• CARDIOVASCULAR DISEASES

• ATHEROSCLEROSIS
• by Vl. Danev, MD
• ATHEROSCLEROSIS
• is a degenerative disease of large and medium-sized arteries, characterized by lipid
deposition and fibrosis of the intima. It leads to narrowing of the arteries that is
why atherosclerosis is the main cause of ischemic heart disease and
cerebrovascular disease and the major primary cause of death in most developed
countries.
• Arteriosclerosis
Is a nonspecific term that denotes thickening and loss of elasticity ("hardening") of the
arteries from any cause.
Changes associated with aging and hypertension often lead to arteriosclerosis.
• Arteriosclerosis
Three patterns are recognized, with different clinical and pathologic consequences:
• Arteriolosclerosis
• Mönckeberg medial calcific sclerosis
• Atherosclerosis
• Arteriolosclerosis
• Is caused by plasma imbibition of arterioles which leads to hyalinosis in arterial
hypertension & diabetes mellitus or to hyperplastic arteriolosclerosis with onion
skinning & stenosis of arterioles in arterial hypertension.
• Mönckeberg Medial Calcific Sclerosis
• Is characterized by calcific deposits in muscular arteries in persons older than age
50.
• The radiographically visible, often palpable calcifications, do not encroach on the
vessel lumen and are usually not clinically significant .
• Epidemiology
• Atherosclerosis is the main cause of ischemic heart disease and cerebrovascular
disease, and it is the major primary cause of death in most industrialized countries.
• In North America and Europe, some degree of atherosclerosis is almost invariably
present in the aorta and muscular arteries after age of 30 years.
• The incidence and severity are generally less in South America, Africa, and Asia ,
that is in the underdeveloped countries.
• Etiology
• Atherosclerosis has no single cause. It is a polyetiologic disease. Many factors
increase the risk of atherosclerosis. They are classified into major (uncontrollable &
controllable) and minor ones.
• Major Uncontrollable
Risk Factors
Are:
• Increasing age;
• Male gender;
• Genetic predisposition
Age is a dominant influence. The disease may begin as early as fetal life, with the
formation of intimal cell masses, or perhaps shortly after birth, when fatty
streaks begin to evolve. However, the characteristic lesion, which is not initially
clinically significant, requires as long as 20 to 30 years to form.
• Major Uncontrollable
Risk Factors
• Increasing age: significant disease is rare under 30 years. Death rates from
IHD rise with each decade even into advanced age.
• Males are affected more than females; female incidence increases after
menopause; sex incidence is equal after age of 65 years.

• Major Uncontrollable
Risk Factors
3. Genetic predisposition involves well-defined derangements in lipoprotein metabolism,
such as familial hypercholesterolemia, that results in excessively high blood lipid
levels.
• Major Controllable
Risk Factors
Are:
• Hyperlipidemia;
• Arterial hypertension;
• Cigarette smoking;
• Diabetes mellitus
• Minor Risk Factors
Are as follows:
• Physical inactivity;
• Stress (“type A” personality);
• Obesity;
• Oral contraceptives;
• Gout;
• High carbohydrate intake.
• Hyperlipidemia
• Is the strongest risk factor for atherosclerosis in patients under the age
of 45.
• Both primary and secondary hyperlipidemias increase the risk.
• Lipoproteins associated with endogenous lipid metabolism such as low-density
lipoprotein (LDL) and intermediate-density lipoprotein (IDL) are much greater risk
factors than chylomicrons associated with exogenous lipid metabolism.
• Apoproteins
• Are proteins that are associated with lipid to form lipoproteins and are genetically
determined. Different apoprotein types are associated with different lipoproteins.
In addition to being structural components of the lipoprotein molecule, apoproteins
function (1) as ligands that interact with cell receptors which bind lipoproteins, and
(2) as cofactors of enzymes of lipid metabolism.
• Increased Levels
• Of the following components of plasma lipids have been identified as
associated with increased risk:
• Total serum cholesterol
• Low density lipoprotein cholesterol
• Total plasma triglyceride
• Plasma lipoprotein A
Decrease of high density lipoprotein cholesterol plays pro-atherosclerotic role
• Saturated Fats Have Pro-atherogenic Effect (Margarine) While
Polyunsaturated Omega-3 From See Food Play A Protective Role.
• Low Density Lipoprotein Cholesterol (LDL-C)
• Levels are greatly elevated in familial hypercholesterolemia, which is caused
by a mutation in the gene coding the LDL receptor on the cell surface.
• Lack (in homozygotes) or decrease (in heterozygotes) of LDL-C receptor leads to
failure of clearing of plasma LDL-C by cells and an increase in plasma LDL-C.
• There is also an increased production of LDL in these patients, due to failure of
metabolism of intermediate density lipoproteins (IDL) by the liver.
liver.
• Low Density Lipoprotein Cholesterol (LDL-C)
• As LDL accumulates in the plasma, it is taken up by tissues that do not depend on
the presence of LDL receptors-macrophages (resulting in xanthomas in the skin
and connective tissues) and probably the arterial intima.
• Homozygotes have extremely high LDL-C levels and develop severe atherosclerotic
disease in their teens.
• Heterozygotes are common (1:500 people in the population), have a twofold to
threefold elevation of plasma cholesterol, and develop premature atherosclerosis.
• Heterozygous familial hypercholesterolemia is found in 3-6% of survivors of
myocardial infarction.
•
High Density Lipoprotein Cholesterol (HDL-C)

• The risk of atherosclerosis bears an inverse relationship to plasma level of

cholesterol associated with HDL-C.
• Low HDL-C levels occur more commonly in (1) males, (2) cigarette smokers, (3)
diabetics, (4) inactive people who do not exercise regularly, and (5) patients with
high triglyceride levels.
• High Density Lipoprotein Cholesterol (HDL-C)
• Regular exercise and a small daily intake of alcohol have been shown to increase
plasma HDL-C levels.
• High-density lipoproteins are believed to remove cholesterol liberated from cell
turnover. It is possible that HDL also removes cholesterol from atheromatous
plaques as part of this function, explaining its protective effect in atherosclerosis.
• Patients who have high-risk lipid levels should be treated to reduce these levels
because reduction has a protective effect and may even cause some regression of
atherosclerosis.
• Patients with borderline levels should be treated if they have two or more of the
highly significant risk factors other than hyperlipidemia.
 • Arterial Hypertension
• Is the most important risk factor in people over 45 years of age . Ischemic
heart disease is five times more common in an individual whose blood pressure is
> 160/95 mm Hg than one who is normotensive (blood pressure < 140/90 mm
Hg). The risk is diminished when blood pressure is controlled with drugs.

• Arterial Hypertension
• Hemodynamic stress is thought to play an important role in endothelial damage.
• Physical shear injuries are maximal at sites of arterial branching, which are the
sites most involved in atherosclerosis, and hypertension would aggravate these
injuries.
• Cigarette Smoking
• People who smoke more than 10 cigarettes a day have a threefold increase in risk.
The risk declines to normal 1 year after cessation of smoking. The association of
smoking with atherosclerosis is thought to be related to the presence of factors
such as carbon monoxide that may cause endothelial cell injury.
• Diabetes Mellitus
• All diabetics who have had the disease for more than 10 years are likely to have
significant atherosclerosis. Part of the risk in diabetes is due to the coexistence of
other risk factors such as obesity, hypertension, and hyperlipidemia.
• Other Suggested Reasons For Increased Risk In Diabetes Mellitus
• Increased glycosylation of collagen, which increases LDL binding to collagen in
atheromatous lesions; and
• The fact that glycosylated HDL is more easily degraded that normal HDL.
Since the latter two mechanisms are dependent on glycosylation, which is dependent
on elevated blood glucose, it may explain how rigid control of diabetes can
reduce the risk of atherosclerosis.
atherosclerosis.

• Pathogenesis
• Now the dominant theory of the pathogenesis of atherosclerosis is Reaction To
Endothelial Injury. It bridges the conceptions of XIX century concerning:
• The primary role of arterial thrombosis (Thrombus Encrustation Theory of K.
Rokitansky) &
• Changes in the vessel wall permeability (Imbibition Hypothesis of R . Virchow)
• Thrombus Encrustation Theory
• According to that theory, the primary event is thrombosis.
• The thrombus becomes incorporated into the intima and then undergoes lipid
degeneration to initiate the lesion.
• Thrombosis is now thought not to be the initial event, but it probably plays a role
in the development and enlargement of the lesion. Lipoprotein promotes
development of atherosclerosis by virtue of its inhibition of plasminogen activity,
which suggests that removal of fibrin is important in preventing progression of the
atheromatous lesion.
• Reaction To Endothelial Injury
• The primary event of atherosclerosis according to this theory is endothelial
injury/dysfunction.
• Non-denuding endothelial injury may be caused by many factors:
• There may be a toxic effect of hypercholesterolemia itself.
• Exogenous toxins such as carbon monoxide are present in the serum of cigarette
smokers.
• Homocysteine-induced end. inj. is responsible for the premature Ath. seen in
homocystinuria (rare autosomal recessive disease caused by mutations in the gene
encoding cystathionine synthetase ).

• Physical shear injuries are maximal at sites of arterial branching, which are the
sites most involved in atherosclerosis, and hypertension would aggravate these
injuries.
• Reaction To Endothelial Injury
• Non-denuding endothelial injury is believed to lead to adherence of blood
monocytes, which are activated, imbibe LDL and actively enter the intima, and
become macrophages.
• Active macrophages release free radicals that oxidize LDL.

• Reaction To Endothelial Injury

• Oxidized LDL is toxic to endothelium, causing endothelial loss and exposure of
subendothelial connective tissue to blood components.
• This leads to platelet adhesion and aggregation and to fibrin deposition, forming
microthrombi.
• Platelets release various factors - one of which has been identified as being
mitogenic - causing migration of smooth muscle into the intima and proliferation
therein.

• The activated macrophages and smooth muscle cells secrete numerous cytokines
that can be found in the early lesion. These include platelet-derived growth factor
(PDGF), tumor necrosis factor (TNF), fibroblast growth factor (FGF), and
interleukin-1, some of which may also have mitogenic capability.

• The smooth muscle cells, macrophages, and matrix accumulate LDL from the
plasma, a process that is enhanced by the presence of increased LDL in the blood.
• Smooth muscle cells and endothelial cells have LDL receptors on their surfaces,
and macrophages are capable of taking up LDL - facts that would explain the high
association of LDL with lesions.
• This sets up a cycle of changes that involves macrophage activation, LDL oxidation,
and endothelial damage that cause progression of the atheromatous lesion.
• Infectious
Infectious Hypothesis
• Seroepidemiologic studies have suggested that some infectious agents may
contribute to atherosclerosis.
• Chlamydia pneumoniae and cytomegalovirus have been the most studied, and
there is also interest in Helicobacter pylori, herpesvirus, and other organisms.
 • Monoclonal Hypothesis
• The smooth muscle cell proliferation in the lesion was shown, at least in some
cases, to be monoclonal.
• This suggested that mitogen-induced smooth muscle proliferation was the primary
event.
• This is unlikely, as it has been shown that monoclonality of the smooth muscle cells
is not a constant feature.
• However, mitogen-induced smooth muscle proliferation is still thought to be
important in the development of the lesion.

• Immunologic theory is based on the involvement of immunocompetent cells &

immune complexes in the atherosclerotic plaque.
• Receptor theory explains quite good hereditary forms of atherosclerosis connecting
them with primary & alimentary hyperlipidemias.
• Neuro-metabolic theory puts first repeated stress situations. Psychological
overstraining interferes with lipid metabolism causing vasomotor disturbances.
Consecutive hyperlipidemia combined with hypercholesterolemia and vasomotor
reactions damages primarily the endothelium.
• Pathology
• The lesions of atherosclerosis are the fatty streak, the fibrous atheromatous
plaque, and the complicated lesion. The latter two are responsible for clinically
significant disease.
• Fatty streaks are thin, flat yellow non-protruding streaks in the intima. They consist
of macrophages and smooth muscle cells whose cytoplasm has become distended
with lipid to form foam cells.
• Fatty Streaks

• Fatty streaks occur maximally around the aortic valve ring and thoracic aorta.
• They are present very early in life, often in the first year, and are seen all over the
world irrespective of sex, race, or environment.
• They increase in number until about age 20 years and then remain static or
decrease.
• There is controversy about whether some fatty streaks progress into fibrous
atheromatous plaques or whether they are independent of atherosclerosis.
• Fatty Streaks
• The Fibrous Atheromatous Plaque
• This is the basic lesion of clinical atherosclerosis.
• It consists of three zones:
• A fibrous cap under the endothelium, consisting of dense collagen and scattered
smooth muscle cells and macrophages;
• The lipid zone, which consists of foam cells (lipid-laden macrophages and
smooth muscle cells) and extracellular lipid and debris; and
• The basal zone, composed of proliferated smooth muscle cells and connective
tissue.
• The Fibrous Atheromatous Plaque
 • The Fibrous Atheromatous Plaque
• Different plaques contain varying amounts of these three layers; some are mainly
fibrous, and others predominantly fatty.
• The fibrous atheromatous plaque appears grossly as a yellow-white elevation on
the intimal surface of the artery.
• The Fibrous Atheromatous Plaque
• When cut across, the center of the plaque consists of semisolid yellow material (Gk
athera = "porridge").
• Microscopically, the three zones are recognizable and are of varying thickness in
different plaques.
• Needle-shaped cholesterol crystals are commonly present in the lipid zone.
• The Fibrous Atheromatous Plaque

• Fibrous atheromatous plaque are present in the aorta in most cases, with maximal
change most commonly in the abdominal aorta.

• Involvement of muscular arteries such as the coronary, carotid, vertebrobasilar,

mesenteric, renal, and iliofemoral arteries is associated with luminal stenosis.
• This is common and is responsible for many of the clinical manifestations of
atherosclerosis.
• Plaques tend to be most prominent at points of branching of the major arteries.
• In severe disease, plaques become confluent, involving much of the intimal
surface.
• The Complicated Plaque
Complications are presented by:
• Thrombosis
• Dystrophic calcification
• Ulceration
• Vascularization
• Hemorrhage
• Thrombosis
• Is the most important complication of atherosclerosis, since it may cause complete
occlusion of the artery. Thrombosis is caused by (1) slowing and turbulence of
blood in the artery in the region of the plaque and (2) ulceration of the plaque.
• Dystrophic Calcification
• Is very common and occurs in the lipid zone of the plaque.
• Severely affected vessels (including the aorta)
may become converted to calcific tubes.
• Ulceration
• Of the endothelium overlying the plaque may cause the lipid contents of the
plaque to be discharged into the circulation as cholesterol emboli.
• Ulceration of the plaque may also precipitate arterial thrombosis at the site.
• Vascularization & Hemorrhage
• Vascularization of the plaque occurs by ingrowth of poorly supported vessels
from the medial aspect.
• These may rupture, leading to hemorrhage into the plaque, which may then
expand sufficiently to occlude the lumen of the artery.
• Hemorrhage may also cause ulceration and thrombosis.
• Clinical Features
• Narrowing of Affected Arteries

• Embolism

• Aneurysm
• Narrowing of Affected Arteries
• Ischemia from arterial narrowing is responsible for most of the clinical effects of
atherosclerosis.
• A decrease in blood flow usually occurs only with severe (> 75%) narrowing of the
vessel.
• Aortic narrowing is almost never sufficient to cause symptoms.
• However, narrowing of coronary, cerebral, renal, mesenteric, and iliofemoral
vessels often causes ischemic changes in the organs and tissues supplied.
• Superimposed thrombotic occlusion of these arteries may cause infarction.
• Embolism
• Ulceration of the atheromatous plaque may result in embolization of the lipid
contents of the plaque.
• This is important in the cerebral circulation, where small emboli produce transient
ischemic attacks.
• Emboli can sometimes be visualized in the retinal arteries on funduscopic
examination.
• Aneurysm
• In severe atherosclerotic involvement of the aorta, the wall may be weakened to
an extent that leads to dilation or aneurysm formation.
• Atherosclerotic aneurysms occur mainly in the lower abdominal aorta and may
appear as a fusiform dilation of the whole vessel circumference or a saccular bulge
on one side of it.
• Clinico-morpholgic Forms Of Atherosclerosis
• Atherosclerosis of the aorta
• Ischemic Heart Disease
• Cerebro-Vascular Disease
• Atherosclerosis of the renal arteries
• Atherosclerosis of the mesenterial arteries
• Atherosclerosis of the arteries of low extremities

• Atherosclerosis Of The Aorta

Is frequently complicated by
• Thromboses
• Thromboembolism &
• Embolization of the lipid contents of the plaque
• They cause acute absolute ischemia – kidney & gut infarctions or gangrene of
lower extremities
• Atherosclerosis Of The Aorta
• Is heaviest in the abdominal aorta where ath. plaques cause pressure atrophy of
the tunica media which leads to dilation or aneurysm formation.
• Aneurysms can appear as a fusiform dilation of the whole vessel circumference or
a saccular bulge on one side of it.
• Aortic Aneurism
• Ischemic Heart Disease
• Cerebro-Vascular Disease
• Liquefaction Necrosis Of The Brain
• Atherosclerosis Of The Renal Arteries
• Atherosclerosis Of The Mesenterial Arteries: arterial stenosis causes pain but occlusive
thrombosis results in hemorrhagic gut infarction
• Atherosclerosis Of The Arteries Of Low Extremities
• Femoral artery is most commonly affected. Its well developed collaterals
compensate blood supply in the long run.
• The increase of stenosis leads to claudicatio intermittens.
• Occlusive thrombosis of femoral artery results in dry gangrene.
• Can We Reach The Americans?
• The incidence of deaths due to atherosclerosis increased in the USA until the mid
1960s, when it leveled off and began to decline.
• By 1986, death rates from atherosclerotic coronary and cerebral arterial disease
had decreased over 50% when compared with death rates in 1968.
• The cause of this trend is is probably related to changes in diet and exercise habits
and better control of hypertension.
• The Glimmer Of Hope
• Prevention of atherosclerosis through changes of life habits & nutrition.
• Improvements in the treatment of Ischemic Heart Disease.
• Protection of the victims of atherosclerotic complications from newer attacks of
the disease.