atherosclerosis pathogenesis

1. PATHOPHYSIOLOGY OF
ATHEROSCLEROSIS
23/05/2016

2. • Atherosclerosis- An epidemic of 21st century
• As populations increasingly survive early
mortality caused by communicable diseases
and malnutrition(as in 18-19th centuries)
• Economic development and urbanization
promoted habits of poor diet (e.g., a surfeit of
saturated fats) and diminished physical
activity, which can favor atherogenesis.

3. • Atherosclerosis is characterized by intimal lesions called
atheromas (also called atheromatous or atherosclerotic
plaques) that protrude into vessel lumens.
• Besides mechanically obstructing blood flow,
atherosclerotic plaques can rupture, leading to
catastrophic vessel thrombosis; plaques also weaken
the underlying media and thereby lead to aneurysm
formation.

4. An atheromatous plaque consists of a raised lesion
with a soft, yellow, grumous core of lipid (mainly
cholesterol and cholesterol esters) covered by a
white fibrous cap.

5. • CABG surgery is the standard of care for patients with three-vessel
disease or left main disease with reduced ejection fraction, as
supported by many studies showing a reduction in morbidity and
mortality relative to percutaneous coronary intervention.
• Of the graft options — vein graft versus internal mammary arteries
(IMAs) — the latter have the better long-term patency; however, only
5–10% of patients receive bilateral IMAs, because of the increased
perioperative morbidity, mortality, duration of operation, and risk of
sternal wound problems that are reported for this type of graft.
• Of note, 10–25% of saphenous vein grafts (SVGs) occlude from
thrombosis within 1 year after CABG surgery, and an additional 1–2%
occlude each year from 1 year to 5 years after CABG surgery.
Moreover, 4–5% occlude each year from 6 years to 10 years
postoperatively, owing to accelerated development of
atherosclerosis.

6. • Currently, percutaneous coronary intervention with
stents (either bare-metal stents (BMS) or drug-eluting
stents (DES)) is the most commonly performed
procedure for the treatment of patients with
symptomatic CAD.
• Delayed arterial healing with poor strut coverage is
recognized as the primary substrate for stent
thrombosis attributed to the first-generation DES.
• However, we have reported that neoatherosclerosis
within the ‘in-stent’ segment is another complication of
first-generation and second-generation DES, resulting
in late stent failure from restenosis or stent thrombosis
induced by plaque rupture.

7. • The temporal presentation of atherosclerosis in
the form of clinical events differs between native
CAD, which develops over decades, and vein graft
atherosclerosis and in-stent neoatherosclerosis,
which occur within months to a few years.
• Todays’ discussion is focused on the structural
characteristics of human atherosclerotic plaques
for these three entities, with emphasis on disease
progression where divergent or shared
characteristics of lesion morphology exist.

8. • Atherosclerosis also displays heterogeneity in
time; this disease has both chronic and acute
manifestations. Few human diseases have a
longer “incubation” period than
atherosclerosis, which begins to affect the
arteries of many Americans in the second and
third decades of life.
• Indeed, many young Americans have
abnormal thickening of the coronary arterial
intima; yet typically, symptoms of
atherosclerosis emerge only after several
decades of delay.

9. Strong JP, Malcolm GJ, McMahan CA, et al: Prevalence and extent of atherosclerosis in
adolescents and young adults. JAMA 281:727, 1999

10. slightly slower progression of lesions affects the right coronary artery
Strong JP, Malcolm GJ, McMahan CA, et al: Prevalence and extent of atherosclerosis in
adolescents and young adults. JAMA 281:727, 1999

11. ATHEROSCLEROSIS
• Heterogenous in time?
• Heterogenous in location?
• Why stenosis in some and ectasia in others?

12. Native coronary artery disease

13. HISTORY
• 1970- Russell Ross- SMC proliferation in
response to injury to arterial wall.
• 1990- libby and co- complex interaction
between risk factors and inflammation
• 1990- Fuster and co- plaque progression a
staged event(endothelium- intima-media)
• Deep plaque fissures and ulcerations were
identified as cause of luminal thrombosis and
clinical presentation of ACS.

14. Basic events are……………..

15. FAILED TO INCLUDE ALL CAUSES OF
THROMBOSIS- PLAQUE RUPTURE, SURFACE
EROSION(25-30%) AND ERUPTIVE CALCIFIED
NODULES(<5%).
NO MENTION OF PRECURSOR LESIONS TO
PLAQUE RUPTURE- VULNERABLE PLAQUES (aka
THIN CAP FIBROATHEROMA)
NO CONCEPT OF PLAQUE HEALING

21. Simplified scheme for
classifying
atherosclerotic lesions
in human coronary
arteries. Solid arrows
indicate the main
pathway of plaque
progression, and
dashed arrows indicate
infrequent pathways.
Abbreviations: MMP,
matrix
metalloproteinase;
SMC, smooth muscle
cell.

22. ATHEROSCLEROSIS INITIATION
• On initiation of an atherogenic diet, typically
rich in cholesterol and saturated fat, small
lipoprotein particles accumulate in the intima
Hyperlipidemia,
hypertension,homocysteine,
smoking,infection,toxins,
hemodynamic factors

23. • These lipoprotein particles appear
to decorate the proteoglycan of
the arterial intima and tend to
coalesce into aggregates.
• The binding of lipoproteins to
proteoglycan in the intima leads
to their capture and retention,
accounting for their prolonged
residence time.
• Lipoprotein particles bound to
proteoglycan have increased
susceptibility to oxidative or
other chemical modifications,
considered by many to contribute
to the pathogenesis of early
atherosclerosis
• Contributors to oxidative stress in
the nascent atheroma could
include reduced (NADH/NADPH)
oxidases expressed by vascular
cells, lipoxygenases expressed by
infiltrating leukocytes, or the
enzyme myeloperoxidase.

24. Oxidized LDL - a potent inflammatory agent
When an elevated serum levels of LDL cholesterol overwhelm the antioxidant
properties of the healthy endothelium, it results in abnormal endothelial
metabolism of LDL.
• Stimulates the expression of adhesion molecules on endothelial cell.
• OxLDL has chemoattractant activity on monocytes and promotes their
differentiation into macrophages and also inhibits their mobility.
• Triggers the release of proinflammatory cytokines in macrophages
Altogether these findings point to a role of oxLDL as a very early
trigger of vascular inflammation.

25. LEUKOCYTE RECRUITMENT AND
RETENTION
• Another hallmark of atherogenesis, leukocyte recruitment
and accumulation also occurs early in lesion generation.
• The normal EC generally resists adhesive interactions with
leukocytes.
• Even in inflamed tissues, most recruitment and trafficking
of leukocytes occurs in postcapillary venules and not in
arteries.
• Very soon after initiation of hypercholesterolemia,
however, leukocytes adhere to the endothelium and move
between EC junctions, or even penetrate through ECs
(transcytosis) to enter the intima, where they begin to
accumulate lipids and become foam cells.

26. • In addition to the monocyte, T lymphocytes also
tend to accumulate in early human and animal
atherosclerotic lesions.
• The expression of certain leukocyte adhesion
molecules on the surface of the EC regulates the
adherence of monocytes and T cells to the
endothelium.
• These include:
– Vascular Cell Adhesion molecule(VCAM-1) (Interacts
with only those classes of leukocytes that accumulate in nascent
atheroma-monocytes and T cells)
– P-Selectin
– Intercellular adhesion molecule-1(ICAM-1)
– E-Selectin

27. So far…..

28. LEUCOCYTE PENETRATION
• Once adherent to the endothelium, leukocytes must
receive a signal to penetrate the endothelial monolayer
and enter the arterial wall.
• The current concept of directed migration of leukocytes
involves the action of protein molecules known as
chemoattractant cytokines or chemokines.
• Among the many chemokines implicated in
atherogenesis, few are of particular interest in
recruiting the mononuclear cells characteristic of the
early atheroma.
– Monocyte chemoattractant protein 1(MCP-1)
– Fractalkine
– Chemoattractants induced by Interferon-gamma

29. Leucocyte retention
• The accumulation of monocytes in plaques
depends not only on their recruitment, but
also on their retention.
• Recent work has implicated netrin-1
interacting with its receptor UNC5b (both
induced by hypoxia) as a protein that retards
macrophages from exiting plaques

30. So far…..

31. INTRACELLULAR LIPID ACCUMULATION:
FOAM CELL FORMATION
• The monocyte, once recruited to the arterial intima, can
imbibe lipid and become a foam cell or lipid-laden
macrophage.
• Although most cells can express the classic cell surface
receptor for LDL, that receptor does not mediate foam cell
accumulation.
• This is evident clinically, because tendinous xanthomas filled
with foamy macrophages still develop in patients lacking
functional LDL receptors (familial hypercholesterolemia
homozygotes).
• The LDL receptor does not mediate foam cell formation,
because of its exquisite regulation by cholesterol. As soon as a
cell collects enough cholesterol for its metabolic needs from
LDL capture, an elegant transcriptional control mechanism
quenches expression of the receptor.

32. WHAT MEDIATES EXCESSIVE LIPID
UPTAKE OF MACROPHAGES?
• SCAVENGER RECEPTORS- These surface
molecules, belonging to several families, bind
modified rather than native lipoproteins and
participate in their internalization.
• CD36
• MACROSIALIN

33. M-CSF
GM-CSF
INTERLEUKIN-3
FOAM CELL
FORMATION
REPLICATION
SCAVENGER
RECEPTORS,
CD36,
MACROSIALIN,
Once macrophages have taken up
residence in the intima and
become foam cells, they can
replicate.
Monocyte recruitment from blood
initially populates the nascent
lesion with mononuclear
phagocytes, but local proliferation
predominates in the established
lesion.
The factors that trigger
macrophage cell division in the
atherosclerotic plaque include
hematopoietic growth factors such
as macrophage colony-stimulating
factor (M-CSF), granulocyte-
macrophage colony-stimulating
factor (GM-CSF), and interleukin-3.
Up to this point in the development of the nascent
atheroma, the lesion consists primarily of lipid-
engorged macrophages.
Complex features such as fibrosis, thrombosis, and
calcification do not characterize the fatty streak, the
precursor lesion of the complex atheroma.
Several lines of evidence suggest that such fatty streaks
can regress, at least to some extent.

36. EVOLUTION OF ATHEROMA

37. SMOOTH MUSCLE CELL MIGRATION
AND PROLIFERATION
• Whereas the early events in atheroma initiation involve
primarily altered endothelial function and recruitment
and accumulation of leukocytes, the subsequent
evolution of atheroma into more complex plaques also
involves SMCs.
• SMCs in the normal arterial tunica media differ
considerably from those in the intima of an evolving
atheroma.
• Some SMCs probably arrive in the arterial intima early
in life; others accumulate in advancing atheroma after
recruitment from the underlying media into the intima
or arise from blood-borne precursors.

38. • The accumulation of
SMCs during
atherosclerosis and
growth of the intima
does not occur in a
continuous and linear
fashion.
• Bursts of SMC replication
may occur during the life
history of a given
atheromatous lesion.
• Episodes of plaque
disruption with
thrombosis may expose
SMCs to potent
mitogens, including the
coagulation factor
thrombin itself. This
results in bursts of
smooth muscle activity.

39. SMOOTH MUSCLE CELL DEATH
DURING ATHEROGENESIS
• In addition to SMC replication, death of these cells also may
participate in complication of the atherosclerotic plaque
Some SMCs in advanced human atheroma exhibit
fragmentation of their nuclear DNA that is characteristic
of programmed cell death or apoptosis. Apoptosis may
occur in response to inflammatory cytokines present in
the evolving atheroma. In addition to soluble cytokines
that may trigger programmed cell death, T cells in
atheroma may participate in eliminating some SMCs.
Thus SMC accumulation in the growing atherosclerotic
plaque probably results from a tug-of-war between
cell replication and cell death

40. ARTERIAL EXTRACELLULAR MATRIX
• Extracellular matrix, rather than cells themselves, makes up
much of the volume of an advanced atherosclerotic plaque.
• Accordingly, extracellular constituents of plaque also require
consideration.
• The major extracellular matrix macromolecules that
accumulate in atheroma include interstitial collagens (types I
and III) and proteoglycans such as versican, biglycan,
aggrecan, and decorin.
• Elastin fibers also may accumulate in atherosclerotic plaques.
• Arterial SMCs produce these matrix molecules in disease,
just as they do during development and maintenance of the
normal artery.
• Stimuli for excessive collagen production by SMCs include
platelet-derived growth factor (PDGF) and TGF-β.

41. ARTERIAL EXTRACELLULAR MATRIX
• Much as with the accumulation of SMCs,
extracellular matrix secretion also depends on a
balance, as noted earlier.
• In this case, the counterpoise to biosynthesis of
the extracellular matrix molecules is breakdown
catalyzed in part by catabolic enzymes, notably the
matrix metalloproteinases (MMPs).
• Dissolution of extracellular matrix macromolecules
undoubtedly contributes to the migration of SMCs
as they penetrate into the intima from the media
through a dense extracellular matrix, traversing
the elastin-rich internal elastic lamina.

42. • Extracellular matrix breakdown also likely plays a role in
arterial remodeling that accompanies lesion growth.
• During the early life of an atheromatous lesion, plaques
grow outwardly, in an abluminal direction, rather than
inwardly, in a way that would lead to luminal stenosis.
• This outward growth of the intima leads to an increase
in the caliber of the entire artery. This so-called positive
remodeling or compensatory enlargement must involve
turnover of extracellular matrix molecules to
accommodate the circumferential growth of the artery.
• Luminal stenosis tends to occur only after the plaque
burden exceeds some 40% of the cross-sectional area
of the artery.

45. ANGIOGENESIS IN PLAQUES
• Atherosclerotic plaques develop their own
microcirculation as they grow, because of endothelial
migration and replication.
• Histologic examination with appropriate markers for
ECs reveals a rich neovascularization in evolving
plaques.
• These microvessels probably form in response to
angiogenic peptides overexpressed in atheroma.
• These angiogenesis factors include vascular endothelial
growth factor (VEGF) forms of fibroblast growth
factors, placental growth factor (PlGF), and oncostatin
M.

46. ANGIOGENESIS IN PLAQUES
• These microvessels within plaques probably have considerable
functional significance.
• provide a relatively large surface area for the trafficking of leukocytes,.
Indeed, in the advanced human atherosclerotic plaque, microvascular
endothelium displays mononuclear cell–selective adhesion molecules
such as VCAM-1 much more prominently than does the macrovascular
endothelium overlying the plaque.
• may allow growth of the plaque, overcoming diffusion limitations on
oxygen and nutrient supply.
• Finally, the plaque microvessels may be friable and prone to rupture
like the neovessels in the diabetic retina.
• Hemorrhage and thrombosis in situ could promote a local round of SMC
proliferation and matrix accumulation in the area immediately adjacent
to the microvascular disruption

47. Intraplaque hemorrhage surrounding neovessels in an atheroma. A, B,
A typical human atherosclerotic plaque, stained for von Willebrand factor (VWF) (A)
and for iron by Prussian blue (B).
The von Willebrand factor stains the endothelial cells that line the microvascular
channels and lakes. Note the extravasated von Willebrand factor, which colocalizes with
iron deposition, indicating hemosiderin deposition consistent with an intraplaque
hemorrhage.

48. PLAQUE MINERALIZATION
• Plaques often develop areas of calcification as they evolve.
• Some subpopulations of SMCs may foster calcification by
enhanced secretion of cytokines such as bone
morphogenetic proteins, homologues of TGF-β.
• Receptor activator of NF-κB ligand (RANKL), a member of the
tumor necrosis factor family, appears to promote SMC mineral
formation through a bone morphogenetic protein 4 (BNP4)–
dependent pathway.
• The transcription factor Runx-2, activated by inflammatory
mediators and oxidative stress among other stimuli, can
promote SMC mineral formation by activating AKT (i.e.,
protein kinase B)
• Microparticles elaborated by macrophages may provide
niduses for plaque calcification, yielding another link between
inflammatory cells and cardiovascular calcification

49. COMPLICATIONS OF
ATHEROSCLEROSIS
SO FAR….INITIATION AND EVOLUTION
OF ATHEROSCLEROTIC PLAQUE

50. ARTERIAL STENOSIS
• The initiation and evolution of the atherosclerotic
plaque generally last many years, during which the
affected person often has no symptoms.
• After the plaque burden exceeds the capacity of the
artery to remodel outward, encroachment on the
arterial lumen begins.
• During the chronic asymptomatic or stable phase of
lesion evolution, growth probably occurs
discontinuously, with periods of relative quiescence
punctuated by episodes of rapid progression

51. • Human angiographic studies support this
discontinuous growth of coronary artery stenoses.
• Eventually, the stenoses may progress to a degree
that impedes blood flow through the artery.
Lesions that produce stenoses of greater than 70%
can cause flow limitations under conditions of
increased demand.
• This type of athero-occlusive disease commonly
produces chronic stable angina pectoris or
intermittent claudication on increased demand.
• Thus the symptomatic phase of atherosclerosis
usually begins many decades after lesion initiation.

52. • In many cases of myocardial infarction, however, no history of
previous stable angina heralds the acute event.
• Several kinds of imaging data suggest that many myocardial
infarctions result not from high-grade stenoses but from lesions
that do not limit flow.
• Acute coronary syndromes often result from thrombi that form as a
consequence of disruption of plaques that do not produce a critical
stenosis.
• These findings do not imply that small atheromas cause most
myocardial infarctions.
• Indeed, culprit lesions of acute myocardial infarction may be sizable;
but they may not produce a critical luminal narrowing because of
compensatory enlargement.
• Of course, critical stenoses do cause myocardial infarctions, and
high-grade stenoses are more likely to cause acute myocardial
infarction than are nonocclusive lesions; yet because the noncritical
stenoses by far outnumber the tight focal lesions in a given
coronary tree, the lesser stenoses cause more infarctions, even
though high-grade stenoses have a greater individual probability of
causing infarction.

53. THROMBOSIS AND ATHEROMA
COMPLICATION
• 2 MAJOR MODES OF PLAQUE DISRUPTION
PROVOKE MOST CORONARY THROMBI :
–PLAQUE RUPTURE (rupture of plaque’s
fibrous cap) 75%
–SUPERFICIAL PLAQUE EROSION 25%

54. PLAQUE RUPTURE AND THROMBOSIS
• IMBALANCE BETWEEN MECHANICAL STRENGTH
OF THE FIBROUS CAP AND THE FORCES THAT
IMPINGE ON IT.
• Interstitial forms of collagen provide most of the
biomechanical resistance to disruption of the
fibrous cap. Hence the metabolism of collagen
probably participates in regulating the propensity
of a plaque to rupture.
• Factors that decrease collagen synthesis by SMCs
can impair their ability to repair and to maintain
the plaque’s fibrous cap.
SO IF THE FACTORS THAT DEGRADE COLLAGEN OUTWEIGH THE
FACTORS RESPONSIBLE FOR ITS PRODUCTION ------IT WILL RESULT IN
A THIN CAP FIBROATHEROMA (previously called VULNERABLE
PLAQUE)

55. • A RELATIVE LACK OF SMCs secondary to
INFLAMMATORY MEDIATORS IS ALSO
RESPONSIBLE.
• PROMINENT ACCUMULATION OF
MACROPHAGES WITH A LARGE LIPID POOL is
also responsible

56. PROMINENT ACCUMULATION OF MACROPHAGES WITH A LARGE
LIPID POOL
• From a strictly biomechanical viewpoint, a large lipid pool can
serve to concentrate biomechanical forces on the shoulder
regions of plaques, where they frequently fracture.
• From a metabolic standpoint, the activated macrophage
characteristic of the plaque’s core region produces the cytokines
and the matrix-degrading enzymes thought to regulate aspects
of matrix catabolism and SMC apoptosis in turn.
• Apoptotic macrophages and SMCs can generate particulate
tissue factor, a potential instigator of microvascular thrombosis
after spontaneous or iatrogenic plaque disruption.
• The success of lipid-lowering therapy in reducing the incidence
of acute myocardial infarction or unstable angina in patients at
risk may result from a reduced accumulation of lipid and a
decrease in inflammation and plaque thrombogenicity.
• Animal studies and accumulated data from monitoring
peripheral markers of inflammation in humans support this
concept

57. THROMBOSIS DUE TO SUPERFICIAL EROSION OF
PLAQUES
• In humans, superficial erosion appears more likely to cause
fatal acute myocardial infarction in women and in persons
with hypertriglyceridemia and diabetes mellitus, but the
underlying molecular mechanisms remain obscure.
• VARIOUS POSSIBLE MECHANISMS OF ENDOTHELIAL
DAMAGE:
Apoptosis of ECs could contribute to desquamation of ECs in
areas of superficial erosion.
Likewise, MMPs, such as certain gelatinases specialized in
degrading the nonfibrillar collagen found in the basement
membrane (e.g., collagen type IV), also may sever the
tetherings of the EC to the subjacent basal lamina and
promote their desquamation.
Vasospasm of atherosclerotic coronary arteries in rabbits can
promote endothelial damage, thrombosis, and myocardial
infarction

60. DO ALL PLAQUE DISRUPTIONS CAUSE
ACS/ARTERIAL OCCLUSION
• Most plaque disruptions do not give rise to clinically
apparent coronary events.
• Careful pathoanatomic examination of hearts obtained
from patients who have succumbed to noncardiac
death has shown a surprisingly high incidence of focal
plaque disruptions with limited mural thrombi.
• Moreover, hearts fixed immediately after explantation
from persons with severe but chronic stable coronary
atherosclerosis who had undergone transplantation
for ischemic cardiomyopathy show similar evidence for
ongoing but asymptomatic plaque disruption.

61. DO ALL PLAQUE DISRUPTIONS CAUSE
ACS/ARTERIAL OCCLUSION
• Experimentally, in atherosclerotic nonhuman primates,
mural platelet thrombi can complicate plaque erosions
without causing arterial occlusion.
• Therefore repetitive cycles of plaque disruption, thrombosis
in situ, and healing probably contribute to lesion evolution
and plaque growth.
• The “burned-out” fibrous and calcific atheroma may
represent a Healed plaque with rupture and thrombosis.
• Such episodes of thrombosis and healing constitute one
type of crisis in the history of a plaque that may cause a
burst of SMC proliferation, migration, and matrix synthesis
Plaque disruptions with healing underlie many thrombi
that cause sudden death, indicating that nonocclusive
thrombosis may precede the fatal event more frequently
than has been previously recognized

62. Thrombosis depends not only on the
“solid state” of the plaque that may
rupture or erode to trigger
thrombosis but also on the “fluid
phase” of blood that determines the
consequences of a given plaque
disruption.
The amount of tissue factor in the
lipid core of a plaque (the solid
state) can control the degree of clot
formation that will ensue after
disruption.
The level of fibrinogen in the fluid
phase of blood can influence
whether a plaque disruption will
cause an occlusive thrombus that
can precipitate an acute ST-
segment elevation myocardial
infarction or yield merely a small
mural thrombus.
Likewise, elevated levels of
inhibitors of fibrinolysis, such as
plasminogen activator inhibitor 1
(PAI-1), will impede the ability of
endogenous thrombolytic enzymes
to limit thrombus growth or
persistence.
Inflammation regulates both the fluid-phase and solid-
state factors delineated earlier, including tissue factor,
fibrinogen, and PAI-1. This notion helps explain the links
between inflammation and thrombotic complications of
atherosclerosis that have emerged from laboratory and
clinical investigations.

63. Why atherosclerosis manifests as
stenosis/aneurysms(directionally opposite manners)??
• Atherosclerosis mostly causes stenosis in the coronaries while ectasia
of the abdominal aorta? WHY?
• Histologic examination shows considerable distinction between
occlusive atherosclerotic disease and aneurysmal disease. In typical
coronary artery atherosclerosis, expansion of the intimal lesion
produces stenotic lesions. The tunica media underlying the expanded
intima often is thinned, but its general structure remains relatively well
preserved.
• By contrast, transmural destruction of the arterial architecture occurs
in aneurysmal disease.
• In particular, the usually well-defined laminar structure of the normal
tunica media disappears with obliteration of the elastic laminae. The
medial SMCs, usually well preserved in typical stenotic lesions, are
notable for their paucity in the media of advanced aortic aneurysms.

64. Note the concentric laminae of elastic tissue that form sandwiches with successive layers of
SMCs. Each level of the elastic arterial tree has a characteristic number of elastic laminae

65. • PATHOPHYSIOLOGY IS STILL OBSCURE.
• Widespread destruction of the elastic laminae suggests a role for
degradation of elastin, collagen, and other constituents of the arterial
extracellular matrix.
• Many studies have documented overexpression of matrix-degrading
proteinases, including MMPs, in human aortic aneurysm specimens.
Clinical trials are testing the hypothesis that MMP inhibitors can reduce
the expansion of aneurysms.
• In atherosclerotic mice, angiotensin II potentiates aneurysm formation.
Alterations in TGF-β signaling can predispose to aneurysm formation.
Mutations in TGF-β receptors can cause arterial ectasia.
• Thus heightened elastolysis may explain the breakdown of the usually
ordered structure of the tunica media in this disease.
• Although extracellular matrix degradation and SMC death also occur in
sites where atherosclerosis causes stenosis, they appear to predominate
in regions of aneurysm formation and to affect the tunica media much
more extensively, for reasons that remain obscure.

66. INFRARENAL AORTA IS HIGHLY PRONE
TO THE DEVELOPMENT OF
ATHEROSCLEROSIS? WHY?
• Data from the Pathobiological Determinants of
Atherosclerosis in Youth (PDAY) study show that the dorsal
surface of the infrarenal abdominal aorta has a particular
predilection for the development of fatty streaks and raised
lesions in Americans younger than 35 years of age who
succumbed for noncardiac reasons .
• Because of the absence of vasa vasorum, the relative lack of
blood supply to the tunica media in this portion of the
abdominal aorta might explain the regional susceptibility of
this portion of the arterial tree to aneurysm formation.
• In addition, the lumbar lordosis of the biped human may
alter the hydrodynamics of blood flow in the distal aorta,
yielding flow disturbances that may promote lesion
formation.

67. Comparison of atherosclerotic
processes In native vessel, vein grafts
and in-stent neoatherosclerosis
• Restenosis Vs Instent stenosis
• In-stent atherosclerosis or ‘neoatherosclerosis’ is
histologically identified by the lipid-laden foamy
macrophages with or without complications of a necrotic
core and/or calcification within the nascent intima.
• In all cases, necrotic cores of neoatherosclerosis do not
communicate with the underlying native plaque.
• Clusters of macrophage-derived foam cells within the
peristrut regions, or near the luminal surface, are the most-
frequent and earliest lesion of neoatherosclerosis.

68. Comparison of atherosclerotic
processes In native vessel, vein grafts
and in-stent neoatherosclerosis
• In contrast to the decades that it takes for
atherosclerosis to develop in native coronary disease,
vein-graft atherosclerosis and in-stent
neoatherosclerosis develop over a period of months to
a few years.
• This temporal difference might reflect the
morphological diversity relative to the natural history
of progression among these entities.
• Adaptive intimal thickening in native arteries within
the first year after stent implantation parallels the
neointimal hyperplasia observed in vein grafts

69. • SMC proliferation without macrophage foam cell
infiltration is frequently observed in BMS
implants, especially in those aged <5 years.
• The most recognized feature of atherosclerosis
common to vein grafts and stents is macrophage
infiltration, which best resembles ‘fatty streaks’.
• Rather than individual foam cells interspersed
throughout the intima, macrophages in vein
grafts and stents have a tendency to accumulate
as surface clusters or in peristrut regions, which is
different from native disease.

70. • Another important distinction is that intimal
xanthomas or ‘fatty streaks’ in native arteries might
regress and are considered nonprogressive lesions,
whereas foamy macrophage clusters in stents or SVGs
seem to progress to form necrotic cores through cell
death.
• In native coronary disease, pathological intimal
thickening with lipid pools are common and
considered a passageway to lesion progression;
however, pathological intimal thickening is rarely
present in vein grafts or DES, but can be seen in BMS.

71. • In native disease, lipid pools and necrotic cores
are localized to the deep intimal layers. The
necrotic cores in neoatherosclerosis are more
frequently superficial and, consequently, rarely
present as early fibroatheromas; they instead
occur as late fibroatheromas or, in some cases,
TCFAs.
• Typical SVG atherosclerosis is often concentric
and diffuse, with a less well-defined fibrous cap
than in native coronary disease; the cap seems
fragile and vulnerable to rupture

72. • Coronary thrombi in neoatherosclerosis are
primarily associated with plaque rupture;
• in-stent erosions are rarely observed in BMS and
DES, although erosions in this setting might not
always be directly tied to the entity of
neoatherosclerosis.
• Plaque erosion in vein grafts is a rare event and
has been mostly observed at distal anastomotic
sites.
• chronic total occlusion lesions consisting of
organized thrombi within the stent can originate
from plaque rupture associated with
neoatherosclerosis in addition to thrombi that
develop as a consequence of incomplete healing
of the stent.

74. CONCLUSIONS
• Natural causes of luminal thrombosis in native
coronary disease predominantly occur from
plaque rupture, but also occur as a result of
erosion.
• Precursor lesion of plaque rupture, identified
as ‘vulnerable plaque’ or ‘TCFA’, seems an
appropriate target for interventional
treatment irrespective of the extent of luminal
narrowing.

75. CONCLUSIONS
• Accelerated atherosclerosis in SVGs or occurring
within stents (known as ‘neoatherosclerosis’) is
typically identified by macrophage foam cell
infiltration, intraplaque haemorrhage, and a thin
fibrous cap.
• Apoptosis of lipid-rich macrophages is thought to
give rise directly to necrosis in accelerated
disease, rather than transitioning through
pathological intimal thickening, as occurs in
native disease.

76. CONCLUSIONS
• Within the past 5 years, neoatherosclerosis
has been identified as a contributing factor to
late thrombosis attributed to percutaneous
coronary intervention with stents. The
incidence of neoatherosclerosis is more
frequent and rapid in DES than in BMS.

77. THANKYOU

81. Criteria for American Heart Association lesion classification system and
correspondence with classification of gross arterial specimens

82. Coronary plaque features responsible for acute thrombosis, which comprise three different morphologies:
rupture, erosion, and calcified nodules. Ruptured plaques are thin fibrous cap atheromas with luminal
thrombi (Th). These lesions usually have an extensive necrotic core (NC) containing large numbers of
cholesterol crystals and a thin fibrous cap (<65 µm) infiltrated by foamy macrophages and T lymphocytes.
The fibrous cap is thinnest at the site of rupture and consists of a few collagen bundles and rare smooth
muscle cells. The luminal thrombus is in communication with the lipid-rich necrotic core. Erosions occur over
lesions rich in smooth muscle cells and proteoglycans. Luminal thrombi overlie areas lacking surface
endothelium. The deep intima of the eroded plaque often shows extracellular lipid pools, but necrotic cores
are uncommon; when present, the necrotic core does not communicate with the luminal thrombus.
Inflammatory infiltrate is usually absent, but if present, is sparse and consists of macrophages and
lymphocytes. Calcified nodules are plaques with luminal thrombi showing calcific nodules protruding into
the lumen through a disrupted thin fibrous cap. There is absence of an endothelium at the site of the
thrombus, and inflammatory cells (macrophages, T lymphocytes) are absent.

83. A) Intimal thickening is normal in all age groups and is characterized by smooth muscle
cell accumulation within the intima.
(B) Intimal xanthoma or so-called fatty streak corresponds to the accumulation of
predominantly macrophages within the intima; these lesions have been shown to
regress in later adult life.
(C) Pathologic intimal thickening marks the first of the progressive lesions and denotes
the accumulation of extracellular lipid in the absence of apparent necrosis.

84. (D) Fibrous cap atheroma indicates the presence of an encapsulated necrotic
core.
(E) The core may eventually become thinned (thin-cap fibroatheroma).
(F) This lesion may rupture, allowing contact of the contents of the necrotic core,
causing a luminal thrombosis.
EL: extracellular lipid; NC: necrotic core; FC: fibrous cap; Th: thrombus.

85. The thrombus of a plaque erosion occurs in the absence of rupture and may overlie a
substrate of pathologic intimal thickening (top left) or fibrous cap atheroma (top right).
Eruptive calcified nodules represent a rare form of coronary thrombus.
Acute rupture may progress to healing (healed plaque rupture) with resolution of the
luminal occlusion.
Ca 2+ : calcification; NC: necrotic core; FC: fibrous cap; Th: thrombus.

86. The lesions of atherosclerosis do not occur in a
random fashion.
•Hemodynamic factors
•activated vascular endothelium
Sites of predeliction:
• regions of branching
•marked curvature

87. activated vascular endothelium :
Two contradictory hypotheses :
•high shear stress (400 dyn/cm2) via
endothelial injury and denudation,
•low shear stress as an atherogenic force : the most accepted.
CONCEPTS:
•Vascular endothelium as a transducer of
haemodynamic forces
•Potential shear stress receptors and associated proteins :
•potassium channel and a stretch-activated channel
•Integrins
•caveolae
•G proteins
Current Opinion in Lipidology 2000,
11:167±177

88. Endothelial gene regulation by complex
shear forces :
PDGF-A expressionPulsatile shear stress :
Turbulent shear stress : PDGF-B
transforming growth factor-b
thrombomodulin
basic fibroblast growth factor
Oscillatory shear stress :
Hemeoxygenase 1
Disturbed shear stress : VCAM-1
PDGFA
connexin-43
Current Opinion in Lipidology 2000,
11:167±177
Fluid shear stresses generated by blood flow influence the phenotype of the endothelial cells
by modulation of gene expression and regulation of expression of surface receptors.

89. AHA Lesion classification 1990s
• The classification involved six distinct categories:
Type I, Intimal thickening;
Type II, Fatty streak;
Type III, Transitional or intermediate lesion;
Type IV, Advanced atheroma with well-defined region
of the intima;
Type V, Fibroatheroma or atheroma with overlaid
new fibrous connective tissue; and
Type VI, Complicated plaques with surface defects,
haematoma or haemorrhage, thrombosis, or a
combination of these characteristics.
FAILED TO INCLUDE ALL CAUSES OF
THROMBOSIS- PLAQUE RUPTURE, SURFACE
EROSION(25-30%) AND ERUPTIVE CALCIFIED
NODULES(<5%).
NO MENTION OF PRECURSOR LESIONS TO
PLAQUE RUPTURE- VULNERABLE PLAQUES (aka
THIN CAP FIBROATHEROMA)
NO CONCEPT OF PLAQUE HEALING