Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3793_Библиотеки_им_академика_М_И_Перельмана
.pdf
CHAPTER 7 Pathophysiology of Acute Coronary Syndromes 69
Ad
Lipid accumulation
Proliferation of
capsule
https://t.me/medicina_free
Endothelium
Intima
Media
ventitia
Fig. 7.1 Classification of vascular injury and vascular response. (From Fuster V, Badimon L,
Badimon J, Chesebro J. The pathogenesis of coronary artery disease and the acute coronary
syndromes. N Engl J Med. 1992;326:242–248.)
with maintenance of an intact elastic lamina. Type III injury is
represented by endothelial denudation and damage to the intima
and media of the vessel wall.
The earliest finding in spontaneous atherosclerosis is an intimal
lesion containing lipid-laden macrophages and a few T lymphocytes.18 In the “response to injury hypothesis” proposed by Ross19
and others, these “fatty streaks” are thought to result from chronic
injury to the arterial endothelium induced by disturbances in
coronary blood flow (type I injury) and an increased vascular
permeability to lipids and monocytes (Fig. 7.2). The chronic
injury is primarily a disturbance in the pattern of blood flow in
certain parts of the arterial tree, such as bending, branch points,
or both. Certain factors—such as hypercholesterolemia, tobacco
abuse, vasoactive amines, glycosylated products, infection, and
immune complexes—may potentiate the effect of type I injury
on the endothelium.20 This chronic, low-grade damage leads to
the accumulation of lipids and macrophages at the site of injury,
producing the characteristic fatty streak. These lipid-laden
macrophages, also known as foam cells, are derived primarily
from tissue macrophages. Foam cells are formed when large
amounts of intracellular lipids, mainly from modified low-density
lipoprotein (LDL), are taken up via a family of macrophage
scavenger receptors and internalized into the macrophage.
There is growing evidence that oxidized LDL is a key active
component in the generation of atheroscleroses rather than a
passive substance that accumulates within macrophages. It is
hypothesized that oxidized LDL has five potentially atherogenic
effects: (1) monocyte chemotactic activity, (2) inhibition of
macrophage migration out of the vessel wall, (3) enhanced uptake
by macrophages, (4) formation of immune complexes, and (5)
cytotoxicity (Fig. 7.3).
In the presence of elevated plasma LDL levels, the concentration of LDL within the intima is increased. By poorly understood
mechanisms, which may involve the generation of free radicals
by cellular lipoxygenases,
tive modification (peroxidation of polysaturated fatty acids) that
alters its metabolism. When the LDL contains fatty acid lipid
peroxides, a rapid propagation amplifies the number of free
radicals and leads to extensive fragmentation of the fatty acid
chains. These fragments of oxidized fatty acids attach covalently
to apoprotein B.
23,24
By means of specialized receptors, distinct
from the LDL receptor, these modified apoprotein B molecules
with the attached fatty acids are recognized by macrophages and
Type I injury
Type II injury
Type III injury
21,22
the LDL molecule undergoes oxida-
and monocyte
adhesion
Moderate
?
?
Platelet deposition
and thrombosis
No
Minor
Moderate
smooth
muscle cells
Mild
Moderate:
surrounding
atheroma
Extensive, with
organization
of thrombus
taken up by the cell (Fig. 7.4).25 All three major cell types within
the artery wall are capable of modifying LDL to a form that is
recognizable by a scavenger receptor. In contrast to the LDL
receptor, the scavenger LDL receptors are not down-regulated
in the presence of excess ligand. Cells are able to accumulate
large amounts of intracellular lipid.
Oxidized LDL within the intima may play a role in the adhesion
of circulating monocytes to the arterial wall. More recent studies
have shown that oxidized LDL, but not native LDL, is a powerful
chemoattractant for circulating monocytes.26 In addition, oxidized
LDL is a potent inhibitor of the migration of macrophages out
of the intima. By these two mechanisms, oxidized LDL may serve
to attract and retain monocytes and macrophages within the
vessel wall.
LDL modification by oxidation causes activation, dysfunction,
apoptosis, and necrosis in human endothelial cells.27 Activated
endothelial cells express leukocyte adhesion molecules, including
vascular cell adhesion molecule 1 and intercellular adhesion
molecule 1, causing blood cells to adhere at the sites of activation.27
Monocytes and lymphocytes preferentially adhere to these sites.
A potent chemotactic agent, monocyte chemotactic protein 1,
is produced by endothelial cells and smooth muscle cells. This
same protein has been found in the intima of atherosclerotic
lesions and in foam cells. Secretion of monocyte chemotactic
protein 1 by endothelial or smooth muscle cells may be induced
by oxidized LDL, suggesting a possible mechanism whereby lipids
induce the recruitment of macrophages, leading to the formation
of early atherosclerotic lesions.
28
Within the vessel wall, monocytes undergo phenotypic
modification by macrophage colony-stimulating factor, inducing
them to differentiate into tissue macrophages. These macrophages
are capable of expressing scavenger receptors, leading to internalization of oxidized LDL and the creation of foam cells and
fatty streaks.
Plaque Formation. With time, fatty streaks progress into mature
atherosclerotic plaques (Fig. 7.5). Macrophages recruited into
the area may release toxic products that cause further damage,
leading to denudation of the endothelium and intimal injury
(type II injury). This deeper form of injury leads to platelet
adhesion. Adherent platelets—along with recruited macrophages
and damaged endothelium—release growth factors, such as
platelet-derived growth factor (PDGF), epidermal growth
70 PART II Scientific Foundation of Cardiac Intensive Care
F
D
https://t.me/medicina_free
A
“INJURY”
(mechanical, LDL,
homocysteine,
immunologic,
toxins, viruses, etc.)
B
E
C
Fig. 7.2 Response-to-injury hypothesis. Advanced intimal proliferative lesions of atherosclerosis
may occur by at least two pathways. The pathway shown by the long arrows has been observed
in experimental hypercholesterolemia. Injury to the endothelium (A) may induce growth factor
secretion (short arrows). Monocytes attach to endothelium (B), which may continue to secrete
growth factors (short arrow). Subendothelial migration of monocytes (C) may lead to fatty streak
formation and release of growth factors such as platelet-derived growth factor (PDGF, short
arrow). Fatty streaks may become directly converted to fibrous plaques (long arrow from C to
F) through release of growth factors from macrophages or endothelial cells, or both. Macrophages
may also stimulate or injure the overlying endothelium. In some cases, plaques may lose their
endothelial cover, and platelet attachment may occur (D), providing additional sources of growth
factors (short arrows). Some of the smooth muscle cells in the proliferative lesion itself (F) may
synthesize and secrete growth factors such as PDGF (short arrows). An alternative pathway for
the development of advanced atherosclerosis lesions is shown by the arrows from (A) to (E) to
(F). In this case, the endothelium may be injured but remain intact. (A) Increased endothelial cell
turnover may result in growth factor synthesis by endothelial cells. (E) This may stimulate migration
of smooth muscle cells from the media into the intima, accompanied by endogenous production
of PDGF by smooth muscle cells and growth factor secretion by the “injured” endothelial cells.
(F) These interactions could lead to fibrous plaque formation and further lesion progression. LDL,
Low-density lipoprotein. (From Ross R. The pathogenesis of atherosclerosis: an update. N Engl
J Med. 1986;314:458–500.)
factor-β, and somatomedin C. These growth factors may lead
to migration and proliferation of vascular smooth muscle cells and
stimulate the production of collagen, elastin, and glycoproteins.
These proteins provide the connective tissue matrix of the newly
formed plaque and give it structural support. Cholesterol, derived
from insudated blood lipid or extruded from dying foam cells,
becomes entrapped within this matrix. The lipid and connective
tissue matrix are covered by a fibromuscular cap consisting of
smooth muscle cells, collagen (types I and III), and a single
layer of endothelial cells. This complex constitutes the mature
atherosclerotic plaque (Fig. 7.6A). Vascular smooth muscle cells
synthesize and assemble the collagen fibrils and furnish the bulk
of the noncollagenous portion of the extracellular matrix of the
cap. The fibromuscular cap is a dynamic structure undergoing
constant remodeling through the synthesis and breakdown of
essential components (Fig. 7.7).
The microscopic changes that occur in spontaneous atherosclerosis have been described by Stary18 and modified by the
American Heart Association (AHA).29 Using autopsy results from
the coronary arteries and aortas of young people, Stary described
five distinct lesions. A Stary I lesion, not apparent macroscopically,
consists of isolated macrophages or foam cells within the intima
CHAPTER 7 Pathophysiology of Acute Coronary Syndromes 71
Circulating
Foam cell
https://t.me/medicina_free
Endothelial
cells
Smooth muscle
cells
Macrophages
Native
LDL
I
Oxidatively
modified
LDL
monocytes
–
Resident
monocyte
macrophage
III
Endothelial
injury
II
IV
Oxidatively
modified
LDL
Native
LDL
Oxygen
free
radicals
Fig. 7.3 Mechanisms by which the oxidation of low-density
lipoprotein (LDL) may contribute to atherogenesis, including the
recruitment of circulating monocytes by means of the chemotactic
factor present in oxidized LDL, but absent in native LDL (I);
inhibition by oxidized LDL of the mobility of resident macrophages
and their ability to leave the intima (II); cytotoxicity of oxidized
LDL, leading to loss of endothelial integrity (III); and uptake of
oxidized LDL by macrophages, leading to foam cell formation
(IV). Formation of immune complexes is not shown. (From
Quinn MT, Parthasarathy S, Steinberg D. Endothelial cell-derived
chemotactic activity for mouse peritoneal macrophages and the
effects of low density lipoprotein. Proc Natl Acad Sci U S A.
1985;82:5949–5953.)
Action of cellular
oxygenase (lipoxygenase?)
Generation of active
oxygen in the cell
Endothelial injury
Adherence of
platelets
Release of
platelet-derived
growth factor
Other
growth
factors
Cell proliferation
Advanced lesion
High plasma LDL level
LDL infiltration
into intima
Oxidized LDL
plus
macrophages
Foam cells
Fatty streak
Fig. 7.5 Linkage between the lipid infiltration hypothesis and
the endothelial injury hypothesis. The lipid infiltration hypothesis
(right column) may account for fatty streaks, and the endothelial
injury hypothesis (left column) may account for the progression
of the fatty streak to more advanced lesions. LDL, Low-density
lipoprotein. (From Steinberg D. Metabolism of lipoproteins and
their role in the pathogenesis of atherosclerosis. In Gotto AM
Jr, Paoletti R, eds. Atherosclerosis Reviews. Vol 18. Stokes J III,
Mancini M, eds. Hypercholesterolemia: Clinical and Therapeutic
Implications. New York: Raven Press, 1988:1–23.)
On cellular lipids
Transfer of oxidized
cell lipids to LDL
On LDL lipids
Generation of LDL containing
Breakdown of lecithin to lysolecithin
and rapid propagation of peroxidation
Degradation of
apoprotein B
Generation of new “epitope”(s) on
apoprotein B recognized specifically
Fig. 7.4 Mechanisms of oxidative modification of low-density
lipoprotein (LDL) by cells. (From Steinberg D. Metabolism of
lipoproteins and their role in the pathogenesis of atherosclerosis.
In Gotto AM Jr, Paoletti R, eds. Atherosclerosis Reviews, Vol 18.
Stokes J III, Mancini M, eds. Hypercholesterolemia: Clinical and
Therapeutic Implications. New York: Raven Press, 1988:1–23.)
Release of active oxygen
into the medium
(superoxide anion?)
oxidized lipids
Conjugation of fragments of
oxidized fatty acids with amino
groups of apoprotein B
by macropage receptor(s)
Foam cells
of the involved vessel. These lesions are noted in 45% of infants
up to 8 months of age and eventually regress. A Stary II lesion,
which is seen in adolescents, is characterized by numerous foam
cells, lipid-containing smooth muscle cells, and a minimal amount
of scattered extracellular lipid. Macroscopically, with Sudan IV
staining, these lesions appear as a flat or raised fatty streak. In
some children, more advanced lesions are noted that are characterized by an increased amount of extracellular lipid and the
appearance of a raised fatty streak (Stary III) or a single confluent
extracellular core (Stary IV). In adults, usually beginning in the
third decade of life, two types of lesions are noted in the coronary
arteries. Some plaques are mostly fibromuscular, whereas others
are fibrolipid with a cap of smooth muscle cells and collagen.
These latter lesions are designated as Stary V lesions.
The first three lesion types in the AHA classification are similar
to those in the original Stary description. In the AHA classification,
a type IV lesion has a predominance of extracellular, mostly
diffuse lipid, whereas a type Va lesion has localized lipid content
surrounded by a thin capsule. Additionally, type V lesions are
classified further according to the amount of stenosis and fibrosis
(types Vb and Vc). Type IV or Va lesions may progress slowly
over time into more advanced type V lesions or undergo disruption, resulting in a type VI lesion represented by a ruptured
plaque with overlying thrombus (Fig. 7.8).
The composition of nonruptured atheromatous plaques is
highly variable, and the factors controlling this process are poorly
understood. Mature plaques consist of two components: (1) soft,
lipid-rich, atheromatous gruel; and (2) hard, collagen-rich,
sclerotic tissue. The relative amounts of each component may
differ with the individual plaque, but generally two populations
72 PART II Scientific Foundation of Cardiac Intensive Care
https://t.me/medicina_free
*
C
A
C
B
D
C
E
Fig. 7.6 Photomicrographs illustrating the relationship between plaque composition and vulner-
ability. (A) A mature atherosclerotic plaque consisting of two main components: soft lipid-rich
gruel (asterisk) and hard collagen-rich sclerotic tissue (blue). (B) Two adjacent plaques, one located
in the circumflex branch (left) and another in the proximal side branch (right). Although both
plaques have been exposed to the same systemic risk factors, the plaque to the left is collagenous
and stable, but the plaque to the right is atheromatous and vulnerable, with disrupted surface
and superimposed nonocclusive thrombosis (red). (C–E) Vulnerable plaque containing a core of
soft atheromatous gruel (devoid of blue-stained collagen) separated from the vascular lumen by
a thin cap of fibrous tissue infiltrated by foam cells that can be seen clearly at high magnification
(E), indicating ongoing disease activity. Such a thin, macrophage-infiltrated cap is probably very
weak and vulnerable, actually disrupted nearby, explaining why erythrocytes (red) can be seen
in the gruel just beneath the macrophage-infiltrated cap. (F) Atherectomy specimen from culprit
lesion in non–Q-wave myocardial infarction. At high magnification it can be seen clearly that this
plaque specimen is heavily infiltrated by red-stained macrophages. (A–E) Trichrome stain. (F)
Immunostaining for macrophages using monoclonal antibody PG-MI from Dako. (From Falk E,
Shah PK, Fuster V: Coronary plaque disruption. Circulation. 1995;92:657–671.)
F
CHAPTER 7 Pathophysiology of Acute Coronary Syndromes 73
Macrophages-
Macrophages-SMC
SMC
https://t.me/medicina_free
Collagenase
Gelatinases
Stromelysin
Other proteases
+ pepidases
+ + + +
Macrophage
foam cell
B
R
E
A
K
D
O
W
N
Amino
acids
Fibrous
Cap
TNF–
M–CSF
MCP–1
etc.
Amino
acids
Lipid core
S
E
H
T
N
Y
S
IFN–
T- Lymphocyte
S
I
Smooth
muscle cell
–
IFN–
Collagen
Elastin
+
Fig. 7.7 Metabolism of collagen and elastin in the plaque’s fibrous cap. The vascular smooth muscle
cell synthesizes the extracellular matrix proteins, collagen, and elastin. In the unstable plaque,
interferon-γ (IFN-γ) secreted by activated T cells may inhibit collagen synthesis, interfering with the
maintenance and repair of the collagenous framework of the plaque’s fibrous cap. The activated
macrophage secretes metalloproteinases that can degrade collagen and elastin. Degradation of
the extracellular matrix can weaken the fibrous cap, rendering it particularly susceptible to rupture
and precipitating acute coronary syndromes. IFN-γ secreted by T lymphocytes can activate the
macrophage. Plaques also contain other activators of macrophages, such as tumor necrosis
factor-α (TNF-α), macrophage colony-stimulating factor (M-CSF), and macrophage chemoattractant
protein-1 (MCP-1). (From Libby P. Molecular bases of the acute coronary syndromes. Circulation.
1995;91:2844–2850.)
lipid droplets
lipid droplets
extrac lipid
NI II III
Confl extracellular lipid
1-SLOW PROGRESSION
Collag and SMC
cap lipid core
Collag and SMC
layer lipid Collagen
• Mural
• Occlusion
• Reocclusion
IV Va Vb Vc VI
3-INTERMEDIATE PROGRESSION
2-RAPID PROGRESSION – DISRUPTION AND THROMBOSIS
Fig. 7.8 Schematic of coronary atherosclerosis progression
according to lesion morphology. See text for details. Collag,
collagen; Confl, confluence; extrac, extracellular; SMC, smooth
muscle cells. (From Fuster V. Mechanisms leading to myocardial
infarction: insights from studies of vascular biology. Circulation.
1994;90:2126–2146.)
of lesions predominate (see Fig. 7.6B). One group consists of
fibrointimal lesions characterized by large amounts of fibrous
tissue and relatively little atheromatous gruel. The second population consists of lipid-laden lesions with a cholesterol-rich central
core and a thin outer capsule.
Differences in plaque composition have important clinical
implications. Plaques causing severe stenosis tend to have a
higher fibrous and lower lipid content than less stenotic lesions.30
However, several studies have shown the less stenotic, lipid-laden
plaques to be the more clinically dangerous lesions.31 As discussed
in this chapter, the soft atheromatous center may predispose
the plaque to rupture, exposing the highly thrombogenic gruel
and subintimal elements to blood flow and leading to the formation of thrombus and acute myocardial ischemia in many
cases.
Progression of Atherosclerosis
Atherosclerosis is a dynamic process that, without intervention,
is progressive. Serial angiographic studies have shown that
atherosclerotic plaques tend to enlarge over time and that a
significant number of lesions progress to total occlusion. The
risk of progression to total occlusion seems to be related to the
initial severity of the lesion, with more obstructive lesions
progressing to total occlusion more frequently than less severe
32
lesions.
pletely understood, but two mechanisms have been proposed.
One mechanism involves continuation of the myointimal proliferative process produced by the chronic endothelial injury
responsible for the early lesions of atherosclerosis.10 The second
mechanism, which may be more important in rapidly growing
plaques, involves recurrent minor fissuring of the atheromatous
plaque (type Va lesion undergoing type III injury) with subsequent
thrombus formation and fibrotic organization.
Chronic Endothelial Injury. In the response-to-injury hypothesis,
progression of atherosclerotic lesions occurs via the same
mechanisms responsible for the initial myointimal lesion. At
The factors that govern plaque progression are incom-
74 PART II Scientific Foundation of Cardiac Intensive Care
https://t.me/medicina_free
least two separate processes seem to be involved. One pathway
involves gross endothelial cell damage and monocyte, macrophage,
and platelet recruitment with growth factor secretion leading
to the formation and progression of fibrous plaques. A second
pathway involves direct stimulation of endothelial cells without
obvious injury. This process may increase endothelial cell turnover
with increased growth factor production leading to smooth
muscle cell migration and increased production of PDGF. Through
these interactions, further growth of the initial fibrous plaque
may occur (see Fig. 7.2).
10
Recurrent Thrombosis. The second proposed mechanism of
atherosclerotic progression involves recurrent minor plaque
disruption with subsequent thrombus formation followed by
fibrotic organization. Plaque disruption is a common event
and may be asymptomatic in many patients.33 As discussed in
greater detail later, rupture of lipid-laden plaque exposes the
highly thrombogenic atheromatous core and subendothelial
components of the arterial wall to the circulation. This exposure
results in platelet adhesion and activation with the release of
growth factors and stimulation of the coagulation cascade.
This sequence of events results in the formation of thrombus,
superimposed on the damaged plaque, which eventually undergoes
fibrotic organization with subsequent incremental narrowing of
the arterial lumen. In this model, recurrent subclinical events
may lead to progressive plaque growth and, ultimately, vessel
occlusion.
Several lines of evidence point to an important role of mural
thrombus formation in the progression of atherosclerosis. Autopsy
studies of coronary artery disease patients who died of cardiac
and noncardiac causes reveal the presence of plaques with healed
fissures with various stages of thrombus formation and organization and old organized coronary thrombi that are difficult to
distinguish from primary atherosclerotic changes seen in the
arterial wall.
33–35
In situ hybridization techniques and monoclonal
antibodies directed at platelets, fibrin, fibrinogen, and their
degradation products reveal increased amounts of these substances
within the intima, neointima, and deeper medial layer in patients
with coronary artery disease.
36,37
These observations suggest that
products of organized thrombus are important in the growth
of atherosclerotic plaques.
Platelets and mural thrombi may contribute to the progression
of atherosclerosis by mechanisms other than the addition of
organized fibrous layers to the plaque. As noted previously,
adherent platelets are capable of secreting various mitogenic
factors, including PDGF, transforming growth factor-β, and
others. These factors may be involved in the proliferation,
hypertrophy, and migration of smooth muscle cells, which are
important steps in intimal thickening and plaque growth.
17
Studies
from animals with thrombocytopenia or lacking von Willebrand
factor (a protein required for platelet adhesion) have shown a
reduced amount of atherosclerotic plaque formation and growth.
Thrombin produced after vascular injury may become incorporated into the thrombus and extracellular matrix, and may
be released slowly over time during periods of spontaneous
fibrinolysis or remodeling of the thrombus. Thrombin may bind
to platelet receptors and cause platelet activation or bind to
smooth muscle cells, resulting in proliferation. Through these
mechanisms, it is possible that platelets and thrombin play a
role in the early and late stages of atherosclerotic progression.
PLAQUE DISRUPTION
The formation of atherosclerotic plaques within the coronary
arteries may gradually impede blood flow by progressive obstruction of the vessel lumen. Initially, these lesions are silent except
during periods of increased myocardial oxygen demand. When
coronary blood flow cannot be increased to meet the demand
of the myocardium, ischemia results and causes characteristic
exertional angina. With time, the atherosclerotic plaque may
slowly enlarge, producing a greater degree of occlusion that results
in symptoms with progressively lesser degrees of exertion.
The pathophysiology of acute coronary syndromes—including
unstable angina, MI, and sudden cardiac death—is significantly
different. These clinical entities represent a continuum of disease
characterized by an abrupt reduction in coronary blood flow.
Current concepts hold that this abruptly reduced coronary
blood flow is caused by atherosclerotic plaque erosion, fissuring or rupturing that leads to the formation of thrombus that,
superimposed on a preexistent lesion, severely limits flow (see
Fig. 7.6B).
intrinsic properties of individual plaques (vulnerability) and
extrinsic factors acting on the plaque itself (rupture triggers).
The former predisposes plaques to rupture, whereas the latter
may precipitate disruption if vulnerable plaques are present.
Vulnerability
Pathoanatomic examination of intact and disrupted plaques and
in vitro mechanical testing of isolated fibrous caps indicate that
the vulnerability of a given plaque to rupture depends on several
factors: size and consistency of the atheromatous core, thickness
and collagen content of the fibrous cap covering the core, the
degree of inflammation within the cap, and cap fatigue (see
Figs. 7.6C–D).
Core Size and Content. The size and consistency of individual
plaques vary greatly from lesion to lesion. As previously described,
atherosclerotic plaques are composed of two main components
whose ratio may vary within a given plaque. The typical plaque,
especially in the most highly stenotic lesions, contains more hard
fibrous tissue than soft atheromatous gruel. Plaques containing
a larger amount of gruel tend to be identified more often beneath
thrombi in acute coronary syndromes, however.
tors have shown that the culprit lesions responsible for acute
coronary syndromes tend to have a lipid-laden core occupying
greater than 40% of the plaque.
important in determining vulnerability. The core is rich in
extracellular lipids, especially cholesterol and its esters.43 Plaques
are softened and made more prone to rupture by an increased
amount of extracellular lipids in the form of cholesterol esters.
Conversely, lipids in the form of cholesterol crystals have the
opposite effect on plaque stability. However, it has been suggested,
38–41
The risk of plaque fissuring or rupturing is related to the
31
Several investiga-
42
The composition and size of the atheromatous core are
CHAPTER 7 Pathophysiology of Acute Coronary Syndromes 75
https://t.me/medicina_free
but not proven, that cholesterol crystals can perforate the intimal
surface of the plaque shoulder.
Cap Thickness and Content. Fibrous caps covering the lipid
cores of atherosclerotic lesions vary in thickness, cellularity, matrix
composition, and collagen content, all of which are important
determinants of plaque stability.44 Disrupted caps tend to contain
fewer cells that synthesize collagen than intact caps.
42,45
This lack
of collagen may weaken the fibrous cap, leaving the plaque prone
to rupturing, which tends to occur in areas where the cap is the
thinnest and often most heavily infiltrated by foam cells. In
eccentric plaques, rupturing usually occurs in the shoulder region,
defined as the junction between plaque and the adjacent, less
diseased vessel wall. The cap in these shoulder regions is often
thin and heavily infiltrated with macrophages.44 Superficial erosion
and fissuring of plaque can also lead to thrombosis.
Inflammation. The concept that the inflammatory response may
play a role in atherosclerosis dates back to Rudolph Virchow in
the late 1800s, who postulated that atherosclerosis results from
the local reaction of the vessel wall to the insudation of blood
products. More recently, a growing body of evidence supports
the concept that inflammation is involved in plaque disruption
leading to acute coronary syndromes.
Several studies have shown that disrupted fibrous caps are
heavily infiltrated by lipid-laden macrophages or foam cells (see
Figs. 7.6E–F).31 Postmortem examination of thrombosed coronary
arteries has shown foam cell infiltration in most plaque rupture
sites. Atherectomy specimens from culprit lesions responsible for
acute coronary syndromes show significantly increased amounts
of macrophages compared with specimens from patients with
stable angina. Although the morphology of the plaque itself may
vary, the cellular composition at the site of rupture is remarkably
consistent with macrophages being the dominant cell.
Experimental evidence from in vitro46 and in vivo systems44
suggests that the macrophages present in atherosclerotic plaques
are involved in active inflammation. Other components of the
inflammatory response, including T lymphocytes, mast cells,
and neutrophils, have been found in atherosclerotic plaques.47
Interferon-γ, a cytokine produced within atheromas by activated
T cells,48 may play a crucial role in this process. Interferon-γ
decreases interstitial collagen synthesis within the fibrous cap,
inhibits smooth muscle cell proliferation, activates the apoptosis
pathway in smooth muscle cells, and activates macrophages.49
Active inflammation in areas of high stress may weaken the
fibrous cap further and contribute to plaque rupture.
T-cell cytokines also induce the production of large amounts
of molecules downstream in the cytokine cascade, resulting in
elevated levels of interleukin-6 and C-reactive protein in the
peripheral circulation, which amplifies local and systemic inflammation. Elevated levels of C-reactive protein and interleukin-6
in patients with acute coronary syndromes are associated with
a worse prognosis.
When activated, macrophages are capable of causing
weakening of plaque structure by several mechanisms. These
cells may degrade the extracellular matrix by secreting various
proteolytic enzymes. One such group of enzymes is the matrix
metalloproteinases (MMPs). The MMPs are a family of zincdependent and calcium-dependent enzymes that are important
in the resorption of the extracellular matrix in normal and
pathologic conditions. These enzymes may be divided into
subgroups based broadly on substrate preference.50 The MMP
subgroups include collagenases, gelatinases, stromelysin, and
membrane-type MMPs that act on various substrates, including
collagen, elastin, proteoglycan, lamin, fibronectin, and basement
membrane components. Taken together, these MMPs are capable
of completely degrading all extracellular components, and may
play a role in atherogenesis and plaque disruption. In addition,
MMPs can be proinflammatory by facilitating inflammatory cells.
MMPs are secreted by macrophages, smooth muscle cells,
and lymphocytes found within atherosclerotic plaques. Production
and secretion of MMPs is a balance between several different
factors. Numerous cytokines and growth factors—including
interleukin-1, PDGF, and tumor necrosis factor-α—have been
shown to induce the synthesis of MMPs. Conversely, several
unrelated substances have been shown to inhibit MMP production, including heparin, corticosteroids, and tumor necrosis
factor-β. MMPs are secreted as proenzymes or zymogens and
require an activation step to become capable of degrading the
extracellular matrix. When activated, the effects of the MMPs
are controlled by a family of naturally occurring specific inhibitors,
the tissue inhibitors of metalloproteinases. Several lines of
investigation point to a possible role for MMPs in plaque rupture.
Messenger RNA transcripts of one MMP family member,
stromelysin, have been identified in macrophages and smooth
muscle cells in fibrous and lipid-laden plaques.51 Other MMPs
have been found in atherosclerotic, but not normal, arteries.52
Atherectomy specimens from patients with unstable angina have
shown increased intracellular gelatinase B production compared
with specimens from patients with stable angina.
53
Chronic immune stimulation within the atheroma may lead
to the elaboration of several factors, including cytokines and
metalloproteinases that alter the structural integrity of the fibrous
cap by inhibiting collagen synthesis and increasing matrix
degradation. Taken together, these factors reduce the structural
integrity of the plaque, rendering the fibrous cap weak and prone
to rupture in a susceptible region of the plaque. More recent
studies using in situ zymographic techniques have revealed a
net excess of metalloproteinase activity and matrix degradation
within fibrous caps, especially at the vulnerable shoulder region
of plaques.
54
Rupture Triggers
Atherosclerotic plaques are constantly exposed to various
mechanical and hemodynamic forces that may precipitate disruption of a vulnerable lesion. The importance of several external
forces has been shown, including cap tension, cap and plaque
compression, intraplaque hemorrhage, circumferential bending,
longitudinal flexion, and hemodynamic forces.
Cap Tension. The blood pressure inside the artery exerts radial
and circumferential forces across the arterial wall, which must
be counteracted by tension within the wall to maintain vessel
integrity. The circumferential tension is described by the law of
76 PART II Scientific Foundation of Cardiac Intensive Care
h
https://t.me/medicina_free
from the interior of the plaque into the vessel lumen may occur.
This process is likely to be secondary to an increase in intraplaque
pressure caused by vasospasm, intraplaque hemorrhage, plaque
p
r
h
t ≈ p • r σ ≈
Fig. 7.9 Circumferential tension on the fibrous cap of an ath-
erosclerotic plaque containing a lipid pool (hatched area) is
determined by the law of Laplace, which relates tension (t) to
the intralumen pressure (p) and the lumen radius (r). The mean
circumferential stress on the fibrous cap is related to circumferential tension and cap thickness (h). (From MacIsaac A, Thomas
JD, Topol EJ. Toward the quiescent coronary plaque. J Am Coll
Cardiol. 1993;22:1228–1241.)
p • r
Laplace, which relates intracavity pressure (blood pressure) and
lumen radius (vessel diameter; Fig. 7.9). The higher the blood
pressure or the larger the luminal diameter, the greater the tension
is within the wall.55 If components within the wall are unable
to bear the tension, the stress may be redistributed to the adjacent
structures. In coronary artery disease, the soft atheromatous
core is unable to bear the imposed load, resulting in a shift of
these forces to the fibrous cap. Studies using simulated and real
plaques have shown that soft eccentric pools of atheromatous
gruel lead to the concentration of stress on the adjacent cap,
especially near the shoulder region.30 These areas of increased
stress correlate with the actual area of plaque rupture in most
specimens.
56
The consistency of the atheromatous gruel and the thickness
of the fibrous cap are important determinants of plaque rupture.
Atheromatous gruel with increased amounts of extracellular lipid
in the form of cholesterol esters tends to be softer. Softer plaques
are less able to handle increased wall stress, and redistribute
these forces to the fibrous cap, predisposing the lesion to rupture.
The thickness of the fibrous cap is also an important factor in
determining the ability of a given lesion to handle circumferential
stress, with the thinner caps developing a greater amount of
stress. Mildly to moderately stenotic lesions are associated with
greater circumferential wall tension rather than more severe
lesions. Active newer plaques are also noted to have positive
remodeling of their vessel size as postulated by Glagov
57
and
confirmed by intravascular ultrasound. This increase in vessel
diameter can also contribute to increased wall stress promoting
plaque rupture. These observations, along with several other
factors, may help to explain why the less occlusive lesions tend
to be the most clinically volatile.
Cap and Plaque Compression. In addition to rupture from
the lumen into the plaque, the reverse process of disruption
edema, and collapse of compliant stenosis.
Vasospasm may rupture plaques by compressing the atheromatous core and displacing the fibrous cap into the lumen.58
Intraplaque hemorrhage is an important contributor to the
transformation of stable plaques into unstable lesions.59 Microvascular incompetence is a likely source of intraplaque hemorrhage, although the exact mechanism is unknown. The rapid
accumulation of erythrocyte-derived cholesterol contributes to
the expansion of the volume of the necrotic core. In addition,
it serves as a potent inflammatory stimulus, resulting in greater
macrophage density. These factors may increase plaque vulnerability to rerupture. Collapse of a severe but compliant stenosis
because of negative transmural pressure may cause buckling of
the vessel wall, which may disrupt the plaque.
Circumferential Bending. The propagating pulse wave generated
by the systolic contraction of the heart produces changes in the
lumen size and shape. The normal cyclic diastolic-systolic change
in lumen diameter is 10%, although this number may be altered
with advancing age or coronary disease.55 The change in lumen
configuration may produce deformation and bending of the
atherosclerotic plaque, especially in the shoulder region.60 Over
time, these cyclic changes may weaken the plaque and lead to
disruption. Sudden changes in vascular tone may also produce
a bending of plaques that may cause rupture.
Longitudinal Flexion. With the beating of the heart, the coronary
arteries tethered to the surface of the myocardium are subjected
to longitudinal deformation. Similar to circumferential bending,
this stretching of the arterial wall may weaken plaques or, with
acute changes in the contractility of the heart, lead to plaque
rupture.
31
Hemodynamic Factors. Hemodynamic stress tends to be less
than the mechanical forces produced by blood and pulse pressure.
Hemodynamic factors, such as shear stress, can cause endothelial
cell injury, however. Increased shear stress through stenotic lesions
can theoretically lead to plaque disruption, although this concept
has not been shown in angiographic studies.
THROMBOSIS
Thrombus formation is central to the development of acute
coronary syndromes. Intrinsic and extrinsic factors may combine
to cause rupture of the fibrous cap with exposure of the plaque’s
central components to the circulating blood and subsequent
thrombosis.
Platelet Biology
Aggregation and activation of platelets play an essential role in
normal hemostasis and acute coronary syndromes. After injury
to the vessel wall, such as in plaque rupture, platelets are involved
in the body’s initial response (primary hemostasis). Effective
primary hemostasis requires three critical events to occur: (1)
61
CHAPTER 7 Pathophysiology of Acute Coronary Syndromes 77
Adhesion Aggregation
PF4
https://t.me/medicina_free
Epinephrine
++
Ca
Fibronectin
ADP
5HT
Va, Xa
Thrombin
Fibrinogen
Tx A
Platelet
++
Ca
IIb
IIIa
18
2
++
Ca
IIIa
IIb
Fibrinogen
++
IIIa
Ca
IIb
6
, thromboxane
2
vWF
Platelet
1c
1b
vWF
PDGF
BTG
Fig. 7.10 Schematic of platelet activation and receptor sites. 1a, 1b, 1c, and IIb/IIIa, glycoprotein
receptor sites; 5HT, serotonin; ADP, adenosine diphosphate; Arach. acid, arachidonic acid; BTG,
β-thromboglobulin; PDGF, platelet-derived growth factor; PF4, platelet factor 4; TxA
A
; Va, activated factor V; vWF, von Willebrand factor; Xa, activated factor X. (From Myler RK,
2
Frink RJ, Shaw RE, et al. The unstable plaque: pathophysiology and therapeutic implications. J
Invasive Cardiol. 1990;2:117–128.)
1a
Collagen
Arach.
acid
platelet adherence, (2) platelet activation with granule release,
and (3) platelet aggregation.
Platelet Adherence. Damage to the vessel wall exposes the
highly thrombogenic subendothelial substrate and atheromatous
core (specifically collagen and tissue factor) to circulating blood.
Platelet adherence to the subendothelial collagen occurs almost
immediately through interaction with platelet glycoprotein VI.
Adhesion of platelets depends on many platelet receptors and
adhesive membrane glycoproteins (Fig. 7.10).62 Glycoprotein Ib
in the platelet membrane is important in the initial contact of
platelets with von Willebrand factor in the subendothelium. von
Willebrand factor forms a link between receptors on platelets
and subendothelial collagen fibrils, allowing platelets to remain
attached to the vessel wall despite high shear forces. The membrane receptor complex, glycoprotein IIb/IIIa, binds many relevant
proteins, including von Willebrand factor, fibrinogen, and
fibronectin.63 This complex plays a crucial role in initial platelet
adhesion and platelet aggregation. Through this series of complex
receptor-substrate interactions, the platelets form a firmly adherent monolayer and provide a foundation for further clot formation. This collagen-initiated pathway for platelet activation is
independent of thrombin.
Platelet Activation and Aggregation. Platelet adhesion leads
to the release of certain intracellular products that result in further
platelet activity. Platelet activation and secretion are regulated
by several factors, including a change in the level of cyclic
nucleotides, the influx of calcium, the hydrolysis of membrane
phospholipids, and the phosphorylation of crucial intracellular
proteins. Binding of agonists such as epinephrine, collagen, and
thrombin to platelet receptors activates phospholipase C and
phospholipase A
, membrane enzymes that catalyze the release
2
of arachidonic acid. Through a series of complex reactions (Fig.
7.11), the released arachidonic acid is eventually converted to
thromboxane A2 and prostacyclin. These two products have
opposite effects on platelet activation and vessel wall tone.
Thromboxane A2 is a powerful stimulus for platelet activation
and aggregation and produces vasoconstriction, whereas prostacyclin acts to inhibit platelet activation and is a vasodilator.
By selective production (or inhibition) of these two substances,
changes in the level of platelet activation and vessel wall tone
may be achieved.
64
Other active products secreted by platelets include endoglycosidases and heparin-cleaving enzymes from lysosomes, calcium,
serotonin, adenosine diphosphate (ADP) from dense granules,
von Willebrand factor, fibronectin, thrombospondin, and PDGF
from α granules. These products have many important roles,
including modification of coronary vascular tone, cellular
proliferation and migration, and interaction with the coagulation
system. It has been shown that PDGF is important in the proliferation and migration of smooth muscle cells after vessel damage.10
Released ADP binds to specific receptors that change the conformation of the glycoprotein IIb/IIIa complex so that it binds
von Willebrand factor, fibrinogen, and fibronectin, linking
adjacent platelets into a hemostatic plug.
Coagulation Cascade
The coagulation cascade system also plays a key role in normal
hemostasis (secondary hemostasis) and acute coronary syndromes.
The coagulation system comprises several plasma proteins involved
in a series of reactions that culminate in the production of
thrombin, which converts fibrinogen to fibrin. The fibrin produced
via this system is important in strengthening the primary
hemostatic plug formed by platelets.
The coagulation cascade can be divided into the intrinsic and
extrinsic pathways (Fig. 7.12). Both involve a series of reactions
that require the formation of surface-bound complexes and the
conversion of inactive precursor proteins into active proteases.
The intrinsic pathway (factors XII, XIIa, XI, and XIa) is activated
by exposure of blood components to the negatively charged,
damaged subendothelium and medial surfaces of the vessel. The
78 PART II Scientific Foundation of Cardiac Intensive Care
Arterial wall
F
H2
Plasminogen
Arterial wall
Surf
inogen
EXTRINSIC
INTRINSIC
https://t.me/medicina_free
Fatty acids
P
L
-
A
Platelets
Collagen
S
E
Arach.
acid
issure
Endothelium
Platelet
adhesion
PDGF
BTG
PF4
Cholesterol
cAMP
Fig. 7.11 Schematic of unstable plaque. 5HT, Serotonin; ADP, adenosine diphosphate; BTG,
β-thromboglobulin; cAMP, cyclic adenosine monophosphate; CO-ASE, cyclooxygenase; FpA/B,
fibrinopeptide A and B; HPO-ASE, hydroperoxidase; PDGF, platelet-derived growth factor; PF4,
platelet factor 4; PG, prostaglandin; PL-ASE, phospholipase A
thromboxane synthetase. (From Myler RK, Frink RJ, Shaw RE, et al. The unstable plaque:
pathophysiology and therapeutic implications. J Invasive Cardiol. 1990;2:117–128.)
SYSTEM
Injury
Tissue
thromboplastin
X
X
a
+
V
+
Ca
XIII
+
VII
Platelet
membrane
Fibr
a
ace
contact
SYSTEM
Platelet
membrane
XII
XII
a
XI
XI
Prothrombinase
IX
a
IX
a
+
VIIl
+
Ca
complex
Prothrombin Thrombin
Fig. 7.12 Intrinsic and extrinsic systems of the coagulation
cascade. Note interaction between clotting factors (XII, XIIa, XI,
XIa, IX, IXa, VII, VIII, X, Xa, and XIIIa) and the platelet membrane.
(Modified from Fuster V, Stein B, Ambrose JA, et al. Atherosclerotic plaque rupture and thrombosis: evolving concepts.
Circulation. 1990;82[Suppl II]:II-47–II-59.)
extrinsic pathway is activated by interaction of tissue factor
released from the damaged vessel wall and factor VII. Ultimately,
these two pathways produce complexes that activate factor X.
Activated factor X interacts with factor V, calcium, and phospholipid to form a complex that catalyzes the conversion of
prothrombin to thrombin. This reaction is accelerated 1000-fold
on the surface of activated platelets.
C
O
-
Fibrin
A
Va, Xa
S
E
Ca
PG
G2
FpA/B
spasm
E
TxA
Thrombus
Fibrin
Platelet
aggregation
2
PGI
Plasmin
2
5HT
ADP
H
P
Prothrombin
E
O
S
-
A
Thrombin
Fibrinogen
Coronary
S
A
-
N
Y
S
x
T
PG
; TxA2, thromboxane A2; Tx SYN-ASE,
2
Thrombin has multiple functions in hemostasis, of which
the primary function is the conversion of plasma fibrinogen to
fibrin. After conversion to fibrin, the modified molecule polymerizes into an insoluble gel. The fibrin polymer is stabilized by
cross-linking with other fibrin strands through the action of
factor XIIIa, which results in an adherent thrombus. In addition,
thrombin activates factors V, VIII, and XIII, and stimulates platelet
secretion and aggregation.
Fibrinolysis
Balancing the prothrombotic events after vessel wall injury are
several hemostatic mechanisms that favor fibrinolysis, decrease
platelet aggregation, and cause vasodilation. Tissue plasminogen
activator is the main physiologic activator of the fibrinolytic
system, with Hageman factor fragments and urokinase playing
a minor role. Tissue plasminogen activator converts plasminogen
adsorbed to the fibrin clot to plasmin. The plasmin acts to degrade
the fibrin polymer into fragments, resulting in clot lysis. Circulating thrombin stimulates several mechanisms designed to limit
clot formation. The thrombin itself is inactivated by plasma
protease inhibitors,
inhibits activated factors VII, IX, and X. The thrombin also
stimulates endothelial cells to release tissue plasminogen activator
and produce prostacyclin and nitrous oxide, which act in concert
to inhibit platelet aggregation and cause vasodilation.
Intact endothelial cells have several other important functions
after vessel wall injury. These cells produce protein C, protein
S, and heparin-like glycosaminoglycans that act to neutralize
thrombin and activated factors V and VIII. In addition, stimulation
of adenyl cyclase and accumulation of cyclic adenosine monophosphate within these cells lead to inhibition of phospholipase
A2 and decreased production of thromboxane A2, which causes
increased vasodilation.
The diverse actions of the intrinsic fibrinolytic system act to
offset the thrombogenic stimulus of vessel wall injury. In the
usual situation, a delicate balance is maintained that results in
the formation of enough thrombus to provide hemostasis at the
65
especially antithrombin III, which also
Соседние файлы в папке Библиотека им академика М.И. Перельмана