1

CHAPTER I

INTRODUCTION

1.1 Background

The term peripheral artery disease (PAD) broadly encompass the vascular
diseases caused primarily by atherosclerosis and thromboembolic pathophysiologic
processes that alter the normal structure and function of the aorta, its visceral arterial
branches, and the arteries of the lower extremity. PAD is the preferred clinical term
and should be used to denote stenotic, occlusive and aneurysmal diseases of the aorta
and its branch arteries, exclusive of the coronary arteries.(1) PAD affects 12%14% of
the general population and its prevalence increases with age affecting up to 20% of
patients over the age of 75.(2) The symptoms of PAD can be typical, such as
claudication, or atypical. The 2005 ACC/AHA guidelines on PAD suggest that classic
claudication is the main clinical presentation of PAD in 40-50% patients aged 50
years old.(3)
Intermittent claudication is defined as a reproducible discomfort, fatigue, or
pain of a defined group of muscles, which is induced by exercise (exercise-induced
ischemia) and relieved with rest.(1,3,4) Intermittent claudication is present in 5% of men
and 2.5% of women over the age of 60.(2) The etiology of leg pain can be divided into
categories that include vascular, neurogenic, and musculoskeletal causes. Classic
claudication is included to vascular pain and its main cause is peripheral
atherosclerosis. With atherosclerosis, fatty material buildsup in the walls of the artery.
Since the arteries in the legs become narrow, not enough blood is flowing to a muscle.
The risk factors for the development of peripheral arterial atherosclerosis are the
same for heart disease, include diabetes mellitus, hyperlipidemia, hypertension,
cigarette smoking, and older age.(3,4)
The severity of symptoms of claudication depends on the amount of stenosis,
the collateral circulation, and the vigor exercise. Patients with claudication can
present with buttock and hip, thigh, calf or foot pain, single or in combination. Calf
claudication is the most common complaint. Physical examination reveals bilateral
2

diminished or absent pulses at the level of the groin, occasionally with bruits over the
iliac and femoral arteries and muscle atrophy and slow wound healing in legs.
Noninvasive vascular tests that could be done to diagnose PAD include the ankle-
brachial index (ABI), exercise treadmill test, segmental limb pressures,
ultrasonography, and segmental volume plethysmography. If surgery is being
considered, an angiogram may be recommended to show narrowing in an artery and
facilitate the surgery or angioplasty.(3,4)
Therapy of patients with claudication involves risk modification (including
exercise program, smoking cessation, and control of blood pressure and blood sugar
level), the use of antiplatelet agents (usually aspirin and cilostazol), and possibly
medical therapy for symptom improvement.(3,4) Amputation is infrequent in
claudicants and occurs in 5.8% of patients at a mean follow-up of 2.5 years. PAD
patients die mostly of cardiac and cerebrovascular-related events and much less
frequently due to obstructive disease of the lower extremities.(2)
3

CHAPTER II
CONTENT
2.1 Definition
Peripheral arterial disease (PAD) is an occlusive vascular condition that
affects up to 15% of the population with patients typically exhibiting reduced
peripheral blood flow, decreased walking ability and poor quality of life. (5) Peripheral
artery disease is circulatory problem associated with pain in the limbs due to reduced
blood flow as a result of blocked or narrowed artery passage. For this student project,
we are talking about claudication. Claudication is referred to the pain that occurs due
to decreased blood flow. This is a typical symptom of peripheral artery disease that
usually occurs while walking.(6) There are several types of claudication namely
intermittent vascular claudication, neurogenic claudication and jaw claudication. For
this student project, we will be focusing on intermittent vascular claudication.(5)
2.2 Etiology and Risk Factors
Intermittent claudication results from the blockage of arteries. As a result,
atherosclerosis is the underlying cause of claudication.(7)
There are several risk factors associated with intermittent claudication. These
risk factors include diet consisting of high amounts of cholesterol and saturated fat
and sodium together with low levels of fibre and folate. (5,6) Inadequate lifestyle also
increases the risk of contracting intermittent claudication. These include lack of
exercise and incorrect eating habits. Smoking is also associated with increased risk of
peripheral artery disease.(5) As a result, claudication is the symptom of blockage of the
peripheral arteries.
2.3 Pathophysiology
Peripheral Artery Disease is develop when there is a disruption in the blood
flow that alters the oxygen and nutrition transport, and the elimination of metabolites
waste products. This changes that occur in human body result in developing a
compensatory mechanism such as vasodilatation, and anaerobic metabolism, when
this mechanism goes fail, ischemia will develop and lead a tissue death. (8)
4

The most primary cause of Peripheral Artery Disease is Atherosclerosis and

associated thrombosis within lower limb through a complex mechanism involves a lot
number of cell, protein and pathway.(8) The cell that contribute or control this
mechanism include vascular endothelial cells, vascular smooth muscle cells,
fibroblast, platelets, resident stem cells, pericytes and inflammatory cells. (9) The
development of atherosclerosis involves endothelial dysfunction, lipid disturbance,
platelet activation, thrombosis, and oxidative stress, also inflammation.(8)
There are four stages in atherosclerotic progression. The first is lesion
initiation, fatty streak formation, fibro proliferative atheroma and advanced level.
Injury to the endothelial cell caused by hypertension, dyslipidemia, inflammation, or
oxidative stress leads to increase permeability and stimulation of endothelial.
Activation of cytokine attracts the monocyte and adhere to the site of injury and
increase the expression of MCP-1, VCAM-1, and ICAM-1 expression. The the
monocyte is converted to macrophage. This macrophage secret the pro inflammatory
mediator such as TNF-alpha, interleukin, chemokine that potentiate inflammation and
also increase the production of reactive oxygen species (ROS).(8)
The production of ROS induce the oxidative stress that caused decrease of
Nitric Oxide (NO) bioavability.(11) NO is a vasodilator, is also have an important role
for defensive mechanism.(8) NO roles in reduce leucocytes adhesion, inhibit of plate
let adhesion and aggregation.(11) NO is also inhibit VCAM-1 gene expression which is
a type 1 membrane protein that oversees leucocytes-endothelial cell adhesion. (8) The
oxidative stress is also have a role in regulate the vascular cell migration and
proliferation during the formation of a great lesion in endothelium. (10) Oxidative
stress also lead to the LDL oxidation into highly oxidize LDL that could be recognize
by most cell and also allows it to remain soluble in plasma and contribute to the
development of the plaque in endothelium.(11) The highly oxidized LDL, smooth
muscle cells, monocyte, B and T lymphocyte once form a fatty streak formation.
Monocyte and leukocytes will generate growth factor and cytokine, also release a
chemotractants that increase the migration of macrophage. Smooth muscle
proliferation also contribute to the development into atheroma.(8,11)
5

The next stage is fibroproliferative atheroma into advanced lesion with a lipid
core and covered by fibrous cap. Rupture of this plaque will lead to the exposed of
pro-coagulants, tissue factors and von Willebrand factor to circulation leads to
stimulation of thrombus formation. By the time, the plaque accumulate and grow,
narrowing the lumen of vessels, decrease in diameter. Decrease in diameter of lumen
will increase the resistance of blood vessel due to friction of blood flow and the
decrease in diameter will lead to circulation restricted, cell are deprived of oxygen
and accumulation of waste product in cells. Nutrition and oxygen also will note
distributed effectively and will cause of tissue edema, ischemia, and cell death.(8)
The body part distally to the occlusion will have a decrease blood perfusion
and blood pressure. The response due to ischemia, especially in the limb, promotes
the angiogenesis and arteriogenesis to increase the blood supply to distally the
affected vessel or arteries. Arteriogenesis is the process of enlargement of pre-
existing collateral arteries to contribute to tissue perfusion. Angiogenesis is describe
as the development of new capillary network. Vascular remodeling, inflammation
and apoptotic pathway also implicated to the ischemic response. In a severe state
like critical limb ischemia, all of these compensatory mechanism are ineffective so
this lead to on-going inadequate perfusion, chronic inflammation, endothelial
dysfunction, and high level of oxidative stress. All these condition will manifest as
mitochondrial injury, free radical generation, muscle fibre damage, myofibrile
degeneration and fibrosis, tissue damage which present as gangrene. (9)

Figure 1. Schematic representation of peripheral artery disease. (2)

Alteration is also occur in skeletal muscle metabolism. In Peripheral artery

disease there is a decrease in mitochondrial enzyme and its activity, but in some
studies also state that there is an increase mitochondrial content in muscle. This
6

increase, is might be improve of oxygen extraction under ischaemic condition or

could reflect a compensatory mechanism. Skeletal muscle that affect to PAD ha a
decrease mitochondrial NADPH dehydrogenase of comple I and ubuquinon-
cytochrome c oxidoreductase (complex III) activity. This changes might be expected
to reduce the ability to perform oxidative metabolism. Impairment of complex III of
the eclectron transport chain result in maintain electron flux and lead too free-radical
leakage in the mitochondria. (10)
In PAD, there is alterations in carnitine metabolism that will lead to the
accumulation of short-chain acylcarnitine in plasma. The accumulation of
acylcarnitine is indicate the acyl coa are not being efficiently oxidize. Acylcoa is an
intermediate substance for complete oxidation in Krebs cycle.(10)
Adaptive response in peripheral artery disease :(11)

1.1 Adaptive vascular growth

Reduction of blood flow to tissues distal to occlusion sites establishes a state

of tissue ischemia that may result in loss of tissue function in these ischemic sites.
Vascular adaptation responses are stimulated to restore blood flow through
various processes including vasculogenesis, arteriogenesis and angiogenesis.

a. Vasculogenesis

Vasculogenesis is defined to occur during vascular development at the

pre-natal level. Differentiation of angioblasts from the mesoderm and the
formation of primitive blood vessels from angioblasts near the site of origin
represent two key steps during onset of vascularization defined as
vasculogenesis. Following pre-natal development, post-natal vasculogenesis
occurs through mobilization of stem cells from bone marrow that home to
ischemic sites. This response correlates with increased levels of angiogenesis
and enhanced blood flow to ischemic tissue. CD14+ monocytes are
proangiogenic helper cells, capable of responding to sites of injury and
releasing proangiogenic cytokines that stimulate production of VEGF and
7

vasculogenesis. Another population of circulating cells actually enhances

vasculogenesis and angiogenesis. These cells are capable of forming colonies
and are referred to as late outgrowth endothelial progenitor cells which
remain poorly defined.

Endothelial progenitor cells (EPCs) can be used as a measure of the

ability of a patient to enter a pro-angiogenicphenotype. Increased circulation
of CD31/CD34 positive cells (EPCs) correlates with increased capillary
density,indicative of neovascularization responses. Importantly, a clinical
study reported that EPCs are increased in the circulation of healthy patients
with a 15-minute experimentally induced ischemic event. However, patients
diagnosed with PAD mobilized far fewer circulating EPCs following
exercise-induced ischemia compared to healthy patients.

b. Arteriogenesis

Arteriogenesis is a process by which vessels, typically minimally

perfused arterioles, undergo remodeling to increase diameter and as a result
blood conductance capacity. These arterioles are remodeled and essentially
become completely new and fully functioning arteries. Blockage of a major
conduit artery proximal to collateral arteries results in increased shear rates
and the formation of a new pressure gradient that leads to remodeling of
these smaller vessels into larger established arteries. The change in physical
forces in these smaller vessels also stimulates the endothelium to release
monocyte chemotactic protein-1 (MCP-1). The release of MCP-1 activates
resident macrophages and also transforms monocytes into macrophages;
these cells in conjunction with smooth muscle cells produce inducible NOS
(iNOS) that cause collateral vessel remodeling in response to arterial
blockage. Increased shear rates also increase production of NF-kB leading to
the recruitment of CD45+ cells which release cytokines leading to the
production of VEGF-A and finally influencing delta-notch signaling which
8

controls arterial branching. However, the NF-kB p50 subunit has been
associated with decreased levels of macrophage influx into growing
collateral vessels.
c. Angiogenesis

Angiogenesis is the process by which endothelial cells shift from a

quiescent state and obtain a migratory and proliferative phenotype following
various stimuli. The initiation of angiogenesis occurs due to an imbalance in
the positive and negative regulators (angiogenic switch), which act on
endothelial cells to maintain a state of quiescence. The process of
angiogenesis is primarily driven by hypoxia and results in new capillary
development. Reduced oxygen tension increases the expression of various
genes, the most commonly studied is hypoxia-inducible factor-1 (HIF-1).
Among other proteins HIF-1 up regulates vascular endothelial growth factors,
namely VEGF that derived from CD11b(+). VEGFR-1 is a kinase impaired
receptor tyrosine kinase, which when coupled with VEGFR-2 promotes
angiogenesis. Expression of TNFR2 appears to be essential in promoting
angiogenesis as well as arteriogenesis.

1.2 Molecular mediators of adaptive response

Numerous signaling and molecular pathways are activated that stimulate

adaptive responses for vascular remodeling includes transcription factors
hypoxia-inducible factor-1 (HIF-1) and nuclear factor kb (NF-kb),
cytokine/growth factors MCP-1, VEGF and bFGF, and the gasotransmitter nitric
oxide (NO).

a. HIF-1

The transcription factor hypoxia inducible factor-1 (HIF-1a and HIF-

1b) serves a critical role in activating the expression of numerous gene
networks that alleviate damaging effects of tissue hypoxia through stimulation
9

of adaptive responses including angiogenesis, arteriogenesis, bone marrow

progenitor cell mobilization and function, red blood cell production, glucose
uptake and antioxidant defense induction. HIF-1 activity is dynamically
regulated by oxygen tension such that under non-hypoxic conditions HIF-1a is
hydroxylated by prolyl-4-hydroxylases (PHDs) resulting in its ubiquination
and targeting to the proteasome.
While experimental models suggest an important role for HIF-1 in
modulating adaptive responses during tissues ischemia, recent clinical results
using Ad2/HIF-1a/VP16 viral gene therapy limb injections in patients with
bilateral atherosclerotic PAD and intermittent claudication failed to
demonstrate improvements.
b. NF-kB

Nuclear factor-kB (NF-kB) is a transcription factor that plays key roles

in vascular growth and remodeling by stimulating cell proliferation,
differential and survival. Activation of NF-kB directly stimulates expression
of intercellular adhesion molecules (e.g., ICAM-1 and VCAM-1) and recruits
monocytes to injured tissues. NF-kB stabilizes the HIF-1a and HIF-2a that in
turn stimulate expression of growth factors including VEGF and PDGF-BB.
Elevated levels of VEGF stimulate capillary formation and arterialization, and
PDGF-BB promotes maturation of arterioles by recruiting pericytes. In
addition, NF-kB stimulates DLL4 expression that in turn regulates the
branching of newly forming network via activating the Delta/Notch signaling
pathway. Therefore, all three processes controlled by NF-kB including
monocyte recruitment, HIF-1a and HIF-2a stabilization and Delta/Notch
signaling pathways play critical roles in vascular growth and remodeling.

c. VEGF

Vascular endothelial growth factor (VEGF ) has been extensively

studied and is widely accepted as a key regulatory angiogenic cytokine with a
complete lack of VEGF resulting in abnormal blood vessel formation and
10

embryonic lethality. VEGFR2, the receptor thought to play the major role in
VEGF-mediated angiogenesis, promotes NF-kB translocation to the nucleus.
VEGF is a potent mediator of endothelial solute permeability that plays an
important role in the initiation of angiogenesis by loosening lateral cellcell
adhesions, stimulating extracellular matrix degradation, and increasing
permselectivity of solutes to establish a provisional matrix for migration.
VEGF stimulates essential cellular and molecular responses necessary for
angiogenesis.

Recent trials suggest that the administration of VEGF resulted in

increased blood flow, increased ABI and increased collateral growth.
Unfortunately, patients showed no significant increase in pain-free walking
after 12 or 26 weeks. Several possibilities may account for this such as the
trial duration may not have been long enough.

d. MCP-1

MCP-1 therapy improves distal limb perfusion in models of hindlimb

ischemia, however MCP-1 is also a mediator of inflammation and contributes
to the development of cardiovascular pathologies. Shear stress activates MCP-
1 up regulation in the endothelial and surrounding smooth muscle cells.
Following increases in MCP-1 production, monocytes and T-cells are
recruited to the adventitial space, where mononuclear cells are responsible for
the degradation of extra-cellular scaffolding allowing for the space needed to
accommodate new cells. The mononuclear cells also produce extra NO
through iNOS activation. The whole process of arteriogenesis can be inhibited
by blockage of either NO production or VEGF activity, thereby limiting
MCP-1 upregulation and consequent tissue, and smooth muscle cell
proliferation.

e. bFGF
11

Basic FGF is a membrane bound protein and member of fibroblast

growth factor family that is also known as FGF-b or FGF-2. bFGF is a
potential pro-angiogenic growth factor which is also extensively studied
particularly in ischemic angiogenesis. bFGF stimulates angiogenesis via
binding with its receptor and heparin sulfate, a proteoglycan that augments the
binding affinity of bFGF as well as angiogenic signaling. Studies from
different laboratories have revealed that bFGF plays a major role in
experimental angiogenesis both in vitro and in vivo. bFGF promotes
angiogenesis in injured tissue by stimulating migration, proliferation, and
proteolytic activity of vascular endothelial cells through autocrine and
paracrine manners. Basic FGF stimulates nitric oxide as well as mitogen
activated kinase (MAPK) signaling pathway to promote angiogenesis.
Moreover, bFGF promotes arteriogenesis by stimulating proliferation,
migration and differentiation of vascular smooth muscle cells via p38 MAPK
and ERK signaling pathway.
bFGF has been examined in therapeutic angiogenesis for PAD. While
bFGF therapy in animal models of tissue ischemia showed promising results,
multicenter randomized clinical trials with bFGF recombinant protein or gene
therapy has shown limited therapeutic benefit for PAD.

f. NOS

NO metabolism and bioavailability is an important factor in vascular

growth response. NO is enzymatically produced by endothelial nitric oxide
synthase (eNOS), inducible nitric oxide synthase (iNOS) and neuronal nitric
oxide synthase (nNOS). Enzymatic production of NO occurs through
successive oxidation and reduction of l-arginine to l-citrulline involving
various co-factors such as tetrahydrobiopterin, oxygen, and NADPH. During
ischemia, such as that experienced in PAD patients, these substrates and co-
factors are reduced leading to decreased NOS enzymatic activity. Besides its
12

role as a vasodilator, NO mediates cytoprotection and has been identified as a

key molecule in therapeutic angiogenesis.
Progression of PAD is marked by dysfunctional endothelium and a
reduced vascular reactivity to stimulation. Erythrocytes and endothelial cells
release ATP following exposure to low oxygen tension, a condition present in
exercising muscles, which leads to the release of substances affecting the
vasculature and decreasing sympathetic vasoconstrictive effects. Arterial flow
is generally regulated by bioavailability of nitric oxide, when
typicallyunperfused arterioles in muscle need increased blood flow vessels
dilate to allow engorgement of tissue. In the case of PAD, bioavailable levels
of nitric oxide are severely diminished which limits the vasodilation of
arterioles in response to the increased perfusion demands of exercise. The
result is increased claudication, as well as an exacerbation of atherosclerotic
plaque deposition further worsening the prognosis for patients with PAD.

2.4 Clinical Manifestation

The hallmark physical finding of PAD is weak or absent pulses, and using the
ankle-brachial index as the objective test to record this finding.(13) Most peripheral
arterial disease (PAD) patients are asymptomatic.(12,13) Classic symptom associated
with PAD is the intermittent claudication. (12,13,14) Claudication is the feeling of fatigue,
discomfort or pain that comes because of an exercise-induced ischemia on a specific
limb muscle groups.(12) It includes cramping, aching, and pain of the muscles in the
lower extremities during walking.(14) The disease distribution affects different muscle
groups.(12)
Buttock and hip (aortoiliac artery disease)
Impotence (bilateral aortoiliac artery disease)
Thigh (common femoral or aortoiliac artery disease)
Upper two-thirds of the calf (superficial femoral artery disease)
Lower one-htird of the calf (popliteal artery disease)
Foot claudication (tibial or peroneal artery disease)

2.5 Diagnosis
13

Diagnosis of PAD is based on the patients symptoms and the physical

examination. The physical examination include comparing blood pressure bilaterally,
palpation the pulse of radial, dorsalis pedis, and posterior tibial artery bilaterally,
inspecting the skin color, temperature, and sensation. Then physician should check if
there is history of walking impairment and specific lifestyle limitation. Based on the
guidelines, the measurement that must be performed to confirm the diagnosis of PAD
is Ankle Brachial Index (ABI).(8,15) The ABI is performed by comparing the systolic
blood pressure between ankle and brachial arm bilaterally. For the ankle, the blood
pressures that should be measured are the posterior tibialis and the dorsalis pedis
arteries bilaterally. The highest of those four measurements divided with the highest
of the two measurements from brachial arms. Normal range for ABI is between 0,90
and 1,30. The ABI value between 0.50 to 0,85 confirm the claudication diagnosis, and
the ABI value lower than 0,30 seen in the patient with resting claudication pain or
gangrene.(3,8)

Beside ABI, there are another tests to confirm if the patients really normal.
The other tests that can be performed are Toe Brachial Index (TBI), exercise treadmill
test, segmental limb pressures, or using duplex ultrasound, Computed Tomography
(CT), or Magnetic Resonance Angiography (MRA) (13). TBI performed the same as
ABI, but using tiny blood pressure cuff placed around the toe and
photoplethysmograph (PPG) infrared light sensor, and the value above 0,80 is
considered normal.(8) If the resting ABI value is at normal range, physician should
measure ABI after exercise, such as exercise treadmill test. In exercise treadmill test,
the patient exercise using a treadmill for five minutes at 2 mph with 12% inclines,
then measured the ABI value. For severe claudication, the patient usually cannot
complete the exercise and the ankle blood pressure is below 50 mmHg.(3)

After the ABI result confirm the diagnosis of PAD, segmental limb pressure
should be performed to detect the level and extent of PAD. The reduction of blood
pressure is significant if there are 20 mmHg differences between some segments
along the leg or between the same level at opposite leg. The placement of the cuff in
14

this measurement can detect the level of PAD. (3) The duplex ultrasound can evaluate
the blockage of blood vessels and can determine the severity. This ultrasound using
Doppler wave and color Doppler to evaluate the vessels. (3,8) Beside the duplex
ultrasound, CT and MRA can be performed to assess the vessels. There is another test
that can be used to assess the vessels anatomy. The arteriography can show the exact
location of stenosis, but it is invasive. (8)

2.6 Differential Diagnosis

Characteristic Intermittent Venous Nerve root pain

claudication claudication
Quality of pain Cramping Bursting Electric shock-
like
Onset Gradual, consistent Gradual, can be Can be immediate
immediate inconsistent
Relieved by Standing still Elevation of leg Sitting down,
bending forward
Location Muscle group Whole leg Poorly localised,
(buttock, thigh, calf) can affect whole
leg
Legs affected Usually one Usually one Often both

Source: Burns Pauls, Gough Stephen, Bradbury Andrew. 2003. Management of

peripheral arterial disease in primary care. BMJ, 326: 584-588.

Vascular claudication typically occurs after activity or ambulation for a

distance due to a vascular insufficiency caused by an imbalance between muscular
oxygen demand and supply. In such cases, resting from activity even in standing
position may help relieve symptoms. On the other hand, neurogenic claudication is
associated with activity and position, because narrowing of the spinal canal and
15

neural foramen is aggravated by standing and relieved by sitting and flexion.

Therefore, neurogenic claudication may be relieved by sitting down or leaning over.
Vascular claudication located below the knees, whereas neurogenic claudication
located above the knees (16,17).

2.7 Treatment

Treatment of claudication can be divided into nonsurgical and surgical.

Nonsurgical treatment consist of nonpharmacologic and pharmacologic.(8,18)
1. Nonsurgical
Primary goals for nonoperative treatment are to control disease progression,
improve physical activity, decrease pain, and prevent and treat symptoms.
a. Nonpharmacologic
i. Exercise
Treadmill and track walking are the most effective exercise for
claudication, which is performed for a minimum of 3045
min/session; sessions are performed at least 3 times/week for a
minimum of 12 week.
ii. Smoking cessation
Smoking cessation include quitting smoking cigarette and
avoiding exposure to environmental tobacco smoke.

b. Pharmacologic
i. Antiplatelet
Antiplatelet therapy with aspirin alone (range 75325 mg per
day) or clopidogrel alone (75 mg per day) is recommended to
reduce MI, stroke, and vascular death
ii. Statin
Treatment with a statin medication is indicated for all patients
with PAD
iii. Antihypertensive
16

Antihypertensive therapy should be administered to patients

with hypertension and PAD to reduce the risk of MI, stroke,
heart failure, and cardiovascular death
iv. Cilostazol
an effective therapy to improve symptoms and increase
walking distance in patients with claudication

2. Surgical
a. Endovascular revascularization
Endovascular procedures are effective as a revascularization option for
patients with lifestyle-limiting claudication, the techniques are covered
stents, drug-eluting stents, cutting balloons, and drug-coated balloons.
Revascularization is performed on lesions that are deemed to be
hemodynamically significant.
b. Surgical revascularization
Surgical procedures for claudication are usually done to patients who
do not derive adequate benefit from nonsurgical therapy, have arterial
anatomy favorable to obtaining a durable result with surgery, and have
acceptable risk of perioperative adverse events. Revascularization is
done by bypassing the popliteal artery with autogenous vein in
preference to prosthetic graft material.
2.8 Prevention and Prognosis
The prevention of claudication is taking action to control risk factors that can
help prevent or delay the claudication and its complications. Controlling risk factors
includes by changing the lifestyles.

Quit Smoking
Patients who smoke should quit, and should avoid second-hand smoke.
Smoking is one of the primary risk factors for PAD and a major cause of
17

complications. Quitting smoking may not make leg pain go away, at least not
in the short term, but it certainly may keep blockages from getting worse.(19)
Be physically active
Exercise training improves blood flow in the legs and, in some cases, can
work as well as medications and surgical procedures in increasing pain-free
walking distance. To maintain benefits, exercise must be regular and
consistent.(20)

Maintain a healthy weight

Create a reasonable weight-loss plan for overweight or obese patient. Any diet
should also help keep blood pressure and weight under control. Choose fiber-
rich food (such as whole grains, legumes, and nuts) as the main source of
carbohydrates, along with a high intake of fresh fruits and vegetables. (19)

Control blood sugar, blood pressure and cholesterol
Patients with diabetes need to strictly control their blood sugar (glucose)
levels. Poor glycemic control is associated with vascular and circulation
complications, atients should aim for an A1C level around 7%. Also Patients
with PAD should aim for blood pressure less than 130/80 mmHg. It is very
important for people with PAD to keep their LDL levels to below 100 mg/dL.
If patients have serious heart disease risk factors (high blood pressure,
diabetes, other unhealthy lipids) in addition, they may need to aim for LDL
levels below 70 mg/dL3. Unhealthy cholesterol levels are major contributors
to atherosclerosis, the common factor in PAD and heart disease. Patients
should avoid saturated fats and foods that are high in cholesterol
Screened for PAD
people with a family history of these conditions should follow the
recommendations of a qualified health care provider and screened for PAD. A
simple office test, called an ankle-brachial index or ABI, can help determine
whether you have PAD(19)
2.9 Prognosis

The prognosis of the diseased extremity is generally favorable. Without

specific therapy, the distance that affected persons are able to walk generally
18

remains stable, worsening in 26 percent of persons and improving in 27

percent. Over five years, approximately 4 to 8 percent of affected persons require
arterial reconstruction, and 2 to 4 percent require amputation. 4Overall, the prognosis
for the diseased extremity is favorable. However, the excessive five- and 10-year
mortality rate is heavily influenced by underlying cardiovascular disease.

CHAPTER III
CONCLUSION

In conclusion, peripheral arterial disease (PAD) is an occlusive vascular condition

that affects up to 15% of the population with patients typically exhibiting reduced
peripheral blood flow, decreased walking ability and poor quality of life. Claudication
is referred to the pain that occurs due to decreased blood flow.There are several types
of claudication namely intermittent vascular claudication, neurogenic claudication
and jaw claudication. The etiology of intermittent claudication is the blockage of
arteries. As a result, atherosclerosis is the underlying cause of claudication. The risk
factors includediet consisting of high amounts of cholesterol and saturated fat and
sodium together with low levels of fiber and folate followed by inadequate, lack of
exercise and incorrect eating habits. Besides that, smoking is also a risk factor.
There are four stages in atherosclerosis which is the main cause of peripheral
arterial disease. The stages are lesion initiation, fatty streak formation, fibro
proliferative atheroma and advanced level followed by the production of ROS which
induce the oxidative stress continued with fibroproliferative atheroma into advanced
lesion with a lipid core and covered by fibrous cap. Lastly, mitochondrial injury, free
radical generation, muscle fibre damage, myofibril degeneration and fibrosis, tissue
damage which present as gangrene. The adaptive responses in peripheral artery
disease are vasculogenesis, arteriogenesis and angiogenesis. Numerous signaling and
molecular pathways are activated such as transcription factors hypoxia-inducible
factor-1 (HIF-1) and nuclear factor kb (NF-kb), cytokine/growth factors MCP-1,
VEGF and bFGF, and the gasotransmitter nitric oxide (NO).
19

The classic symptom associated with PAD is the intermittent claudication.

Clinical manifestation includes feeling of fatigue, discomfort or pain that comes
because of an exercise-induced ischemia on a specific limb muscle groups which
includes cramping, aching, and pain of the muscles in the lower extremities during
walking. The diagnosis of PAD is based on the patients symptoms and the physical
examination. Ankle Branchial Index (ABI) must be performed to confirm the
diagnosis of PAD. Other tests that can be performed are Toe Brachial Index (TBI),
exercise treadmill test, segmental limb pressures, or using duplex ultrasound,
Computed Tomography (CT), or Magnetic Resonance Angiography (MRA).
The treatment of claudication can be divided into nonsurgical and surgical.
Nonsurgical treatment consists of nonpharmacologicalfor example exercise and
smoking cessation and pharmacologic for example antiplatelet, statin,
antihypertensive and cilostazol. Overall, the prognosis for the diseased extremity is
favorable.