Atherosclerosis PATH 310 by rt3463df


     PATH 310
       Iain Young
    February 02, 2010
    Atherosclerosis: The Scope of the
•    Overwhelmingly most important
     contributor to mortality and morbidity in
     Western world
•    Direct cause of 50% of North American
•    In US, 500,000 die annually of
     myocardial infarction caused by coronary
    Atherosclerosis: Risk Factors
•   Increasing age
•   Male gender
•   Family history
•   Genetic abnormalities
    Atherosclerosis: Risk Factors
    Non-Modifiable              Modifiable
•   Increasing age          •   Cigarette smoking
•   Male gender             •   Hypertension
•   Family history          •   Diabetes mellitus
•   Genetic abnormalities   •   Hyperlipidemia
Atheromatous Plaque: The Basic
   Lesion of Atherosclerosis
Atheromatous Plaque: The Basic
   Lesion of Atherosclerosis
Coronary Atherosclerosis Causes
     Myocardial Infarction
Coronary Atherosclerosis Causes
     Myocardial Infarction
Intracerebral Atherosclerosis
 Causes Cerebral Infarction
Atherosclerosis is a Disease of
 Elastic and Muscular Arteries
       Endothelial Cell Functions

•   Permeability barrier
•   Matrix synthesis (collagen and proteoglycans)
•   Regulation of inflammation
•   Oxidation of lipoproteins
•   Regulation of cell growth
•   Inhibition of coagulation
        Endothelial Activation is a
           Response to Injury
•   Activation: expression of traits not seen
    under homeostatic conditions
•   Hemodynamic stresses and some lipid
    products are important injurious stimuli
•   Endothelial activation includes:
    – Inflammatory cell adhesion molecule
    – Cytokine-mediated cell growth stimulation
    – Increased endothelial permeability
 Smooth Muscle Cell Functions

• Maintain integrity of arterial wall
• Control blood flow by contracting/relaxing
• Synthesize extracellular matrix
    Smooth Muscle Cell Response to
          Endothelial Injury

•   Migration from media to intima
•   Proliferation within intima
•   Extracellular matrix thickening
•   Intimal thickening results
Atheromatous Plaque: The Basic
   Lesion of Atherosclerosis
  Components of the Established
     Atheromatous Plaque

• Cellular component: SMCs and inflammatory
  cells (lymphocytes, macrophages)
• Lipid: intracellular (foam cells) and extracellular
• Extracellular matrix (collagen, proteoglycans)
Components of the Established
   Atheromatous Plaque
Components of the Established
   Atheromatous Plaque
Pathogenesis of Atherosclerosis:
 Response-to-Injury Hypothesis
                •   Endothelial injury is
                    critical initiating
                •   Potential injurious
                    – Hyperlipidemia
                    – Hypertension
                    – Smoking
                    – Hemodynamic
                    – Many others
Pathogenesis of Atherosclerosis:
 Response-to-Injury Hypothesis
                •   Injury causes endo.
                    – Permeability to lipid
                      increases and lipid
                      enters intima
                    – VCAM-1 expression
                    – Monocytes adhere to
                    – Monocytes emigrate
                      into intima to become
Pathogenesis of Atherosclerosis:
 Response-to-Injury Hypothesis
                •   SMC emigration into
                    intima occurs
                •   T-lymphocytes enter
                    intima through
                    VCAM-1 binding
Pathogenesis of Atherosclerosis:
 Response-to-Injury Hypothesis
                •   Macrophages and
                    muscle cells engulf
                    lipid to become foam
                •   Fatty streak, the
                    earliest grossly
                    identifiable lesion,
The Fatty Streak: Postulated Earliest
  Stage of Atherosclerotic Plaque
Pathogenesis of Atherosclerosis:
 Response-to-Injury Hypothesis
                •   Progression to full
                    plaque ensues:
                    – Intimal SMC
                      emigration and
                    – SMC elaborate
                      collagen which forms
                      fibrous cap
                    – Progressive lipid
The Complications and Clinical
  Phase of Atherosclerosis
Vulnerable Atherosclerotic Plaques
Vulnerable Atherosclerotic Plaques
I.        Introduction

Atherosclerosis is a disease of global proportions and a scourge of the industrialized world. It
is the direct cause of about 50% of all deaths in the West and it is the overwhelmingly most
significant contributor to the overall burden of diseases in North America. In the United
States, approximately 500,000 people die annually of heart disease caused by the involvement
of the coronary arteries that serve the heart by atherosclerosis and myocardial infarction (heart
attack), the acute manifestation of coronary atherosclerosis, accounts for 20-25% of all deaths
that occur in the US. Apart from the huge toll in human suffering caused by atherosclerosis,
the financial costs incurred by the health care system in diagnosing, treating and attempting to
prevent the complications of atherosclerosis are staggering.

In this section of the course, you will be introduced to the pathology of the atheromatous
plaque (the fundamental lesion of atherosclerosis), the current understanding of the
pathogenesis of the disease (i.e. how the plaque develops) and the critical role hyperlipidemia
(high blood cholesterol levels) plays in the initiation and progress of the disease. The section
concludes with an illustration of how advances in the technology applicable to the medical
diagnosis of coronary atherosclerosis raise wide-ranging moral, ethical, social and political
I.           The Structure and Function of Arteries

1.            Structure
All arteries in the body have the same basic structural organization and composition. There are three major components of
arterial walls:

1.           endothelial cells
2.           smooth muscle cells
3.           extracellular matrix, a component of connective tissue that includes various macromolecules, notably
collagen, elastin and proteoglycans

Arteries are arranged structurally in three concentric layers, or tunica (Figure 1):

1.            the tunica intima is comprised of a monolayer of endothelium that rests on a very thin layer of connective
2.            the tunica media is comprised of multiple layers of smooth muscle cells and is demarcated on its inner and
outer surfaces by two prominent but discontinuous layers of elastic fibres termed the internal and external elastic laminae,

3.           the tunica adventitia is the outer-most connective tissue layer of the arterial wall.

There is variation in the specific structural features of different arteries in the body, depending on their specific functions.
Arteries are categorized based on their particular characteristics and size, as follows:

1.           elastic arteries (large), such as the aorta
2.           muscular arteries (medium-sized), such as the coronary arteries that serve the heart
3.           small arteries

Different diseases affect the different types of arteries. Atherosclerosis affects both elastic and muscular arteries but it is
through its involvement of muscular arteries that it has its greatest effect on human health.
2.            The Functions of Endothelial and Smooth Muscle Cells
Endothelial cells and smooth muscle cells play dynamic and very important roles in vascular biology and most diseases
that affect arteries result, to at least some degree, from abnormalities of endothelial and/or smooth muscle cell function.

i)           Endothelial Cell Function
Endothelial cells have a very wide range of functions in the normal arterial wall, some of which are as follows:

1.           Permeability barrier – endothelial cells regulate the passage of many substances into the vessel wall.
2.           Synthesis of extracellular matrix, particularly proteoglycans and collagen.
3.           Regulation of inflammation – endothelial cells produce numerous molecules that regulate the process of
inflammation including the synthesis of cell-surface molecules that render the endothelial cell adhesive to inflammatory
4.           Oxidation of low-density lipoproteins.
5.           Regulation of cell growth – endothelial cells can produce molecules that stimulate the migration of smooth
muscle cells from the media into the intima and their proliferation once they arrive.
6.           Thromboresistance – through the production of molecules that inhibit coagulation (the formation of thrombi,
or blood clots) and promote fibrinolysis (blood clot digestion), endothelial cells prevent the formation of thrombi.

Normal endothelial cells react to injurious stimuli by expressing traits that they do not express under normal, homeostatic
conditions. The stimuli that can induce this state of “endothelial activation” are numerous but those that are critically
relevant to the development of atherosclerosis include hemodynamic stresses and some lipid products. Many genes are
induced during this state of endothelial activation and include adhesion molecules for inflammatory cells, molecules that
regulate blood coagulation and a variety of cytokines that stimulate cell growth and affect the functions of smooth muscle
cells and inflammatory cells as well as endothelial cells, themselves. For example, endothelial activation is often
associated with an increase in endothelial permeability.
ii)       Smooth Muscle Cell Function
The principal functions of the smooth muscle cell of the normal arterial media are to
maintain the integrity of the vessel wall in the face of high-pressure pulsatile blood flow
and to contract and relax in order to constrict and dilate the artery and thereby control blood
flow. Smooth muscle cells also produce extracellular matrix macromolecules.

In response to an injury to, or prolonged dysfunction of, the endothelium, smooth muscle
cells migrate from the media into the intima, proliferate and synthesize extracellular matrix
as part of a normal repair reaction (Figure 2). This repair reaction, which is seen during the
process of atherosclerosis, leads to thickening of the intima (intimal hyperplasia).

Figure 2. Diagram of the process of intimal thickening following endothelial/intimal injury
II.            The Atheromatous Plaque: Its Composition and Complications

Atherosclerosis is a disease that develops in the intima of elastic and muscular arteries. The essential lesion of atherosclerosis is the atheromatous
plaque, also called an atheroma or fibrofatty plaque. As these plaques enlarge, they impinge on the arterial lumen and gradually obstruct blood
flow. Although the slowly progressive reduction of blood flow to various organs such as the heart, brain and kidneys may have significant effects
on their function that manifest as clinical disease, it is the secondary complications that occur in atherosclerotic plaques that cause the major
manifestations of atherosclerosis: myocardial infarction (“heart attack”) and cerebral infarction (“stroke”).

There are three major components of fully established atherosclerotic plaques:

1.             The cellular component – includes smooth muscle cells and inflammatory cells such as lymphocytes and macrophages.
2.             The lipid component – both intracellular (in “foam cells”) and extracellular.
3.             The extracellular matrix component.

The plaque (Figure 3) is formed by a tough superficial fibrous cap of extracellular matrix and smooth muscle cells that overlies a soft central core
of intracellular and extracellular lipid (mostly cholesterol and cholesterol esters). On the margins of the fibrous cap, there is a more cellular area,
termed the “shoulder”, that contains several cell types including the inflammatory cells lymphocytes and macrophages.

The structure of atherosclerotic plaques is variable as the proportions of the individual constituents may differ between individual plaques. For
example, some atherosclerotic plaques contain very little lipid, being comprised predominantly of dense extracellular matrix and smooth muscle
cells; these are called “fibrous plaques”.

The advanced atherosclerotic plaque that contains a significant core of lipid is prone to several complications including rupture or fissuring of its
endothelial surface and hemorrhage (bleeding) into the plaque core. Such destabilizing complications often expose the deeper, markedly
thrombogenic (i.e. blood clot-inducing) substances of the inner plaque to the circulating blood. If thrombosis occurs and a blood clot forms, it
may rapidly enlarge to completely occlude the artery. It is this catastrophic sudden total obstruction to arterial blood flow that causes most cases
of myocardial infarction. Some plaques are more predisposed to destabilization (so-called vulnerable plaques) and factors that may increase the
probability of their rupture include the extent of inflammation in the plaque, large size of the lipid core and a thin fibrous cap. Fibrous plaques,
however, have very little, if any, propensity to suffer these complications.
III.           The Pathogenesis of Atherosclerosis

Atherosclerosis is now widely considered to be a consequence of a chronic inflammatory reaction of the arterial wall that is provoked by injury to
endothelial cells. In this response-to-injury hypothesis, the phases of development of an atherosclerotic plaque are conceptualized as follows
(Figure 4):

1.               Endothelial Cell Injury
Central to the response-to-injury hypothesis is the notion that injury to endothelial cells is the critical initiating event. Numerous potential
injurious factors have been identified or postulated but two of likely major significance are hemodynamic factors and hyperlipidemia (high blood
levels of lipids, particularly cholesterol).

Atherosclerotic plaques tend to develop at points in arteries that are normally subjected to turbulent flow whereas those parts of arteries that
experience smooth (laminar) flow are relatively protected.

2.              Endothelial Cell Dysfunction: The Initial Response to Injury
As a consequence of the injury they sustain, endothelial cells become activated and express characteristics not seen in the normal non-injured
state. The permeability of the endothelium increases, facilitating the entry of circulating lipids (primarily low density lipoproteins that contain
abundant cholesterol) into the intima. The endothelial cells begin to express vascular cell adhesion molecule-1 (VCAM-1), a cell surface
adhesion molecule that is specific for circulating monocytes. Monocytes then adhere to the endothelium and pass between endothelial cells to
enter the intima, where they transform into macrophages. The macrophages engulf the lipid (primarily oxidized low density lipoproteins that are
injurious to endothelial and smooth muscle cells) accumulating in the intima, thereby becoming foam cells (so-called because the cytoplasm of
the cells contains so much lipid that it appears “foamy” by microscopy). T-lymphocytes also enter the intima through their binding to VCAM-1.

At this point in the evolution of the atherosclerotic plaque, the postulated earliest lesion of atherosclerosis, the fatty streak, becomes
apparent in the artery. The fatty streak is small (~1-10 mm) and composed of collections of lipid-laden macrophages (foam cells), a
few T-lymphocytes and small amounts of extracellular lipid. Fatty streaks begin to form in coronary arteries during adolescence in
North Americans. Not all fatty streaks become fully established atherosclerotic plaques and it appears likely that some fatty streaks
regress. Nonetheless, some fatty streaks likely progress to become atherosclerotic plaques.

3.            Progression to Atherosclerotic Plaque
Medial smooth muscle cells are induced to migrate into the intima, where they then proliferate and synthesize and deposit
extracellular matrix proteins, most significant among which is the tough, fibrous protein, collagen. This process contributes to the
gradual enlargement and stabilization of the plaque. With the concomitant ongoing and progressive accumulation of lipid, these
processes eventuate in an established fibrofatty atheromatous plaque.
4.          The Clinical Phase
With progressive encroachment on the lumen
of the artery, an atherosclerotic plaque will
cause a gradual and eventually significant
reduction in blood flow that can compromise
organ function. However, as mentioned above,
it is the complications of plaque rupture, fissure
and hemorrhage that may cause the rapid
development of a superimposed thrombus that
can suddenly occlude an artery and stop blood
flow completely. If this occurs in a coronary
artery then a myocardial infarction (heart
attack) occurs. There is currently no way to
determine whether the atherosclerotic plaques
in a given individual are vulnerable to, or likely
to develop, the potentially catastrophic
complications of disruption and thrombosis.

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