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Coronary artery disease

Coronary artery disease (CAD) occurs when the arteries


that supply blood to the heart muscle (the coronary
arteries) become hardened and narrowed.
The arteries harden and narrow due to buildup of a
material called plaque on their inner walls. The buildup of
plaque is known as atherosclerosis.
As the plaque increases in size, the insides of the coronary
arteries get narrower and less blood flows through them.
Eventually, blood flow to the heart muscle is reduced, and,
because blood carries much-needed oxygen, the heart
muscle is not able to receive the amount of oxygen it
needs.

Developmental process of atherosclerosis

Reduced or cutoff blood flow and oxygen supply to


the heart muscle can result in:
Angina Angina is chest pain or discomfort that
occurs when the heart does not get enough blood.
Heart attack. A heart attack happens when a
blood clot develops at the site of plaque in a
coronary artery and suddenly cuts off most or all
blood supply to that part of the heart muscle. Cells
in the heart muscle begin to die if they do not
receive enough oxygen-rich blood. This can cause
permanent damage to the heart muscle.

Angina

When severely affected by atherosclerosis, the flow of blood through


the aorta can be hindered and oxygen deficiency (ischemia) or
gangrene can develop.
Atherosclerosis is also the primary underlying cause of heart attacks,
strokes, arrhythmias and aortic aneurysms, which are blood-filled
dilations of the vessel wall. The rupture of an aneurysm can be deadly
due to the hemorrhaging it causes.
Atherosclerosis is generally thought to result from the gradual build-up
of cholesterol, fibrin, fatty materials, calcium, and other substances
inside the arteries, where they form plaques.
Many scientists believe that these plaques develop at sites of arterial
injuries related to high blood pressure, smoking, diabetes, and other
known atherosclerosis risk factors.

Coronary artery disease (CAD) is caused by arteriosclerosis (the


thickening and hardening and loss of elasticity of the inside walls of
arteries).
Arteriosclerosis can be catagorized into three patterns based on
pathophysiology and clinical and pathological consequences.
1. Atherosclerosis: The most important and frequent pattern
characterized by intimal lesions called atheromas, or atheromatous or
fibrofatty plaques.
2. Monckeberg medial calcific sclerosis : Characterized by palpable
calcific deposits in muscular arteries but do not encroach on the vessel
lumen. Seen in persons above age 50.
3. Arteriosclerosis: affects small arteries and arterioles. Two anatomic
variants: a) hyaline and b)hyperplastic, both associated with thickening
of vessel walls with luminal narrowing that may cause downstream
ischemic injury. Often associated with hypertension and diabetes
mellitus.

This is a normal coronary artery with


no atherosclerosis and a widely
patent lumen that can carry as much
blood as the myocardium requires.

.The degree of atherosclerosis is much


greater in this coronary artery, and
the lumen is narrowed by half. A small
area of calcification is seen in the
plaque at the right

Monckeberg's medial calcific sclerosis, the most insignificant form


of arteriosclerosis (both atherosclerosis and arteriolosclerosis are definitely significant).
Note the purplish blue calcifications in the media; note that the lumen is unaffected by
this process. Thus, there are usually no real clinical consequences.

This is hyperplastic arteriolosclerosis, which most often


appears in the kidney in patients with malignant hypertension.
The arteriolar wall is markedly thickened
and the lumen is narrowed

Atherosclerosis
Atherosclerosis is characterized by intimal lesions
called atheromas, or atheromatous or fribrofatty
plaques, which protrude into and obstruct vascular
lumens and weaken the underlying media.
They may lead to serious complications.
Atherosclerotic lesions are classified into six
types : isolated foam cells(fatty dots), fatty
streaks,
intermediate
lesions,
atheromas,
fibroatheromas and complicated lesions

American Heart Association classification of human athrosclerotic lesions


from the fatty dot (type I) to the complicated type VI lesion.

Fatty streaks earliest lesion of atherosclerosis, composed


of lipid-filled foam cells.Begin as multiple yellow, flat spots
less than 1 mm in diameter that coalesce into elongated
streaks 1cm long or longer.
They contain T lymphocytes and extracellular lipid in
smaller amounts than in plaques.
Fatty streaks appear in aortas of some children below age
1 year and all children older than 10 years.
Coronary fatty streaks begin to form in adolescence and in
anatomic sites prone to develop plaques.
Fatty streaks often occur in areas of the vasculature that
are not susceptible to developing atheromas later in life.
Although fatty streaks may be precursors of plaques, not
all fatty streaks are destined to become fibrous plaques or
more advanced lesions.

Atherosclerotic plaques develop primarily in elastic arteries


(e.g., aorta, carotid and iliac arteries) and large and
medium-sized muscular arteries (e.g., coronary and
popliteal arteries).
Symptomatic atherosclerotic disease most often involves
the arteries supplying the heart, brain, kidneys and lower
extremities.
Consequences : Myocardial infarction (heart attack),
Cerebral infarction (stroke), aortic aneurysms and
peripheral vascular disease (gangrene of the legs). Also
acutely or chronically diminished arterial perfusion, such as
mesenteric occlusion, sudden cardiac death, chronic
ischemic heart disease and ischemic encephalopathy.

Atheroma or atheromatous plaque consists of a raised focal lesion


initiating within the intima, having a soft, yellow grumus core of lipid
(cholesterol and cholesterol esters), covered by a firm, white fibrous
cap.
Also called fibrous, fibrofatty, lipid or fibrolipid plaques, atheromatous
plaques appear white to whitish yellow and impinge on the lumen of
the artery. Size : 0.3 to 1.5cm in diameter but sometimes coalesce to
form larger masses.
Atherosclerotic lesions usually involve only a partial circumference of
the arterial wall (eccentric lesions) and are patchy and variable along
the vessel length.
Distribution of atherosclerotic plaques : in humans, the abdominal
aorta is usually much more involved than the thoracic aorta and lesions
tend to be much more prominent around the origins (ostia) of major
branches.
In descending order (after the lower abdominal aorta),the most heavily
involved vessels are the coronary arteries, the popliteal arteries, the
internal carotid arteries and the vessels of circle of Willis.

In small arteries, atheromas can occlude lumens,


compromise blood flow to distal organs and cause
ischemic injury
Plaques can undergo disruption and precipitate
thrombi that further obstruct blood flow.
In large arteries, plaques encroach on the
subjacent media and weaken the affected vessel
wall, causing aneurysms that may rupture.
Extensive atheromas can be friable and shed
emboli into the distal circulation.

Here is occlusive coronary atherosclerosis. The coronary at the left is narrowed


by 60 to 70%. The coronary at the right is even worse with evidence for previous
thrombosis with organization of the thrombus and recanalization such that there
are three small lumens remaining, one of which contains additional recent thrombus

Atherosclerotic plaques have three principal components :


1) cells, including SMCs, macrophages and other
leukocytes
2) ECM, including collagen, elastic
proteoglycans and

3) intracellular and extracellular lipid.

fibers

and

These components occur in varying proportions and


configurations in different lesions.

Schematic diagram of the mechanism of intimal thickening, emphasizing


smooth muscle cell migration to and proliferation and extracellular matrix
Elaboration in the intima.

The superficial fibrous cap is composed of SMCs and


relatively dense ECM.
Beneath and side to the cap (shoulder) is a cellular area
consisting of macrophages, SMCs and T lymphocytes.
Deep to the fibrous cap is a necrotic core, containing a
disorganized mass of lipid (cholesterol and cholesterol
esters), cholesterol clefts, debris from dead cells, foam
cells, fibrin, variably organized thrombus, and other plasma
proteins.
Foam cells are large, lipid-laden cells that derive from
blood monocytes (tissue macrophages), SMCs also can
imbibe lipid to become foam cells.
Though typical atheromas contain abundant lipid, many socalled fibrous plaques are composed mostly of SMCS and
fibrous tissue.

Plaques generally continue to change and


progressively enlarge through cell death and
degeneration,
synthesis
and
degradation
(remodelling) of ECM, and organization of
thrombus.
Atheromas often undergo calcification.
Patients with advanced coronary calcification
appear to be at increased risk for coronary events .

A. Mild atherosclerosis composed of fibrous plaques, one of which


is denoted by the arrow
B. Severe disease with diffuse and complicated lesions.

Advanced lesions of atherosclerosis :


Focal rupture, ulceration or erosion of the luminal surface
of atheromatous plaques , resulting in exposure of highly
thrombogenic substances that induce thrombus formation
or discharge of debris into the bloodstream, producing
microemboli composed of lesion contents (cholesterol
emboli or atheroemboli).
Superimposed thrombosis, the most feared complication,
usually occurs on disrupted lesions (those with rupture,
ulceration, erosion or hemorrhage) and may partially or
completely occlude the lumen. Thrombi may heal and
become incorporated into and thereby enlarge the intimal
plaque.

A coronary thrombosis is seen microscopically


occluding the remaining small lumen of this
coronary artery. Such an acute coronary thrombosis
is often the antecedent to acute myocardial infarction.

Coronary artery with atherosclerotic plaques. There is recent hemorrhage


into the plaque. This is one of the complications of atherosclerosis. Such
hemorrhage could acutely narrow the lumen and produce an acute coronary
syndrome with ischemia and/or infarction of the myocardium.

Hemorrhage into a plaque, especially in the coronary


arteries, may be initiated by rupture of either the overlying
fibrous cap or the thin walled capillaries that vascularize
the plaque. A contained hematoma may expand the plaque
or induce plaque rupture.

Aneurysmal dilation may result from ATH-induced atrophy


of the underlying media, with loss of elastic tissue, causing
weakness and potential rupture.

This large abdominal atherosclerotic aortic aneurysm below the renal


arteries at the right and above the bifurcation at the left has been opened
to reveal abundant layered mural thrombus within the aneurysm
[Image contributed by Dr. John Nicholls, Hong Kong University].

Epidemiology and Risk factors


Atherosclerosis is ubiquitous among most developed
nations; less prevalent in Central and South America, Africa
and Asia.
The mortality rate for ischemic heart disease (IHD) in the
United States is among the highest in the world and is
approximately five times higher than in Japan.
The prevelance and severity of the disease among
individuals and groups are related to a number of factors,
some constitutional but others acquired and potentially
controllable.
The constitutional factors include age, sex and genetics.

Age : Age is a dominant influence. Death rates from IHD rise with each
decade into advanced age. Atherosclerosis is not clinically evident until
middle age or later, when the arterial lesions precipitate organ injury.
Between ages 40 and 60 the incidence of myocardial infarction increases
five-fold.

Sex : Males are much more prone to atherosclerosis and its consequences
that are females. In postmenopausal women, the incidence of
atherosclerosis-related diseases increases, probably owing to a decrease
in natural estrogen levels. The frequency of myocardial infarction
equalizes that of males by the seventh to eighth decade of life.

Genetics : The genetic propensity relates to familial clustering (polygenic)


of other risk factors such as hypertension or diabetes. Less commonly
involves well-defined hereditary genetic derangements in lipoprotein
metabolism that result in excessively high blood lipid levels, such as
familial hypercholesterolemia.

Other nongenetic risk factors, particularly diet, lifestyle and personal


habits are to a large extent potentially reversible.

The four major risk factors potentially responsive to change are


hyperlipidemia, hypertension, cigarette smoking and diabetes.

Hyperlipidemia
Hyperlipidemia or hypercholesterolemia is a major risk factor for
atherosclerosis. Elevated levels of serum cholesterol are sufficient to
stimulate lesion development, even if other risk factors are absent.
Low-density lipoprotein (LDL) cholesterol presents an increased risk,
and has a physiologic role as a vehicle for the delivery of cholesterol to
peripheral tissue.
High-density cholesterol (HDL) mobilizes cholesterol from developing
and existing atheromas and transport it to the liver for excretion in the
bile. The higher the level of HDL, the lower is the risk. Exercise and
moderate consumption of ethanol both raise the HDL level, whereas
obesity and smoking lower it.
Statins lower circulating cholesterol indirectly by inhibiting HMG CoA
reductase, a key enzyme required for cholesterol biosynthesis in the
liver.

Hypertension
Hypertension is a major risk factor for
atherosclerosis at all ages. Men between ages 45
and 62 whose blood pressure exceeds 169/95 mm
Hg have a more than fivefold greater risk of IHD
than those with BP of 140/90mm Hg or lower.
Antihypertensive therapy reduces the incidence of
atherosclerosis-related
diseases
particularly
strokes and IHD.

Cigarette Smoking
Cigarette smoking is a well-established risk factor in men.
In women it is thought to account for the relatively recent
increase in the incidence and severity of atherosclerosis in
women.
Smoking one or more packs of cigarettes per day for
several years increases the death rate from IHD by upto
200%.
Cessation of
substantially.

smoking

reduces

the

increased

risk

Diabetes Mellitus
Diabetes mellitus induces hypercholesterolemia
and
an
increased
predisposition
to
atherosclerosis.
The incidence of myocardial infarction is twice as
high in diabetics as in nondiabetics.
There is also an increased risk of strokes and
perhaps
a
100-fold
increased
risk
of
atherosclerosis-induced gangrene of the lower
extremities.

Other factors
Persons with homocystinuria (inborn error of metabolism) resulting in
high levels of circulating homocysteine (>100 mol/L) and urinary
homocysteine, have premature vascular disease (peripheral) or
coronary artery disease, stroke or venous thrombosis.
Hyperhomocystinemia can be caused by low folate and vitamin B
intake, hence folate and vitamin B6 ingestion may reduce the incidence
of cardiovascular disease.
Several markers of hemostatic and thrombotic function and
inflammation are potent predictors of risk for major atherosclerotic
events, including myocardial infarction and stroke. Such markers
include those related to fibrinolysis (e.g., elevated plasminogen
activator inhibitor-1) and inflammation (e.g., C-reactive protein)
Coronary and cerebrovascular disease have a corelation with
increased blood levels of Lp(a) lipoprotein (an altered form of LDL that
contains the apolipoprotein B-100 portion of the LDL linked to
apolipoprotein A.

Factors associated with a less pronounced risk include


lack of exercise; competitive, stressful life style with type
A personality behaviour; and unrestrained weight gain
(because obesity induces hypertension, diabetes,
hypertriglyceridemia and decreased HDL).
Multiple risk factors may have a multiplicative effect; two
major risk factors increase the risk approximately fourfold.
When three risk factors are present
hypertension and smoking), the
infarction is increased seven times.

(e.g.,
rate

hyperlipidemia,
of myocardial

However, atherosclerosis and its consequences may


develop in the absence of any apparent risk factors also.

Pathogenesis

Two hypotheses for atherogenesis were dominent


a) cellular proliferation in the intima
b) organization and repititive growth of thrombi lead to
atherosclerosis.

A new concept called the response to injury hypothesis,


considers atherosclerosis to be a chronic inflammatory
response of the arterial wall initiated by injury to
endothelium.
Lesion progression is sustained by interaction between
modified lipoproteins, monocyte-derived macrophages, T
lymphocytes and the normal cellular constituents of the
arterial wall.

Response to injury Hypothesis


Chronic endothelial injury with resultant endothelial dysfunction,
yielding increased permeability, leukocyte adhesion and thrombotic
potential.
Accumulation of lipoprtoteins, mainly LDL, with its high cholesterol
content in the vessel wall.
Modification of lesional lipoproteins by oxidation
Adhesion of blood monocytes and other leukocytes to the endothelium,
followed by their migration into the intima and their transformation into
macrophages and foam cells.
Adhesion of platelets
Release of factors from activated platelets, macrophages or vascular
cells that cause migration of SMCs from media into the intima.
Proliferation of smooth muscle cells in the intima and elaboration of
extracellular matrix, leading to the accumulation of collagen and
proteoglycans.
Enhanced accumulation of lipids both within cells (macrophages and
SMCs) and extracellularly.

The Role of Endothelial Injury

Chronic or repetitive endothelial injury is the basis of the response-toinjury hypothesis.

Early human lesions begin at sites of morphologically intact endothelium


or endothelial dysfunction causing increased endothelial permeability,
enhanced leukocyte adhesion and alterations in expression of
endothelial cell gene products.

Potential causes of endothelial dysfunction include circulating


derivatives of cigarette smoke, homocysteine, viruses and other
infectious agents, inflammatory cytokines such as tumor necrosis factor
(TNF) and some hemodynamic disturbances that accompany normal
circulatory function and adverse effects of hypercholesterolemia.

Areas of disturbed, turbulent flow and low shear stress such as ostia of
the vessels arising from the aorta, branch points and along the posterior
wall of the abdominal aorta, are prone to atherosclerosis.

Steady laminar flow protects against atherosclerosis and induction of socalled atheroprotective genes in areas of laminar flow could explain the
nonrandom localization of early atherosclerotic lesions.

The Role of Inflammation


Inflammatory mechanisms mediate initiation, progression
and the complications of atherosclerotic lesions.
In early atherogenesis, arterial endothelial cells begin to
express on their surface, selective adhesion molecules
such as vascular cell adhesion molecule-1 (VCAM-1), that
bind various classes of leucocytes such as monocytes and
T lymphocytes
After monocytes adhere to the endothelium, they
1) migrate between ECs to localize in the intima,
largely stimulated by chemokines; and
2) transform into macrophages and engulf lipoproteins,
largely oxidized LDL.

The Role of Inflammation


Although recruitment of monocytes and their subsequent
differentiation into macrophages and ultimately into foam cells is
initially protective as they remove potentially harmful lipid
particles, progressive accumulation
results in lesion
progression.
Macrophages produce chemokines like monocyte chemotactic
protein-1 (MCP-1), IL-! And TNF which increase adhesion of
leucocytes and recruit more leucocytes into the plaque.
Macrophages produce toxic oxygen species that also cause
oxidation of the LDL in the lesions and they elaborate growth
factors that may contribute to SMC proliferation.
Cross-talk between macrophages and T cells (CD4+ and CD8+),
results in cellular and humoral immune activation characteristic
of a chronic inflammatory state.

The Role of Inflammation


T cells encounter signals that cause them to
elaborate inflammatory cytokines, such as IFN-
and lymphotoxin, which in turn can stimulate
macrophages as well as vascular endothelial cells
and SMCs.
The activated leucocytes and intrinsic arterial cells
can release fibrogenic mediators, including a
variety of peptide growth factors that can promote
replication of SMCs and contribute to elaboration
by these cells of a dense extracellular matrix
characteristic
of
the
more
advanced
atherosclerotic lesion.

The Role of Lipids


Various classes of blood lipids are transported as
lipoproteins complexed to specific apoproteins.
Dyslipoproteinemias result from either mutations that yield
defective apolipoproteins or some other disorders such as
the nephrotic syndrome, alcoholism, hypothyroidism or
diabetes mellitus.
Lipoprotein abnormalities: 1) increased LDL cholesterol
levels, 2) decreased HDL cholesterol levels and 3)
increased levels of the abnormal lipoprotein Lp(a).
The major lipids in atheromatous plaques are plasma
derived cholesterol and cholesterol esters.
Oxidized LDL is observed in macrophages in arteries at
sites of fatty streaks.

The Role of Lipids


Genetic
defects
in
lipoprotein
metabolism
causing
hyperlipoproteinemia
are
associated
with
accelerated
atherosclerosis.
Other genetic or acquired disorders (e.g. diabetes mellitus,
hypothyroidism) that cause hypercholesterolemia lead to
premature and severe atherosclerosis.
The severity of atherosclerosis can be corelated to the levels of
total plasma cholesterol or LDL cholesterol.
Experimental animals fed high-cholesterol
atherosclerosis-like vascular lesions.

diets

develop

Lowering levels of serum cholesterol by diet or drugs slows the


rate of progression of atherosclerosis, causes regression of
some plaques and reduces the risk of cardiovascular events.

The Role of Lipids


The mechanisms by which hyperlipidemia contributes to
atherogenesis:
Chronic hyperlipidimia, hypercholesterolemia may directly impair
EC function through increased production of oxygen free radicals
that deactivate No, the major endothelial-relaxing factor.
With chronic hyperlipidemia, lipoproteins accumulate within the
intima at sites of increased endothelial permeability.
Chemical change of lipid induced by free radicals generated in
macrophages or ECs in the arterial wall yields oxidized LDL.
Oxidized LDL :
1) is ingested by macrophages through the scavenger receptor,
distinct from the LDL receptor, thus forming foam cells;
2) increases monocyte accumulation in lesions;
3) stimulates release of growth factors and cytokines; and
4) is cytotoxic to ECs and SMCs.

The Role of Smooth Muscle Cells


SMCs migrate from the media to the intima, where they
proliferate and deposit ECM components, converting a fatty
streak into a mature fibrofatty atheroma and contribute to
the progressive growth of atherosclerotic lesions.
Growth factors implicated in the proliferation of SMCs
include PDGF, FGF and TGF-.
SMCs may also take up modified lipids, contributing to
foam cell formation.
Vascular SMCs synthesize extracellular matrix molecules
(collagen and proteoglycans) that stabilize atherosclerotic
plaques.

Other Factors in Atherogenesis


Oligoclonality of Lesions:
The monoclonal hypothesis of atherogenesis
(1977) proposes that some human plaques are
monoclonal or oligoclonal.
Atherosclerotic plaques could arise in a preexisting clonal patch present even in normal artery.
Infection : Infections of Chlamydia pneumoniae
and
cytomegalovirus
may
contribute
to
atherosclerosis.

The risk factors for atherosclerosis are diagrammed here in relation to the
mechanisms that favor development of arterial atheroma formation.

Clinicopathologic Effects of
Atherosclerotic CAD
The complications of atherosclerotic CAD occur through
impaired coronary perfusion relative to myocardial demand
(myocardial ischemia).
The vascular changes that may cause ischemia in the
heart and other organs involve a complex dynamic
interaction among fixed atherosclerotic narrowing of the
epicardial coronaty arteries, intraluminal thrombosis
overlying a disrupted atherosclerotic plaque, platelet
aggregation and vasospasm.

Prevention
The impact of atherosclerosis and the consequences can
be reduced by :
Primary prevention programs, aimed at either delaying
atheroma formation or causing regression of established
lesions in persons who have never suffered a serious
complication of atherosclerotic CAD.
Secondary prevention programs intended to prevent
recurrence of events such as myocardial infarction in
patients with symptomatic disease.
Risk-factor modification: abstention from of cessation of
cigarette smoking, control of hypertension, weight
reduction and increased exercise, modification of alcohol
consumption and lowering total and LDL cholesterol levels
while increasing HDL.

Coronary artery balloon angioplasty - series: Procedure,


part 1

Coronary artery balloon angioplasty - series: Procedure,


part 2

Coronary artery balloon angioplasty series: Procedure, part 3

Coronary artery balloon angioplasty - series:


Procedure, part 4

Coronary artery balloon angioplasty - series:


Procedure, part 5