PATHOGENESIS OF ATHEROSCLEROSIS

Various hypotheses have been proposed for the pathogenesis of atherosclerosis. They are

Encrustation hypothesis
Insudation hypothesis
Monoclonal/ oligoclonal hypothesis
Response to injury hypothesis

Encrustation hypothesis

This was proposed by Rokitansky in 1852
According to this theory thrombus formation is primary event
Thrombus slowly becomes incorporated in the intima and then undergoes lipid degeneration to initiate the lesion

According to the recent concept thrombus formation is not the initial event but plays a role in development and enlargement of the lesion

Insudation hypothesis

This concept was proposed by Virchow in 1856
According to this theory there is proliferation of intimal cells due to insudation of lipids and plasma proteins into the vessel wall. However how lipids enter the vessel wall is not clear

Monoclonal/ oligoclonal hypothesis

According to this hypothesis smooth muscle cell proliferation starts either from a single cell (monoclonal) or from few cells (oligoclonal).
Theory of monoclonality is supported by the evidence that the proliferating smooth muscle cells have one of the two forms of G6PD isoenzyme. Monoclonal proliferation of smooth muscle may be initiated by mutations caused by chemicals like cigarette smoke, endogenous metabolites like lipoproteins and viruses like herpes virus

Response to injury hypothesis

According to this hypothesis atherosclerosis is a chronic inflammatory and healing response of the arterial wall to the endothelial injury
Lesion progresses by interaction of modified lipoproteins, monocyte derived macrophages and T lymphocytes with endothelial cells and smooth muscle cells of the arterial wall

Endothelial injury

Endothelial cell loss and dysfunctional endothelial cells play major role
Intact but dysfunctional endothelial cells exhibit increased endothelial permeability, enhanced leukocyte adhesion and altered gene expression
Two most important causes of endothelial dysfunction are hemodynamic disturbances and hypercholesterolemia
Some of the factors which are contributing to endothelial cell dysfunction are cigarette smoke, homocysteine and even infectious agents and inflammatory cytokines (eg. TNF)

Hemodynamic disturbances

Non-turbulent laminar flow leads to the induction of the endothelial genes whose products (eg. Antioxidant superoxide dismutase ) which actually protect against atherosclerosis
Sites like ostia of exiting vessels, branch points and along the posterior wall of the abdominal aorta have turbulent flow which causes endothelial dysfunction leading to atherosclerosis

Hypercholesterolemia

Chronic hyperlipidemia, particularly hypercholesterolemia can directly impair endothelial function by increasing local reactive oxygen species production.
These oxygen free radicals cause membrane, mitochondrial damage and accelerate nitric oxide decay, damping its vasodilator effect
Endothelial dysfunction causes increased expression of adhesion molecules like
- ICAM 1 – causes adhesion of monocytes
- E- Selectin – causes adhesion of monocytes
- VCAM 1 – Causes adhesion of T lymphocytes and monocytes
With chronic hyperlipidemia, lipoproteins accumulate within the intima, where they aggregate or become oxidized by free radicals produced by inflammatory cells
Such modified LDL is then engulfed by macrophages through a variety of receptors. As these modified lipoproteins cannot be degraded, they accumulate in macrophages forming foam cells
Smooth muscle cells can similarly transform into lipid laden foam cells by ingesting modified lipids through LDL receptor related proteins
Modified lipoproteins are not only toxic to endothelial cells, smooth muscle cells and macrophages but their binding and uptake also stimulates the release of growth factors, cytokines and chemokines that create a vicious cycle of monocyte recruitment and activation

Inflammation

Chronic inflammation contributes to the initiation and progression of atherosclerotic lesions
Inflammation is triggered by accumulation of cholesterol crystals and free fatty acids in macrophages and other cells
These cells sense the presence of abnormal materials via cytosolic innate immune receptors that are the components of inflammasome. Resulting inflammasome activation leads to production of IL-1.
Proinflammatory cytokines IL-1 serves to recruit leukocytes, including monocytes
Activated macrophages produce reactive oxygen species that enhance LDL oxidation and elaborate growth factors that drive smooth muscle cell proliferation
Activated T cells in the growing intimal lesions elaborate inflammatory cytokines (IFN γ) which in turn activates macrophages, endothelial cells and smooth muscle cells and in turn they release growth factors which causes smooth muscle cell proliferation .

Infection

Though Herpes virus, cytomegalovirus, chlamydia pneumoniae are thought to be associated but no established causal role of infection is established

Smooth muscle proliferation and matrix synthesis

Adhesion of platelets and macrophages activates them and they secrete growth factors
Growth factors are also secreted by endothelial cells
Growth factors are
- PDGF (Platelet derived Growth Factors)
- EGF (Epithelial Growth Factors)
- TGF α (Transforming Growth Factor α )
Growth factors lead to smooth muscle migration and proliferation
Smooth muscle cells synthesize collagen, elastin and mucopolysacharides forming extracellular matrix
Intimal smooth muscle proliferation and extracellular matrix deposition convert fatty streak into a mature atheroma and contribute to progressive growth of atherosclerotic lesion

SUMMARY

References

Vinay kumar, Abul K.Abbas, Nelson Fausto, Jon C. Aster. Robbins and Cotran. Pathologic basis of disease. 8th edition.

PATHOGENESIS OF ATHEROSCLEROSIS

Various hypotheses have been proposed for the pathogenesis of atherosclerosis. They are

Encrustation hypothesis

Insudation hypothesis

Monoclonal/ oligoclonal hypothesis

Response to injury hypothesis

Encrustation hypothesis

This was proposed by Rokitansky in 1852

According to this theory thrombus formation is primary event

Thrombus slowly becomes incorporated in the intima and then undergoes lipid degeneration to initiate the lesion

According to the recent concept thrombus formation is not the initial event but plays a role in development and enlargement of the lesion

Insudation hypothesis

This concept was proposed by Virchow in 1856

According to this theory there is proliferation of intimal cells due to insudation of lipids and plasma proteins into the vessel wall. However how lipids enter the vessel wall is not clear

Monoclonal/ oligoclonal hypothesis

According to this hypothesis smooth muscle cell proliferation starts either from a single cell (monoclonal) or from few cells (oligoclonal).

Response to injury hypothesis

According to this hypothesis atherosclerosis is a chronic inflammatory and healing response of the arterial wall to the endothelial injury

Lesion progresses by interaction of modified lipoproteins, monocyte derived macrophages and T lymphocytes with endothelial cells and smooth muscle cells of the arterial wall

Endothelial injury

Endothelial cell loss and dysfunctional endothelial cells play major role

Intact but dysfunctional endothelial cells exhibit increased endothelial permeability, enhanced leukocyte adhesion and altered gene expression

Two most important causes of endothelial dysfunction are hemodynamic disturbances and hypercholesterolemia

Some of the factors which are contributing to endothelial cell dysfunction are cigarette smoke, homocysteine and even infectious agents and inflammatory cytokines (eg. TNF)

Hemodynamic disturbances

Non-turbulent laminar flow leads to the induction of the endothelial genes whose products (eg. Antioxidant superoxide dismutase ) which actually protect against atherosclerosis

Sites like ostia of exiting vessels, branch points and along the posterior wall of the abdominal aorta have turbulent flow which causes endothelial dysfunction leading to atherosclerosis

Hypercholesterolemia

Chronic hyperlipidemia, particularly hypercholesterolemia can directly impair endothelial function by increasing local reactive oxygen species production.

These oxygen free radicals cause membrane, mitochondrial damage and accelerate nitric oxide decay, damping its vasodilator effect

Endothelial dysfunction causes increased expression of adhesion molecules like

ICAM 1 – causes adhesion of monocytes

E- Selectin – causes adhesion of monocytes

VCAM 1 – Causes adhesion of T lymphocytes and monocytes

With chronic hyperlipidemia, lipoproteins accumulate within the intima, where they aggregate or become oxidized by free radicals produced by inflammatory cells

Such modified LDL is then engulfed by macrophages through a variety of receptors. As these modified lipoproteins cannot be degraded, they accumulate in macrophages forming foam cells

Smooth muscle cells can similarly transform into lipid laden foam cells by ingesting modified lipids through LDL receptor related proteins

Modified lipoproteins are not only toxic to endothelial cells, smooth muscle cells and macrophages but their binding and uptake also stimulates the release of growth factors, cytokines and chemokines that create a vicious cycle of monocyte recruitment and activation

Inflammation

Chronic inflammation contributes to the initiation and progression of atherosclerotic lesions

Inflammation is triggered by accumulation of cholesterol crystals and free fatty acids in macrophages and other cells

These cells sense the presence of abnormal materials via cytosolic innate immune receptors that are the components of inflammasome. Resulting inflammasome activation leads to production of IL-1.

Proinflammatory cytokines IL-1 serves to recruit leukocytes, including monocytes

Activated macrophages produce reactive oxygen species that enhance LDL oxidation and elaborate growth factors that drive smooth muscle cell proliferation

Activated T cells in the growing intimal lesions elaborate inflammatory cytokines (IFN γ) which in turn activates macrophages, endothelial cells and smooth muscle cells and in turn they release growth factors which causes smooth muscle cell proliferation .

Infection

Though Herpes virus, cytomegalovirus, chlamydia pneumoniae are thought to be associated but no established causal role of infection is established

Smooth muscle proliferation and matrix synthesis

Adhesion of platelets and macrophages activates them and they secrete growth factors

Growth factors are also secreted by endothelial cells

Growth factors are

PDGF (Platelet derived Growth Factors)

EGF (Epithelial Growth Factors)

TGF α (Transforming Growth Factor α )

Growth factors lead to smooth muscle migration and proliferation

Smooth muscle cells synthesize collagen, elastin and mucopolysacharides forming extracellular matrix

Intimal smooth muscle proliferation and extracellular matrix deposition convert fatty streak into a mature atheroma and contribute to progressive growth of atherosclerotic lesion

References

Vinay kumar, Abul K.Abbas, Nelson Fausto, Jon C. Aster. Robbins and Cotran. Pathologic basis of disease. 8th edition.