At Hero Sclerotic Plaque Development Press

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. 2. 3. 4.

5.

Accumulation of lipoprotein particles in the intima. Oxidative stress and elaboration of local cytokines Recruitment of leukocytes uptake of modified lipoprotein particles by monocytes and promotion of development of foam cells Recruitment of smooth muscle cells into the intima from the media

Evolution of atherosclerotic plaque 1. 2. 3. 4.

Elaboration of extracellular matrix by migrated smooth muscle cells Evolution of fatty streak into the fibrofatty lesion Calcification and fibrosis and apoptosis of smooth muscle cells 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  The

endothelial cell experiences the laminar shear stress of normal flow and decreased shear stress of disturbed flow at predilected sites. – Superoxide dismutase – nitric oxide synthase  vasodilating

actions  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  Intraplaque

hemorrhage might be caused by microfracture of intimal layer

Definition of fatigue  In

materials 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

 In

biologic 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 atherosclerosis. Biochim Biophys Acla 1529:299. 2000 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 

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

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.