1) The document discusses the medical management and decision making for patients with chronic ischemia, distinguishing between those with intermittent claudication versus critical limb ischemia. 2) Key aspects of treatment include risk factor modification through smoking cessation, blood sugar control, blood pressure reduction, and lipid lowering. Medical management focuses on relief of symptoms through antiplatelet therapy, vasodilators, and exercise rehabilitation. 3) The risks and benefits of various pharmacologic agents for treating claudication symptoms are reviewed, including pentoxifylline, cilostazol, and naftidrofuryl. Intermittent pneumatic compression is also discussed.

1. CHROINC ISCHEMIA
Medical management &Decision making
Mohammed salah

2. introduction

3. Patients with lower extremity ischemia are typically divided a into two groups—
1-intermittent claudication
2-critical Limb ischemia (CLI(
Claudication and CLI are managed differently because of major differences in
their
natural histories and expected clinical outcomes after treatment.
in general, there is more consensus among clinician regarding decision making
for
CLI because the natural history of untreated CLI more frequently leads to limb
loss
than does claudication.
. Patients with CLI often have severe associated cardiovascular comorbidities and
are generally older and in poorer health than those with claudication.
Treatment must therefore be structured accordingly. In contrast, patients with
claudication typically seek treatment for the relief of lifestyle limiting pain with
ambulation.

4. In general, there is more consensus among clinician regarding decision making
for CLI because the natural history untreated CLI more frequently leads to limb
loss than does claudication.
Because atherosclerosis is a systemic disease, the initial treatment of lower
extremity PAD should include risk fact modification in an effort to limit
progression of the atherosclerotic process.
Pharmacologic treatment is directed toward The relief Of symptoms and The
stabilization of Existing atherosclerosis is also essential.
Patients presenting with PAD are at significantly increased risk for premature
cardiovascular events, including myocardial infarction (MI), stroke, and death.
Detection of occult PAD is an important marker for systemic atherosclerosis

5. Any patient older than 40 years who has an ankle-brachial index (ABI) of less than 0.90
has significant PAD, even in the absence of symptoms.
An ABI of less than 0.90 is 95% sensitive in identifying angiographically confirmed PAD .
Interestingly, more than 50% of patient with an abnormal ABI fail To show typical
symptoms Of claudication or CLI because of the coexistence of other major
comorbidities, a condition sometimes referred to as “chronic subclinical
lower extremity ischemia.”

6. Treatment:
RISK FACTOR MODIFICATION:
Smoking Cessation
Rigorous BSL control
BP reduction
Lipid Lowering Therapy
MEDICAL MANAGEMENT:
Antiplatelet therapy e.g.
Aspirin/Clopidogrel
Phosphodiesterase Inhibitor e.g.
Cilostazol
Foot Care
EXERCISE:
Claudication exercise rehabilitation
program
30-45mins 3x weekly for 12 weeks

8. Smoking
. Smoking cessation has been shown to reduce the risk of MI
and death in patients with PAD and to delay the progression
of lower extremity symptoms from claudication to CLI and
limb loss.
Nicotine inhalation has been demonstrated to
1- reduce high density lipoprotein (HDL) levels,
2- increase platelet aggregation,
3- decrease prostacyclin, increase levels of thromboxane,
and promote vasoconstriction.
Each of these effects contributes to the development and
progression of atherosclerotic process.

9. BENEFITS OF SMOKING CESSATIN
Beneficial effects of smoking cessation
1- improvement in claudication,
2- modest improvement in the ankle-brachial index,
3- reduction in the likelihood of amputation.
4- improvement in the patency rates of arterial bypass grafts
5- improvement in overall survival.
The importance of smoking cessation extends to patients
who have undergone lower extremity revascularization
because there is a threefold increased risk of graft failure in
smokers compared with nonsmokers
The role of the physician is to educate patients about the
consequences of this high-risk behavior, provide emotional
support, and prescribe pharmacologic aids aimed at treating
the addiction

10. SUMMERY OF SMOKING
CESSATION therapy
NRT buccal mucosa spray patch
1ST
LINE DRUGS bupropion varenicline
2ND
LINE nortriptyline clonidine
EMERGING THERAPY nicotine vaccine NIXCVAX

13. Contraindication to NRT
Active smoking
Pregnancy lactation
Post MI
Burger disease can be replaced by pharmacotherapy
Worsen angina pectoris pain
Severe arrythmia
Side effect nausea, constipation ,GIT irritation
headache, insomnia ,irritability ,arrhythmia up to AF

14. Pharmacotherapy
The addition of pharmacologic agents, such as bupropion,
have increased smoking cessation rates in randomized
studies of patients with PAD More recently, varenicline
(Chantix, Pfizer Inc., New York, NY) has been approved for
use in the United States, with remarkable early results. This
pharmacologic agent acts as a partial agonist of the α 4 β 2
nicotine acetylcholine receptor and was developed for the
sole purpose of treating tobacco addiction.

16. Diabetes Mellitus
The association between DM and atherosclerotic vascular disease is well
documented.
Diabetes is widely prevalent among patients with lower extremity ischemia. It
has been estimated that each incremental 1% increase in glycosylated
hemoglobin is associated with a 28% increase in risk for PAD.
1- Alterations in nitric oxide availability to endothelial cells and the
2- stimulation of proatherogenic activity in vascular smooth muscle cells by the
reduction of phosphatidylinositol-3 kinase.
3- enhanced platelet aggregation,
4- increased blood viscosity, and elevation of fibrinogen levels .

19. Effect of hypertension on atheroscelorsis

20. Most patients require multiple agents for adequate blood pressure control.
Angiotensin-converting enzyme (ACE) inhibitors are particularly beneficial, as
shown in the Heart Outcomes Prevention Evaluation (HOPE) study.
Patients with adequate blood pressure control using the ACE inhibitor, ramipril,
experienced a reduction in subsequent stroke, MI, and vascular-related
mortality.)
ACE inhibitors approved as a cardioprotective drug in high risk patient.
The target BP level is 14090 in non DM patient 13080 in DM or patient with
chronic renal insufficiency .
Target of therapy

23. HYPERLIPIDEMIA
Total serum cholesterol levels greater than 200 mg/dL (5.18 mmol/L) are
associated with an increased risk of cardiac-related events, especially in
combination with a low HDL fraction (<40 mg/Dl) .
Lipid lowering agents, specifically 3-hydroxy-3-methylglutaryl coenzyme A
(HMG-CoA) reductase inhibitors (“statins”), have been shown to decrease the
risk of MI-related death in high-risk patients.
Improvements in leg function, ABI, walking performance, symptoms of
claudication, and perioperative and long-term mortality have been demonstrated

24. HYPERLIPIDEMIA
The beneficial effects of statin therapy are:
-pleomorphic , independent of their lipid lowering
properties;
- altering the lipid content of platelets, thereby decreasing
platelet aggregability
- stabilizing existing atherosclerotic plaques,
- decreasing oxidative stress,
-reducing vascular inflammation.

25. Homocystenemia
The important influence of homocysteine metabolism on premature
atherosclerosis was suspected in the 1990s when distinct group of
young patients with advanced atherosclerosis and no other established
risk factors was investigated.
Plasma levels of homocysteine are regulated in part by B vitamins, and
vitamin supplementation lowers plasma homocysteine levels.
Thus, low levels of folate and vitamin B are also associated with the risk
of PAD, perhaps through the modulation of homocysteine levels.
Early studies found elevated homocysteine to be an independent risk
factor for coronary artery disease and stroke.

26. Homocysteinemia

- Elevated circulating homocysteine results in
1- endothelial dysfunction and injury,
2-followed by platelet activation and thrombus formation.
3- production of hydrogen peroxide (which mediates
endothelial injury),
4- increases in factors XII and V, decreases in protein C,
and
5- inhibition of thrombomodulin and heparin sulfate.

27. Homocystenemia
serologic evaluation for elevated homocysteine
levels is still recommended for patients with:
1- family histories of multiple thrombotic events,
2- premature cardiovascular symptoms in the
absence of conventional risk factors, and
3- coronary artery disease, PAD, stroke, deep venous
thrombosis, and pulmonary embolism.
- Supplemental B vitamins or folic acid therapy may
be worthwhile.

28. TREATMENT
1- VASODILATORS
2- ANTIPLATELET
3- EXERCISE THERPHY
4-IPC

29. EXERCISE THERAPY
Multiple reports have clearly demonstrated improvements in pain-free
ambulation and overall walking performance with Data from more than
20 randomized trials have confirmed that exercise therapy is the best
initial treatment of intermittent claudication.
The benefits Of Exercise Extend Beyond improvement In The
symptoms Of claudication. Regular aerobic exercise reduces
cardiovascular Risk By Lowering Cholesterol And Blood Pressure And
By Improving glycemic control.
structured exercise The guidelines suggest that exercise training, In
The Form Of walking, Should Be Performed For a minimum of 30 to 45
minutes per session, three to four times per week, for a period not less
than 12 weeks.

30. EXERCISE THERAPY
During each session, the patient should be encouraged
to walk until the limit of lower extremity pain tolerance is
reached, followed By A short period of rest until pain relief
is obtained, then a return to exercise.
This cycle should be followed for the duration of the
session.
Although exercise therapy appears to be easy to
implement, Effectiveness Is often limited by poor patient
compliance. Studies have shown the superiority of clinic-
based exercise programs over home-based programs.

31. .
antiplatelets
There is convincing evidence that antiplatelet agents such as aspirin and
clopidogrel are effective in preventing cardiac and stroke events in patients with
PAD.
it is therefore recommended that an antiplatelet drug should be prescribed for
these patients unless there is a clear contraindication to such therapy.
Antiplatelet therapy is now widely accepted among physicians For the treatment
of cardiovascular disease, and it has been shown to reduce the risk of nonfatal
MI, ischemic stroke, and vascular-related death. It should be used in all patients
with Clopidogrel (Plavix, Bristol-Myers Squibb, New York, NY) is the only
antiplatelet agent approved by the FDA for the secondary prevention of
atherosclerotic vascular disease, including PAD
Dual antiplatelet has no role in prevention of CVD in PAD . Associated with
increase risk of bleeding .pictomaide is prevent stroke in DM pt more efficient
than aspirin .

32. pentoxifylline (Trental, sanofi-aventis, Paris, France) the first drug approved by
the FDA for the treatment of intermittent claudication.
Mechanism of action
It is a methylxanthine derivative that is thought to improve oxygen delivery
because of its rheolytic effect on red blood cell wall flexibility and deformability,
ultimately reducing blood viscosity.
Pentoxifylline is also believed to inhibit platelet aggregation and to increase
fibrinogen levels.
PENTOXFYILLINE

33. Pentoxifylline is well tolerated, safe, and relatively inexpensive.
Although its clinical impact has been modest, pentoxifylline
represents one of the earliest successful pharmacologic advances for
The Treatment Of claudication.
Dosing recommendations For pentoxifylline begin at 400 mg orally
three times daily and can be increased as tolerated up to 1800 mg/day.
Pentoxifylline can interfere with blood clotting, Especially If Taken
withSodium warfarin. Pentoxifylline Has rarely been associated with
nausea, headache, anxiety, insomnia, drowsiness, and loss of appetite.
Increased blood pressure can occur, so blood pressure should be
monitored

34. Cilostazol
Cilostazol (Pletal, Otsuka Pharmaceutical Ltd., Tokyo, Japan) gained FDA
approval in 1999 for the treatment of intermittent claudication.
Mechism of action
phosphodiesterase III inhibitor increases cyclic adenosine monophosphate
(cAMP) And Results In A Variety Of Physiologic effects, Including the inhibition
of smooth muscle cell contraction and platelet aggregation. Cilostazol is also
thought to decrease smooth muscle cell proliferation, a process that has been
implicated in coronary artery restenosis after percutaneous transluminal
angioplasty. Finally, cilostazol has a beneficial effect on plasma lipid
concentrations, resulting in a decrease in serum triglycerides and an increase in
HDL. There is also increasing evidence that cilostazol may modulate the
synthesis of vascular endothelial growth factor (VEGF), potentially stimulating
angiogenesis in patients with chronic lower extremity ischemia claudication is
unknown, it is likely a combination of these effects.

35. Cilostazol has a moderate but notable adverse effect profile
that includes headache, diarrhea, and gastrointestinal discomfort. Its
use is contraindicated in patients with Congestive heart failure, and high
plasma drug levels may result when taken in combination with other
medications metabolized by the liver via the cytochrome-P450 pathway.
The adverse effects of cilostazol can be minimized by initiating
A progressiveTreatment regimen, Starting At 50 mg/day for 1 week,
increasing to 50 mg twice daily the following week, and finally achieving
the standard dose of 100 mg twice daily in week 3. Of the
pharmacologic agents used to treat claudication, cilostazol has the
most use. data supporting its clinical

36. Naftidrofuryl
Mechanism of action
Naftidrofuryl is a serotonin antagonist thought to improve aerobic
metabolism in ischemic tissue by stimulating the entry of carbohydrate and
fat into the Krebs cycle at the mitochondrial level, as well as by promoting
peripheral vasodilatation. Studies have documented increased tissue oxygenation,
increased ADP levels, and reduced lactic acid.
It has been widely available in Europe for the treatment of claudication for more
than 20 years. Several trials have demonstrated a clinical benefit ranging from 15%
to 100% improvement in pain-free walking distance, but with no significant effect
on maximal walking distance.
The primary adverse effects of naftidrofuryl include minor gastrointestinal
symptoms, flatulence, and abdominal discomfort. Naftidrofuryl is not currently
approved for use in the United States
The recommended maximum dose is 200 mg three times a day..

40. . Intermittent Pneumatic Compression for
Peripheral Artery Diseas
Intermittent pneumatic compression (IPC) in combination with
appropriate risk factor modification may be a viable method of
treatment for patients with unreconstructable vascular disease, for
those who are physiologically unfit for surgical intervention, or for
patients with intermittent claudication Who Do Not Want Invasive
treatment.
IPC involves sequential Inflation and deflation Of pneumatic pressure
cuffs positioned at the foot or calf. Inflation-deflation rates vary
according to the system used, each applying a pressure up to 120 mm
Hg for 2 to 3 seconds before deflating. This sequence is continued at a
rate of three cycles per minute throughout the treatment session. The
physiologic effects of IPC are thought to be a consequence of three
mechanisms: an increase in the arteriovenous pressure gradient;
reversal of vasomotor paralysis; and enhanced release of nitric oxide

41. Peripheral arterial disease is a marker of systemic atherosclerosis.
Patients with PAD are at high risk for MI and stroke.
Thus, risk factor modification and the prevention of the sequelae of
atherosclerosis is the mainstay of therapy.
Patients must be advised to “stop smoking and keep walking.” In
addition, antiplatelet therapy (e.g., aspirin) is indicated in all patients
with peripheral
Arterial disease in whom there is no contraindication.
Hypertension must be appropriately treated and diabetes mellitus
detected and managed optimally.
The medical management of the symptoms of intermittent claudication
should also be addressed If these are significantly impairing the
patient’s lifestyle.
Summary

42. DECISION MAKING FOR REVASCULARIZATION
Although the TASC II classification system can be helpful in the revascularization
decision making Process (i.e., endovascular or open), atherosclerotic burden as
measured by arteriography is not the sole factor upon which treatment decisions
should be made.
The TASC classification system lacks any features related to degree of ischemia,
wounds, infection, functional status, and conduit availability, all of which are
extremely important determinants of revascularization success. Clearly,
angiographic anatomy alone cannot guide therapy .

43. TASC II
In January 2000, the TASC for the Management of Peripheral Arterial Disease
published a document authored by a working group of representatives from 14
surgical vascular, cardiovascular, and radiologic societies. An updated documen
(TASC II) was published in January 2007.
Recognizing the importance of the pathologic anatomy for decision making, the
TASC working group has classified anatomic patterns of disease involvement
(types A through D) for both the aortoiliac and femoropopliteal .
segments, based on recommended treatment (endovascular versus open
surgery).
The TASC working group advocated endovascular treatment for TASC type A
lesions and open surgical treatment for TASC type D lesions.
For TASC type B and C lesions, the authors concluded that there was insufficient
evidence to definitively recommend one modality over the other.

46. Other Classification
Bollinger Classification
he Bollinger score, which was used by the BASIL trial, utilizes A Scoring System To
Classify Angiographic lesion In Terms of Pattern And severity
There is then an additive component that categorizes severity of lesions into four
classes: plaques, stenoses <25%, stenoses <50%, stenoses >50%, or occlusion.
Graziani Classification
The Graziani scoring system proposed a new morphologic categorization for
disease severity among diabetic patient with CLI. Unlike the Bollinger score, this
system described the frequency of various patterns of disease, and correlated
angiographic findings with transcutaneous oxygen tension
values.

47. LIMITATION OF TASCII
Another critical element of decision making focuses on the determination of
whether or not a patient will experience a meaningful benefit from a
technically successful procedure.
Technical success does not always equate directly with clinical success. As a
result, it is important to assess baseline functional status and the burden of
comorbid conditions.
Patients who are either bedridden at baseline or who have prohibitive medical
risks may significantly more benefit from a treatment that differs from the TASC
II recommendations (based on lesion type alone), to more appropriately balance
the chances for functional limb salvage with the risks of periprocedural
morbidity. An assessment of the available conduit, if bypass is required, is
included in this evaluation. The challenge of decision making in PAD is
accurately assessing each of these factors and synthesizing a plan that optimizes
The Likelihood Of A Favorable Outcome for Each patient.

48. LEGS SCORE WIFI CLSS.

49. LEGS SCORE
The Lower Extremity Grading System (LEGS) was proposed in 2002. The LEGS
score is a standardization tool for decisions regarding revascularization strategies
for PAD.
The LEGS score, which is applicable to patients with either claudication or CLI,
can be applied once the decision to intervene has been made., the score
considers five objective criteria
1—angiographic pattern of disease,
2- presenting complaints,
3-Functional status of the patient,
4-Medical comorbidities,
5-and technical factors.
to recommend the most appropriate interventional therapy (angioplasty, open
surgery, or major limb amputation).

51. WIFI CLASSIFICATION
create a more comprehensive classification system to serve as a more
decision making tool.
the SVS Threatened Limb Classification System, incorporates three major
factors that affect amputation rise and clinical management: wound, ischemia,
and foot infection (WIfI).
In the SVS WIfI system,
1-wounds are classified from grade 0 to grade 3 based on size, depth, severity,
and anticipated difficulty achieving wound healing.
2-Ischemia is classified from grade 0 to grade 4 according to ABI, ankle systolic
pressure, toe systolic pressure, or transcutaneous oximetry.
3-Infection is classified from grade 0 to grade 3 based on simple objective
clinical observations.

53. Traditional treatment recommendations for intermittent claudication have
balanced the risk With the goal of preserving Life And limb.
Many Experts Agree That The Best strategy is to initiate systemic medical
therapy aimed at reducing cardiac morbidity. This strategy is based on the low
relative risk of limb loss in patients with claudication compared with high risk
CVD ,stroke.
Cardiovascular Risk Factor Modification And Medical Therapy As the best initial
treatment for patients with PAD symptoms limited to intermittent claudication.
Revascularization is recommended only in cases of severe disabling claudication
or failure of medical ttt.
Medical treatment for intermittent claudication consists of smoking cessation,
exercise training, and pharmacologic therapy, as already described.

57. Ultimately, the selection of the best method of revascularization
For An Individual With Claudication Is Based On A Balance Between
The Risks Of The Specific Intervention And The Degree And Durability
Of Improvement That Can Be Expected From The intervention.
.
Endovascular therapy is generally preferred to open surgery for most
case of claudication.
However, it is important to note that growing body of evidence suggests
that the concept that an endovascular option “does not burn any
bridges” is false.

58. long-term patency and success using angioplasty were documented In
1_focal arterial lesions
2_larg-diameter with good out flow.
3-were more favorable in nondiabetic patients presenting with claudication than in
those with CLI.
the common iliac artery, a vessel with all the favorable anatomic characteristics
identified by the Atherosclerotic lesions in this segment are usually focal and
possess good outflow. .
conversely, long-segment arterial disease, such as a long superficial femoral
artery occlusion, is probably best treated with open bypass.

60. Critical Limb Ischemia CLI is defined as chronic lower extremity PAD with either
ischemic rest pain or the tissue loss (nonhealing ulcers or gangrene) .
Typically, symptoms have to be present for more than 2 weeks and associated with an
ankle pressure of less than 50 mm Hg or a toe pressure of less than 30 mm Hg.ABI less
than .0,4.
Decision making for CLI commonly poses three dilemmas:
1-whether to treat medically or with intervention;
2-if treating with intervention, whether to amputate or revascularize;
3-and if revascularizing, whether to employ endovascular intervention Or Open surgery.

61. Revascularization is an essential component in the relief of CLI.
1-Although medical adjunctive to revascularization i.e risk factor
modification may be important to slow the progression of systemic
atherosclerotic disease, they play a secondary role in the treatment
of the severely ischemic limb.
2-In those rare cases in which vascular disease is truly
unreconstructable, a trial of intensive wound care, preferably at a
dedicated wound care center, may yield satisfactory healing rates
for motivated patients with superficial ulcerations, or it may avoid
major limb amputation in high-risk patients who are. approaching
the end of life

62. For the majority of patients with CLI, revascularization is
the interventional treatment of choice. However, primary
limb amputation continues to be required in 10% to 40% of
CLI patients because of
1-overwhelming infection
2-unreconstructable vascular disease.
Unreconstructable vascular disease accounts for nearly
60% of patients requiring secondary amputation. In many
of these cases, revascularization has failed because of
progression of disease, recurrent ischemia, or persistent
Infection Or Necrosis Despite A Patent revascularization.
.

63. Patients too sick or infirm to realize the benefit of limb revascularization should
undergo palliative primary above knee amputation. However,. Obviously, a
non ambulatory, elderly, nursing-home patient with knee contractures and
neuropathic heel ulcers would qualify for a palliative above-knee
amputation.
limb amputation and prosthetic rehabilitation can be an excellent option,
offering an expedient return to a reasonable QoL in selected cases.
Maintenance of ambulation can exceed 70%, and maintenance of
independence Can exceed 90% in young patient.
For patients who are minimally ambulatory, with multiple comorbidities, the
decision is less clear cut. An individualized judgment is required to
determine whether these patients will be better served by primary
amputation or limb revascularization.

64. Endovascular Treatment
versus Open Surgery
CLI is usually associated with multilevel arterial disease that is not
ideally suited to percutaneous intervention. Diffuse, extensive PAD
causing CLI in both aortoiliac and femoropopliteal locations and is best
treated by surgical bypass according to TASC.
However, the primacy of surgical bypass for CLI management has been
challenged in recent years and has become the subject of intense debate.
Those who favor open surgery for the treatment of CLI often cite
superior reconstruction patency and increased durability.
However, open surgery is usually associated with higher perioperative
morbidity and longer hospitalization.
Also, long-term postoperative graft surveillance is necessary to maintain
a patent infrainguinal bypass.

65. cont.
hose who favor interventional treatment cite the low
morbidity and mortality associated with a procedure
that is usually performed on an outpatient basis.
Although limited reconstruction patency rates
associated with endovascular treatment, especially for
the high-risk lesions often encountered in CLI, they
arguethat restenosis rarely jeopardizes subsequent
surgery.

66. Situational Perfusion
Enhancement
They argue that there is a population of asymptomatic patients with subclinical
lower extremity ischemia and very low perfusion pressures. These patients
become symptomatic only when they develop incidental foot ulceration and do
not have the circulatory reserve to heal.
An increase in arterial perfusion, even transiently, usually allows healing of the
ulcer. Once the ulcer is healed, maintenance of enhanced perfusion is not
critical, and recurrent ischemia is usually well tolerated as the patient resumes
the subclinical ischemic state.

67. When should open surgery be the
initial option for CLI?
P.F. Lawrence, A. Chandra EJVES November 2009
Take home message:
Parameters for “ open first” revasc. approach:
-Anatomical: CFA, infragenicular pop. and trifurcation
-Pathological: extrinsic compression as in pop.
Entrapment, cystic advintitial, exostoses
-Physiological: extensive gangrene
-Durability: young patients

70. ANGIOGENESIS FOR PERIPHERAL ARTERIAL
DISEASE
For patients with CLI who lack a revascularization option, novel alternative
therapies may offer benefit. Angiogenesis is a naturally occurring phenomenon
in response to tissue ischemia, and is promoted by proangiogenic factors,
including VEGF, fibroblast growth factor, hypoxia-inducible factor-1α, and
hepatocyte growth factor.
The concept of therapeutic angiogenesis entails efforts to increase the
concentration of proangiogenic factors thereby stimulating growth of new blood
vessels from preexisting blood vessels to treat ischemic disease; this may be
accomplished by administration of recombinant proteins or gene therapy that
induces overexpression of these factors. Therapeutic angiogenesis may also be
induced by implantation of endothelial progenitor cells.

71. angiogenesis
The mechanism by which angiogenesis improves limb perfusion is through the
enlargement of collateral blood vessel and possible direct stimulation of wound
healing by growth Factor.
Many different growth factors involved in angiogenesis have been individually tested
in clinical trials. Because the half-life of the recombinant protein is short, most trials
have used gene therapy to allow for a more prolonged expression of the protein.
Growth factors that have been studied include various VEGF isoforms, fibroblast
growth factor (FGF), hepatocyte growth factor (HGF), and the transcription factor,
hypoxia-inducible factor-1α.
Gene therapy has usually been delivered in either a plasmid or an adenovirus via
intramuscular injection into the ischemic limb.

76. Stem Cell Therapy
Stem cell therapy is another developing technique to induce therapeutic
angiogenesis.
Autologous stem cell therapies have used bone marrow mononuclear cells or
endothelial progenitor cells obtained from bone marrow harvest or, less
frequently, from circulating peripheral blood stem cells. Endothelial progenitor
cells .
can be identified by cell sorting for CD34-positive, VEGF receptor-2–positive
cells. Once concentrated, the cells can be injected into the ischemic limb to
induce angiogenesis.
injection of bone marrow–derived mononuclear cell injections resulted in a
significant increase in ABI and tcPO compared with controls.