Chapter 13

BLOOD VESSELS
Sr. No. TOPIC Page No.
1 Atherosclerosis 2

2 Aneurysm 9

3 Vasculitis 15

4 Important questions 15

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 ATHEROSCLEROSIS

Definition

Atherosclerosis in Greek means “gruel” or “hardening”. It is a disease of large elastic

arteries, and large and medium-sized muscular arteries characterized by intimal lesions
that protrude into vessel lumen. These raised lesions have soft, yellow lipid core (mainly of
cholesterol and cholesterol esters) covered by a white fibrous cap.

Risk factors

NONMODIFIABLE MODIFIABLE ADDITIONAL

Increasing age Dyslipidemia Inflammation (C. Pneumoniae1 is
Male gender Hypertension the most common infective agent)
Family history Cigarette smoking Hyperhomocystinemia
Genetic abnormalities Diabetes Metabolic syndrome
C-reactive protein Lipoprotein (a)
Factors affecting hemostasis
Others:
1. Lack of exercise2
2. Type ‘A’ personality
3. Competitive
4. Obesity

Non-modifiable (constitutional):
Age: Though early lesions may be present from childhood, atherosclerosis and resultant
ischemic heart disease (IHD) clinically manifests in middle age or later.

Gender: Males are more affected, while premenopausal women are relatively protected
from atherosclerosis. The probable cause is the protective effect of estrogen.

Family history: It is the most significant independent risk factor for atherosclerosis.

Genetic abnormalities: Familial hypercholesterolemia is associated with increased risk of

atherosclerosis.

Modifiable:
Dyslipidemia: Virchow, in 19th century was the first to identify cholesterol clefts in
atheromatous plaques. Lipids are insoluble and therefore are carried bound to apoproteins
for transport. Total serum cholesterol reflects the different types of lipoproteins in the
serum. Important lipids and their desirable range are as follows:
Lipoproteins Desirable
Total cholesterol <200 mg/dl
Triglyceride <150 mg/dl
HDL cholesterol 60 mg/dl
LDL cholesterol 60-130 mg/dl
Cholesterol/HDL ratio 4.0
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LDL or “bad” cholesterol is that form of cholesterol, which is delivered to the peripheral
tissues. HDL or “good” cholesterol mobilizes cholesterol from tissue and transports it to the
liver for excretion. High level of LDL is associated with increased risk.

Dietary habits and exercise influence cholesterol levels. High intake of saturated fat, like
egg yolk, animal fat, butter etc. increase total cholesterol. Omega-3 fatty acid (fish oil) and
exercise increases HDL, while obesity and smoking decreases it.

Familial hypercholesterolemia, an autosomal disorder is characterized by increased level of

LDL and normal triglyceride. The disease is associated with xanthomas and premature
coronary artery disease.

Hypertension: increases risk of atherosclerosis by 60%. It causes left ventricular

hypertrophy, which is a predisposing factor for IHD.

Cigarette smoking: Prolonged years of one pack or more of cigarette smoking doubles death
rate from IHD. Cessation of smoking is associated with reduced risk. Smokers have reduced
level of HDL, deranged coagulation system and accumulation of carbon monoxide in the
blood that produces carboxyhemoglobin and eventually hypoxia of arterial wall, favoring
atherosclerosis.

Diabetes Mellitus: induces hypercholesterolemia, increased LDL and reduced HDL,

endothelial dysfunction and increased aggregation of platelets, thereby markedly
increasing risk of atherosclerosis. The risk of atherosclerosis is twice in diabetics than in
non-diabetics.

Inflammation: Inflammation is present in all stages of atherogenesis. C-reactive protein

(CRP) is secreted from inflammatory cells within the atherosclerotic intima. This activates
local endothelial cells, inducing a prothrombotic state; thus, increasing risk of MI, stroke,
peripheral arterial disease and sudden cardiac death.

Hyperhomocystinemia: Elevated homocysteine levels are seen in homocystinuria due to

inborn error of metabolism and folic acid/vitamin B12 deficiency. Elevated homocysteine
levels are strongly associated with coronary artery disease, peripheral vascular disease,
stroke and venous thrombosis.

Metabolic syndrome: It is associated with glucose intolerance, insulin resistance,

dyslipidemia, hypertension and central obesity. Dyslipidemia leads to endothelial cell
dysfunction, predisposing to vascular thrombosis.

Lipoprotein (a): It is an altered form of LDL. Higher levels are associated with increased risk
of coronary and cerebrovascular disease, independent of total cholesterol or LDL levels.

Other factors affecting hemostasis: lack of exercise, competitive, stressful lifestyle (type ‘A’
personality), obesity. Infections like herpesvirus, cytomegalovirus and Chlamydia
pneumonia have been detected in atheromas.
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Pathogenesis

Response to injury hypothesis: This theory incorporates the hypothesis of the older
theories, ‘Lipid’ theory by Virchow and ‘Encrustation (thrombogenic)’ theory by
Rokitansky. It states that atherosclerosis results from a chronic inflammatory3 and healing
response to endothelial injury4.

According to this theory, following pathogenic events produces atherosclerosis:

1. Endothelial injury: causes increased vascular permeability, leukocyte adhesion and
thrombosis. The important causes of endothelial cell dysfunction/injury are
hemodynamic disturbances, hypercholesterolemia, hypertension, toxins from
cigarette smoke, homocysteine and other infectious agents.

Atherosclerotic plaques tend to occur at ostia of exiting vessels, branch points and
along the posterior wall of abdominal aorta, where there are disturbed flow
patterns. Thus, hemodynamic disturbance contributes to endothelial injury.

2. Role of dyslipidemia: Dyslipoproteinemia results from mutation in apoproteins that

carry lipids or mutation of lipoprotein receptor on cells or disorders that affect
circulating lipids like nephrotic syndrome, DM, alcoholism, hypothyroidism.
Dyslipoproteinemia occurs in the form of increased LDL or LDL (a), or decreased
HDL cholesterol. Dyslipidemia initiates endothelial injury.

3. Role of monocytes: Normal vessels do not bind inflammatory cells. Dysfunctional

endothelial cells express vascular cell adhesion molecule 1 (VCAM-1), which bind
monocytes and T-cells. Upon adhesion, the cells migrate into the intima under the
effect of locally produced chemokines.

Monocytes transform into macrophages and engulf lipoproteins. Engulfed oxidized

LDL activates macrophages, which secrete cytokines (e.g. TNF). This recruits’
additional inflammatory cells. Activated macrophages also produce reactive oxygen
species, which cause smooth muscle cell proliferation through release of growth
factors.

Activated T cells through secretion of inflammatory mediators (like INF-γ) activate

macrophages, endothelial cells and smooth muscle cells.

4. Role of platelets (thrombosis): Endothelial injury exposes platelets to highly

thrombogenic subendothelial connective tissue, resulting in formation of small
platelet aggregates. The resultant thrombus later becomes a part of the
atheromatous plaque.

5. Smooth muscle cell proliferation and ECM production: Intimal smooth muscle cells
can be recruited from circulating precursors and underlying medial smooth muscle
cells. Smooth muscle cell proliferation occurs under the effect of various growth
factors like PDGF, FGF and TGF-α. The recruited smooth muscle cells synthesize
ECM.
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Morphology

Fatty streaks:

• Occur as early as infancy. All children older than 10 years have fatty streaks.
• Begin as multiple minute flat yellow spots, which coalesce into elongated streaks of
≥1 cm length
• Are not significantly raised, therefore do not cause flow disturbance
• Composed of foamy macrophages
• They may be precursors of atheromatous plaques, though not all evolve into
atheroma.

Atherosclerotic plaque:

Most common sites:

In descending order, the most extensively involved vessels are:
1. lower abdominal aorta
2. coronary arteries (most commonly left anterior descending5)
3. popliteal arteries
4. internal carotid arteries
5. vessels of the circle of Willis

Vessels of the upper extremities, mesenteric and renal arteries are spared6, except at
their ostia.

Gross appearance:
• Lesions are patchy initially, found where there is local blood flow disturbance, like
turbulence at branch points. With time they become more numerous and more
diffuse.
• Plaques usually involve only a portion of arterial wall, rarely circumferential
• Vary in size from 0.3 to 1.5 cm diameter; may coalesce to form larger mass
• White to yellow in color
• Superimposed thrombus over ulcerated plaque imparts red-brown color
• Plaque is raised, so impinges on the lumen of the artery obstructing blood flow

Microscopic appearance:
Atherosclerotic plaques have 3 principal components:
1. Cells: smooth muscle cells, macrophages, T cells
2. ECM: collagen, elastic fibers, and proteoglycans
3. Lipid: intracellular and extracellular

The plaque consists of:

1. Superficial fibrous cap (convex part7): composed of smooth muscle cells and dense
collagen
2. Shoulder: Beneath and to the side of the cap, is the “shoulder”, which is more cellular
comprised of macrophages, T cells, and smooth muscle cells.
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 3. Necrotic core: Lies deep to the fibrous cap and comprises of lipid8, debris from dead
cells, foam cells [lipid-laden (oxidized LDL9) macrophages and smooth muscle cells],
fibrin, thrombus, and other plasma proteins. Cholesterol is frequently present as
crystalline aggregates that are washed out during routine tissue processing, leaving
behind empty clefts, called “cholesterol clefts10”. The periphery of the lesions shows
neovascularization.

The plaque rests on tunica media, which is concave in shape.

Typical atheromas contain abundant lipid, but some plaques are more fibrous.
Atheromas may undergo calcification.

Complications of atherosclerosis

1. Calcification: may be seen in advanced cases

2. Acute plaque change:

a. Plaque rupture, ulceration, or erosion exposes blood to highly thrombogenic
substances and induces thrombus formation. Thrombosis can cause
ischemia. Thrombus may also embolize.

b. Hemorrhage in a plaque results from rupture of the overlying fibrous cap

(plaque rupture), or of thin-walled vessels in the areas of neovascularization
(intra-plaque hemorrhage)

Factors that trigger acute plaque change include:

a. Intrinsic (e.g., plaque structure and composition): Plaques that contain
clusters of inflammatory cells, abundant foam cells and extracellular lipid, or
have thin fibrous cap, or few smooth muscle cells11, are more likely to
rupture, and are called “vulnerable plaques”.
b. Extrinsic (e.g., blood pressure, platelet reactivity): adrenergic stimulation can
increase systemic blood pressure or induce local vasoconstriction, thereby
increasing the physical stresses on a given plaque. Adrenergic stimulation is
associated with waking and rising. The peak time of onset of acute MI is
therefore between 6 am and 12 noon.

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 Intense emotional stress can also contribute to plaque disruption.

3. Atheroembolism: Plaque rupture can discharge atherosclerotic debris into the

bloodstream, producing microemboli.

4. Aneurysm: Atherosclerosis-induced pressure or ischemic atrophy of the underlying

media, with loss of elastic tissue, causes weakness resulting in aneurysmal dilation.

Clinical consequences of atherosclerosis

Most commonly affected vessels:
1. large elastic arteries (e.g., aorta, carotid, and iliac arteries)
2. large and medium-sized muscular arteries (e.g., coronary and popliteal arteries)

Most commonly affected organs: heart, brain, kidneys, and lower extremities

Most common clinical consequences: The clinical consequences are due to atherosclerotic
stenosis resulting into compromised blood flow and ischemic injury:
1. MI, chronic IHD
2. cerebral infarction (stroke)/ ischemic encephalopathy
3. aortic aneurysm
4. peripheral vascular disease (intermittent claudication/ gangrene of the legs)
5. mesenteric occlusion and bowel ischemia

1. Infective agent causing atherosclerosis:

A. M. Pneumoniae
B. C. Pneumoniae
C. H. Influenza
D. C. Diphtheriae

2. Following are the modifiable risk factor of atherosclerosis EXCEPT:

A. Physical inactivity
B. Family history
C. Diabetes
D. Hypertension

3. True about atherosclerosis:

A. Chronic inflammatory disorder of vessel wall
B. Does not lead to complications of vessel wall
C. Thoracic aorta more commonly involved than abdominal aorta
D. Atherosclerotic plaques do not demonstrate extracellular matrix deposition

4. Atherosclerosis causes fibroblast plaque formation by injury to:

A. Endothelium
B. Fibroblast
C. Macrophage
D. Smooth muscle cells

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5. The coronary artery most commonly involved in atherosclerosis:
A. Left anterior descending artery
B. Left main coronary artery
C. Right coronary artery
D. Circumflex coronary artery

6. The following arteries are usually spared from extensive atherosclerosis:

A. Popliteal artery
B. Internal carotid artery
C. Arteries of circle of Willis
D. Mesenteric arteries

7. True about the basic structure of atherosclerotic plaque is:

A. Concave part is formed by fibrous cap
B. Convex part is formed by tunica media of the vessel
C. Convex part is formed by fibrous cap
D. Necrotic core contains collagen, elastin and proteoglycans

8. The necrotic core of an atherosclerotic plaque contains:

A. T cells
B. Collagen
C. Lipid
D. None of the above

9. Foam cells in atherosclerosis contain lipid in the form of:

A. Oxidized LDL
B. Reduced LDL
C. Oxidized VLDL
D. Reduced VLDL

10. Cleft-like space in atheromatous plaque mainly contains:

A. Smooth muscle cell
B. Fibrous tissue
C. Cholesterol
D. Macrophages

11. Changes seen in atherosclerotic plaque at the time of rupture, are all EXCEPT:
A. Thin fibrous cap
B. Multiple foam cells
C. Smooth muscle cell hypertrophy
D. Cell debris

KEYS: 1. B, 2. A, 3. A, 4. A, 5. A, 6. D, 7. C, 8. C, 9. A, 10. C, 11. C

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 ANEURYSM

Definition

Aneurysm: Aneurysm is a localized abnormal dilation of a blood vessel or the heart.

1. True aneurysm: When an aneurysm involves an intact attenuated arterial wall or
thinned ventricular wall of the heart. E.g. atherosclerotic, syphilitic, congenital
aneurysm (Berry’s aneurysm of circle of Willis).

True aneurysms are classified according to their shape into:

a) Saccular aneurysm: is spherical out-pouching involving only a portion of the
vessel wall. They vary from 5-20 cm in size and often contain a thrombus.
b) Fusiform aneurysm: is a diffuse circumferential dilation of a long vascular
segment. They vary in diameter up to 20 cm and length; can be extensive
involving aortic arch, abdominal aorta and iliac arteries
c) Cylindrical
d) Serpentine: tortuous dilation
e) Racemose: interconnecting mass of arteries and veins

2. False aneurysm (pseudo-aneurysm): is a defect in the vascular wall leading to an

extravascular hematoma that freely communicates with the intravascular space
(“pulsating hematoma”). They can result from trauma1, surgical complications and
rarely infection. E.g. ventricular rupture after MI, a leak at the sutured junction of a
vascular graft.

Arterial dissection: arises when blood enters the arterial wall itself, as a hematoma
dissecting between its layers.

Pathogenesis of Aneurysms

1. Connective tissue disorders: Arteries undergo continuous remodeling to maintain

their integrity by synthesizing, degrading, and repairing ECM. Aneurysms can occur
when the structure or function of the connective tissue within the vascular wall is
compromised. Examples of connective tissue disorders associated with aneurysm:

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 Disorder Cause for aneurysm
Marfan syndrome defective synthesis of fibrillin, leads to increased TGF-β
activity and weakening of elastic tissue
Vitamin C deficiency altered collagen cross-linking

2. Local inflammation: Local inflammatory infiltrate causes an imbalance between

collagen synthesis and degradation, through release of proteolytic enzymes or
suppression of inhibitors of proteolytic enzymes; e.g. increased secretion of matrix
metalloprotein (MMP) by macrophages and decreased expression of tissue inhibitor
of metalloproteinase (TIMP).

3. Atherosclerosis and hypertension: The two most important disorders that predispose
to aortic aneurysms are atherosclerosis2 and hypertension.

Atherosclerosis Systemic hypertension

Mechanism: Atherosclerotic thickening Mechanism: Systemic hypertension can
of the intima increases the distance that also cause significant narrowing of
oxygen, nutrients and waste can diffuse. arterioles of the vasa vasorum (e.g., in
This causes ischemia of the inner media. the aorta), which can cause outer medial
Ischemia leads to smooth muscle cell ischemia.
loss and destruction of elastic tissue,
thus weakening the vessel wall.
More commonly associated with More commonly associated with
abdominal aortic aneurysms ascending aorta aneurysms

4. Infections (mycotic aneurysms): Mycotic aneurysms can originate from:

a. embolization of a septic embolus; e.g. infective endocarditis
b. extension of an adjacent suppurative process
c. bacteremia from a primary focus; e.g. tertiary syphilis, salmonella gastroenteritis

5. Congenital defects: e.g. berry aneurysms in the circle of Willis

6. Trauma
7. Vasculitis

Abdominal aortic aneurysm (AAA)/ Atherosclerotic aneurysm

AAA occur more frequently in men and in smokers, and rarely develop before age 50.
Atherosclerosis is a major cause of AAAs.

Morphology:
Site: Usually seen between renal arteries and bifurcation of the aorta
(infrarenal aneurysm). AAA may be accompanied by smaller aneurysms
in the iliac arteries.

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Shape: saccular or fusiform
Diameter: up to 15 cm
Length: up to 25 cm
Microscopically • Intima: shows complicated atherosclerosis and frequently an
accompanying mural thrombus
• Media: thinned out; smooth muscle cells replaced by fibrous tissue
• Adventitia: shows mild chronic inflammation

Clinical consequences of AAA:

1. Rupture into the peritoneal cavity or retroperitoneal tissues with fatal hemorrhage.
The risk of rupture is directly proportional to the size of aneurysm:
≤4 cm Nil
4-5 cm 1%/year
5-6 cm 11%/year
>6 cm 4 25%/year

2. Obstruction of branch artery leading to ischemic injury of downstream tissues; e.g.:

Iliac artery (leg)
Renal (kidney)
Mesenteric (GIT)
Vertebral (spinal cord)

3. Embolism from atheroma or mural thrombus

4. Compression of adjacent structure, e.g., ureter or vertebrae

Indications of aneurysm repair:

1. Symptomatic aneurysm of any size (abdominal/back/flank pain, evidence of
embolization, frank rupture)
2. Asymptomatic aneurysm of >5.5 cm5 in diameter or that expands >0.5 cm within
6 months period

Thoracic aortic aneurysms

Thoracic aortic aneurysms are most commonly associated with hypertension, Marfan and
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Loeys-Dietz syndromes, and tertiary syphilis.

Marfan syndrome (MFS):

Most common site of aneurysm in MFS is aortic root aneurysm (60-80%) followed by
descending aorta aneurysm. Type I aortic dissection and rupture of ascending aorta6 are
dreadful complications of aortic root aneurysm in MFS.

Syphilitic (luetic) aneurysms:

Cardiovascular syphilis:
• is seen in tertiary stage in 10% of cases of syphilis
• manifests at the age of 50 years
• more common in men
• characterized by syphilitic aortitis of proximal aorta and cerebral arteritis
• 40% cases of syphilitic aortitis develop syphilitic aneurysms

Pathogenesis of syphilitic aneurysm: The process begins with inflammatory infiltrate around
the vasa vasorum of the adventitia, followed by endarteritis obliterans. This results to
ischemic injury to the media causing destruction of the smooth muscle and elastic tissue of
the media and scarring.

Morphology:
Site: ascending aorta7 and arch of aorta
Shape: Saccular; less often fusiform or cylindrical
Diameter: 3-5 cm in diameter
Length: Up to 25 cm
Grossly Intimal surface shows tree-bark wrinkled appearance
Microscopically • Intima and media: show fibrosis
• Adventitia: shows fibrous thickening with endarteritis obliterans of
vasa vasorum. Rarely spirochetes may be demonstrable.

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Clinical consequences:
1. Rupture: is associated with fatal hemorrhage into the pleural cavity, pericardial sac,
trachea and esophagus.
2. Compression: The aneurysm may press on trachea causing dyspnea, on esophagus
causing dysphagia, on recurrent laryngeal nerve leading to hoarseness; and erosion
of vertebrae, sternum and ribs due to persistent pressure.
3. Cardiac dysfunction: may lead to aortic valvular insufficiency causing left
ventricular hypertrophy due to volume overload. Massively enlarged heart in
syphilitic aneurysm is called ‘cor bovinum’. Most patients with syphilitic aneurysms
die of heart failure induced by aortic valvular incompetence.

Narrowing of the coronary ostia may cause MI.

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Visceral artery aneurysms

Visceral artery aneurysms are seen in splenic8 (60%), hepatic (20-50%%), superior
mesenteric (6%), celiac artery (4%).

1. Which of the following causes pseudoaneurysm?

A. Trauma
B. Atherosclerosis
C. Congenital disease
D. Infection

2. Most common cause of aneurysm:

A. Syphilis
B. Atherosclerosis
C. Cystic medial necrosis
D. Monkebergs sclerosis

3. Which of the following is not a cause of aneurysm?

A. Atherosclerosis
B. Cystic medial necrosis
C. Syphilis
D. Monkebergs sclerosis

4. Risk of aneurysm rupture is >25% per year when the size is greater than:
A. 4 cm
B. 6 cm
C. 7 cm
D. 8 cm

5. For asymptomatic abdominal aortic aneurysm, surgery is indicated if the size is greater
than:
A. 4. cm
B. 4.5 cm
C. 5 cm
D. 5.5 cm

6. In Marfan Syndrome, rupture of aortic aneurysm usually occurs at:

A. Ascending aorta
B. Descending aorta
C. Arch of aorta
D. Abdominal aorta

7. Syphilitic aneurysm is seen most commonly in:

A. Ascending aorta
B. Arch of aorta
C. Descending aorta
D. Abdominal aorta

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 8. Visceral aneurysm is most commonly seen in which of the following artery:
A. Splenic
B. Renal
C. Hepatic
D. Coronary

KEYS: 1. A, 2. B, 3. D, 4. B, 5. D, 5. A, 6. A, 7. A, 8. A

VASCULITIS

Large-vessel vasculitis Giant cell (temporal) arteritis

Takayasu arteritis
Medium-vessel vasculitis Polyarteritis nodosa
Small-vessel vasculitis Wegener granulomatosis
Churg-Strauss syndrome
Microscopic polyangitis

IMPORTANT QUESTIONS

SHORT NOTES:
1. Morphology and major risk factors of atherosclerosis
2. Hyperlipidemia and atherosclerosis

SHORT ANSWERS:

1. Name two most common causes of aortic aneurysm.

Ans. Atherosclerosis, hypertension, syphilis
2. List major risk factors of atherosclerosis.
Ans. Modifiable: dyslipidemia, hypertension, cigarette smoking, diabetes, CRP
3. Write any two causes of small vessel vasculitis.
Ans. Wegener granulomatosis, Microscopic polyangitis

The End

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