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The Beginnings. A Multicentric Disease: Proteoglycans and The Extracellular Matrix
The Beginnings. A Multicentric Disease: Proteoglycans and The Extracellular Matrix
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.
1-2
Atherosclerosis The Beginnings
1-3
Atherosclerosis The Beginnings
Early Atherosclerotic Lesions because the IA has been present and active for a
longer period of time than in adjacent sections. Fig-
Figure 1 shows early changes of atherosclerosis in ure 1E shows the most advanced changes in terms
a 31-year-old white male who died of non-cardiac of tissue degeneration, cell loss, and lipid accumula-
causes. Asymmetric intimal thickening begins near tion, located approximately midway between the
the left coronary ostia (Figures 1B, 1C), and contin- first proximal intimal thickening (Figure 1C), and the
ues through all contiguous coronary segments, distal thickening in Figure 1H. Therefore, Figure 1E
ending at Figure 1H. Focal areas of relative acellu- could be the site of initial injury and the develop-
larity can be identified in Figures 1C–1H, consistent ment of intimal thickening, proximally and distally,
with increased production of PGs and ECM by resi- may reflect direct spread of the IA agent in both
dent intimal cells, presumably in response to wall directions. A review of Figures 1C–1H confirms that
injury [21]. Lipid retention in the form of lipid-laden the amount of intimal hickening and the severity of
macrophages or extracellular lipid, or evidence of the degenerative changes tend to decrease in both
tissue injury are not evident in unaffected intima directions from Figure 1E.
(Figure 1B) nor in mild intimal thickening (Figure
1C). This finding supports the view that intracellular
The histologic changes observed in Figures 1C and
or extra-cellular lipid deposition does not occur in
1H may represent the leading edge of the injury that
the normal artery wall, but only follows the devel-
is spreading longitudinally from the central site in
opment of intimal thickening [2,8]. The asymmetric
Figure 1E. Furthermore, if the IA can spread longi-
intimal thickening involving only a portion of the
tudinally then it may also spread circumferentially,
luminal circumference indicates that the injury is
with the leading edge of the injury expanding in the
focal and that the IA is present and presumably
direction of the plaque shoulder (Figure 2). If this is
active at this particular site. Why the IA enters or
the correct interpretation of these histologic
affects the wall at a particular site has not been fully
changes, it means an IA can establish a foothold in
worked out, but it is probably related to local sus-
the artery wall in spite of defensive responses. It
ceptibility, increased vulnerability, and/or focal injury
then has the potential to spread by direct contiguity
to the endothelium by a various agents [1,2].
in all directions from this central focus.
Advanced Degeneration
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.
Unanswered Questions
The plaque in Figure 2A extends proximally into the
adjacent coronary section and distally into two addi- What is the IA and what is the mechanism of injury?
tional segments, again suggesting active longitudi- What kind of an IA can enter the wall and injure or
nal spread of the IA. The remainder of the coronary stimulate resident SMC to produce excess amounts
artery distal to the segment illustrated in Figure 2 of abnormal PGs without stimulating the prolifera-
showed two additional focal, widely separated tion of SMC or attracting other SMC from the
asymmetric intimal thickenings, similar to, but less media? Does the IA enter the SMC without injuring
severe than those shown in Figure 1. Altogether the extracellular matrix? Why does this particular
there were four separate lesions separated by nor- form of PGs retain lipid, when the normally present
mal arterial wall in this one artery. Wilens [11] noted PGs do not? What is the relationship between the
that IAs can attack the wall at multiple sites, setting IA and the retained lipid? What is the mechanism by
in motion atherosclerotic disease at multiple points, which the IA spreads throughout the intima? Why
emphasizing atherosclerosis is a multicentric dis- do some mucoid swellings degenerate and become
ease. necrotic very early in plaque development while
others do not? These questions will be explored in
In Review subsequent chapters.
1-6
Atherosclerosis The Smooth Muscle Cell
The Fibroproliferative Response This chapter presents evidence supporting the view
that the intimal SMC is specifically targeted, its
Atherosclerosis is generally considered a fibroprolif- intracellular functions altered by an IA, to produce a
erative (FP) disease because atherosclerotic specific type of pathologic fibrous tissue. We
plaques contain large amounts of fibrous tissue [2]. hypothesize that inherent SMC functions are altered
This FP response is believed to be a defensive, to such an extent that the SMC becomes a partici-
protective, physiologic response to injury, designed pant, mediator, and perpetrator of the disease
to wall off, contain, enclose, or sequester the IA, process, as illustrated in the following examples.
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
Atherosclerotic Fibrous Tissue
fashion.
Typical plaque fibrous tissue, illustrated in Figures
Continued plaque growth suggests the resident 3A and 3B, is found throughout atherosclerotic
intimal SMCs and any SMCs migrating from the plaques. The tissue architecture consists of a
media are being stimulated to produce more and meshwork of collagen bundles embedded in ECM,
more fibrous tissue, but this continued growth does with many lacunar-like spaces containing SMCs
not prove that the FP response is a physiologic staining positive with SMC actin antibody (Figure
defensive response to injury. If the growth and pro- 3C). The collagen and other components of the
liferation of fibrous tissue were a defensive ECM are believed to be produced by these SMCs
response, then why isn’t the disease process halted (2,4,12,27), forming an unusual and distinctive type
in its very earliest stages, and why does the FP of fibrous tissue. The SMC nucleus is flattened
response progress above and beyond that required against one side, suggesting compression or
to repair a small area of injury [2,12]? 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
Plaque tissue is produced primarily by intimal
larger and enclosed in a uniform fibrous meshwork.
SMCs, not by fibroblasts, the usual cell type nor-
Other investigators have observed these flattened,
mally involved in wound repair: it therefore differs
attenuated SMCs [28,29].
from the normal fibrotic response to injury [12,27].
The FP response may not be a defensive mecha-
2-1
Atherosclerosis The Smooth Muscle Cell
2-2
Atherosclerosis The Smooth Muscle Cell
However, these SMCs do not seem to neutralize or Figure 4 illustrates degeneration and destruction of
remove the lipid or toxic compounds, but simply tissue surrounding the necrotic core. Figure 4A
ingest more and more of them, resulting in fibrous shows a relatively small plaque with a necrotic core
tissue laced with lipid-laden SMCs of different size and an overlying fibrous cap. A fibrous cap is gen-
(Figures 3A, 3B). Nor is there any evidence that the erally considered to be a protective layer of fibrous
IA and/or the injurious process have been slowed,
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].
2-6
Atherosclerosis Inflammation
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
“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 (%)
Adventitial inflammation in patients with atheroscle- Seventy-six percent of all coronary segments with
rosis is commonly present as discrete foci of T >80% luminal stenosis had adventitial inflammation,
lymphocytes that have congregated at a particular compared with 30% of coronary segments with
site in the adventitia. They are easily recognized <50% luminal stenosis, p=<0.001, proving that the
histologically (Figures 5B–5E), and were graded on frequency of adventitial inflammation is directly
the basis of I to IV according to the following sys- related to plaque size. Comparing the frequency of
tem: The circumference of each coronary segment Grades III/IV adventitial inflammation in the 178
was divided into three, 120° quadrants, with the coronary segments with >80% luminal stenosis to
presence or absence of adventitial inflammation in the 58 segments with <50% stenosis shows Grades
each quadrant recorded. Grade I, the T cells were III/IV inflammation is significantly more common in
rather diffusely scattered in the adventitia overlying those with >80% stenosis, p=<0.001. Both the fre-
a plaque without a definite discrete focus (Figures quency and severity of adventitial inflammation, in
5A,5B). Grades II, III and IV showed discrete foci in terms of circumferential extent, are directly related
one, two, or all three of the 120° quadrants (Figures to plaque size [52,55]. We conclude that the size of
5C–5E). Segments with Grades I, and II inflamma- the plaque and the circumferential extent of adventi-
tion were considered a “mild” injury, whereas tial inflammation are directly related to the severity
Grades III and IV were considered “severe” injury of or magnitude of the arterial wall injury.
the artery wall.
without narrowing the lumen [15]. For example, Fig- cant luminal stenosis, it is still a vulnerable plaque
ure 2A is a very small plaque with “advanced” with a relatively thin fibrous cap. Theoretically it
changes, including calcification and necrosis, but could ulcerate early in plaque development [57].
without adventitial inflammation or stenosis. The IA Figures 5C–5E are examples of Grades III and IV
may be sufficiently potent, or present in sufficient adventitial inflammatory involvement associated
amounts, to cause focal but severe injury. Although with increasing luminal stenosis that illustrate the
the IA may be potent, toxic, or virulent, because this association between inflammation and luminal
is still a small plaque, the IA is not yet present in stenosis.
sufficie/nt amounts to activate the immune system
or present long enough to cause a large plaque to Failure of Inflammatory Defenses
form. In considering the pathogenesis of atheroscle-
rotic injury, we may be dealing not only with the
The inflammatory defensive responses detailed
amount, but also the potency, toxicity, virulence, or
above appear to be no match for the IA. Specifi-
antigenic potential of the IA.
cally, these inflammatory defenses, in spite of what
appears to be a vigorous response, fail to neutral-
Luminal Stenosis and ize, contain, or remove the IA and/or to halt the
Inflammation 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
Figure 5 illustrates the direct relationship between
that the FP response also failed to halt the spread
luminal stenosis and adventitial inflammation. Fig-
of the IA. The failure of these defensive measures
ures 5A and 5B show a small asymmetric plaque
suggests the monocytic and/or T lymphocyte
causing approximately 20–30% luminal stenosis
responses are either inadequate to deal with the
along with a Grade I adventitial inflammatory infil-
strength or toxicity of the offending agent, or that
trate, consistent with a small area of focal injury and
these inflammatory responses have been altered
beginning activation of the immune system. The
changed, or subverted in some way from performing
presence of a necrotic core suggests the presence
their usual protective, reparative functions following
of an IA sufficiently potent to cause early destruction
wall injury [47]. Leibovich and Ross [36] noted the
and necrosis of tissue, similar to, but more
importance of normally functioning macrophages in
advanced than in Figure 2A. Of 23 coronary seg-
wound healing. Therefore, continued plaque growth
ments examined from this artery in Figure 5A, 14
may reflect either an overwhelming or resistant IA
showed various degrees of plaque development
and/or a disabled inflammatory response to injury
causing <50% luminal stenosis. Seven of the seg-
on the part of macrophages and/or T lymphocytes.
ments showed Grade I adventitial inflammation, and
one segment showed Grade II inflammation. There
were no ulcerated plaques (UP) or thrombotic Natural History of Wall Injury
lesions in this artery, nor any coronary calcification.
This artery may have been injured in multiple focal What is the natural history of atherosclerotic wall
areas by a potent IA, actively growing and expand- injury and the associated inflammatory response
ing and beginning to cause activation of the immune caused by the IA? Is the IA ever completely neutral-
system, but not yet causing any plaque ulceration ized and removed, or can it persist indefinitely in a
(PU), erosion, or calcification. However, even dormant, inactive state? Table 1 showed 24% of all
though the plaque is small and produces no signifi- coronary segments with stenosis greater than 80%
3-4
Atherosclerosis Inflammation
were without adventitial inflammation, similar to the plaque size, and reflect the magnitude of the injury.
results of other investigators [54]. Some arteries Plaque growth and the development of luminal
seem able to heal, and the inflammation may sub- stenosis may be due to the continued presence of
side. This implies that the IA can, in some circum- an active IA that spreads to adjacent tissue, expand-
stances, be neutralized, removed, or become ing the area of injury and producing increased
dormant, with the injured area undergoing resolution inflammatory responses. Atherosclerosis and
and healing. Plaque growth may be phasic with adventitial inflammation are diffuse and widespread
exacerbations and remissions of the active inflam- in patients who die of ACD. The magnitude of the
matory disease process, but the factors causing injury and the speed of plaque development appear
remission are not known. to be directly related to the amount, potency, toxic-
ity, or virulence of the IA and/or individual suscepti-
Atherosclerotic Inflammation 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
One of the great mysteries surrounding active
lymphocyte functions may have been subverted,
atherosclerosis is the absence of clinical manifesta-
thereby preventing their neutralizing the IA.
tions of inflammation in spite of diffuse inflammatory
involvement of the coronary tree (Table 1). Virtually
all clinical symptoms of active, progressive Unanswered Questions
atherosclerosis are related to obstruction of coro-
nary blood flow, and to resultant ischemia or infarc- What kind of an IA is this that can apparently alter
tion of the myocardium. They are not related directly intracellular mechanisms without killing the cell and
to inflammation. Patients with active atherosclerosis can subvert normal defensive responses? What is
do not exhibit fever, pain, increased sedimentation the mechanism of spread and expansion of the IA?
rate, or a significant increase in white blood count, Does the IA replicate and, if so, by what mecha-
or other signs of an active inflammatory disease. nism? Why is the adventitia the site of such heavy
This suggests that the IA is not exposed to the nor- infiltration of T lymphocytes compared with the
mal bodily defenses that recognize and remove intima, the area of injury? Does the IA, or a byprod-
most IAs. The IA may be residing within a cell and uct thereof, pass to the adventitia via the lymphat-
thus escape detection. 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
In Review and expansion of the plaque?
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 (%)
* = p =<0.001; a = p =<0.001
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
4-3
Atherosclerosis Atheromas Are Caseous Abscesses
4-5
Atherosclerosis Atheromas Are Caseous Abscesses
4-7
Atherosclerosis Atheromas Are Caseous Abscesses
actively and forcibly extruded under pressure from bacterial abscess [65,71]. Although virtually all UP
within the necrotic core. This alignment of choles- are associated with inflammation and could there-
terol crystals may be a marker of impending PU in fore be considered “hot,” there are many plaques
the intact atheroma. with associated severe inflammation that have not
ulcerated [57]. Therefore the use of this tool to iden-
Figure 8F illustrates an explosion-like eruption of a tify the vulnerable plaque ready to ulcerate may be
relatively small atheroma, preceded by parallel ori- difficult. At present, the determination of thermal
entation of cholesterol crystals within an exit tract. If heterogeneity is an invasive technique, but its
disruption of the fibrous cap were caused by exter- potential for identifying the most active plaques
nal hemodynamic stress, we would not expect to would be a major step forward.
see such uniform orientation, but rather a total dis-
organization of the cholesterol crystals. These In Review
findings provide further support for, and are consis-
tent with, increased intraplaque pressure and spon- Atherosclerosis is initially an FP disease, but it
taneous rupture or ulceration of the necrotic core evolves into a destructive process that leads to
[66,70]. luminal stenosis, caused primarily by the growth
and expansion of lipid-laden, necrotic atheromas.
We propose actively growing atheroma result in PU and subsequent drainage of plaque contents are
increased pressure within the necrotic core. This components of and a natural consequence of the
increased pressure contributes to spontaneous growth of an atheroma, not, per se, a pathologic
ulceration and drainage of plaque contents, similar event. Attempts to prevent PU may not be appropri-
to that observed with bacterial abscesses. ate. Atheromas grow primarily by the digestion of
degenerated, lipid-rich, fibrous tissue, through the
The parallel orientation of the cholesterol crystals in action of proteolytic digestive enzymes, particularly
Figures 8D and 8E, raises further questions about MMPs. The growth and expansion of atheromas
these crystals. Are they actually sharp and needle- result in increased pressure within the necrotic core,
like as they appear, and could they act like a batter- leading to the formation of cleavage planes that
ing ram to pierce or damage tissue, thereby communicate with adjacent atheromas and to the
facilitating or promoting PU? If so, then this is formation of exit tracts and/or UP, primarily at the
another mechanism to consider in the pathogenesis shoulder of the plaque. Decompression and/or
of PU. debulking of atheromas through PU, early in plaque
development, prior to significant luminal stenosis,
may be beneficial in stabilizing the plaque, reducing
Thermal Heterogeneity luminal stenosis, and halting active progression of
the disease process at that site.
Further evidence that atheromas are actively grow-
ing, inflammatory abscesses is provided by studies
of thermal heterogeneity. These studies show Unanswered Questions
active, progressive, growing, inflammatory athero-
mas are “hot” compared with adjacent normal What is the natural history of an UP that is not com-
tissue. Increasing vascularity is associated with this pletely drained of necrotic contents at the time of
inflammation and is similar to the increased temper- plaque rupture or ulceration? Do such partially
ature associated with an inflamed and swollen drained atheromas act like an incompletely drained
4-9
Atherosclerosis Atheromas Are Caseous Abscesses
4-10
Atherosclerosis Calcification
can assume, based on the multiple foci of calcifica- spreading, IA for a long period of time. Age, per se,
tion, that the IA was active at multiple locations plays no direct role in the pathogenesis of coronary
within the coronary tree, spreading proximally, dis- calcification.
tally, and circumferentially, with fusion of adjacent
plaques. Calcification and Luminal
Stenosis
Extensive calcification in young persons, Figure 9A,
and less extensive calcification in older persons, Table 3 compares the relationship between coro-
Figure 9D, demonstrate calcification is not, per se, nary calcification and luminal stenosis in the same
an aging or age-dependent process [81], even 83 patients who died of ACD, shown in Table 1,
though the extent and amount of vascular calcifica- Chapter 3, and Table 2, Chapter 4. The amount of
tion tend to increase with age. If calcification were calcification was determined histologically by view-
an aging process, then all older persons would ing each microscopic slide and estimating the
show calcification, and the amount and extent of circumferential extent of calcification. Each coronary
calcification would be directly related to age. Calcifi- segment was divided into four 90° quadrants and
cation reflects and is related to atherosclerotic graded according to the presence or absence of
injury, caused by an IA that can and does occur at calcification in each quadrant. Grade I indicated one
any age. The increase in extent and severity of cal- quadrant showed calcification whereas Grades II,
cification that occurs with increasing age is due to III, and IV indicated the number of additional quad-
the patient’s harboring and surviving an active, 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 (%)
* = p =<0.001; a = p =<0.001
5-3
Atherosclerosis Calcification
5-4
Atherosclerosis Calcification
Luminal Stenosis without size the difficulty of predicting the extent and sever-
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-
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
5-9
Atherosclerosis Calcification
Osteoid
regulated by cytokines, binds readily to HA, and is active calcification may have ceased. The MSB
found at the sites of early calcification [74,99,101]. If stain may be a convenient method of identifying
atherosclerotic vascular calcification and bone are osteoid in the artery wall. To further explore the
similar in formation and composition, then osteoid or possibility that this amorphous tissue in the artery
osteoid-like tissue should be present in atheroscle- wall may be osteoid, we performed similar stains on
rotic plaques. Demer [99] believes some of the normal bone.
atherosclerotic matrix resembles osteoid, but
osteoid, per se, has not been identified in calcified Normal Bone and Cartilage
atherosclerotic plaques.
Figure 13 illustrates the staining features of normal
Figures 11D–11F, are examples of tissue in the wall bone, cartilage, osteoid, and matrix vesicles in the
of a calcified coronary artery that has features con- bone and cartilage found within the sheep heart
sistent with osteoid. These deposits consist of an [102]. Cancellous bone, Figure 13A, is immature
amorphous, relatively acellular mass of tissue, stain- bone, recently formed from osteoid, that stains
ing bright red with MSB stain, knobby in appear- bright red with MSB like the amorphous masses in
ance, and located adjacent to a calcified plaque. Figures 11D, 11E. Figure 13B shows osteoblasts at
Immunohistochemistry staining of this tissue with the periosteal surface, the site of new bone forma-
osteopontin monoclonal antibodies shows intense tion, stain strongly with osteopontin antibody, con-
staining, (Figure 11F), suggesting this material may sistent with active bone matrix formation. Normal
be osteoid. Connected to the amorphous mass is a cartilage, (Figure 13C), does not stain red with the
calcification front, also staining bright red with MSB MSB stain, confirming that normal cartilage does
(Figures 11D, 11E), and also with osteopontin anti- not contain osteoid. However, osteoid-like tissue
body, Figure 12A. The amorphous mass and the appears to be advancing into and replacing the car-
calcification front may be related to and composed tilage. Finally, in Figure 13D, the matrix vesicles,
of the same tissue. If this amorphous tissue is like the matrix vesicles in Figure 11A, are contained
osteoid, then it may be a site of active calcification within degenerating chondrocytes, and stain bright
and of an active expanding, spreading calcification red with MSB. This is strong evidence that the
front. amorphous mass, staining bright red with MSB stain
in Figures 11D and 11E, is osteoid.
leading edge of the calcification front and associ- bone or bone-like deposits in the wall of an
ated matrix vesicles stain red with MSB, but those atherosclerotic artery?
defense against the action of the IA or is it a patho- ing for the deposition of calcium salts. A second
logic process, a complication, of atherosclerosis, evolutionary purpose of calcification may be to
that should be prevented, as theorized by some delay the longitudinal spread of the IA by creating
investigators [82,83]? If vascular calcification is the barriers between adjacent plaques, preventing or
same as normal bone, formed by the same bio- delaying the formation of cleavage planes between
chemical reactions as normal bone, it is difficult to plaques and adjacent necrotic cores. Atheroscle-
understand how this physiologic process suddenly rotic calcification is an abnormality, but that does
becomes a pathologic process, a complication that not prove it is pathologic in nature. Seen from the
must be prevented. standpoint of a threatening, advancing, destructive,
IA, calcification may be an essential physiologic
defense, in delaying destruction of the artery wall.
Calcification, in general, is often regarded as an
important component of the healing process, gener-
ated as a physiologic defense designed to contain, Reversibility of Coronary
wall off and stabilize injured or damaged tissue and/ Calcification
or foreign agents [99]. Calcification of a ghon com-
plex is an example. Atherosclerotic calcification,
Several histologic observations suggest coronary
however, appears to have a different purpose
calcification is reversible. Patients who died from
because the IA is not sequestered or walled off. In
malignant disease have a very low frequency of
fact, calcification appears to have little if any direct
coronary calcification, indicating that calcification
influence on the activity of the IA because the dis-
may be reversed in wasting conditions [75]. Clinical
ease continues to progress. The preservation of the
studies of patients receiving HMG-CoA reductase
fibrous tissue architecture behind the calcification
inhibitors to lower blood cholesterol show a reduc-
front, as illustrated in Figures 11C and 12A, indi-
tion in calcium score on serial testing with EBCT
cates the injured and degenerated tissue was
[79,80]. Apparently the activity of the IA can be
calcified quickly, before the onset of necrosis. If
slowed or arrested, and calcification can be
there is prompt formation of pericytes or osteoblast-
reversed. Figures 14A–14D, are typical calcified
like cells and these cells produce osteoid, calcifica-
plaques from two patients of different ages. In Fig-
tion of degenerated fibrous tissue by an advancing
ure 14A and B the central portion of the calcified
calcification front could occur rapidly, utilizing the
plaque contains many lacunae, of different size,
same biochemical mechanisms as normal bone
apparently formed from dead SMC, that appear to
formation that are already present. The rapid calcifi-
be fusing or coalescing as a result of degeneration,
cation of degenerating fibrous tissue may be viewed
destruction, or resorption of the calcified fibrous
as a physiologic defense that can be mobilized rela-
septa between them. In Figure 14C and 14D, these
tively quickly and efficiently.
lacunae have fused to form a small lipid lake pre-
sumably formed by the fragmentation, erosion, and
Therefore, one evolutionary purpose of vascular dissolution of the calcified, lipid-rich, fibrous tissue.
calcification may be to preserve the fibrous tissue Resorption, destruction, or dissolution of the central
architecture by rapidly calcifying this tissue to main- portion of calcified plaques may have important
tain wall integrity, delaying the onset of necrosis. It implications for plaque progression.
is important to remember that necrotic tissue, per
se, does not undergo calcification, primarily
because necrotic tissue has no structure or scaffold-
5-12
Atherosclerosis Calcification
What is the mechanism of this apparent resorption? Support for this view is provided in Figure 15D,
Several possibilities can be considered. First, another calcific deposit at the rim of a necrotic core,
Jeziorska, et al [103], found multinucleated giant but stained with osteopontin monoclonal antibody.
cells in close apposition to carotid calcification that Again, we have the irregular moth-eaten border
demonstrated all the normal features of bone forma- consistent with degeneration and resorption, and
tion and resorption. Vascular calcification may this degeneration is associated with free-floating
seemingly undergo resorption in the same manner fragments within the necrotic core, also staining
as bone. Second, bone undergoes resorption and positive for osteopontin. The calcific deposit
avascular necrosis when deprived of its blood sup- appears to be breaking up rather than forming. The
ply. The same may be true of vascular calcification rim of calcification commonly found at the edge of a
that has no nutrient blood supply [104]. Third, SMC necrotic core may be a remnant of a previously cal-
produce and contain MMPs. These enzymes may cified plaque and the necrotic core may have origi-
remain active after the SMC dies and be a signifi- nated and been formed by the resorption and
cant factor in the degradation and resorption of dissolution of the calcified plaque. If this is correct,
calcified vascular tissue [94,105], particularly when then the chemical agents and biologic compounds
resorption originates within the central part of calci- that are by-products of calcification resorption will
fied plaque. Vascular calcification may not be a be added to all the other compounds present within
permanent or inert deposit, but an active, dynamic, the necrotic core. Since HA is very irritating when
changing structure capable of being reversed, injected into joints [96] it is possible that it may also
removed, and/or remodeled [99]. If this is correct, be very irritating and toxic when present in the
then all calcified plaques have the potential to necrotic core.
undergo reversal and resorption.
5-14
Atherosclerosis Calcification
Sequence of Events
the formation of a necrotic core. This evidence sup- formation of an atheroma by adding the byproducts
ports our view that many atheromas have their of resorption to the necrotic core. The sequence of
origins within a calcified plaque. The reversal or events in plaque development following injury is
resorption of plaque calcification may explain why inflammation, followed by calcification of the dam-
EBCT studies are not reproducible, and why plaque aged tissue, ending ultimately in the formation of a
volume cannot be quantitated from the amount of necrotic core.
calcification present [88].
In Review
Evolutionary Purpose of
Adventitial Thickening
to the coronary arteries in pigs. They noted striking adventitia is an extremely strong barrier that, in
similarities between ordinary wound healing and the essence, serves to restrict the IA to the intima,
adventitial response to injury. In circumstances of where the only outlet for the expanding necrotic
traumatic injury, clearly the adventitia plays a key core is into the arterial lumen.
role in resolution and repair, with fibromyoblasts
migrating to the intima [108]. Perhaps the adventitial Histologic Features of Adventitial
thickening associated with active atherosclerosis is Thickening
produced in response to intimal injury, particularly to
progressive and expanding injury by the IA. What characteristics of the adventitia combine to
make it resistant to atherosclerotic injury? Typical
What role or what evolutionary purpose does adven- features of adventitial thickening, shown in Figures
titial thickening play in atherosclerosis? Is adventitial 16A and 16D, are tight, thick layers of sparsely cel-
thickening a pathologic response that should be lular collagen, wavy in appearance and oriented,
prevented, or is it a physiologic response to injury? band-like fashion, circumferentially around the
The most logical explanation is that the thickening is artery. These histologic features are markedly dif-
a physiologic, defensive response to outward ferent from the intimal FP response shown in Fig-
spread and expansion of the IA, similar to the FP ures 3A and 3B. There are significant structural
response observed in many chronic inflammatory differences between the fibrous tissues of the intima
conditions [109]. and the adventitia to support the observed differ-
ences in their physiologic responses.
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 Surface Erosions
7. Surface Erosions
Endothelial Vulnerability or
“Erosion of proteoglycan-rich and smooth muscle cell-rich Dysfunction
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 observation that surface erosions are limited to
the endothelial surface overlying a plaque suggests
the endothelium in this region has become altered
The IA causing atherosclerosis is believed to enter in some way [18,111] and may be more vulnerable,
the artery wall from the circulating blood through a dysfunctional, or susceptible to the IA than is the
breach in endothelial integrity, localizing in the endothelium over normal wall. Something or some
intima and initiating the injurious, destructive pro- agent contained or acting within an atherosclerotic
cess that leads to plaque development [18]. The IA, plaque appears to adversely affect the overlying
however, is not necessarily confined to the depths endothelium, particularly in its ability to withstand
of the intima, but may also localize at the endothe- injury by the IA [111]. Endothelial dysfunction or
lial surface overlying the plaque and cause injury, injury is apparently multifactorial in origin [18], but
erosion, and destruction of the endothelium and this does not mean the IA is also multifactorial.
subendothelial tissue (Figure 7)[110]. The histologic However, surface erosions are not present over
features surrounding these surface erosions are every plaque so there may be variable responses
similar if not identical to those found in the deeper by the endothelium overlying atherosclerotic
necrotic core, including the presence of plaques.
macrophage foam cells, tissue debris, and evidence
of tissue digestion and destruction. Both deep and
Judging by the histologic changes taking place at
superficial lesions may be caused by the same IA.
the endothelial surface, an IA, such as a virus, may
actually enter the endothelial cell and alter intracel-
Surface erosions occur only over atherosclerotic
lular mechanisms and functions [112]. For example,
plaques, not over normal wall. They therefore follow
Figure 17A shows a single layer of endothelial cells
and are superimposed on an already established
distended with lipid, suggesting they have trans-
plaque. This means there is a time interval between
formed into macrophages, ingested lipid, and sub-
initial plaque formation and the subsequent devel-
sequently developed into macrophage foam cells.
opment of surface erosions, suggesting that the IA
The plaque tissue underlying this layer of endothe-
initially traversed the endothelial barrier without
lial cells, although diseased and abnormal, does not
affecting or injuring the endothelial cell. If both deep
contain macrophage foam cells. The IA may have
and superficial lesions are caused by the same IA,
targeted and entered these endothelial cells directly.
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 The macrophage foam cell is an afflicted cell that is
surface erosion results in two active, destructive unable to migrate within tissue, to regulate the
processes proceeding simultaneously, but at sepa- uptake of lipid or to maintain endothelial integrity
rate locations within a plaque, with surface erosions [30]. The protective, defensive responses that char-
arising separately, independent of the deeper injuri- acterize a normally functioning macrophage have
ous process. apparently been altered in some way by the IA, pre-
7-1
Atherosclerosis Surface Erosions
7-2
Atherosclerosis Surface Erosions
Proteolytic Enzymes
Destruction of the Fibrous Cap fibrous cap. Such chronic lesions could result in
elevation of acute phase reactants, like fibrinogen
Figure 17, figure F illustrates a surface erosion that and C Reactive Protein, that persist for long periods
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
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
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
8-3
Atherosclerosis Blind Pockets and False Channels
Frequency of False Channels or dividing the necrotic core, a very thick and/or
strong fibrous cap covering the distal extent of the
How often do false channels develop in the course core, calcification of intimal tissue distal to the core,
of active progressive atherosclerotic disease? Is the and the presence of an arterial bifurcation. These
development of false channels a rare phenomenon, anatomic features will be different in every patient
or a common occurrence with ulcerating athero- and every plaque and may help to explain the great
mas? Are spontaneous coronary dissections or variation among UPs and their associated complica-
8-5
Atherosclerosis Blind Pockets and False Channels
8-7
Atherosclerosis Thrombosis and the Injurious Agent
Thromboregulatory Control
in men with atherothrombotic disease, the ratio is ters. The creation or development of a prothrom-
1:50 [130], indicating that these patients suffer from botic state in patients with active disease appears to
a systemic abnormality of the thromboregulatory be another example of subversion of normal regula-
system, resulting in a prothrombotic state. The tory and defensive responses by the IA. In other
cause of this imbalance is not clear. It appears to be words, the IA, directly or indirectly, is the cause of
due, at least in part, to increased production of PAI- and actively promotes thrombus formation as a
1 by one or more of the following mechanisms: component of active, progressive atherosclerotic
disease (136). What other mechanisms related to
First, as recent studies show, increased production the activity of the IA alter or affect the thromboregu-
of PAI-1 by endothelial cells and vascular SMCs latory system and promote thrombus formation?
that have been stimulated by various growth factors,
including fibroblast growth factor and platelet Luminal Stenosis and
derived growth factor, are produced by Thrombosis
macrophages or lipid-laden foam cells [131–133].
Chapters 3, 4, and 5 showed the direct relationship
Second, studies show a marked increase in between active atherosclerotic disease, caused by
Angiotensin Converting Enzyme (ACE) activity in the IA, and the development of luminal stenosis.
the endothelium and other intimal vascular cells, Luminal stenosis is an essential element required
especially lipid-laden macrophages within for thrombus formation, primarily by causing shear
atherosclerotic plaques [134]. This increased ACE forces that activate platelets and thus promote
activity results in increased conversion of thrombosis [121,137,138]. However, luminal steno-
Angiotensin I into Angiotensin II. Angiotensin II has sis and associated platelet activation alone do not
been shown to be a strong stimulus of the increased necessarily lead to pathologic thrombosis, and
production of PAI-1 [134,135]. The increase in ACE many severely stenotic lesions remain relatively
activity within the plaque , producing an increased unchanged and stable for many years [139]. Lumi-
amount of PAI-I, may disturb the thromboregulatory nal stenosis is not synonymous with thrombosis, but
balance within the plaque and attenuate inherent the activation of platelets may have implications for
thrombolytic mechanisms [134]. other acute lesions, such as UPs [57], within the
coronary tree. Although luminal stenosis is essen-
Third, Angiogtensin II is also involved in platelet tial, other factors must be present for thrombi to
activation and aggregation and could contribute to form.
the continued and excessive platelet responses
involved in thrombus formation, increasing the Wall Injury and Thrombosis
thrombogenic potential [134,135].
Breach of endothelial integrity will activate platelets
The increase in PAI-1 and the failure of the and provide the substrate for thrombus formation.
thrombo-regulatory system can be traced to the The IA, by producing active, expanding, atheroscle-
lipid-laden macrophages and foam cells within the rotic disease that affects the overlying endothelium,
atherosclerotic plaque. These are the same SMC is responsible, directly or indirectly, for producing
and lipid-laden macrophages formed in response to the pathologic substrate necessary for thrombus
the IA that are responsible for many of the formation. Data show that virtually all surface ero-
atherosclerotic lesions described in previous chap- sions or UPs are associated with adventitial inflam-
9-3
Atherosclerosis Thrombosis and the Injurious Agent
matory cell infiltrates, an objective sign of active, thrombus development beyond that required for
injurious atherosclerotic disease [57]. We believe tissue repair. Patient management should aim to
that excessive, pathologic thrombosis is caused by reestablish thromboregulatory balance, prevent fur-
and promoted by the IA by altering hemostatic fac- ther injury or breach of the endothelium, and pre-
tors, producing luminal stenosis and injuring or vent the development of luminal stenosis [129].
eroding the endothelium, Virchow’s Triad [130].
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
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.
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
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)
10-2
Atherosclerosis Chronic Ulcerated Plaques
Table 5:. Comparison of the degree of luminal stenosis with the severity of the plaque ulceration in
109 ulcerated plaques without thrombosis.
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
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
10-3
Atherosclerosis Chronic Ulcerated Plaques
CATEGORY # of lesions IC % CA % NP %
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 To continue this hypothesis, the 28 UPs without
Stenosis thrombosis in the 70–79% stenosis range (Table 5),
have been present longest and have resulted in the
If UPs without thrombosis persist indefinitely as most severe stenosis. The 27 UPs associated with
chronic lesions, what is the relationship between <50% stenosis are the most recently formed, with
chronic UPs and the development of fibrotic, non- the least fibrotic stenosis. The age of the 18 UPs
atheromatous, luminal stenosis? Chronic inflamma- associated with 50–59% stenosis and the 24 asso-
tory diseases, in general, are characterized by ciated with the 60–69% stenosis would be interme-
inflammation, tissue destruction, and a FP response diate in age. These UPs without thrombosis may
at the site of the inflammation [47]. We postulate then persist as chronic UPs until the underlying
that the bodily response to chronic inflammation in stenosis approaches 80% of the cross sectional
the coronary artery will be the same or very similar area, at which point the conditions and substrate
to the bodily response to chronic inflammation favoring thrombosis are present.
elsewhere in the body, i.e., fibrous tissue will form
around the lesion. We would expect an FP Sudden development of acute coronary syndromes
response at the site of a chronic, persistent UP to as a result of thrombotic occlusion naturally leads to
be manifested by the development of progressive, the assumption that the UP beneath the acute
fibrotic, luminal stenosis. Chronic UPs and the thrombus is also an acute event. This assumption is
associated release of growth factors could account unproved. We know of no way in which the age of
for rapid progression of insignificant lesions [154]. an UP can be accurately determined histologically.
Luminal stenosis, in this circumstance, would be The chronic UP and the chronic FP response may
directly related to the inflammatory activity surround- have been actively brewing for months or years
ing the chronic UP. It would be the result of and without overt symptoms, before the acute event.
would develop after, not before, the plaque ulcer-
ates. The luminal stenosis would then increase, not Component versus Complication
because the plaque reseals but because the UP
stimulates a FP response similar to healing by sec- The well known association between UPs, thrombus
ondary intention [57,148,150]. The UP does not formation, and acute coronary events does not
resolve, but persists as luminal stenosis increases. show PU to be a complication of the disease pro-
The longer the UP persists, the greater will be the cess, but only shows that it has the potential to
fibrotic luminal stenosis. More specifically, the develop into a complication under certain circum-
severity of fibrotic luminal stenosis found in associa- stances. A complication, strictly speaking, describes
tion with an UP may reflect the age of the UP. 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 Chronic Ulcerated Plaques
out apparent clinical effects [63,120], PU, per se, sense that it is an efficient method of reverse trans-
cannot technically be called a complication. If PU is port, debulking and decompressing the plaque core
a component of active disease, it is not necessarily by extruding plaque contents [15,57].
a pathologic event that must be, should be, or even
can be prevented [155]. Absence of Thrombus
The distinction between PU as a component rather Table 4 shows that, consistent with previous inves-
than a complication gives us insight into the nature tigations [57,120,156,157], many UPs within the
of the IA and the disease process. It also alters our coronary tree of patients who have died of ACD are
approach to the prevention and treatment of the not associated with luminal thrombosis. The obser-
disease. If PU is a component of active atheroscle- vations in this study of 83 patients demonstrate that
rotic disease, then all inflammatory atheromas may PU is not synonymous with thrombosis, and throm-
be expected to ulcerate at some point, the large bosis does not automatically form on exposed
vulnerable plaques [150,153] posing the greatest subendothelial tissue [158]. Exposed subendothelial
danger. If such vulnerable plaques could be identi- tissue, including collagen, may not be as thrombo-
fied in vivo, before ulceration, it may be possible to genic as previously believed [159].
devise an intervention to control or remove the
plaque before ulceration develops, or devise a Figure 22 shows several examples of UPs without
treatment to neutralize the effects of ulceration associated thrombosis. They appear to be open,
when it does occur. draining, abscess-like cavities. The fibrous cap has
been breached, exposing plaque contents and
If PU is a complication of active disease, then it is a subendothelial collagen to flowing blood, with result-
random event, possibly affecting only a few ing extrusion and partial emptying of the necrotic
plaques, with many atheromas never undergoing core (Figures 22A-C). Why is thrombus absent if
ulceration. Identifying vulnerable plaques and per- plaque contents or exposed subendothelial tissue
forming an intervention, may not be appropriate are so thrombogenic [160]?
because not all such plaques may require interven-
tion. Devising treatments to manage plaques that The absence of thrombus in some UPs may be
will spontaneously ulcerate and drain at some point explained by the presence of MMPs and other pro-
in the future is decidedly different than devising teases within atheromas. These enzymes dissolve
treatments for complications that may or may not tissue proteins, play an important role in degrading
develop. and digesting dead or damaged tissue within the
necrotic core, and erode the surrounding fibrous
Early PU Is the Norm tissue, including the fibrous cap [114,161]. T cells
trigger macrophages to secrete MMPs, showing
We believe that the norm is for plaques to ulcerate these MMPs also to be a component of active,
early in their development. It is their failure to do so atherosclerotic disease [53,162,163]. MMPs are
that is abnormal and pathologic in nature. Failure of also capable of digesting fibrin and of preventing
a plaque to ulcerate early leads to the formation of a thrombus formation and have also been shown to
large necrotic core, such as illustrated in Figure 6, negatively affect platelet adhesion and aggregation
and to the large vulnerable plaque. Early ulceration [163]. Thus, the pro-teases contained within
of a necrotic core may be quite beneficial in the atheromas may prevent thrombus formation in UPs,
10-5
Atherosclerosis Chronic Ulcerated Plaques
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 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 What Is the Injurious Agent?
cells, and can alter intracellular mechanisms macrophages, and endothelial cells, causing the
involved in the uptake, metabolism, and degradation same intracellular abnormalities in each infected
of cholesterol, with resulting lipid-laden cells [177– cell.
179]. The lipid-laden SMCs in Figures 1–4 may all
be infected with an infectious organism that specifi- Single versus Multiple Infectious
cally alters intracellular metabolism concerned with Agents
the uptake of lipid, presumably for some purpose
beneficial to the IA. For example, Cp is an energy
If the IA responsible for initiating atherosclerosis is
parasite that utilizes host cell mechanisms to supply
an infectious organism, is it a single infectious
adenosine triphosphate [174]. The uptake of lipid by
agent, a single family of agents, or multiple, differ-
an SMC infected with Cp may be caused by or pro-
ent, infectious agents that are able, through molecu-
moted by the organism to secure an energy supply
lar mimicry, to produce similar types of injury
from the ingested lipid [174,177]. Cp may stimulate
(166,167)? The objections raised earlier in this
the expression of scavenger receptors by the SMC
chapter to multiple IAs causing the same series of
to take up oxidized LDL, in the same way H. Pylori
complex cellular and molecular changes in the
stimulates the formation of iron-scavenging systems
artery wall also apply to multiple and different infec-
[180]. Lipid retention in the ECM, and the excessive
tious agents. It is unlikely that different types of
uptake of lipid by the SMCs may be orchestrated by
infectious agents, such as Cp, HSV, CMV, H. Pylori,
Cp or other organisms for their own benefit [174].
or other unknown infectious agents, could all pro-
duce exactly the same cellular changes and lead to
The driving force behind the growth and expansion the same atherosclerotic lesions in all patients. The
of the atherosclerotic lesion may be a replicating, possibility exists atherosclerosis may be caused not
expanding, growing, infectious organism. We specu- only by a single injurious agent, but a single infec-
late the infectious organism continues to be present, tious organism [181].
active, and replicating as long as an adequate sup-
ply of the necessary lipid is available to it. Restric-
A single infectious organism entering the SMC and
tion or lowering of blood lipid may affect lipid
altering specific intracellular functions could be
metabolism within the plaque as well as the avail-
responsible for the highly specific cellular and
ability of the type of lipid required by the organism.
molecular re sponses of plaque formation and the
This could explain why lesion growth is retarded
uniformity of atherosclerotic lesions [18]. A single
and acute events decreased in those patients
infectious organism, circulating in the blood, enter-
whose serum lipids are reduced [170–172].
ing the artery wall at any vulnerable or injured site,
could explain the multicentric origin (Chapters 1 and
Based on the evidence presented, we hypothesize 5) and the histologic similarity of widely separated
that atherosclerosis is caused by an infectious lesions. The growth, contiguous expansion and
organism that alters intracellular functions and spread of a single, replicating, infectious organism
mechanisms, creating an increase in lipid uptake could explain the circumferential and longitudinal
and retention by SMCs. The intracellular infectious spread of the disease, the findings of infectious
organism then utilizes the retained lipid, either organisms within plaques [182], and the fusion of
directly or indirectly, as a source of energy to fuel adjacent plaques. An infectious cause of atheroscle-
replication, growth, and expansion of atherosclerotic rosis could explain the consistent presence of
lesions. Eventually it infects other SMCs, inflammatory cells surrounding plaques, and the
11-3
Atherosclerosis What Is the Injurious Agent?
reason why atherosclerosis is a chronic inflamma- without killing the cell. Intracellular mechanisms are
tory disease. A single infectious organism that altered in ways that foster the replication, expan-
infects and alters SMC function to such an extent sion, and spread of the infectious organism [183].
that the cell ultimately dies could explain why This particular mechanism of injury appears to be
plaque tissue degenerates and a necrotic core is repeated over and over again, and is similar to the
formed. These observations provide insight into the way a virus utilizes host cell mechanisms for replica-
nature of the IA, and lead us to advance the follow- tion [164,192]. The affected and infected cell then
ing hypothesis: becomes a tool of the infectious organism, a com-
ponent and participant in the disease process,
Mechanisms of Injury
2. Subversion of normal intracellular functions of the
We postulate that the basic method or mechanism SMC results in the secretion of an abnormal form of
of injury utilized by the infectious organism is to CSPG that reacts with and retains lipid within the
enter and infect an intimal cell, injuring the cell and interstices of the extracellular matrix [10]. This sub-
altering or subverting normal intracellular functions, version may explain why lipid is a major component
11-4
Atherosclerosis What Is the Injurious Agent?
of atherosclerotic tissue [35]. The retention of lipid is the immune system and the proliferation of B and T
a component, not a complication of atherosclerotic lymphocytes, commonly associated with later, more
disease, and all plaque tissue containing such lipid advanced stages of atherosclerosis.
is not normal tissue. It is diseased and pathologic.
Early plaque growth is associated with proliferation 5. In some way, the infectious organism is able to
of SMCs, not normal SMCs but SMCs altered in subvert or to avoid the killing immune responses
some way, inhibited from healing the area of injury employed by T and B lymphocytes after the immune
[12]. 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-
3. The infectious organism subverts the intracellular
ing active, continuing injury by the IA, along with
mechanisms of the SMC, monocyte-derived
generation of more and more antigen. Activation of
macrophages, and endothelial cells governing the
the immune system leads to the proliferation of
uptake, metabolism, and degradation of extracellu-
antigen-specific T lymphocytes, the number of T
lar lipid, particularly the expression of scavenger
and B cells being directly related to the amount of
receptors [167,175]. Disturbing, altering, or subvert-
the antigen produced or presented to the T cells
ing these lipid regulatory mechanisms results in
[192,193].
excessive uptake of lipid and results in the forma-
tion of lipid-laden SMC, macrophages, and endothe-
However, activation of the immune system and the
lial cells. The purpose behind this lipid up take may
associated activation of T lymphocytes, although
be to allow the host cell, directly or indirectly, to
quite vigorous and progressive to judge by the
metabolize the lipid into a form that can be utilized,
number of T cells, is not effective in neutralizing the
such as oxidation of LDL and/or the esterification of
IA, or in halting the growth and spread of the dis-
cholesterol, by the infectious organism (195). Oxi-
ease. Plaques continue to grow and expand in spite
dized LDL may be one form of lipid required by the
of a vigorous immune response. If these immune
infectious organism [175].
responses were effective, growth and spread of the
infectious organism would be stopped, plaque
4. The ingestion of excess lipid by intimal SMCs is growth would cease, and the number of T cells
associated with loss of cellular mobility within the would decrease. Although the T cell and other
tissue, limiting the ability to migrate and transport immune responses appear to be intact and function-
lipid back into the circulation [37]. Continued lipid ing normally, the IA is able to avoid, subvert, or
ingestion, over and above that required by inherent overcome these various defenses and survive,
cellular metabolism and/or the infectious organism, replicate, grow, and expand.
altering their surface antigens. This could be true in the growth and replication of the organism, possibly
atherosclerosis if the infectious organism is able to through increased or more readily available lipid
subvert the immune system. [140].
Autoimmunity
What immune mechanisms are subverted or altered
to allow an infectious organism survive in
Perhaps atherosclerosis is an autoimmune disease,
atherosclerotic plaques? Insight is gained from stud-
and arterial wall injury is caused by immune com-
ies of the Acquired Immunodeficiecy Syndrome
plexes [166]. We visualize autoimmune disease as
(AIDS) virus. The AIDS virus enters, subverts, and
similar to a vicious circle. Once established, it is
eventually destroys the helper T lymphocytes that
very difficult to stop, and it is not subject to the
play a key role in presenting viral antigens to the
exacerbations and remissions seen with atheroscle-
killer T lymphocytes [192,193,196]. Helper T lym-
rotic disease. We would also visualize an autoim-
phocytes secrete 2 cytokines, Interluken-2 and
mune disease, caused by circulating immune
Interferon-gamma, essential for the immune system
complexes, to be a diffuse disease, not a multi cen-
to function normally and effectively [193,196]. If
tric, focal disease. Further, we would expect an
these two cytokines are absent, the immune
autoimmune disease to respond to the administra-
response is blunted, killer mechanisms are com-
tion of corticosteroids, but steroids have not been
promised, infectious organisms are not killed, and
shown to affect the course of human atherosclero-
the infectious organism continues to replicate, grow,
sis. It is possible that autoimmune mechanisms may
and spread [196]. Something similar may happen in
play a role in contributing to the cellular injury and
atherosclerosis, preventing the infectious organism
cell death within a plaque and in this way contribute
from being neutralized and eliminated by the
to the expansion and spread of the IA.
immune system.
In Review
6. An infectious organism subverts normal defen-
sive responses by altering the hemostatic response Based on the evidence presented, we believe the
to injury. Hemostatic abnormalities are produced by primary IA causing atherosclerosis is a single infec-
altering the phenotype of the endothelial cells from tious organism, an obligate intracellular pathogen
anticoagulant to procoagulant, generating the for- residing in a circulating cell, probably the monocyte.
mation of thrombin [181]. SMCs and endothelial Whether the organism is a bacterium or a virus is
cells infected with Cp express PAI-1, T factors, and unknown. Both classes of agents appear to infect
Interlueken-6, all procoagulants [197]. Excessively intimal cells and to alter intracellular mechanisms
high levels of PAI-1 disturb the thrombo-regulatory with the potential to produce atherosclerotic lesions.
balance between TPA and PAI-1, producing a pro- The infectious organism is activated after entry into
thrombotic state. The result is an increase in hemo- the artery wall, infects intimal cells, and establishes
static responses to endothelial injury over and a foothold within the wall. The organism proceeds to
above that required for injury repair. If this action of replicate, expand, and grow in all directions from a
the infectious organism does produce a prothrom- central focus. We speculate that the organism
botic state, to what purpose? The most logical requires lipid, probably oxidized LDL, to fuel replica-
explanation is that thrombus in some way facilitates tion and growth, and that it subverts normal cellular
functions and defense mechanisms to procure this
11-6
Atherosclerosis What Is the Injurious Agent?
11-7
Atherosclerosis The Toxic Atheroma
died of cardiac causes within minutes of the injec- taneous discharge of these toxins at the time of PU
tion. These sudden cardiac deaths were believed to may be expected to produce immediate symptoms
be due to direct, toxic effects of the chemical agents and injury when the toxins circulate to downstream
contained in these extracts on the heart [Connor, structures [202]. The effect of these plaque toxins
personal communication]. Nine of these rats also discharging directly into the coronary circulation
showed pulmonary emboli, indicating these toxins may be similar to infusing absolute alcohol directly
and/or plaque contents are quite thrombogenic into the first septal branch of the LAD to produce a
[198]. The possibility that chemical agents con- focal, controlled, myocardial infarction in the treat-
tained within the necrotic core are potent cellular ment of hypertrophic cardiomyopathy [210,211].
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].
12-3
Atherosclerosis The Toxic Atheroma
12-4
Atherosclerosis The Toxic Atheroma
12-5
Atherosclerosis The Toxic Atheroma
Downstream Structures
The pathogenesis of the pain of angina pectoris anginal-type pains, could explain some of the chest
remains in doubt [217,226]. Lewis advanced the pain variations in angina pectoris. For example,
theory that the “P” (pain) factor, a chemical agent direct stimulation of adventitial sympathetic nerves
derived from ischemic cells, stimulates sympathetic by plaque toxins may produce different anginal
nerves, producing the pains of angina pectoris pains from ischemic metabolites that stimulate
[227]. The specific chemical agent(s) were not iden- intramyocardial sympathetic nerves. Similarly, stim-
tified. Lewis attemped to explain the wide variety of ulation of adventitial nerves by plaque toxins in the
anginal pains on the basis of one mechanism, right coronary artery may produce a different type
myocardial ischemia. He did not consider the possi- and distribution of chest pains than the same toxic
bility that two different mechanisms might produce stimulation of adventitial nerves in the left coronary
the pains. Many investigators, including Lewis, artery. The same reasoning applies to the toxic
believe cardiac sympathetic nerves within the stimulation of adventitial nerves in the proximal
myocardium are stimulated by chemical metabolites compared with the distal portion of the artery [216].
of exertion, suggest it takes time for cells to become the amount, potency, and speed of release of the
sufficiently ischemic to produce the metabolites that toxin, and the specific nerves stimulated. The sec-
ultimately stimulate the nerves and produce the ond mechanism would be expected to produce a
chest pain. wide range and variety of chest pains because there
are so many variable precipitating factors.
The development of myocardial perfusion defects The presence of one or more chronic UPs that
following an episode of VA indicates some type of intermittently discharge plaque toxins could explain
myocardial injury has occurred [229–231]. Recovery many of the following observations and findings in
of myocardial perfusion can occur in a matter of the patient with VA. For example, the increase in
hours or can be prolonged and require several heart rate following an episode of VA [231] could be
days, indicating the injury was temporary but was due to the release of catecholamines secondary to
severe enough to cause ventricular dysfunction toxic stimulation and/or injury of the myocardium.
[229–231]. Had myocardial injury been caused Multiple sites of coronary spasm [238] could be due
solely by vasoconstriction or spasm, we would to the presence of multiple, actively discharging
expect the spasm to subside with the symptoms, UPs [57]. The coronary spasm associated with
and the ventricular dysfunction to reverse in a mat- PTCA [203,239] could be caused by the release of
ter of minutes. Prolonged ventricular dysfunction plaque toxins when the plaque is split by balloon
suggests additional factors, over and above spasm inflation, its contents discharged. The S-T elevation
of the epicardial artery or the myocardial arterioles, characterizing an episode of VA, mimicking AMI,
caused the perfusion defects. We believe those and with associated perfusion defects [231], can be
additional factors are primarily plaque toxins origi- explained by the release of a large amount of highly
nating from UPs that supply that segment of potent toxins that cause temporary transmural dys-
myocardium. Embolic material [64,128,212–216], as function, similar to that of a transmural infarction.
discussed above, would add to and aggravate the
13-3
Atherosclerosis Plaque Toxins and Clinical Coronary Syndromes
atherosclerosis. The clinical and pathologic evi- tion, an early histologic sign of injury, have been
dence supporting this hypothesis are as follows: found in the myocardium and in the conduction sys-
tem of many SCD patients [250–252]. Contraction
bands in the conduction system suggest injury
First, SCD in these patients occurs much too rapidly occurred at approximately the same time as the
to be caused by acute myocardial or conduction onset of the lethal arrhythmia (Figures 24 and 25).
system ischemia [207,218]. Ischemic injury and The effect of plaque toxins on the myocardium and
occlusive thrombosis take time to develop [241]. the conduction system may be quite similar to the
Even acute total occlusion of a coronary artery, as immediate effects of absolute alcohol [210,211]. We
with a balloon during PTCA, does not produce sud- propose that plaque toxins caused the contraction
den lethal arrhythmias [219]. bands in the conduction system and are responsible
for causing the lethal arrhythmia through sudden,
direct injury to the conduction system [252].
Second, Holter monitor recordings of patients taken
at the time of SCD, frequently do not show S-T Fifth, the lethal arrhythmia causing SCD is poten-
changes to support a sudden onset of acute tially reversible. Successful defibrillation and resus-
ischemia, certainly not the massive ischemia, to be citation of the SCD patient are not necessarily
expected if that was the cause [242,243]. Holter followed by an immediate recurrence of the original
recordings do, however, often show an increase in episode, indicating the triggering agent is transiently
heart rate, plus the development of complex ven- present. This observation, not consistent with a
tricular ectopy just before the onset of the lethal fixed coronary obstruction or an occlusive thrombus
arrhythmia [242,243]. The increase in heart rate causing severe ischemia, is consistent with rapid
may be due to the release of catecholamines by washout of a plaque toxin. Furthermore, SCD sur-
plaque toxins (244), postulated earlier regarding the vivors do not necessarily go on to develop occlusive
VA patient. Complex arrhythmias indicate a serious thrombosis and/or AMI, so the arrhythmia was not a
disturbance of the conduction system. precursor to these events [245,248,253]. AMI is
found in a minority of SCD patients, providing addi-
13-4
Atherosclerosis Plaque Toxins and Clinical Coronary Syndromes
tional evidence the arrhythmia was not related to a determined to be approximately 80% of the cross-
prior, unrecognized, or silent AMI [57,240,244,253– sectional area, was evident on the post-mortem
255]. Our pathologic studies of 26 SCD patients angiogram (Figure 24A). Gross and microscopic
without AMI showed 59 UPs, but only 23 (39%) examination of the stenotic area showed a shelled
were associated with luminal thrombosis. Of these out plaque, with a small false channel (Figures 24B,
only 9 thrombi (39%) were totally occlusive [57]. C), but no evidence of thrombosis. No other acute
coronary lesions were present in this patient.
here could explain adverse clinical events, and the Thrombolytic drugs are contraindicated because
paradoxical response that follows thrombolysis in they dissolve intraintimal thrombus, reopen sealed
patients with UA and NSTEMI [264]. UPs (Figure 26), and lead to the discharge of more
plaque toxins, and activate platelets leading to
Aiming therapy at ischemia and thrombosis with acute events. Therapeutic efforts aimed at stabiliz-
thrombolytic drugs in patients with UA and NSTEMI ing the UP and neutralizing plaque toxins would
fail [69] because ischemia and thrombosis are the focus on the right target, in the right patient, for the
wrong targets. The target is the UP and the associ- right reasons.
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].
Myocardial Rupture and these toxins. The trapped toxin could cause exces-
Thrombolytic Drugs sive softening, liquefaction, and, if not neutralized,
rupture of the myocardium. This could explain
Myocardial rupture is a well-recognized complica- myocardial rupture in patients with small infarctions
tion of thrombolytic therapy for STEMI, occurring involving secondary branches [276], probably with
much more frequently in these patients than in limited collateral and/or anastomotic flow where a
patients not receiving a thrombolytic drug [272– toxin could be highly concentrated.
274]. Myocardial rupture occurs only in patients with
transmural infarctions [273] and appears to be
related to excessive softening and liquefaction of The use of primary PTCA and stents without throm-
infarcted tissue, beyond what is observed in the bolytic drugs for the treatment of STEMI has
majority of transmural infarctions. Infarction and resulted in a decrease in myocardial rupture com-
necrosis are not synonymous terms [200] because pared with results following the use of thrombolytic
fully necrotic tissue has no structure while infarcted drugs [277]. The reduction of myocardial rupture
myocardium still has many structural elements following PTCA may be explained by the removal of
intact. Therefore, when the infarcted tissue the obstructing luminal thrombus, restoring blood
becomes excessively necrotic and is without any flow without disturbing intraintimal thrombus, not
residual fibrous structure, it is prone to rupture. reopening sealed UPs, and the washout of any
retained toxins by restored blood flow.
thrombolytic agents, transform stable UPs into required for injury repair (Chapter 9). As a conse-
unstable plaques, leading to the discharge plaque quence, the UPs are not reopened, plaque toxins
toxins that initiate acute coronary events. 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
Why are intravenous IIB/IIIA inhibitors successful in
associated with the release of thrombogenic plaque
preventing many of the complications associated
contents [207], in this way preventing or reducing
with coronary interventions, including stent place-
the number and size of platelet microemboli passing
ment in patients with STEMI, NSTEMI, and UA
into the distal circulation during acute plaque rup-
[290]? In our view the difference lies in the duration
ture.
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, Conclusions
but they prevent new thrombus formation at the site
of the PTCA and/or stent. In contrast oral agents We believe, based on the foregoing evidence, that
are given for long periods of time and prevent nor- atherosclerosis is caused by a single infectious
mal hemostatic responses of UPs, essential to agent, or by multiple infectious agents through
control bleeding and resolution of injury. It is the molecular mimicry, which enter the artery wall at
prevention of these normal hemostatic responses any breach of endothelial integrity and establish a
that results in bleeding into the plaque core, focus of infection. This organism then grows and
swelling of the core, the creation of an unstable expands, causing first a proliferation of diseased
lesion, and the production of acute coronary events. fibrous tissue, then destruction of this tissue to form
atheromas. The organism grows and expands by
Aspirin (ASA), UPs, and Plaque direct contiguity in both circumferential and longitu-
vent outward expansion into the pericardial space successful and we are able to eradicate the infec-
and confining the organism to the intimal layer. The tious organism, would this remove the necessity to
only outlet for an expanding atheroma is to ulcerate stop smoking, reduce cholesterol, blood pressure,
and drain into the lumen of the coronary artery. and other risk factors? Would preventive measures
Although the organism is usually most active deep go by the board in favor of antibiotics, taken when-
within the intimal layer, it may also localize to the ever the organism becomes active?
endothelial surface and spread, erysipelas-like, in
all directions from a central focus. We visualize that current preventive measures will
continue to be necessary, even if an infectious
The natural course of events for any necrotic focus organism is identified and we have a specific antibi-
is to spontaneously rupture and drain into a body otic or a vaccine. We know organisms that give rise
cavity, to the external surface of the body, or to be to chronic infectious diseases may become resistant
replaced by fibrous tissue. We believe most to antibiotics and emerge in even more resistant
atheromas ulcerate and drain at some time during forms, as with tuberculosis. AIDS is treated with
their existence, usually when the plaque is relatively drugs whose aim is to force the virus into remission,
small. rather than an attempt to eradicate the organism
from the body. The same may be true of atheroscle-
UPs frequently persist as chronic, indolent, fester- rosis. If we can identify patients who are carriers of
ing, gradually progressive, inflammatory lesions, are the organism, then we may be able to institute spe-
asymptomatic, but provide the substrate for rapid cific measures to prevent transmission. Identifying
progression leading to acute coronary events. UPs the organism may allow us to institute measures
are the fundamental lesion underlying all ACSs, and that keep it in a state of remission, even if not eradi-
the variety of ulcerations is what gives rise to the cated. Adding an antibiotic or antiviral treatment to
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
13-12