Atherosclerosis: Practical Implications for Pathologists
Section 2 -
Atherosclerosis - Its Pathogenesis
This 60- year-old (12.12.42) male was admitted for elective repair of a stenosed
and incompetent aortic valve. Of note, he had grade 2 LV function and mitral regurgitation. He was not
a diabetic, but was moderately obese with mild hypertension. He underwent aortic valve replacement with
a porcine aortic valve. Post operatively he came off the cardio-pulmonary bypass easily. However,
approximately 24 hours post operative, it became difficult to maintain his blood pressure. He died soon
Case 1: Major Autopsy findings: Cardiomegaly
2.Satatus post aortotomy and aortic valve repair
- Coronary arteries-mild to moderate disease,
- Proximal LAD; Moderate disease with inflamed plaque
- acute plaque disruption intraplaque hemorrhage and
A: atherosclerosis of aorta, moderate in thoracic aorta and severe in abdominal
The Native Artery:
All arteries are relatively simple structures morphologically. They are comprised of three layers:
the tunica intima, which forms the barrier between the artery wall and the circulating blood. The media,
which is a multilayered zone comprised of a thick layer of smooth muscle and variable amounts of elastic
tissue. The tunica adventitia comprised largely of connective and elastic tissue, which blends into the
surrounding connective tissue of adjacent structures and organs and has blood vessels and nerve fibers in
and around it.
The Endothelial Cell
The endothelial cell is a spindly, elongated cell, specialized to provide a non-thrombogenic barrier
and control blood artery permeability. The borders of these cells, between adjacent endothelial cells,
have junctional complexes with specialized structure that increase the mechanical strength and control
macromolecule permeability. Endothelial cells lining the arteries, veins, capillaries and the heart,
comprise a continuous monolayer of polygonal cells, which fit tightly into each other through these
Functions (See Table 1):
- Controls blood -
- Controls vascular tone and
regulates the vascular surface properties with regard to hemostasis
- Regulates vascular surface reaction to inflammation
Endothelial Permeability :
This is delicately controlled and is dependent on the size and the physical chemical properties of
molecules. Uncharged, small molecules such as oxygen diffuse without much restriction, across the
endothelium, moving along the concentration gradient from blood to the subendothelial space. Other small
molecules such as glucose exhibit little restriction against diffusion across the endothelium. This is
the process by which the supply of oxygen and nutrients occurs.
In contrast, macromolecules can penetrate only to a limited extent, dependent on their size. Small
proteins can pass through the interendothelial clefts while large proteins and particles can only reach
the subendothelial space through endocytotic vesicles. Lipoproteins are one particle that penetrates the
endothelium in this manner. They play a major role in the initiation of atherosclerosis.
On a superficial basis, it is the contraction of the smooth muscle cells in the tunica media that
controls the degree of contraction of the vessel and hence maintains its tone. However, it is the
endothelial cell, which controls smooth muscle contractility by releasing vasoactive mediators. The most
characterized of these mediators is nitrous oxide (NO). This is an inert, inorganic gas that is
produced from L-arginine, by an endothelial enzyme - nitric oxide synthase. This mechanism and its
modulation are key factors in our understanding of vascular tone, as well as the treatment of clinical
problems associated with vascular tone. NO production is increased when the intracellular calcium level
is raised in the endothelial cells, possibly as a result of acetylcholine, bradykinin and other
circulating mediators. NO activates an enzymatic cascade in smooth muscle cells. This leads to a
tendency for relaxation and reduced vascular tone. Other vasoactive factors can counteract or balance
this effect, and these include the vasoactive vasoconstrictor peptide Endothelin-1. This is expressed as
a large pre proendothelin polypeptide by the endothelial cell and proteolytically processes generate
active endothelium-1 during the endothelial activation. Similarly, angiotensin 2 also acts on smooth
muscle cells and the intimal contact. Normally present as a circulating angiotensinogen, it is processed
into angiotensin 2 by endothelial cells.
Amongst other functions performed by endothelial cells are:
Hemostasis : a role in inflammatory processes and the setting of the
vascular tone. For these, the endothelial surface, has a set of factors which allow platelet adhesion or
control platelet adhesion, coagulation and fibrinolysis, the Von Willebrand factor, surface active
platelet adhesion molecules, coagulation regulating factors such as thrombomodulin and fibrinolysis
regulating factors such as plasminogen activators (tissue and urokinase types), as well as plasmogenic
activator inhibitor. Several of these are stored in intracellular organelles such as Weibel-Palade
bodies, which discharge their contents to the cell surface, when thrombin or other similar mediators
activate the cell.
Endothelial cells control or participate in the inflammatory process by expressing leukocyte adhesion
molecules such as E-selectin and the intercellular adhesion molecule-1 (otherwise known as ICAM-1),
chemokines that promote leukocyte recruitment (MCP-1 and interleukin 8) in cytokines that activate immune
cells such as interleukin-1.
The vascular media is comprised largely of smooth muscle cells with an elastic tissue layer between
adjacent rows of smooth muscle cells. Smooth muscle cells are arranged circumferentially in the vessel
wall. The innermost layer of elastic tissue is more compact - the internal elastic lamina. Similarly,
the outermost layer of elastic tissues is also compact - the external elastic lamina. The amount of
elastic tissue present between smooth muscle fibers varies according to the size of the vessel. In large
elastic arteries such as the aorta, twenty to fifty such lamellae of elastic tissue may be present in the
media. In smaller arteries, the organization is not as developed and the amount of elastic tissue is
correspondingly less, generally being seen as small strips of elastic tissue rather than circumferential
layers of elastic tissue.
The adventitia and its connective tissue are continuous with the external elastic lamina on the inner
surface and the surrounding stromal connective tissue on its outer aspect. Its inner part is therefore
fibrous and comprised of compact collagen and elastic tissue, which gradually becomes more loosely
arranged as the distance from the media increases. The adventitia contains fibroblasts, mast cells,
adipocytes and nerve endings (predominantly sympathetic). Blood and lymph vessels are present and these
can penetrate the outer third of the media.
Smooth Muscle Cells
These are by far the commonest of cells in the vessel wall, especially the artery, and comprise 95% or
more of all cells. Like muscle cells everywhere they contain actin and myosin filaments. However, the
contractile apparatus is less developed than that of striated muscle and the vascular smooth muscle cell
is especially primitive and has a capacity to change its tone, as well as the ability to transform itself
into a fibroblast-like cell, which produces large amounts of extracellular matrix in the vessel wall.
Smooth muscle cells are also believed to be the produces of the elastic tissue, seen as elastic lamellae
in the arterial wall.
In the adult artery, smooth muscle cells are almost all seen in the medial layer and are packed
against each other by junctional complexes which include tight and gap junctions, which allow for rapid
transfer of signaling molecules between the cells. A direct result of the ability of vascular smooth
muscle cells to contract is the ability to permit and regulate fluctuation of blood pressure and also to
regulate perfusion of organs.
Regulation of Smooth Muscle Tone :
There are several mechanisms, which regulate smooth muscle tone.
Local regulation: Endothelium is the local regulator of smooth muscle tone
and its function is critical (discussed above under the Endothelial cell and Nitric Oxide).
The surrounding tissues metabolites, autonomic nerves, control by sympathetic nerve endings and the
circulating mediators control smooth muscle tone. All of these stimulate and fine tune regulation of
vascular tone. Smooth muscle cells can produce a matrix comprised of two types of fibers: elastic
fibers and collagen fibers, along with a ground substance containing a loose network of proteoglycans.
Elastic fibers are important for the functional, mechanical properties of the vessel wall, while the
collagen is secreted by smooth muscle cells in the intima and to a lesser extent in the media.
Smooth muscle as well as endothelial cells are normally quiescent cells that do not divide. Vascular
injury however provides the stimulus for proliferation and results in medial smooth muscle cells dividing
and migrating into the intima, where they divide again to give rise to a focal intimal thickening. This
activation of smooth muscle and endothelial cells are controlled by growth factors initiated by the basic
isoform of fibroblast growth factor (B-FGF), released from the extracellular stores in the tissue.
Subsequent migration and ongoing proliferation of smooth muscle cells depends on stimulation by platelet
derived growth factor (PDGF), released when activated platelets adhere to the vascular surface from
infiltrating monocytes and at certain stages from vascular endothelial and smooth muscle cells
Other cells in the vessel wall:
Macrophages form a small but significant part of the cell population seen in a normal artery. At the
same time, mast cells may also be seen in the connective tissue surrounding the vessel wall and in the
adventitia. They are derived from blood monocytes and enter by interacting with the leukocyte adhesion
molecules on the endothelium. They are localized in the intima and the adventitia.
Lymphocytes are also seen in the artery though much less commonly than macrophages. T-cells may be
seen in the intima or the adventitia and B-cells are confined largely to the adventitia. Periarterial
lymph nodes are normally present along the aorta and its major branches. Their function is to allow
immune activation by circulating antigens that penetrate the vessels wall, which are then transported to
the local lymph nodes (lymphatics in the arterial wall). Adipocytes may be found, generally, in the
adventitia and in the surrounding loose connective tissue.
Pathogenesis of Atherosclerosis :
Atherosclerotic lesions have been recognized for over 150 years. It was first recognized by the
German pathologist, Rudolf Virchow who in 1856 proposed that atherosclerosis was caused by plasma
components (lipids), which elicited an inflammatory response in the arterial wall. Soon after, another
pathologist, Von Rokitanksy suggested that atherosclerotic lesions were formed by organization of
thrombi, on the intimal surface of arteries. Anitschkow in St. Petersburg noted the presence of large
lipid deposits in atherosclerotic plaques and speculated that these might be the cause of
atherosclerosis. He tested this hypothesis by feeding rabbits cholesterol, which lead to the
atherosclerotic lesions, which were similar to those seen in humans. A few years later Starokadomaskij
and Sobolev, showed that mechanical injury to the aorta also leads to intimal lesions, which resemble
Florey and others tied many of these observations together into one theory by showing that a
deendothelializing injury increased the accumulation of lipid and macrophages in the artery. 
More specific hypothesis, which explains the pathogenesis of atherosclerosis, followed from Ross and his
group in 1974. He proposed that arterial injury leads to release of EDGF and other factors from
platelets and other cells, initiating a proliferative reaction in smooth muscle cells and leading
ultimately to atherosclerotic lesions. 
Brown and Goldstein  discovered LDL
receptors and mechanisms of cholesterol metabolism. Their findings allowed the "cholesterol hypothesis"
to be tested. They showed clearly that in humans, as well as in experimental models a direct correlation
existed between serum cholesterol (especially LDL cholesterol) and the extent of atherosclerosis.
The new genetic models of disease based on changes in lipid metabolism in mice with knock out genes
have permitted a more detailed dissection of the steps of pathogenesis and allowed a marked increase in
our understanding of atherosclerosis, in these past few years .
The first detectable changes in the experimental animal, subject to proatherogenic stimuli such as
hypercholesterolemia, is the appearance of blood derived lipids in the subendothelial intima and the
expression of leukocyte adhesion molecules on the endothelial surface. The over abundant LDL is trapped
in the extracellular matrix. Matrix proteoglycans have an infinity for LDL, which leads to their binding
of LDL to the matrix and the accumulation of a lipid pool. Here, LDL undergoes a series of
modifications, which include aggregation, oxidation, and degradation of LDL components. (Remaining
question: Antioxidants, which protect the LDL from oxidation in the blood, are unable to prevent the
same process in the intima. Why?) Some of the modified lipids released by the oxidation of the LDL can
act as signaling molecules, which activate endothelial and smooth muscle cells. This leads to expression
of leukocyte adhesion molecules, vascular cell adhesion molecule-1, a receptor for monocytes and
T-cells. Such cells express factors (counter-receptors - VLA4), which can ligate VCAM-1. Amongst other
things, surface adhesions molecules, VCAM-1, ligation leads to the aggregation of monocytes and T-cells
to the endothelial surface at sites of lipid accumulation.
The Role of Inflammation:
Inflammation is now recognized as being pivotal in the pathogenesis of atherosclerosis. The key
concepts in appreciating the role of inflammation in the initiation, progression and complications of
atherosclerosis are as follows :
The normal endothelial cell has a broad spectrum of functions and these include anti-inflammatory,
anti-thrombotic and vasodilator properties, which maintain blood, flow and at the same time prevent
thrombus formation as well as the entry of leukocytes. These properties can be lost, and Pro atherogenic
factors occur and these result in endothelial cell dysfunction. Nitric oxide availability can be reduced
and this leads to and that the impaired vasodilatation. At the same time it permits the activation of
proinflammatory transcription factors which lead to increased expression of cell adhesion molecules,
cytokines and chemokines. All of these facilitate attachment of leukocytes to the endothelial cell and
their transmigration into the extracellular matrix. Changes in endothelial cell vasodilator properties
appear to precede other structural changes of atherosclerosis and may be a useful clinical marker of
The recruitment of leukocytes is a multi step process , and
monocytes /macrophages, T cells, and dendritic cells and mast cells are also recruited into the
The integrity of the fibrous plaque of the atherosclerotic lesion is essential for plaque stability.
Its formation and maintenance of this endothelial cell covered fibrous plaque, is most likely a smooth
muscle cell driven process for enhancing plaque stability. The macrophage tissue factor, the von
Willebrand factor and the subendothelial collagen are all highly thrombogenic and their exposure to
circulating blood can trigger the coagulation cascade as well as platelet aggregation, leading very
rapidly to arterial thrombosis, characteristic of the acute current syndromes.
What triggers the inflammatory cascade and the initiation as well as
progression of atherosclerosis, is to not really clear. Current evidence does suggest that the
established risk factors for atherosclerosis as well as the new risk factors such as infectious agents,
likely play a role. The implicated infectious agents include Chlamydia pneumoniae. The obvious question
about the role of antibiotics and secondary prevention strategies was reviewed by several
studies/authors. While initial study suggested that antibiotics played a beneficial role in acute
coronary syndromes, later and larger studies have not borne this out
Clinical implications: The substantial progress and the understanding and
appreciation of the inflammatory component of vascular disease, does help to understand some of the
clinical benefits of contemporary therapy. The H M G. Co A inhibitors (statins) were believed to play
their beneficial role through the lowering of cholesterol. However, there is evidence now to show that
this benefit is also likely related to their anti-inflammatory and anti- thrombotic actions. These
latter may stabilize plaques. Other significantly beneficial new drugs may also have a similar basis.
The increasing availability of plasma inflammatory cell markers, such as CRP, appear to be able to
predict the risk of future cardiovascular events in patients with established coronary artery disease and
also in the" apparently healthy "population ).
a) Chemotactic cytokines are produced by macrophages, endothelial cells, as well as smooth muscle
cells and when inducted, appear to lead to the accumulation of lipid and the oxidation of lipid.
(Question: How? The mechanism by which this occurs is not yet understood).
It is likely that there are other substances, which can stimulate endothelial cell activation and
allow leukocyte recruitment to the intima. Heat shock protein expressed during cell injury may have the
(Question: Interesting observation: Immunization with this heat shock protein substantially
In the intima, monocytes differentiate into macrophages, a process promoted by M-CSF (cytokine
monocyte colony stimulating factor).
Histopathology of Atherosclerosis: Pathogenesis
Foam Cells: The macrophage is a key cell in the formation of
atherosclerotic plaques. This is based largely on its ability to engulf and store lipoproteins (oxidized
lipoproteins), which accumulate and transform the appearance of the cell into that of a foam cell, when
stained with hematoxylin and eosin. This cell is accepted as being prototypic of atherosclerosis. It is
essential to keep in mind that macrophages cannot take up any significant amount of native LDL, but can
take up large amounts of oxidized LDL, by a mechanism of specialized cell surface receptors. The
mechanism by which the oxidized LDL is converted to cholesterol esters which form the droplets in the
"foam" cells or macrophage, is as follows: cholesterol esters present in the oxidized LDL are hydrolyzed
and free cholesterol escapes into the cytoplasm. This, in the cytoplasm, is re-esterified by cytosolic
enzymes, creating a pool of cholesterol esters, whichform intracellular droplets. These continue to
accumulate in the cytoplasm and give the macrophage the appearance of the "lipid-choked" foam cell.
Fatty streaks are essentially an accumulation of foam cells along with some T-cells and
extracellular cholesterol (predominantly lipoproteins) with an overlying intact endothelium. In addition
to oxidized LDL, which acts as an antigen for immune mediated interactions in the forming atherosclerotic
lesion, other antigens have also been proposed. They include heat shock protein 60, chlamydia
pneumoniae, cytomegalovirus and herpes simplex type I.
A number of immune cytokines and effector mechanisms have been postulated as playing arole in the
activation of macrophages, endothelial cells, smooth muscle cells and also likely that they inhibit
inflammation and promote fibrosis.
The Atherosclerotic Plaque
The fatty streak is by itself of no clinical importance. Many of these fatty streaks, which develop
around vascular branch or bifurcation points, in fact disappear spontaneously. Others progress to larger
and more complex lesions. The fatty streaks that persist, progress to fibrofatty plaque. They typically
occur at sites of hemodynamic turbulence and strain.
In these lesions, smooth muscle cells from the media have been activated and multiply and migrate to
the subendothelial space, where they divide and synthesize extracellular matrix. The net result of this
is a fibrous cap, which separates the lipid filled core from the endothelial surface. The stimuli that
promote smooth muscle cell migration and multiplication have been mentioned previously. Some theories
postulate that since these lesions occur in localized areas, there must be focal / local factors in the
artery wall, which activate smooth muscle cells. Some of these factors have been mentioned already and
it is established that basic fibroblast growth factor (BFGF) and PDGF promote proliferation and migration
of arterial smooth muscle cells in-vivo. PDGF released by endothelial cells can be increased by
turbulence through a sheer stress response element in the PDGF promoter  Platelets and
macrophages can also release growth factors.
In summary it is said that the mechanism of transition from the fatty streak to fibrous plaque may be
a hemodynamic stress or inflammatory activation which causes release of PDGF from platelets and / or
macrophages, which in turn stimulate smooth muscle cell migration, proliferation and the deposition of
the fibrous cap. The net result of this is a progressive increase in plaque size and corresponding
decrease in arterial lumen.
It is essential to remember that vascular remodeling is an ongoing process. As the plaque grows, the
vessel wall undergoes remodeling and the media shows areas of thinning, so that the resultant narrowing
of the lumen of the vessel is not in keeping with the increasing plaque size. The lumen is initially
preserved by compensatory dilatation of the vessel and outward remodeling. However, at some stage the
compensating mechanisms no longer help preserve vessel size and the plaque protrudes into the lumen and
alters vascular function.
It is accepted that plaque size per se, is not the critical factor in acute coronary syndromes. On
the other hand, acute coronary syndromes are often seen with luminal stenosis of only 30 - 50%.
Progressive decrease in vascular lumen size can lead to clinical syndromes such as angina on exercise or
stress and intermittent claudication. However, even significantly sized or large plaques can be totally
The development of acute coronary syndromes (ACS) or complications generally requires an additional
pathogenic event to occur such as the formation of a thrombus on the plaque or the disruption of a
plaque. Acute coronary syndromes such as myocardial infarction often develop in a plaque, which
undergoes additional pathogenic events such as disruption of the plaque or thrombus formation on the
Question: Why do plaques rupture? Clues supporting the observation that plaque rupture precedes
thrombosis and ACS is the morphological observation that plaque rupture occurs in areas that are rich in
activated macrophages, T-cells and mast cells are common, in the vicinity of the rupture.
Once the components of blood are exposed to the subendothelium, the platelets are activated and the
cascade of thrombosis begins.
[Question: Is atherosclerosis a degenerative, metabolic, inflammatory, infectious or hemodynamic
Many authors have debated the above issue, whether this is a disease of altered cholesterol
metabolism, an inflammatory disease process with deposition of fibrous tissue or an abnormality of
hemodynamic hemostasis. It is likely that all of these factors played a role, and that the chain of
events, which leads to the full-fledged atherosclerotic lesion likely starts with hypercholesterolemia
and oxidized LDL. The discussion is more or less unending.
Genetic basis of atherosclerosis:
As the preceding discussion shows, atherosclerosis, the primary cause of vascular disease, involves a
number of cell types, organs and several physiological processes. Understandably therefore, its genetic
basis is complex. Rodent model studies using transgenic and gene-targeted mice show that the there are
at least > 100 genes that can influence the development of atherosclerotic lesions.
First described by Carl Miller, over 70 years ago, the most significant genetic trait that affects
atherosclerosis and therefore heart disease is that of Familial Hypercholesterolemia
(FH). They showed that FH results from mutations that destroy the ability of the LDH receptor to
mediate the binding, internalization and degradation of LDH. Since effective treatments for the
heterozygous form of the disease are now available, it would seem to make sense to undertake DNA
screening for the disease. Rapid screening methods for FH are available.
The other relatively common hypercholesterolemia gene is Familial defective apolipoprotein (apo B).
It is the result of mutations of apo B, the major protein of LDL. This prevents it from binding to the
LDL receptor. In contrast to FH, this is a homozygous disorder, and these patients have elevated
cholesterol levels though not as high as in FH.
Many other candidate genes have been studied using transgenic mice and these show that genetic factors
acting on vascular cells and/or blood cells contribute significantly to the susceptibility to
atherosclerosis and CHD. The ongoing genetic studies provide an understanding for new novel diagnostic
techniques and the development of new and novel diagnostic tests for the early diagnosis of
Diabetes mellitus: Patients with diabetes mellitus have a higher incidence
and severity of ischemic heart disease. This leads to increase use all medical resources, chorion tree
interventions including surgery as well as a higher incidence of acute Kari syndromes. The incidence of
diabetes mellitus has reached epidemic proportions, with a prevalence of over 5%, in developed countries
and considerably higher (likely close to 40%) in developing countries such as the South Aisan countries.
The incidence in those over 60 even in developed countries is greater than 20%. The risk of developing
coronary artery disease, in these individuals, is 2 to 6x that in non-diabetics and over 75% of
individuals with diabetes mellitus, die of vascular causes (in comparison to one third of the general
These increased risks are related to specific
risk factors resulting from insulin resistance and hyperinsulinemia that increase the risk of coronary
- Dyslipidemia: Increased LDL and triglyceride rich VLDL and reduced HDL
- Endothelial dysfunction: Increased plasminogen activator (PAI-1) and cellular
- Inflammation: Increased oxidized LDL
- Impaired vasomotor activity
- Abnormalities of coagulation and fibrinolysis
- Glycation of proteins: Formation of pro-atherogenic advanced end products
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