in the formation of the necrotic core [61].
Reactive oxygen species are known to be highly
toxic metabolites, causing immediate injury to cells,
but the source of these free radicals has not been
fully determined [202]. Atheromas contain reactive
oxygen species and may serve as a source of these
toxic metabolites at the time of PU [203–205].
Based on our observations of resorption and possi-
ble reversal of vascular calcification (Chapter 5), the
necrotic core may also contain products of bone
metabolism, such as HA, a particularly irritating
compound [96]. HA may produce similar effects
when discharged directly into the coronary circula-
tion. Atherosclerosis is the only disease where
necrotic material and all associated chemical toxins,
are consistently discharged directly into the coro-
nary circulation, the most important blood supply in
the body.
How toxic are the contents of an atheromatous
core? Our reference to “plaque toxins” in this chap-
ter is meant to include any and all non-physiologic
chemical agents, present in the necrotic core, that
could produce direct stimulation and/or injury to
cardiac tissues when released into the coronary
circulation. Lyford and Connor, et al. [206], using
extracts made from human atheromas, injected the
extracts intravenously into 10 rats. Six of the 10
12-1
Atherosclerosis The Toxic Atheroma

died of cardiac causes within minutes of the injec-
tion. These sudden cardiac deaths were believed to
be due to direct, toxic effects of the chemical agents
contained in these extracts on the heart [Connor,
personal communication]. Nine of these rats also
showed pulmonary emboli, indicating these toxins
and/or plaque contents are quite thrombogenic
[198]. The possibility that chemical agents con-
tained within the necrotic core are potent cellular
toxins that could cause sudden and immediate
direct injury to cardiac tissues when released into
the coronary circulation must be considered in the
pathogenesis of ACD [207].
taneous discharge of these toxins at the time of PU
may be expected to produce immediate symptoms
and injury when the toxins circulate to downstream
structures [202]. The effect of these plaque toxins
discharging directly into the coronary circulation
may be similar to infusing absolute alcohol directly
into the first septal branch of the LAD to produce a
focal, controlled, myocardial infarction in the treat-
ment of hypertrophic cardiomyopathy [210,211].

The quantity of plaque toxins and other necrotic

material discharged at the time of PU will depend on
the anatomic features associated with each plaque,
the location of the plaque within the coronary tree,
the size of the plaque, and the size of the PU [57].
No two PUs are identical. Figures 8, 17–20, 22, 24,
and 26, illustrate various types of PUs, ranging from
tiny shoulder ulcerations to completely shelled-out
plaques. The amount of plaque contents, and,
therefore, the amount of plaque toxins released at
the time of PU may be expected to vary widely from
plaque to plaque. We assume the effects of these
plaque toxins will depend upon the concentration,
dose, the speed of release, the duration of the dis-
charge, the inherent toxicity of the agents, and how
quickly these agents can be neutralized and
removed. Consideration must also be given to the
number and age of the UPs in any given patient
because multiple, chronic UPs are the rule in
patients with acute coronary disease
[57,148,150,156,208,209].

For example, a small amount of toxin discharged

intermittently from a tiny shoulder ulceration (Figure
8) may produce no clinical symptoms, whereas a
large bolus of toxin from a shelled-out plaque (Fig-
ures 18, 24), may precipitate a sudden, acute
coronary event. Furthermore, the sudden and spon-
12-2
Atherosclerosis The Toxic Atheroma

Figure 24: Pathologic lesions of a 39-year-old white male who

died SCD outside the hospital. A, Dissected coronary artery
showing moderate stenosis in the mid-LAD branch. Asterisk =
main left coronary artery. B, Gross view of the narrowing in A
showing 80% luminal stenosis with an intact fibrous cap (white
arrow) overlying an empty, shelled out, necrotic core (white
asterisk). No occlusive thrombus is present. Black asterisk =
normal lumen. C, Histologic section of the UP in B, showing a
remnant of the fibrous cap (white arrow) and an empty necrotic
core (white asterisk) without evidence of thrombosis. D,
Cholesterol crystals and other plaque debris in a small branch of
the vasa vasorum supplying the artery wall distal to the UP in B.

12-3
Atherosclerosis The Toxic Atheroma

epicardial arteries and passed to the distal microcir-

culation. If embolic material circulates to these
structures, then so do any associated plaque toxins.

If the embolic plaque tissue is friable, as might be

expected of necrotic tissue (Figures 6,8), and
undergoes easy dispersion, the obstruction to flow
in the microcirculation may be insignificant. Large
tissue fragments (Figure 6F), may be more serious
Figure 26: A, X-ray of proximal left coronary artery in a 38-year- because such fragments will not be easily dispersed
old male who died SCD outside the hospital. Asterisk = Left main
and could cause prolonged obstruction of relatively
coronary artery. White arrow = Acute thrombotic obstruction of
the LAD coronary artery proximal to a bifurcation. C = CIRC large arteriolar branches. The result may be the
artery. I = Intermedius branch. B, Microscopic view of the production of focal ischemia or even infarction of the
thrombus in A showing plaque contents and cholesterol crystals myocardium [64,128,212,214]. Obstruction of the
(long black arrows) mixed with thrombus (short black arrows). C,
microcirculation by embolic plaque material, even
X-ray of proximal RCA in an 86-year-old female who died of
myocardial rupture several hours after receiving streptokinase for transient obstruction, may delay the dilution, neutral-
acute anterior myocardial infarction. White arrow = Site of ization, or washout of any associated plaque toxins,
intraintimal thrombus. D, Microscopic view of intraintimal resulting in greater toxic injury.
thrombus shown in C. Black arrows identify thrombus mixed with
blue injection mass indicating thrombus formed within a non-
obstructing UP. E, X-ray of proximal RCA of 37-year-old male
who died SCD outside the hospital. White arrow = Site of UP with
intraintimal thrombus shown in F. F, Note injection mass has
replaced plaque contents and fibrin strands have formed (black
arrows). B, D & E all H & E stain.

Embolization of Plaque Tissue

Embolic particulate matter, tissue fragments, and

platelet microemboli from UPs are found in the
majority of patients who died of ACD [64,128,212–
216]. The effect of this embolic material will depend
upon such factors as consistency, number, size, the
speed with which they are released, the speed with
which they are removed, and the specific cardiac
structures affected. Figure 23 shows several exam-
ples of embolic material in the lumen of the epicar-
dial arteries, the vasa vasorum, the myocardial
arterioles, and in the nutrient arteries to the conduc-
tion system of different patients. All emboli shown in
Figures 23–25 were located distal to UPs in the

12-4
Atherosclerosis The Toxic Atheroma

relieve thrombotic occlusion causing acute inferior myocardial

infarction. C, Microembolus in an arteriole (long arrow) lying
adjacent to the proximal left bundle branch (short arrows). D,
Small myocardial arteriole, adjacent to left ventricular
endocardium and distal left bundle branch (black arrows),
containing a small microembolus (white arrows). E, Embolic
plaque contents in the upper interventricular septum of an 82-
year-old white female who died of cardiogenic shock in the
hospital. F, Large intramyocardial microembolus (white arrow) of
a 34-year-old white male with a history of chest pains who died
SCD outside the hospital. This microembolus was distal to a non-
occlusive thrombus in the LAD artery.

Figure 23: A, Low-power and B, high-power view of

microembolus in the vasa vasorum (arrow) in the mid-CIRC
artery of a 39-year-old white male who received streptokinase to

12-5
Atherosclerosis
Figure 25: The photographs shown here are from the same
patient in Figure 24 and distal to the UP in Fig. 24B. A, Plaque
contents and debris (white arrow) in the LAD distal to the UP. B,
Small microembolus (arrows) in a myocardial arteriole. C,
Section of the myocardium showing contraction bands (arrows).
D, Section showing contraction bands (black arrows) in the left
bundle branch.
Initial Symptoms
By “initial symptoms” we mean those symptoms and
signs occurring within minutes after the onset of an
ACS. If initial symptoms of ACD are caused by
direct stimulation and/or injury of cardiac tissues by
plaque toxins discharged from UPs, and the effects
are immediate [202], then the initial symptoms
should coincide with the moment of PU or the
moment the toxins are released.
The onset of symptoms should mark the moment
when plaque toxins reach the myocardium or other
structures. The initial symptoms, then, could reflect
toxic stimulation or injury, rather than ischemic
injury. Time is required for ischemic injury to
develop and for ischemic metabolites to form [217].
Ischemic metabolites would not be present in suffi-
cient amounts to cause immediate stimulation or
injury of cardiac structures in the first few minutes
after the onset of symptoms, even when coronary
flow is acutely reduced [218,219]. We postulate the
initial symptoms associated with ACSs are due to
toxic rather than ischemic injury.
The Toxic Atheroma
Downstream Structures
If the initial symptoms of ACD are caused primarily
by the discharge of plaque toxins, we should see
histological evidence consistent with such toxic
injury by examining downstream structures. The first
tissue to be potentially affected by plaque toxins is
the endothelium of the artery containing the UP and
the endothelium of the microcirculation fed by that
artery. Recent studies show microparticles of
endothelial origin are present in the circulating blood
of patients with ACD, indicating endothelial injury
somewhere in the vascular system [220]. We have
observed extensive, circumferential, endothelial
erosions extending over a distance of several cm
(Figure 17D and E), consistent with injury by an
erosive toxin. Such erosions, localized to one coro-
nary artery and distal to an UP, provide evidence
the endothelium and the subendothelial tissue have
been injured by local substances, presumably origi-
nating from the UP. If the offending agent causing
this erosion were a circulating systemic toxin, then
we would expect all arteries, not selected arteries,
to show similar erosions.
Endothelial injury by plaque toxins from UPs has
implications for the pathogenesis of new atheroscle-
rotic lesions because any endothelial injury may
provide a point of entry for the IA [1]. Endothelial
injury produced by plaque toxins may be important
in the pathogenesis of multiple, separate plaques in
a single coronary artery (Figures 1 and 2), produc-
ing multicentric lesions (Chapters 1 and 5). Further,
these injurious chemical agents may injure and
weaken the fibrous cap of a distal plaque (Figures
17B,C, and F) and may contrib ute to the formation
of a second UP within the same coronary artery. We
have found as many as 3 or more widely separate
UPs within the same coronary artery in 13 of 83
(16%) patients who died of ACD [57].
12-6
Atherosclerosis The Toxic Atheroma

In addition, the circulation of large amounts of

In Review
potent toxins to the distal myocardial microcircula-
Considerable histologic and clinical evidence exists
tion may severely injure or destroy the capillary
that plaque toxins, originating from UPs, have the
endothelium and thus obstruct blood flow through
potential to produce the initial symptoms by stimulat-
the affected area, even with adequate antegrade
ing or injuring many cardiac structures. These toxins
flow. This mechanism may be one explanation for
may play an important role, in both the initial clinical
the no-reflow phenomena observed in some ACSs
and subsequent manifestations as well as the prog-
[221,222], discussed in Chapter 13 in the section on
nosis of various ACSs.
acute myocardial infarction (AMI). The release of
plaque toxins from UPs may affect other cardiac
structures, including the SMC and nerves of the
media and adventitia of the epicardial artery, the
conduction system, and the cardiac chemorecep-
tors.

The artery wall overlying an atherosclerotic plaque

often has a highly developed vasa vasorum [223]
that could carry any circulating plaque toxins quickly
to the adventitia. Injury and/or stimulation of the
media and/or adventitial nerves by plaque toxins
could potentially produce vasoconstriction of a focal
portion of the coronary artery, as well as chest pain,
by stimulating sympathetic nerves.

If the artery containing an UP supplies a portion of

the conduction system, these toxins may cause
direct injury or dysfunction of the pacemakers and/
or the peripheral conduction system, leading to var-
ious arrhythmias in the absence of ischemia
[218,224].

Plaque toxins may also stimulate the cardiac

chemoreceptors, activating reflexes such as the
Von Bezold Jarish (VBJ) reflex [225], producing the
bradycardia and hypotension often observed when
this reflex is activated during acute coronary events.
By definition, the VBJ reflex is produced by chemi-
cal stimulation of the cardiac chemoreceptors
located throughout the heart, further implicating a
chemical agent in the pathogenesis of the initial
symptoms.
12-7
Atherosclerosis
13. Plaque Toxins and Clinical Coronary
Syndromes
“…Different morphologic patterns of myocardial necrosis
suggest that various pathogenetic mechanisms with different
biochemical derangements may interact in the natural history
of the coronary heart disease.”
G Baroldi [251]
The Pathogenesis of Angina
Pectoris Pain
The pathogenesis of the pain of angina pectoris
remains in doubt [217,226]. Lewis advanced the
theory that the “P” (pain) factor, a chemical agent
derived from ischemic cells, stimulates sympathetic
nerves, producing the pains of angina pectoris
[227]. The specific chemical agent(s) were not iden-
tified. Lewis attemped to explain the wide variety of
anginal pains on the basis of one mechanism,
myocardial ischemia. He did not consider the possi-
bility that two different mechanisms might produce
the pains. Many investigators, including Lewis,
believe cardiac sympathetic nerves within the
myocardium are stimulated by chemical metabolites
derived from ischemic myocardium [217,227], but
this does not explain many features of angina pec-
toris.
We hypothesize the pain of angina pectoris is
caused by the stimulation of cardiac sympathetic
nerves by two different, broad classes of chemical
agents, derived by two separate and distinct mech-
anisms. Chemical agents derived by the first mech-
anism are those metabolites produced by ischemic
cells and stimulate intramyocardial sympathetic
nerves, producing typical anginal chest pain. These
metabolites, localized to the area of myocardial
ischemia, are subsequently neutralized and/or
removed by flowing blood (227), and do not reach
Plaque Toxins and Clinical Coronary Syndromes
the adventitia of the epicardial arteries. Chemical
agents derived by the second mechanism are chem-
ical toxins discharged from UPs (discussed above),
and circulate to all distal cardiac structures, includ-
ing the adventitial nerves distal to the UP.
These two different mechanisms, each associated
with different chemical agents that stimulate sympa-
thetic nerves in different locations, both producing
anginal-type pains, could explain some of the chest
pain variations in angina pectoris. For example,
direct stimulation of adventitial sympathetic nerves
by plaque toxins may produce different anginal
pains from ischemic metabolites that stimulate
intramyocardial sympathetic nerves. Similarly, stim-
ulation of adventitial nerves by plaque toxins in the
right coronary artery may produce a different type
and distribution of chest pains than the same toxic
stimulation of adventitial nerves in the left coronary
artery. The same reasoning applies to the toxic
stimulation of adventitial nerves in the proximal
compared with the distal portion of the artery [216].
If this hypothesis is correct, it may be possible to
distinguish these two different mechanisms clini-
cally. For example, the anginal pains produced by
ischemic metabolites from myocardial cells may
produce the typical substernal tightness, heaviness,
and pressure associated with stable angina pec-
toris. Chest pains of this type are commonly precipi-
tated by exertion, relieved by rest, and are fre-
quently associated with one or more significant,
fixed, coronary stenoses. The relationship between
exertion and the chest pain provides strong evi-
dence in favor of ischemia. These chest pains,
which are usually gradual, not sudden or dramatic in
onset, and which are directly related to the amount
13-1
Atherosclerosis Plaque Toxins and Clinical Coronary Syndromes

of exertion, suggest it takes time for cells to become
sufficiently ischemic to produce the metabolites that
ultimately stimulate the nerves and produce the
chest pain.
the amount, potency, and speed of release of the
toxin, and the specific nerves stimulated. The sec-
ond mechanism would be expected to produce a
wide range and variety of chest pains because there
are so many variable precipitating factors.

The anginal pains produced by chemical toxins dis-

charged from UPs may be expected to be sudden in
The possibility that two different broad classes of
onset when the toxin, discharged from the UPs,
chemical agents with different chemical characteris-
strikes distal sympathetic nerves [202]. Chest pains
tics, originated by two mechanisms that stimulate
produced by this second mechanism would be
different sympathetic nerves differently, must be
expected to come on at any time, at rest or during
considered in the pathogenesis of the pain of
sleep, without exertion or other obvious precipitating
angina pectoris (228).
cause, whenever the plaque ulcerates and the dis-
charge of toxins occurs.
Variant (Prinzmetals) Angina
(VA)
These two mechanisms may also be distinguished
by the mode of relief. Chest pain caused by the first
The VA syndrome is the prototype we will use to
is relieved by rest, presumably because the produc-
illustrate how plaque toxins and embolic plaque
tion of ischemic metabolites ceases when exercise
contents may be involved in the pathogenesis of the
stops. The administration of vasodilators, such as
initial symptoms in ACSs. In patients with VA, the
nitroglycerin, may assist in neutralizing or removing
sudden onset of severe anginal chest pain, S-T
these metabolites through increased blood flow
segment elevation, cardiac arrhythmias, and
(227). Chest pains produced by the second mecha-
myocardial perfusion defects, all developing simul-
nism are similar to those described for unstable
taneously, are consistent with spontaneous PU and
angina, often subsiding spontaneously without spe-
discharge of plaque toxins into the coronary circula-
cific treatment, suggesting that the offending chemi-
tion. The quick reversal of these symptoms and
cal toxin is no longer present, presumably neutral-
signs, with the exception of the myocardial perfu-
ized or removed by flowing blood. Such
sion defects [229–231], is consistent with prompt
spontaneous relief of chest pains suggests coronary
neutralization, dilution, and/or washout of these
blood flow was not significantly obstructed by a
same toxins. Prompt reversal of the entire syn-
fixed stenosis.
drome is also consistent with unobstructed coronary
flow.
The third possible way the two mechanisms could
be distinguished is by the overall character, somatic
distribution, and reproducibility of the anginal chest Many investigators attribute VA to acute ischemia
pain. We would expect anginal chest pains associ- caused by reversible coronary vasospasm
ated with the first mechanism to be reproducible, [229,231]. The triggering agent responsible for pro-
non-progressive, and localized to the same somatic ducing this spasm has not been identified
distribution with each episode. The character and [69,232,233]. Until it is, it cannot be stated with cer-
distribution of the chest pains produced by the sec- tainty that VA is caused by coronary vasospasm
ond mechanism would be expected to vary in because the triggering agent may have a number of
intensity, distribution, and duration, depending on effects including, but not limited to, coronary spasm.
13-2
Atherosclerosis
Angiographic, intravascular ultrasound, and post-
mortem examinations of the area of coronary spasm
commonly show the presence of atherosclerotic
plaques and, in a few cases, the presence of acute
lesions [69,229,234–237]. The triggering agent that
precipitates spasm appears to be related in some
way to active atherosclerotic disease, possibly an
acute lesion at or near the site of spasm [229]. Our
pathologic studies of patients who died as a result
of ACD show the presence of one or more UPs,
many of them unrecognized on angiography
[57,147]. Because patients with VA are at risk of
developing acute coronary events, we postulate that
patients with VA also have one or more unrecog-
nized, chronic UPs in their coronary tree. If this is
correct, patients with VA have a source of plaque
toxins and plaque contents with the potential to dis-
charge plaque toxins into the coronary circulation
and produce, directly or indirectly, the VA syn-
drome. Plaque toxins may be the “local factor”
mentioned by Maseri as playing a role in coronary
spasm and the VA syndrome [234].
The development of myocardial perfusion defects
following an episode of VA indicates some type of
myocardial injury has occurred [229–231]. Recovery
of myocardial perfusion can occur in a matter of
hours or can be prolonged and require several
days, indicating the injury was temporary but was
severe enough to cause ventricular dysfunction
[229–231]. Had myocardial injury been caused
solely by vasoconstriction or spasm, we would
expect the spasm to subside with the symptoms,
and the ventricular dysfunction to reverse in a mat-
ter of minutes. Prolonged ventricular dysfunction
suggests additional factors, over and above spasm
of the epicardial artery or the myocardial arterioles,
caused the perfusion defects. We believe those
additional factors are primarily plaque toxins origi-
nating from UPs that supply that segment of
myocardium. Embolic material [64,128,212–216], as
discussed above, would add to and aggravate the
Plaque Toxins and Clinical Coronary Syndromes
effect of the toxins. This direct toxic suppression of
ventricular function could explain why some VA
episodes are prolonged and unresponsive to treat-
ment [231].
Figure 8 illustrates several UPs discharging plaque
contents into the lumen. We have suggested the
plaque contents from plaques such as these are
intermittently “milked” into the lumen by pulsatile
arterial pressure. The intermittent discharge of
embolic plaque contents and toxins may be
expected to produce intermittent symptoms. The VA
syndrome could be caused by the discharge of tox-
ins from plaques with this configuration, triggering
not only intermittent coronary spasm, but also injury
or dysfunction of the distal myocardium and/or the
conduction system. Although the prognosis is gen-
erally good for patients with VA, an sudden cardiac
death rate of 3.6% and an AMI rate of 6.5% indicate
VA is not a benign condition but is another manifes-
tation of active, ulcerative, coronary disease [231].
The presence of one or more chronic UPs that
intermittently discharge plaque toxins could explain
many of the following observations and findings in
the patient with VA. For example, the increase in
heart rate following an episode of VA [231] could be
due to the release of catecholamines secondary to
toxic stimulation and/or injury of the myocardium.
Multiple sites of coronary spasm [238] could be due
to the presence of multiple, actively discharging
UPs [57]. The coronary spasm associated with
PTCA [203,239] could be caused by the release of
plaque toxins when the plaque is split by balloon
inflation, its contents discharged. The S-T elevation
characterizing an episode of VA, mimicking AMI,
and with associated perfusion defects [231], can be
explained by the release of a large amount of highly
potent toxins that cause temporary transmural dys-
function, similar to that of a transmural infarction.
13-3
Atherosclerosis
We believe coronary spasm is not the cause, but is
one of many components of the VA syndrome trig-
gered by plaque toxins.
Sudden Cardiac Death (SCD)
We hypothesize that SCD, an ACS whose initial
symptom is a sudden lethal arrhythmia, is caused
by the sudden dramatic arrest or disruption of car-
diac conduction by plaque toxins, not by acute
ischemia. SCD, as discussed here, refers to those
patients with apparently normal hearts, and no
symptoms of coronary heart disease, who collapse
and die suddenly without warning [240]. The major-
ity of these patients have unrecognized coronary
atherosclerosis. The clinical and pathologic evi-
dence supporting this hypothesis are as follows:
First, SCD in these patients occurs much too rapidly
to be caused by acute myocardial or conduction
system ischemia [207,218]. Ischemic injury and
occlusive thrombosis take time to develop [241].
Even acute total occlusion of a coronary artery, as
with a balloon during PTCA, does not produce sud-
den lethal arrhythmias [219].
Second, Holter monitor recordings of patients taken
at the time of SCD, frequently do not show S-T
changes to support a sudden onset of acute
ischemia, certainly not the massive ischemia, to be
expected if that was the cause [242,243]. Holter
recordings do, however, often show an increase in
heart rate, plus the development of complex ven-
tricular ectopy just before the onset of the lethal
arrhythmia [242,243]. The increase in heart rate
may be due to the release of catecholamines by
plaque toxins (244), postulated earlier regarding the
VA patient. Complex arrhythmias indicate a serious
disturbance of the conduction system.
Plaque Toxins and Clinical Coronary Syndromes
Third, careful pathologic studies show the majority
of SCD patients have one or more UPs in their
coronary arteries and, therefore, have the lesions
that could serve as a source of plaque toxins
[57,64,150,156,245–247]. In addition, immediate
coronary angiograms of SCD patients who are suc-
cessfully resuscitated show the presence of com-
plex UPs similar to those seen on postmortem
examination [247–249]. Thus, the majority of SCD
patients have acute structural abnormalities in the
coronary arteries, along with the sudden, lethal,
disruption of cardiac rhythm [57,139,156]. Abnormal
structure correlates with abnormal function.
Fourth, contraction bands or myofibrillar degenera-
tion, an early histologic sign of injury, have been
found in the myocardium and in the conduction sys-
tem of many SCD patients [250–252]. Contraction
bands in the conduction system suggest injury
occurred at approximately the same time as the
onset of the lethal arrhythmia (Figures 24 and 25).
The effect of plaque toxins on the myocardium and
the conduction system may be quite similar to the
immediate effects of absolute alcohol [210,211]. We
propose that plaque toxins caused the contraction
bands in the conduction system and are responsible
for causing the lethal arrhythmia through sudden,
direct injury to the conduction system [252].
Fifth, the lethal arrhythmia causing SCD is poten-
tially reversible. Successful defibrillation and resus-
citation of the SCD patient are not necessarily
followed by an immediate recurrence of the original
episode, indicating the triggering agent is transiently
present. This observation, not consistent with a
fixed coronary obstruction or an occlusive thrombus
causing severe ischemia, is consistent with rapid
washout of a plaque toxin. Furthermore, SCD sur-
vivors do not necessarily go on to develop occlusive
thrombosis and/or AMI, so the arrhythmia was not a
precursor to these events [245,248,253]. AMI is
found in a minority of SCD patients, providing addi-
13-4
Atherosclerosis
tional evidence the arrhythmia was not related to a
prior, unrecognized, or silent AMI [57,240,244,253–
255]. Our pathologic studies of 26 SCD patients
without AMI showed 59 UPs, but only 23 (39%)
were associated with luminal thrombosis. Of these
only 9 thrombi (39%) were totally occlusive [57].
Sixth, infarction of the conduction system is rarely
found at post-mortem examination, even with large
trans-mural infarctions. The conduction system
appears to be relatively resistant to ischemia and,
presumably, relatively resistant to developing lethal
arrhythmias caused by ischemia [252,256]. This
inherent resistance is probably related to the rich
collateral and anastomotic blood supply to the con-
duction system [257], and the rich and preferential
blood supply to the peripheral conduction system
via the left ventricular subendocardium [258]. In
addition, since conducting fibers do not contract and
may not have the same energy requirement as reg-
ular myocardium, they may be able to tolerate
ischemia without serious injury or malfunction [252].
A serious insult is required to injure the conduction
system, and to disrupt normal cardiac conduction,
and to produce lethal arrhythmias.
Seventh, such interventions as coronary artery
bypass surgery, PTCA with or without stents, aimed
at relieving presumed myocardial ischemia in SCD
survivors, have been generally unsuccessful [249],
providing further evidence the lethal arrhythmia may
not be caused by ischemia. We believe ischemia is
an infrequent and remote pathogenetic factor in
precipitating the lethal arrhythmia responsible for
SCD.
Figures 24 and 25 show the pathologic findings in a
39-year-old white male who died SCD outside the
hospital, shortly after complaining of chest pains.
The patient had no prior history of heart disease,
and the postmortem examination showed no evi-
dence of AMI. Luminal stenosis, subsequently
Plaque Toxins and Clinical Coronary Syndromes
determined to be approximately 80% of the cross-
sectional area, was evident on the post-mortem
angiogram (Figure 24A). Gross and microscopic
examination of the stenotic area showed a shelled
out plaque, with a small false channel (Figures 24B,
C), but no evidence of thrombosis. No other acute
coronary lesions were present in this patient.
Large amounts of plaque contents were present in
the lumen distal to the UP (Figure 25A), as well as
microemboli in the vasa vasorum (Figure 24D), and
in the microcirculation of the distal myocardium
(Figure 25B). Contraction bands were found in the
myocardium and in the peripheral conduction sys-
tem (Figures 25C,D), indicating recent injury. The
clinical history plus the histologic evidence are con-
sistent with sudden PU, the discharge of a large
amount of plaque contents and plaque toxins, caus-
ing direct injury to the conduction system and the
adjacent myocardium. The findings in this patient
illustrate a common mechanism that could be
responsible for SCD.
Unstable Angina (UA) and Non
S-T Segment Elevation
Myocardial Infarction (NSTEMI)
The prevailing opinion is that the UA syndrome and
closely related NSTEMI are caused by acute
myocardial ischemia secondary to plaque rupture
[69], thrombus formation, and reduced coronary
flow [259]. The diagnosis of myocardial ischemia is
based on anginal chest pain, S-T segment depres-
sion, and, when present, the elevation of cardiac
enzymes [69]. However, angiographic and patho-
logic studies often show one or more acute lesions,
in the form of complex UPs, in the coronary arteries
[57,69], but not necessarily thrombus formation or
obstruction to coronary flow. Therefore, the UA
patient, like the patient with SCD, has UPs that
could serve as a source of plaque toxins. If VA and
SCD are caused by plaque toxins, not by ischemia,
13-5
Atherosclerosis
it is reasonable to postulate UA and NSTEMI are
also produced by the same mechanism. What evi-
dence supports this hypothesis?
The sudden onset of rest angina, nocturnal angina,
or new onset severe angina [259], like SCD, occurs
too rapidly for either thrombosis or ischemia to
develop and precipitate these symptoms [241].
Moreover, anginal-type chest pain and S-T depres-
sion are not specific for ischemia and can be pro-
duced by other agents, particularly by toxic chemi-
cals [210,211]. Anginal chest pain and S-T
depression represent presumptive evidence, not
proof, of ishemia. Thrombolytic drugs, intended to
relieve ischemia, have not only failed to help the
patient, they have led to an increase in fatal and
nonfatal AMI [69]. As a result, these drugs are no
longer recommended for the treatment of UA and
NSTEMI [69]. There is reason to question ischemia
in the pathogenesis of UA and NSTEMI syndromes.
If plaque toxins can stimulate sympathetic nerves in
the heart to produce angina pectoris and are suffi-
ciently potent to cause S-T changes and myocardial
injury, then toxic injury mimics, and is indistinguish-
able, from ischemic injury. We hypothesize UA and
NSTEMI syndromes are not due to ischemia at all,
but are caused primarily by plaque toxins. Further-
more we believe that plaque toxins are sufficiently
potent in themselves to cause myocardial injury and
NSTEMI, without implicating ischemia, thrombosis,
or obstruction of coronary flow. The subsequent
development of thrombotic occlusion, ischemia, and
S-T Elevation Myocardial Infarction (STEMI) in
some UA or NSTEMI patients does not nullify our
hypothesis. Once thrombotic occlusion develops,
ischemic injury becomes superimposed on toxic
injury, and an entirely different syndrome is present.
This hypothesis could explain why thrombolytic
drugs are contraindicated in the patient with UA and
NSTEMI and sheds light on the mechanisms
involved.
Plaque Toxins and Clinical Coronary Syndromes
Many of the multiple, chronic UPs found in patients
with ACD contain intraintimal and mural thrombi,
with plaque contents incorporated into the body of
the thrombus (Figure 26) [198]. An intraintimal
thrombus acts to seal the UP [148] and to prevent
the discharge of plaque contents and plaque toxins.
A thrombolytic drug, by causing lysis of intraintimal
thrombus, reverses the normal repair responses
(Chapter 9), and reopens what is essentially a
sealed UP [148,260]. Multiple UPs may be present
in all 3 major coronary arteries [57], and may be
reopened by these drugs and discharge plaque tox-
ins to the entire myocardium. This could result in
global myocardial dysfunction in spite of adequate
coronary blood flow [222,261]. In addition to reopen-
ing the core, the lysis of thrombus also releases any
plaque contents and toxins contained within the
body of the thrombus, adding to the toxins liberated
from the reopened core itself. Microembolic obstruc-
tion of the microcirculation could also contribute to
toxic injury by obstructing antegrade, collateral, and
anastomotic flow, as discussed above [128].
The lysis of intraintimal thrombus also allows blood
to re-enter the now empty, or partially empty,
necrotic core [262]. This reentry may change the
dynamics within the core. For example, the reentry
of blood could lead to dissection of blood along
cleavage planes (Figure 7, Chapter 4), the forma-
tion of blind pockets (Figure 20), or the disruption
and/or dislodging of the fibrous cap to form an
occluding flap of tissue (Figure 20). Administering a
thrombolytic drug is also associated with the activa-
tion of platelets [263,264]. Activation of platelets
may lead to the formation of a new intraintimal
thrombus in a newly reopened necrotic core, and
lead to an occlusive thrombus and acute events.
Therefore, thrombolytic drugs may convert a rela-
tively stable UP into an unstable UP, resulting in
fatal and non-fatal AMI. The mechanisms described
13-6
Atherosclerosis
here could explain adverse clinical events, and the
paradoxical response that follows thrombolysis in
patients with UA and NSTEMI [264].
Aiming therapy at ischemia and thrombosis with
thrombolytic drugs in patients with UA and NSTEMI
fail [69] because ischemia and thrombosis are the
wrong targets. The target is the UP and the associ-
ated discharge of plaque contents and plaque
toxins. Therapeutic efforts should be aimed at the
identification and elimination of the culprit UP
responsible for discharging the plaque toxins and
other material. How is this best accomplished?
At the present time, the approach offering the best
chance of eliminating an actively draining UP is to
intervene with a cardiac catheterization, identify the
culprit UP, perform PTCA and place a stent in the
area (Chapter 4). This approach would stabilize the
UP by doing two things. First, the plaque would be
completely drained by splitting the fibrous cap with a
balloon, allowing coronary blood flow to carry away
any remaining plaque contents and toxins. Second,
the placement of a stent would stabilize the plaque
by occluding any cleavage planes, would close any
blind pockets, tack up any loose fragments of
fibrous cap, and would produce unobstructed coro-
nary flow across the lesion. Any complications, such
as spasm or sudden ventricular arrhythmias result-
ing from the liberation of toxins during PTCA could
be handled at the catheterization table. This view is
supported by clinical studies that show early inter-
vention in the patient with UA and NSTEMI results
in a decrease of recurrent events and improvement
in the long-term prognosis [265–268]. This
approach would not disturb or affect intraintimal
thrombi in UP elsewhere in the coronary tree or
create more unstable lesions.
We believe UA and NSTEMI syndromes are caused
by plaque toxins released from chronic UPs, not by
ischemia secondary to thrombotic obstruction.
Plaque Toxins and Clinical Coronary Syndromes
Thrombolytic drugs are contraindicated because
they dissolve intraintimal thrombus, reopen sealed
UPs (Figure 26), and lead to the discharge of more
plaque toxins, and activate platelets leading to
acute events. Therapeutic efforts aimed at stabiliz-
ing the UP and neutralizing plaque toxins would
focus on the right target, in the right patient, for the
right reasons.
S-T Elevation Myocardial
Infarction (STEMI)
Why are thrombolytic drugs recommended for the
treatment of STEMI [122,269], but not for UA and
NSTEMI [69], if all have the same pathologic sub-
strate in terms of UPs and the same overall plaque
burden? The major difference is STEMI IS caused
by ischemia secondary to acute obstruction of coro-
nary flow, commonly by occlusive thrombosis, but
UA and NSTEMI are not. The administration of a
thrombolytic drug to the patient with STEMI is
appropriate because this treatment is aimed at the
right target, occlusive thrombosis, for the right rea-
son, to restore coronary blood flow. Relieving the
thrombotic occlusion with a thrombolytic agent
relieves the ischemia, reduces the size of the infarc-
tion, and improves the prognosis [122,269].
Since the majority of occlusive thrombi are super-
imposed on a UP, we assume plaque toxins are
discharged from the core prior to the formation of
the thrombus [262], producing injury, initial enzyme
elevation, and symptoms, before thrombosis and
ischemia develops (Figure 8). After the formation of
the occlusive thrombus, subsequent enzyme eleva-
tion is due to ischemic injury and infarction, super-
imposed on the initial toxic myocardial injury or
infarction. These two different mechanisms for pro-
ducing STEMI could explain the two different histo-
logic types of myocardial infarction described by
13-7
Atherosclerosis Plaque Toxins and Clinical Coronary Syndromes

Baroldi [251]. It is possible that we are dealing with the infarction, but also causing post-infarction
two entirely different mechanisms in the pathogene- angina despite adequate coronary flow [222]. Tox-
sis of STEMI. ins may also injure the peri-infarction tissue, caus-
ing re-entrant arrhythmias, and/or they may directly

If two mechanisms are present, one ischemic and injure the conduction system and precipitate the

one toxic, they might offer an explanation of some various arrhythmias often observed following

of the observations, clinical findings, and complica- thrombolysis [270,271]. These observations may

tions following the administration of thrombolytic explain why a bigger, more wide open artery is not

agents to the patient with STEMI [222]. The most necessarily better if this flow brings with it more tox-

important observation is that thrombolytic drugs are ins or more emboli [222]. These toxins may be the

not 100% effective in opening acutely occluded “untreated factor” or unrecognized factor responsi-

coronary arteries, as might be expected if the occlu- ble for the no-reflow phenomena referred to by

sion were pure thrombus. We believe that the failure Gibson [126].

of thrombolytic agents to reperfuse an acute occlu-

sion is due to the presence of a blind pocket and/or Thrombosis versus Plaque Toxins
a flap of fibrous cap that do not respond to the lytic
agent (Figure 20). Perforating this blind pocket or
Although thrombolytic drugs relieve thrombotic
flap with a guide wire may be all that is necessary
occlusion and improve survival in patients with
for the thrombolytic drug to perfuse the artery and
STEMI, it is becoming increasingly apparent that
lyse any associated thrombus [123].
thrombosis and resultant ischemia are not the pri-
mary cause nor the primary pathologic lesion in
Reperfusion of an obstructed artery with a throm-
many other ACSs. In other words, “Ischemic Heart
bolytic agent or with PTCA may be followed by
Disease” may not be ischemic at all, in many
reperfusion injury, manifested by failure of the
patients, but “Toxin Induced Heart Disease.” It is a
injured myocardium to recover contractility despite
mistake to attempt to explain all the facets of ACD
adequate coronary flow, the no-reflow phenomena
on the basis of ischemia and/or occlusive thrombo-
[222]. It is our theory that reperfusion injury and the
sis. If the fundamental lesion underlying all ACS is
no-reflow phenomena are caused by plaque toxins
the UP, and UPs discharge plaque toxins capable of
liberated from UPs, both before the thrombotic
causing direct injury to cardiac tissues, then it is
occlusion and then again after reperfusion. Throm-
reasonable to consider plaque toxins as a major
bolysis restores coronary flow, but it also liberates
additional etiologic factor in the pathogenesis of
any toxins contained within the thrombus, reopens
ACD. Thrombosis is but one of the many compo-
the necrotic core, and releases more plaque toxins.
nents, reactions, and responses that characterize
ACD. Thrombosis is not inherently pathogenic, but
No-reflow is believed to be due to severe injury to becomes pathologic only in certain circumstances
the microcirculation, particularly the endothelial lin- (Chapter 9). Therefore, preventing or treating
ing of these vessels, obstructing flow. Toxic injury to thrombogenic responses per se is not appropriate
the microcirculation may be so severe that angio- for all ACSs and correcting thrombosis corrects only
graphic dye leaks into the myocardium and results one component of ACD. There are many other
in the myocardial staining or blush often observed at components to consider.
angiography [222]. Further, these toxins may circu-
late to the peri-infarction zone, not only enlarging
13-8
Atherosclerosis
Myocardial Rupture and
Thrombolytic Drugs
Myocardial rupture is a well-recognized complica-
tion of thrombolytic therapy for STEMI, occurring
much more frequently in these patients than in
patients not receiving a thrombolytic drug [272–
274]. Myocardial rupture occurs only in patients with
transmural infarctions [273] and appears to be
related to excessive softening and liquefaction of
infarcted tissue, beyond what is observed in the
majority of transmural infarctions. Infarction and
necrosis are not synonymous terms [200] because
fully necrotic tissue has no structure while infarcted
myocardium still has many structural elements
intact. Therefore, when the infarcted tissue
becomes excessively necrotic and is without any
residual fibrous structure, it is prone to rupture.
What is the pathogenesis of myocardial rupture in
general, and after thrombolysis in particular? Why
does excessive liquefaction occur, and why does it
occur more frequently in the patient receiving
thrombolytic drugs? Myocardial rupture has been
attributed to a lack of collateral and/or anastomotic
blood flow to the infarcted area [275]. Embolic
obstruction of these alternate channels could occur
as a result of emboli originating from the culprit
occlusive thrombus as it undergoes lysis, or from
emboli originating from mural or intraintimal thrombi
in UPs in uninvolved coronary arteries [64] that
supply collateral flow to the obstructed, culprit
artery. Lack of well developed collateral flow in
patients who develop their first infarction may also
be a factor in rupture as well [275].
We hypothesize the liquefaction of infarcted
myocardium is caused primarily by excess plaque
toxins that become trapped or localized in the
infarcted area. Obstruction of antegrade flow and
embolic obstruction of collateral or anastomotic flow
may delay or prevent neutralization or washout of
Plaque Toxins and Clinical Coronary Syndromes
these toxins. The trapped toxin could cause exces-
sive softening, liquefaction, and, if not neutralized,
rupture of the myocardium. This could explain
myocardial rupture in patients with small infarctions
involving secondary branches [276], probably with
limited collateral and/or anastomotic flow where a
toxin could be highly concentrated.
The use of primary PTCA and stents without throm-
bolytic drugs for the treatment of STEMI has
resulted in a decrease in myocardial rupture com-
pared with results following the use of thrombolytic
drugs [277]. The reduction of myocardial rupture
following PTCA may be explained by the removal of
the obstructing luminal thrombus, restoring blood
flow without disturbing intraintimal thrombus, not
reopening sealed UPs, and the washout of any
retained toxins by restored blood flow.
Stunned Myocardium
Stunned myocardium is defined as viable but dys-
functional, akinetic, dyskinetic, noncontractile
myocardium in the presence of adequate coronary
blood flow. Myocardial stunning is usually a tempo-
rary phenomenon, lasting only hours to days, often
associated with ACSs including VA, SCD, UA and
NSTEMI [278,279]. Most investigators believe stun-
ning is related in some way to ischemia produced
by obstruction or partial obstruction of blood flow,
sufficient to cause cellular dysfunction and loss of
contractility, but not of viability [201,279]. However,
stunned myocardium is non-contractile, yet it has
normal perfusion on thallium scintigraphy, resulting
in a “perfusion-contraction” mismatch [279]. If the
stunning were due to ischemia, the perfusion scan
should show a decreased uptake of thallium to go
along with the proposed decrease in coronary flow.
The failure to establish the presence of ischemia by
this objective method is strong evidence stunning is
not caused by ischemia.
13-9
Atherosclerosis Plaque Toxins and Clinical Coronary Syndromes

temporary injury caused by toxins and quick

We believe myocardial stunning is another ACS,
washout of these toxins by circulating blood, as in
which could be explained on the basis of plaque
myocardial stunning [284]. We hypothesize that
toxins liberated from unrecognized UPs. Myocardial
patients with SI develop ACSs because the plaque
injury caused by a plaque toxin may be temporary
discharging the toxins develops a larger ulceration
and reversible, depending upon the amount of toxin
and discharges sufficient toxins to produce clinical
discharged from the necrotic core and the speed
syndromes, such as UA or NSTEMI, or proceed on
with which it is neutralized or washed away by flow-
to develop coronary thrombosis and STEMI
ing blood. If stunning is caused primarily by plaque
[286,287]. If this is correct, identifying patients with
toxins and not by obstructed blood flow, this could
silent and reversible S-T depression on Holter moni-
explain the quick reversal of stunning after an
tors may identify patients with active, open, unstable
episode of VA, UA, or focal myocardial dysfunction
UPs in whom an intervention could prevent an acute
in patients with unobstructed coronary arteries
event. Our hypothesis is supported by recent stud-
[280,281]. The discharge of plaque toxins from a
ies confirming early intervention with PTCA and
non-obstructive UP during exercise could also
stent placement reduces the acute event rate in SI
explain stunning associated with exercise testing
patients [287].
and its quick reversal in the post-exercise period
[280]. Furthermore, stunning is attenuated by the
use of superoxide dismutase, an enzyme that tends Oral IIB/IIIA Inhibitors
to neutralize free radicals, which offers further evi-
dence that stunning may be related to toxic injury
Oral IIB/IIIA inhibitors have been dropped from clini-
[201,282,283]. It is interesting that Kloner, et al.,
cal testing because of an unexplained increase in
concluded that myocardial stunning consists of two
adverse clinical events, including bleeding and fatal
components, an ischemic component and a toxic
and non-fatal AMI [141,288,289]. The oral IIB/IIIA
component caused by reactive oxygen species, with
inhibitors were given on the assumption that acute
the toxic component appearing to be larger than the
coronary syndromes such as UA and NSTEMI,
ischemic component [201]. We believe stunned
were caused by ischemia related to thrombus for-
myocardium is caused primarily by plaque toxins
mation. As discussed above, we hypothesize these
from UPs, quickly washed away before permanent
ACSs are NOT caused by thrombosis or ischemia,
injury or infarction can occur, not by ischemia.
and this explains why the IIB/IIIA inhibitors did not
benefit these patients. We believe the oral IIB/IIIA
Silent Ischemia (SI) inhibitors were given to the wrong patients for the
wrong reasons, causing harm rather than benefit
SI may not be caused by ischemia at all, but by the [141].
recurrent release of subclinical amounts of plaque
toxins, discharged from asymptomatic, unrecog-
nized chronic UPs (Figure 8). The diagnosis of SI is The failure of the oral IIB/IIIA inhibitors is the same
commonly based on S-T segment depression on a as that postulated for thrombolytic drugs. These
Holter monitor recording or during exercise testing agents cause excessive bleeding and fail to prevent
[284,285]. S-T depression is not specific for ACSs in unstable coronary syndromes because
ischemia and could be caused by plaque toxins, as they unseal UPs and prevent the normal hemostatic
already discussed. The prompt reversal of S-T responses required for repair. IIB/IIIA inhibitors, like
depression in the patient with SI is consistent with
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Atherosclerosis
thrombolytic agents, transform stable UPs into
unstable plaques, leading to the discharge plaque
toxins that initiate acute coronary events.
Why are intravenous IIB/IIIA inhibitors successful in
preventing many of the complications associated
with coronary interventions, including stent place-
ment in patients with STEMI, NSTEMI, and UA
[290]? In our view the difference lies in the duration
of treatment. The intravenous IIB/IIIA inhibitors are
given for a very short period of time. They do not
significantly disturb intraintimal thrombus in UPs,
but they prevent new thrombus formation at the site
of the PTCA and/or stent. In contrast oral agents
are given for long periods of time and prevent nor-
mal hemostatic responses of UPs, essential to
control bleeding and resolution of injury. It is the
prevention of these normal hemostatic responses
that results in bleeding into the plaque core,
swelling of the core, the creation of an unstable
lesion, and the production of acute coronary events.
Aspirin (ASA), UPs, and Plaque
Toxins
Why is ASA, a platelet inhibitor, successful in pre-
venting primary and secondary acute coronary
events [291] when oral IIB/IIIA inhibitors, powerful
anti-platelet agents, precipitate acute coronary
events? What does ASA actually do, and what is
involved in the prevention of acute coronary events?
ASA has no known effect on either the formation or
prevention of PU, but appears to have significant
effect on those developments that take place after
PU [291,292]. We hypothesize ASA acts by prevent-
ing the growth of thrombus, but has little or no effect
on thrombus that is already present, whether occlu-
sive, mural, or intraintimal thrombus. If this is cor-
rect, ASA prevents acute events by NOT disturbing
the normal hemostatic and thrombogenic responses
aimed at injury repair, but prevents the tendency for
a thrombus to grow above and beyond what is
Plaque Toxins and Clinical Coronary Syndromes
required for injury repair (Chapter 9). As a conse-
quence, the UPs are not reopened, plaque toxins
are not released, an unstable lesion is avoided, and
resolution and repair of an UP can occur. ASA may
also prevent the platelet aggregation response
associated with the release of thrombogenic plaque
contents [207], in this way preventing or reducing
the number and size of platelet microemboli passing
into the distal circulation during acute plaque rup-
ture.
Conclusions
We believe, based on the foregoing evidence, that
atherosclerosis is caused by a single infectious
agent, or by multiple infectious agents through
molecular mimicry, which enter the artery wall at
any breach of endothelial integrity and establish a
focus of infection. This organism then grows and
expands, causing first a proliferation of diseased
fibrous tissue, then destruction of this tissue to form
atheromas. The organism grows and expands by
direct contiguity in both circumferential and longitu-
dinal directions, fusing with adjacent atheromas.
The organism grows and expands by subverting
normal defensive responses to its own purposes.
Lipid is retained in all plaques because the organ-
ism requires oxidized LDL, or some variant thereof,
as a source of energy to fuel replication and expan-
sion.
Control of risk factors, particularly the reduction of
cholesterol and other lipids, may cause the organ-
ism revert to a dormant state for an indefinite
period. A chronic inflammatory response develops
because the IA is a foreign organism, and inflamma-
tory defenses mobilize against it. Calcification,
which occurs quickly on degenerated tissue and
uses normal bone-forming mechanisms, is effective
in delaying the growth and expansion of the infec-
tious organism. Adventitial tissue is inherently
resistant to the infectious agent, thickening to pre-
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Atherosclerosis
vent outward expansion into the pericardial space
and confining the organism to the intimal layer. The
only outlet for an expanding atheroma is to ulcerate
and drain into the lumen of the coronary artery.
Although the organism is usually most active deep
within the intimal layer, it may also localize to the
endothelial surface and spread, erysipelas-like, in
all directions from a central focus.
The natural course of events for any necrotic focus
is to spontaneously rupture and drain into a body
cavity, to the external surface of the body, or to be
replaced by fibrous tissue. We believe most
atheromas ulcerate and drain at some time during
their existence, usually when the plaque is relatively
small.
UPs frequently persist as chronic, indolent, fester-
ing, gradually progressive, inflammatory lesions, are
asymptomatic, but provide the substrate for rapid
progression leading to acute coronary events. UPs
are the fundamental lesion underlying all ACSs, and
the variety of ulcerations is what gives rise to the
many different ACSs.
The atheromatous core contains many plaque tox-
ins. These toxins, when discharged from an UP,
stimulate and/ or injure all cardiac structures. The
effect of these toxins depends on the amount
released, their potency, the structures affected and
how quickly the toxins are removed by circulating
blood. We believe the release of plaque toxins is
primarily responsible for VA, SCD, UA, and
NSTEMI, myocardial rupture after AMI, myocardial
stunning, and silent ischemia.
Future Directions
If atheroscherosis is found to be caused by an infec-
tious organism, we assume an antibiotic or antiviral
method will be developed to treat the organism in
order to eliminate the disease. If this approach is
Plaque Toxins and Clinical Coronary Syndromes
successful and we are able to eradicate the infec-
tious organism, would this remove the necessity to
stop smoking, reduce cholesterol, blood pressure,
and other risk factors? Would preventive measures
go by the board in favor of antibiotics, taken when-
ever the organism becomes active?
We visualize that current preventive measures will
continue to be necessary, even if an infectious
organism is identified and we have a specific antibi-
otic or a vaccine. We know organisms that give rise
to chronic infectious diseases may become resistant
to antibiotics and emerge in even more resistant
forms, as with tuberculosis. AIDS is treated with
drugs whose aim is to force the virus into remission,
rather than an attempt to eradicate the organism
from the body. The same may be true of atheroscle-
rosis. If we can identify patients who are carriers of
the organism, then we may be able to institute spe-
cific measures to prevent transmission. Identifying
the organism may allow us to institute measures
that keep it in a state of remission, even if not eradi-
cated. Adding an antibiotic or antiviral treatment to
risk factor modification may accelerate a remission,
forcing the organism into a dormant state. This
would have the same effect as eradication if the
organism could be kept dormant indefinitely.
Based on the observations put forth in these chap-
ters, particularly the infectious organisms ability to
subvert normal defense mechanisms, we believe it
may be difficult to eradicate and will present a con-
tinuing challenge in the future. As with tuberculosis,
the fight requires ongoing vigilance to diagnose,
treat and limit the growth of this organism.
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