atherosclerotic plaque

development

Amir Norouzpour
Medical student
Mashhad university of medical science
(MUMS)
Introduction
This disease has a venerable history, having
left traces in the arteries of Egyptian
mummies.
Atherosclerosis became epidemic as
populations increasingly survived early
mortality caused by infectious diseases.
Introduction
Until very recently, most physicians viewed
arteries as inanimate tubes rather than
living. dynamic tissue.
A controversy raged between Virchow, who
viewed atherosclerosis as a proliferative
disease, and Rokitansky, who believed that
atheromata derived from healing and
resorption of thrombi (Libby et al. 2000).
Structure of normal arteries
 They have a well-developed trilaminar
structure include
– the tunica intima
– Tunica Media
– Adventitia
atherosclerosis
Atherosclerosis can involve both large and
mid-size arteries diffusely.
At the same time, atherosclerosis is a focal
disease that constricts areas of affected
vessels much more than others.
Understanding of the biological basis of the
predilection of certain sites to develop
atheroma is just beginning to emerge
(Gimbrone et al. 1997).
Evolution of atherosclerotic plaque
1. Accumulation of lipoprotein particles in the
intima.
2. Oxidative stress and elaboration of local
cytokines
3. Recruitment of leukocytes
4. uptake of modified lipoprotein particles by
monocytes and promotion of development of
foam cells
5. Recruitment of smooth muscle cells into the
intima from the media
Evolution of atherosclerotic plaque
1. Elaboration of extracellular matrix by
migrated smooth muscle cells
2. Evolution of fatty streak into the
fibrofatty lesion
3. Calcification and fibrosis and apoptosis
of smooth muscle cells
4. acellular fibrous capsule surrounding a
lipid-rich core
Angiogenesis in plaques

 As the plaque enlarges, the ensuing

hypoxia or inflammatory cell infiltration is
thought to promote angiogenesis (Virmani
et al. 2005).
 Angiogenesis results in supplying oxygen
and nutrients and also leukocytes to the
plaque (Moreno et al. 2006).
Focality of Lesion Formation
 The spatial heterogeneity of
atherosclerosis has proved challenging to
explain in mechanistic terms.
 the location of sites of lesion predilection
at proximal portions of arteries after
branch points or bifurcations at flow
dividers suggests a hydrodynamic basis for
early lesion development.
Focality of Lesion Formation
 Locally disturbed flow could induce
alterations that promote the steps of early
atherogenesis.
 the laminar flow usually prevails at sites
that do not tend to develop early lesions.
Focality of Lesion Formation
 Theendothelial cell experiences the
laminar shear stress of normal flow and
decreased shear stress of disturbed flow at
predilected sites.
– Superoxide dismutase
– nitric oxide synthase
 vasodilatingactions
 anti-inflammatory action on endothelial cells
Focality of Lesion Formation
 An increased heterogeneity of vasa
vasorum among different vascular beds
may explain the propensity for the
differential expression of atherosclerotic
disease at varied anatomic locations
(Virmani et al. 2005)
Focality of Lesion Formation
 study of vascular developmental biology may aid
atherosclerosis at different rate and in different
ways.
– upper body arteries can recruit smooth muscle from
neurectoderm,
– in the lower body smooth muscle cells derive
principally from mesoderm.
– After injury or transplantation, arteries can repopulate
with smooth muscle cells derived from bone marrow
hypotheses
 the location of sites of lesion predilection
at proximal portions of arteries after
branch points or bifurcations at flow
dividers suggests a hydrodynamic basis for
predilection
 Lowered shear stress induces larger lesions
with a vulnerable plaque phenotype
(Cheng et al. 2006)
 Traditional teaching held that atheroma
formation followed an inexorably
progressive course with age
 Current thinking suggests an alternative
model, a step function rather than a
monotonically upward course of lesion
evolution in time
 each crises might follow an episode of
plaque disruption, with mural thrombosis,
and healing
 This process might be caused by
intraplaque hemorrhage (Moreno et al.
2006).
 Also, Intraplaque vessels suggested to be
fragile
Intraplaque hemorrhage
 It leads to
– Formation of necrotic core with deposition of
free lipid and cholesterol
– Release of hemoglobulin which results in
 Inflammation

 Increased radical oxygen species

Mechanisms of hemorrhage
 rupture of fragile microvessels within
plaques (Braunwald’s heart diseases.
2005)
 Thus in addition to lower shear stress as a
suggested as inducer of plaque
development, intraplaque hemorrhage
suggested to explain pattern of plaque
revolution
Our hypothesis
 Intraplaquehemorrhage might be caused
by microfracture of intimal layer
Definition of fatigue
 Inmaterials science, fatigue is the progressive
and localized structural damage that occurs
when a material is subjected to cyclic loading
(Braithwaite F. 1854).
Fatigue fracture
 Fracture of an
Aluminium.
 Dark area: slow
crack growth.
 Bright area: sudden
fracture (Schutz W.
1996).
Fatigue fracture
 Micrographs
showing how surface
fatigue cracks grow
as material is further
cycled (Ewing and
Humfrey. 1903)
Fatigue characteristics
 The maximum stress values are less than
the ultimate tensile stress limit, and may be
below the yield stress limit of the material
 Fatigue life is considered number of cycles
before material failure (it breaks)
factors affecting the fatigue life
 Magnitude of stress
 Number of stress cycles
 Residual stress
 Quality of the surface
 Material type
 Surface defect geometry
 Grain size
 Environmental conditions
 Temperature
Fatigue life
 In physics, to
predict fatigue
life of each
material these
factors should be
considered
 Inbiologic systems, tissues turn over
continuously
 For example
– Callus formation in response to fatigue
fracture
 There are cycles of fracture and repair
 Fatigue fracture of ulna
 Microcracks induced
by fatigue loading
 Left ulna: only
microcracks were
found 1 day after
fatigue loading
 Right ulna: besides
microcracks, woven
bone (W) on the
periosteal surface (Li
et al. 2005)
references
1. Libby P, Aikawa M, Schonhod. U. Cholesterol and
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2. Gimbrone MA Jr. Nagol T. Topper IN: Biomechanical
activation: An ",merging paradigm in endotholial
adhesion hiology. J Clln Invest 100:SfH. 1997.
3. Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK,
Tulenko TN, Wrenn SP, Narula J. Atherosclerotic Plaque
Progression and Vulnerability to Rupture: Angiogenesis
as a Source of Intraplaque Hemorrhage Arterioscler
Thromb Vasc Biol. 2005;25(10):2054-2061.
4. Moreno PR, Purushothaman KR, Sirol M, Levy AP,
Fuster V. Neovascularization in Human Atherosclerosis.
Circulation. 2006;113:2245-2252.
references
 Li J, Miller MA, Hutchins GD, Burr DB.
Imaging bone microdamage in vivo with
positron emission tomography. Bone.
2005;37:819–824.
 Braithwaite F. On the fatigue and consequent
fracture of metals. Institution of Civil
Engineers, Minutes of Proceedings. 1854;463–
474.
 Schutz W. A history of fatigue. Engineering
Fracture Mechanics. 1996;54: 263-300.
references
 Cheng C, Tempel D, Haperen RV, Baan A,
Grosveld F, Daemen MJAP, Krams R, Crom R.
Atherosclerotic Lesion Size and Vulnerability
Are Determined by Patterns of Fluid Shear
Stress. Circulation. 2006;113:2744-2753.
 Zipes DP, Libby P, Bonow RO, Braunwald E.
Braunwald’s heart disease: A textbook of
cardiovascular medicine. 7th edition. Elsevier
Saunders publishing. 2005.