Atherosclerosis: disease of large and medium-sized arteries characterized by endothelial

dysfunction, vascular inflammation and accumulation of lipids, cholesterol, calcium and cellular
debris within the intima of the vessel wall.
Inflammatory activation of vascular cells
In contrast to the homeostasis that exists between the endothelium and smooth muscle cells
(SMCs) of healthy vessels, inflammatory activation of vascular cells in diseased vessels corrupts
their normal functions and favours processes that contribute to the atherosclerotic plaque
development.
Table 1. Consequences of inflammatory activation in vascular cells
Endothelial cells Smooth muscle cells
 Disrupted permeability barrier
 Increased production of inflammatory cytokines
(e.g. IL-1, TNF-α) – increases permeability
 Increased production of leukocyte adhesion
molecules (e.g. VCAM-1, ICAM-1, E-selectin, P-
selectin) – recruits more immune cells
 Decreased production of vasodilatory molecules
(e.g. NO, prostacyclins)
 Decreased production of antithrombotic molecules
(e.g. NO, prostacyclins)
 Increased production of
inflammatory cytokines (e.g.
IL-1, TNF-α)
 Increased extracellular matrix
synthesis
 Increased migration and
proliferation into subintima
Stages of plaque development
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1. Fatty streak
 Earliest visible lesions that appear as areas of yellow discoloration on artery’s inner
surface; blood flow is not yet impeded at this stage
 Central to this process is endothelial dysfunction, which allows entry and modification
of lipids in the vessel subintima; these lipids then serve as pro-inflammatory mediators
that initiate leukocyte recruitment and foam cell formation
Endothelial dysfunction
 Triggered by injury to the arterial endothelium
o Exposure to physical forces, e.g. shear stress
o Chemical irritants and toxins
 Increased production of reactive oxygen species (ROS) in cigarette
smoking, elevated circulating low density lipoprotein (LDL) levels and
diabetes
 Resulting activated state (Table 1) sets the stage for subsequent development of
atherosclerosis
Lipoprotein entry and modification
 Accumulation of lipoprotein particles in the intima
o Increased endothelial permeability allows for entry of LDL into the vessel intima
o LDL binds to proteoglycans in the extracellular matrix and becomes trapped
 Chemical modification of lipoproteins
o Oxidation – by local ROS derived from endothelial cells or macrophages that
penetrate the vessel wall
o Glycation – in diabetic patients with sustained hyperglycemia
 Modified LDL has antigenic and pro-inflammatory properties and contributes to
leukocyte recruitment and foam cell formation
Leukocyte recruitment
 Modified LDL induces local pro-inflammatory cytokine elaboration (e.g. IL-1, TNF-α)
by endothelial and SMCs
 Cytokines promote increased expression of:
o Adhesion molecules (e.g. VCAM-1, ICAM-1, E-selectin, P-selectin) – bind
leukocytes
o Chemoattractant molecules (e.g. MCP-1, IL-8) – direct leukocyte migration into
the vessel intima
 Monocytes, and to a lesser extent T lymphocytes, are attracted to the vessel wall
Foam cell formation
 Upon entering the intima, monocytes differentiate into phagocytic macrophages and
upregulate their expression of scavenger receptors in response to local macrophage
colony-stimulating factor (M-CSF)
 Scavenger receptors mediate the uptake of modified LDL into macrophages
 Macrophages develop into foam cells which produce additional cytokines that perpetuate
the process of atherosclerotic plaque formation
2. Plaque progression
 Thickening of the intima due to migration of SMCs from the media to the intima,
proliferation of SMCs and extracellular matrix production
o Foam cells, activated platelets and endothelial cells release cytokines and growth
factors (e.g. TNF-α, IL-1, FGF, TGF-β) that stimulate SMC migration and
proliferation
o SMC activation and cytokine release reinforces and maintains inflammation in the
lesion
 Fatty streak evolves into a fibrofatty lesion
 Calcification can occur at later stages and fibrosis continues
 Apoptosis of SMCs yields a relatively acellular fibrous capsule that surrounds a lipid-rich
core
 Late plaque growth can significantly restrict the vessel lumen and impede perfusion
o Flow-limiting plaques can lead to tissue ischemia and cause symptoms such as
angina pectoris or claudication
3. Plaque disruption
 Fibrous cap integrity depends on net extracellular matrix metabolism
o SMCs synthesize constituents of the fibrous cap such as collagen and elastin
o Foam cells synthesize proteolytic enzymes including collagen-degrading matrix
metalloproteinases
 Over time hemodynamic stresses and degradation of extracellular matrix increase the risk
of fibrous cap rupture
 While plaques with thicker fibrous caps tend to cause more pronounced arterial
narrowing, they have less propensity to rupture (stable plaques); conversely, thinner less
obstructive plaques tend to be more fragile and rupture (vulnerable plaques)
 When the fibrous cap ruptures, pro-thrombotic molecules within the lipid core are
exposed and can sometimes, but not necessarily, precipitate formation of an acute
thrombus which occludes the arterial lumen
o This is the underlying mechanism in most acute coronary syndrome
Risk factors for atherosclerosis
Modifiable risk factors
 Dyslipidemia (elevated LDL, decreased HDL)
o Excess LDL accumulates in the intima and undergoes modifications that initiate
and perpetuate the development of atherosclerotic lesions
 Tobacco smoking
o Enhances oxidative modification of LDL, contributes to endothelial dysfunction
via oxidant stress and increases expression of leukocyte adhesion molecules,
among other factors
 Hypertension
o Increases permeability of vessel wall to lipoproteins and promotes retention of
LDL in the vessel intima by accentuating production of LDL-binding
proteoglycans by SMCs
 Diabetes mellitus
o Enhances glycation of LDL and is associated with endothelial dysfunction
 Obesity and lack of physical activity
o Contribute to dyslipidemia, hypertension and insulin resistance
Non-modifiable risk factors
 Advanced age
 Male gender
o Lack of atheroprotective properties of estrogen which raises HDL and lowers
LDL
 Heredity – history of coronary artery disease (CAD) among first-degree relatives at a
young age (before 55 for males and before 65 for females)
Biological markers
 Homocysteine
o High levels may promote oxidative stress, vascular inflammation and platelet
adhesiveness
 Lipoprotein particle Lp(a)
o Detrimental effect may be attributed to competition with normal plasminogen
activity
 C-reactive protein and other markers of inflammation
o Activates complement and contributes to a sustained inflammatory state
Complications of atherosclerotic plaques
 Calcification – makes vessel more rigid and increases its fragility
o Myocardial ischemia, peripheral artery disease, renal artery stenosis
 Rupture – plaque rupture exposes pro-coagulant molecules within the plaque to
circulating blood and can potentially lead to formation of a thrombus and infarction of the
supplied tissue
o Unstable angina, myocardial infarction, thrombotic stroke
 Hemorrhage – an intramural hematoma can form secondary to plaque rupture
o Myocardial infarction, thrombotic stroke
 Embolization – disrupted fragments from the atherosclerotic plaque can embolize to
distal vascular sites
o Embolic stroke
 Aneurysm – the fibrous plaque increases pressure in the vessel media and can provoke
weakening of elastic tissue, with subsequent dilatation of the artery
o Abdominal aortic aneurysm