The ABI provides objective data about arterial perfusion of the lower limbs (Table 45-1). Pressures are obtained using blood pressure cuffs placed around the patient’s lower calves or ankles. A hand-held Doppler detects systolic blood movement in the dorsalis pedis and the posterior tibial arteries. The brachial (arm) pressure is measured in the standard fashion. In normal individuals, there should be no inter-arm systolic pressure gradient, or this pressure difference should be minimal (<12 mm Hg). If the arm blood pressures are not equal, a subclavian or axillary arterial stenosis is present in the arm with the lower pressure. The higher of the two blood pressures is then used for subsequent blood pressure ratio (ABI) calculations. In a healthy individual, due to peripheral amplification of the pulse pressure, the ankle pressure should be higher than the brachial arterial systolic pressure; the normal ankle-to-arm systolic blood pressure ratio is, therefore, greater than 1.0. ABI values are considered to be low-normal when they are less than 1.0 and more than 0.90, mildly diminished when they are less than 0.90 and more than or equal to 0.80, moderately diminished between 0.50 and 0.80, and severely decreased when less than 0.50. An ABI identifies individuals who are at risk for developing rest pain, ischemic ulcerations, or gangrene, and it is a marker of generalized atherosclerosis (1). The risk for death, usually from a cardiovascular event, increases dramatically as the ABI decreases. The 5-year mortality rate in patients with an ABI less than 0.85 is 10%; when the ABI is less than 0.40, the 5-year mortality rate approaches 50% (2,3).

The ABI is not accurate when the systolic blood pressure cannot be abolished using a blood pressure cuff. The incidence of noncompressible (artifactually high), calcified conduit arteries is highest in diabetic, elderly, and chronic renal failure patients. Despite high recorded systolic pressure, these individuals may have severe disease. Patients with severely stenotic or occluded iliofemoral arteries may also have a normal ankle pressure if sufficient collateral circulation is present. If such patients have symptomatic evidence of arterial disease, the test should be repeated after exercise. Other diagnostic tests (segmental pressure measurement, Doppler waveform analysis, or pulse volume recording [PVR]) may also be performed to rule out significant arterial occlusive disease.

Arterial pressures can be measured using blood pressure cuffs placed at various levels (upper thigh, lower thigh, upper calf, and lower calf above the ankle) sequentially along the limb. Systolic blood pressures obtained in this manner can be indexed relative to the brachial artery pressure in a manner analogous to the ABI. Segmental pressure analysis is often used to determine the location of arterial stenoses. The presence of a significant systolic pressure gradient (>10 to 15 mm Hg) between the brachial artery pressure and the upper thigh systolic pressure usually signifies the presence of aortoiliac obstruction. A pressure gradient located between the upper and lower thigh cuff signifies obstruction in the superficial femoral artery. A gradient between the lower thigh and upper calf cuff indicates distal superficial femoral or popliteal artery obstruction. A gradient between the upper and lower calf cuffs identifies infrapopliteal disease. Gradients of 10 to 15 mm Hg between adjacent sites may represent physiologically important obstruction. Segmental pressure measurements may be artifactually elevated or unpredictable in patients with calcified or noncompressible vessels (as described with ABI). In such individuals, Doppler waveform analysis, arterial duplex studies, or transcutaneous oximetry studies may be of benefit.

PVR is used to assess the arterial pulsatility of the limb (4). An external pneumatic cuff is filled to a low pressure (typically 40 to 60 mm Hg). The pneumatic cuff is connected by a flexible hose to a pressure transducer. The blood ejected from the left ventricle during cardiac systole causes a transient distention of the limb, which in turn produces a transient rise in cuff pressure. The cyclic changes in cuff pressure with each heartbeat provide an index of arterial pulsatility. Measurements are typically made at multiple levels along the limb (as described with segmental pressures). The tracings are analyzed to determine whether the waveform changes shape or pulse dampening occurs at a particular level (5). When an altered pulse volume waveform is present, it can be inferred that there is a hemodynamically significant lesion proximal to the site of the cuff.

Photoplethysmography is a noninvasive optical technique used to measure changes in the cutaneous microcirculation by detecting the reflection of infrared light. The probe contains infrared light sources and a photoelectric cell to measure reflected light. Blood is more opaque to red light than the other components of the skin and subcutaneous tissue. The amount of blood under the source beam affects the absorption of light. Photoplethysmography can be used in two ways. Using the alternating current component, the pulses recorded resemble those obtained with a strain gauge. These tracings can be used to show distal arterial disease in the hands or feet. The photoelectric cell also documents changes in extremity flow, with positional changes of the arm. This may be used to evaluate possible arterial compression at the thoracic outlet. A second method is the direct current coupling component. The DC component of the signal varies slowly and reflects variation of total blood volume of the examined tissue. With this mode, blood volume changes are recorded without major distortion. This application is used to record venous refilling after exercise (see “Venous Plethysmography”).

Waveform analysis can provide important information that may confirm arterial patency or identify occlusive lesions (Fig. 45-1). In many circumstances, a change in blood velocity or pulse waveform such as a change from a triphasic to monophasic waveform provides reasonable, accurate information about the location and extent of specific lower extremity lesions. Doppler waveform analyses are reliable even in highly calcified vessels that are not amenable to pressure determinations.

Transcutaneous oximetry (TcPO₂) determinations provide a very sensitive means to assess skin perfusion and the potential for cutaneous healing at a specific site (6). TcPO₂ measurements are relatively simple and reproducible. Surface oxygen-sensing electrodes calibrated to 45°C are attached to the skin and allowed to equilibrate before recording the TcPO₂ value. The feet are then elevated to 30 degrees for 3 minutes, and the TcPO₂ values are again recorded. Normal TcPO₂ values are greater than 50 to 60 mm Hg. TcPO₂ values less than 20 to 30 mm Hg suggest severe local ischemia and bode poorly for future wound healing (7). A decrease in the TcPO₂ value of 10 mm Hg with an elevation is significant (6) and suggests tenuous perfusion.

Duplex scanning using B-mode imaging combined with directional Doppler can visualize and assess arterial aneurysms and detect flow velocity changes at sites of localized stenosis or occlusion. Duplex studies can assess plaque morphology, surgical graft patency, and establish the presence of arteriovenous fistulae. This technique requires a technically proficient examiner, may require extensive time for a complete examination, and is significantly more expensive than most physiologic noninvasive testing methods. Duplex scanning is particularly helpful in assessing proximal iliofemoral stenosis that may be amenable to angioplasty, providing follow-up data to assess continued patency of both venous and prosthetic arterial grafts, and evaluating the patency of prior angioplasty sites or intravascular stents.

Technological advances are enabling computed tomography (CT) and magnetic resonance angiography (MRA) to replace conventional angiography as a means of identifying arterial stenoses and occlusions.

Contrast angiography has been the traditional “gold standard” for lower extremity arterial evaluation. Angiography remains the definitive approach for preoperative evaluation in patients requiring revascularization. Pre-procedure arteriography is an essential part of endovascular procedures. Digital subtraction angiography allows enhanced visualization of the structures of interest.

Conventional angiography is associated with an overall minor and major complication rate of about 8%. Most of the complications result from the side effects of the iodinated contrast material and access site complications. Patients with preexisting renal insufficiency, diabetes, or dehydration are at greatest risk for contrast-induced renal failure. To minimize the risk of nephrotoxicity, bicarbonate hydration and oral acetylcysteine can be used starting the day prior to the procedure. The risk for contrast reaction varies from 0.04% to 0.22% (11,12). The arterial puncture necessary for the study may be associated with bleeding, hematoma, pseudoaneurysm, and pain at the site. There is also modest risk for contrast allergy, which can be associated with anaphylaxis, or death, and contrast-induced worsening of renal function (11).

Continuous wave Doppler (described previously) is also used clinically to test the integrity of the venous system (Table 45-2). This method can identify the presence of venous obstruction or incompetence, quantify severity of the venous disease, and roughly localize these abnormalities to a particular segment of the limb. The venous flow signal is obtained at several sites in the limb. Normal venous flow is spontaneous and phasic with respiration. With continuous wave Doppler, the patency, spontaneous flow, phasicity, augmentation, competency, and pulsatility of the venous flow are determined and graded. Obstruction of a vein is characterized by the absence of normal spontaneous venous flow or by the loss of phasic variation with respiration. If the Doppler probe is placed directly over an obstruction, there is absence of spontaneous flow. If the probe is placed below the site of obstruction, there is a loss of phasic change in the venous flow with respiration (a monophasic low-frequency signal). Several maneuvers (deep breathing, Valsalva, and distal compression of the calf or forearm) can produce augmentation of venous flow. Because continuous wave Doppler provides subjective information, if positive for obstruction, findings should be followed by an objective test.

Venous Doppler ultrasound examination is portable and inexpensive. Validation studies of continuous wave Doppler ultrasound for lower extremity deep vein thromboses (DVT) report a sensitivity of 31% to 96% and a specificity of 51% to 94% (13,14). Limitations with venous Doppler ultrasound include (a) the need for examiner expertise; (b) only thrombi in the major deep veins in direct continuity with the heart can be detected (an isolated thrombi in
tributaries such as the internal iliac, deep femoral, peroneal, gastrocnemius, and soleus veins will likely be missed); (c) to be detected, the thrombus must produce a flow disturbance (nonocclusive thrombi may be missed because venous flow is present in anatomically adjacent collaterals); and (d) external compression of the vein cannot be distinguished from internal thrombosis. Because of these limitations, continuous wave Doppler ultrasound has largely been replaced by venous duplex scanning for the diagnosis of DVT (combines Doppler principles with real-time B-mode and color-flow ultrasound imaging).

Plethysmography is a noninvasive method of detecting blood volume changes in an extremity (Fig. 45-3). Plethysmographic techniques have been developed to measure the changes in limb volume that occur when venous return is enhanced (venous insufficiency) or impeded (venous obstruction). With normal venous outflow, positional change (leg elevation) or release of an externally inflated cuff results in rapid emptying of the leg veins. If the valves are competent, refilling occurs in an antegrade fashion through the arteries and capillaries. In normal individuals, this takes a minute or more.

With venous incompetence, the leg volume returns to baseline more rapidly than normal. If the incompetence is primarily superficial, tourniquets placed around the leg or using a finger to compress an incompetent superficial vein will normalize the refilling time. In venous obstruction, the peripheral venous pressure and baseline venous volume are elevated (increased venous outflow resistance). In this case, leg elevation or a rapid release of the cuff results in slower emptying of the leg veins.

Segmental plethysmography uses a sleeve to demonstrate changes in limb volume. Sequential timed inflation and deflation of a proximal cuff produces changes in limb volume, which are measured to determine the venous capacitance and maximal venous outflow. The presence of a proximal lower extremity DVT causes (a) minimal change in the limb volume with cuff inflation and (b) a decreased change in limb volume when the cuff is released.

Duplex ultrasound (a) directly visualizes and locates intraluminal obstruction; (b) assesses the characteristics of venous flow distal to the inguinal ligament; (c) identifies the presence of collateral veins around an obstructed venous segment; (d) permits direct detection of valvular reflux; (e) allows visualization of specific venous valves and valve leaflet motion; (f) quantitates the degree of incompetence; (g) locates and assesses veins before harvest for bypass procedures; (h) evaluates venous perforator incompetence; and (i) evaluates conditions that may mimic venous disease. Duplex scanning has become the method of choice for testing individual veins of the superficial, deep, and perforating systems.

D-Dimer is a global indicator of coagulation activation and fibrinolysis. D-Dimer level is measured in plasma by use of well-standardized assays that are widely used for the diagnosis of acute venous thromboembolus (VTE). In patients with a first VTE, measuring D-Dimer level allows a global assessment of their thrombotic tendency and a stratification into high-and low-risk patients with regard to risk of recurrence. Patients with a first spontaneous VTE and a D-Dimer level of less than 250 ng/mL after withdrawal of oral anticoagulation have a low risk of VTE recurrence (15). In patients with thrombosis with a very low risk of recurrence, extensive screening for thrombophilic risk factors may be unnecessary.

Lower extremity contrast venography remains a powerful, but decreasingly used tool, in the evaluation of both acute and chronic DVT. At this time, ascending leg venography is rarely used to confirm acute DVT. With advances in duplex ultrasonography, venography has been largely replaced by duplex scanning to evaluate patients with suspected deep venous obstruction or incompetence. It is indicated when a high clinical suspicion of thrombosis is present and noninvasive testing is negative or equivocal (16). In chronic venous disease, ascending venography demonstrates the location and extent of postthrombotic disease, as manifested by occlusion, venous recanalization, collateral channels, and superficial varicosities. Ascending venography may also help with planning of endovascular and open surgical procedures such as iliac and Inferior vena cava (IVC) recanalizations and venous bypass grafts. Ascending contrast venography is performed primarily in patients with significant chronic deep venous occlusive disease who are candidates for endovascular treatment with stents, surgical venous bypass, venous valve repair, or valve transplantation. Descending venography is used in concert with ascending venography to distinguish primary valvular incompetence from thrombotic disease. Descending venography identifies the level of deep vein reflux and evaluates the morphology of the venous valves. With decreasing experience using this technique, the “gold standard” is uninterpretable in 5% to 15% of patients (17). Unfortunately, the numbers of poor-quality examinations will likely increase in the future as the need for venography continues to decline.

The two advantages of CT in venous imaging are the speed and resolution of image acquisition. The disadvantages include radiation exposure and the necessity for administration of iodinated contrast material. Patients with a significant allergic reaction to iodinated contrast material or decreased renal function should be evaluated with alternate imaging techniques.

The effectiveness of MRI for detection of DVT has been compared with that of contrast venography in a number of trials. Sensitivity and specificity values as high as 100% have been reported (18). MRI can also be used to distinguish acute from chronic DVT. Because MRI is more expensive than a duplex scan, it is rarely used to diagnose DVT.

Lymphoscintigraphy, performed by injecting a radioactive colloid and observing uptake into the lymphatic system, has become the standard evaluation tool to establish lymphatic flow patterns (19,20). This test can be performed in both upper and lower extremities by injecting the colloid between the digits of the hands or toes, respectively. Lymphoscintigraphy assesses the most basic function of the lymphatic system, namely the clearance of interstitial macromolecules that are too large to reenter the blood capillaries directly. When lymphedema is present, the images often show a highly characteristic dermal backflow pattern or re-routing of tracer away from the main lymphatic trunks and into fine collateral lymphatic vessels of the skin. Images may also suggest distal or proximal lymphatic obliteration, hyperplasia, or aplasia/hypoplasia of lymphatic vessels. Because lymphatic disease occurs so rarely, the skills for administration and accurate interpretation of this test are often available only in larger medical centers where higher volumes of testing occur.

Lymphangiography should not be considered unless specific surgical intervention is being contemplated. It is invasive and may damage the (remaining) lymphatic vessels (21).

The studies described earlier help distinguish venous disease from lymphatic disease. CT scan of the abdomen is helpful to discover the underlying obstructive pathology and should be part of an evaluation of new edema in the lower extremity (22,23). MR imaging is useful in studying the swollen limb without obvious etiology because fluid, fat, soft tissue, and tumor can all be identified (24). Ultrasound imaging may provide accurate measurement of clinical lymphedema in the future.

The management of patients with intermittent claudication has traditionally focused on relief of symptoms. The goals of medical care should be to reduce cardiovascular risk and alleviate symptoms of intermittent claudication. Medical therapies can effectively modify both the natural history of arthrosclerotic lower extremity arterial occlusive disease and significantly reduce the morbidity of this disorder.

Screening for elevated homocysteine should be considered in young patients with peripheral arterial disease (PAD). An elevated plasma homocysteine level is emerging as a prevalent and strong predictor for atherosclerotic vascular disease in the peripheral, coronary, and cerebral vessels and is recognized as an independent predictor of PAD (27). An increased plasma total homocysteine level confers an independent risk for vascular disease similar to that of smoking or hyperlipidemia. It further increases the risk associated with smoking and hypertension (28). Elevated homocysteine levels can be lowered by folic acid and other vitamin supplementation; however, no studies to date have examined how this treatment affects atherosclerosis or intermittent claudication symptoms (29).

Among apparently healthy men, elevated baseline levels of C-reactive protein (CRP), a marker for systemic inflammation, may predict future risk for developing symptomatic peripheral arterial occlusive disease. CRP may serve as a molecular marker for underlying systemic atherosclerosis (30).

Risk factor management. All patients presenting for treatment of peripheral arterial occlusive disease should have their risk factors rigorously assessed (31). Patients with known PAD should be treated aggressively with a combination of a HMG CoA reductase inhibitor (statin), an angiotensin-converting enzyme (ACE) inhibitor, an antiplatelet agent, and a β-blocker (if there is a history of coronary disease). They should also control their blood pressure and blood sugar level. Smokers should be encouraged to stop smoking (32). On average, an age-matched control group has an all-cause mortality rate of 1.6% per year. This rate increases to 4.8% per year for patients with PAD. Cardiovascular mortality rates are similarly affected, with an overall event rate of 0.5% per year in controls and 2.5% per year in patients with PAD. The presence of PAD is an independent risk factor for mortality even when other known risk factors are controlled (32, 33, 34, 35). Treatment needs to focus on both the effects of atherosclerosis in the peripheral circulation
and the systemic nature of the disease. Appropriate therapy should be instituted to decrease the risk for both peripheral progression and cardiovascular mortality.

The increased cardiac event rate in patients with PAD underscores the importance of intensive medical management to reduce the risks for cardiovascular morbidity and mortality.

Diabetic management. The effect of diabetic management on large vessel arterial occlusive disease has not yet been evaluated in a controlled prospective clinical trial. Optimal diabetic management is presumed to improve the rate of lower extremity disease progression and to decrease the incidence of wound infection, gangrene, and amputation (36).

Nicotine cessation. Cigarette smoking is an exceptionally positive risk factor for lower extremity PAD. It is 2 to 3 times more likely to cause lower extremity PAD than coronary artery disease (37). Cigarette smoking nearly doubles the risk for progression of peripheral arterial occlusive disease, independent of other associated risks factors (31). Patients should be informed that continued tobacco use is likely to accelerate disease progression and cause progressive symptomatic worsening. Eighteen percent of patients with claudication who continue to smoke cigarettes develop rest pain over the subsequent 5 years of observation (38). In contrast, in those patients who stop smoking, the development of rest pain is exceedingly rare. The 5-year mortality rate for patients with claudication who continue to smoke may be as high as 40% to 50%.

Lipid management. Effective lipid management should be considered a mandatory component of the medical therapy of patients with objective evidence of atherosclerotic peripheral arterial occlusive disease. Patients should be treated with diet and pharmacologic therapy to achieve low-density lipoprotein (LDL) cholesterol levels of less than 100 mg/dL (39). Statins have favorable effects on multiple interrelated aspects of vascular biology important in atherosclerosis. In particular, they have beneficial effects on inflammation, plaque stabilization, endothelial dysfunction, and thrombosis. Statins have also been shown to be beneficial in acute vascular events.

Hypertension management. The goal of treated hypertension in patients with PAD should be similar to that in patients who have other cardiovascular disease. Antihypertensive therapies should be administered to hypertensive patients with lower extremity PAD to achieve a goal of less than 140 mm Hg systolic/90 mm Hg diastolic (nondiabetics) or less than 130 mm Hg systolic/80 mm Hg diastolic (diabetics and individuals with chronic renal disease) to reduce the risk of MI, stroke, congestive heart failure, and cardiovascular death (36,37).

ACE inhibitors. ACE inhibitors have been shown to reduce cardiovascular morbidity and mortality rates in patients with PAD by 25% regardless of the presence or absence of hypertension (28).

Antiplatelet therapy. Antiplatelet therapy may decrease the rate of atherosclerotic disease progression, decrease the incidence of thrombotic events in the limbs, and decrease the rate of adverse coronary and cerebral vascular ischemic events. Aspirin in doses of 75 to 325 mg is recommended as safe and effective antiplatelet therapy to reduce the risk of MI, stroke, or vascular death in individuals with atherosclerotic lower extremity PAD (36). Patients with documented arterial occlusive disease may benefit from antiplatelet therapy unless otherwise contraindicated. The relative benefits of newer antiplatelet drugs on limb ischemic event rates and patient survival are presently under investigation. Ticlopidine and clopidogrel are thienopyridines that selectively inhibit the adenosine diphosphate (ADP) platelet receptor with no direct effects on arachidonic acid metabolism (40,41). Ticlopidine has been evaluated in patients with intermittent claudication. In a multicenter, randomized, controlled trial of patients undergoing treatment with ticlopidine versus placebo (STIMS), the need for subsequent vascular surgery was reduced by about 50% over a 7-year time period (42). The use of ticlopidine has dropped markedly owing to blood aplastic side effects. In platelet-aggregation studies, clopidogrel, 75 mg once daily, produced inhibition of ADP-induced platelet aggregation equivalent to that of ticlopidine, 250 mg twice daily. Long-term administration of clopidogrel in patients with atherosclerotic vascular disease has been reported to be more effective than aspirin in reducing the combined risk for ischemic stroke, myocardial infarction, or vascular death (43).

Prostaglandins. Prostacyclin and its analogues prostaglandin E₁, prostaglandin I₂, and iloprost (a prostaglandin I₂ analogue) have been shown to improve perfusion through (a) inhibition of platelet aggregation, (b) decreased leukocyte migration and activation, (c) vasodilation (possibly through an effect on resting sympathetic tone), and (d) profibrinolytic effects. Iloprost is typically infused for 6 hours per day for 28 days (2 ng/kg/min). Iloprost was shown to decrease the probability of dying or requiring major amputation during treatment and the subsequent 3 to 6 months (44). Oral vasodilator prostaglandins such as beraprost and iloprost are not effective medications to improve walking distances in patients with intermittent claudication (36).

Vasodilator drugs. In general, vasodilator drugs do not improve symptoms in patients with arterial claudication. Direct-acting vasodilators have minimal effect at the focal atherosclerotic site. Vasodilator drugs do not vasodilate lower extremity collateral vessels. In addition, this class of medications may elicit a fall in blood pressure and limb perfusion pressure if a preferential vasodilatory effect occurs in other nondiseased circulation (45).

β-Blockers. Although β-blockers were previously believed to have detrimental clinical effects in patients with claudication, clinical trials have demonstrated a symptom-neutral effect for these agents in most patients (46). Because β-blocker therapy may be efficacious for the treatment of associated coronary artery disease or myocardial infarction, these drugs do not need to be empirically withdrawn from the patient with claudication.

Agents for intermittent claudication. Cilostazol inhibits the action of phosphodiesterase and increases the amount of intracellular cyclic adenosine monophosphate. This results
in significant platelet and vasodilatory activity as well as antiproliferative properties. Since antiplatelet and vasodilatory drugs have been shown to have no positive effect on claudication-limiting walking distance, the mechanism by which Cilostazol achieves improvement in PAD patients remains speculative (47). Cilostazol (100 mg orally two times per day) is indicated as an effective therapy to improve symptoms and increase walking distances in patients with lower extremity PAD and intermittent claudication (in the absence of heart failure) (36). This medication is contraindicated in patients with congestive heart failure.

Pentoxifylline has received variable reports of success in patients with arterial occlusive disease (48). Minimal efficacy and caffeine-like side effects limit use of this medication.

Antioxidants. Antioxidant agents may render LDL cholesterol resistant to oxidation and make that lipid fraction less atherogenic. In addition, antioxidants may improve endothelium-dependent vasodilation by reducing oxidative degradation of nitric oxide (49). A number of descriptive and case-controlled studies have shown an association between antioxidant agents (vitamins E, C, and β-carotene) and reduction in cardiovascular events (50). Further studies are required to evaluate if oxidative stress and antioxidant status are implicated in the clinical progression of disease and to define the formulation and dosing of antioxidant vitamins. Although the basic science is promising, large randomized controlled trials have yet to show a compelling agent that will bring these clinical effects to fruition.

In summary, although there are few widely accepted pharmacologic interventions for PAD, current recommendations are that all PAD patients should receive antiplatelet therapy, stop smoking, exercise, and be screened and treated for hyperlipidemia, hypertension, diabetes, and hypercoagulability in accordance with national guidelines and community standards (51).

General self-care measures. Patients with PAD should be instructed to wear protective footwear at all times (never walk barefoot or in socks) and monitor their extremities carefully for redness or skin breakdown. Extremes of temperature should be avoided. The feet should be washed carefully with mild soap and warm water. Drying is best performed by blotting or patting with a soft clean towel (rubbing should be avoided because it may injure the skin). The skin between the toes should be carefully dried to avoid maceration. Emollients without preservative or perfume should be used (avoid between the toes) to prevent cracking of the skin. Proper footwear, which avoids producing areas of point pressure, should be used. Whenever new shoes are purchased, the patient should gradually (over a period of a week) wear-in shoes to make sure there are no areas of point pressure with the new footwear. Warm outer footwear should be used in the winter to protect against cold injury.

Decreased activity secondary to symptomatic lower extremity arterial occlusive disease can result in deconditioning, which further contributes to disease impairment. Deconditioning may also be “iatrogenic” as a result of a prolonged period of limited mobility to avoid trauma to ischemic wounds.

Exercise. Regular exercise training produces a reduction in the inflammatory markers associated with endothelial damage (37). Evidence suggests that patients following an exercise regimen improve both their claudication distance and cardiovascular risk profile (51). Exercise training may elicit improvements in maximal walking time of 25% to 200% (52). On average, patients can expect to double their intermittent and absolute claudication distances. Exercise training has been postulated to improve performance in patients with claudication by directly augmenting limb flow, improving blood viscosity, biomechanically improving the efficiency of gait, and altering the ischemic pain threshold or tolerance. To optimize the benefits of an exercise program, patients should receive a structured claudication exercise rehabilitation program for at least three sessions weekly over a period of 12 weeks (52, 53, 54, 55, 56). Continued improvement can be seen over 24 weeks of training. Strength training, whether sequential or concomitant, does not augment the response to a walking exercise program (57). The optimal exercise program for improving claudication pain distances in patients with PAD is intermittent walking to near maximal pain during a program of at least 6 months. Such a program should be a part of the standard medical care for patient with intermittent claudication (58). Patients should be instructed to walk until claudication occurs, rest until it subsides, and continue, repeating the cycle for 1 hour each day. Improved walking performance has also been demonstrated through upper limb aerobic exercise training in patients with PAD (59).

Molecular therapies to induce angiogenesis are appealing in the claudicant population because: ischemia is subacute, time is available for angiogenesis to occur, and collateral development is associated with increased walking distance. Molecular therapies that result in increased levels of vascular endothelial growth factor, fibroblast growth factor, and hepatocyte growth factor have been used in claudication populations. The RAVE trial (regional angiogenesis with vascular endothelial growth factor in PAD) concluded that a single IM administration of endoviral vascular endothelial growth factor was not associated with improved treadmill exercise performance or quality of life over placebo (60).

Previously, surgical revascularization was considered for patients with rest pain, pending tissue loss, or significant limitations of lifestyle who failed medical treatment. Endovascular intervention coupled with aggressive proactive medical management is replacing these conventional paradigms (51).

Endovascular. Endovascular therapy is a broad term that encompasses several treatment modalities: percutaneous transluminal angioplasty (PTA), stenting, stent-grafting (e.g., Viabahn and aortic stent grafts), atherectomy, cryoplasty, cutting-balloon angioplasty, and laser-directed atherectomy.
PTA is indicated for focal stenosis or short segmental occlusions in which the adjacent vessels are relatively free of disease. A localized stenosis of the common iliac artery (<5 cm in length) is the most favorable situation for angioplasty (61). Iliac PTA for focal iliac disease is also a valuable adjunct when combined with distal surgical revascularization in appropriate patients with multilevel disease (62). Angioplasty is a controlled injury to the vessel wall (51). Smooth muscle cell proliferation within the media (normal <1%), increases to more than 20% within 48 hours after angioplasty. After balloon angioplasty, there is thrombosis formation, intimal hyperplasia development, elastic recoil, and remodeling. In contrast after stent placement, elastic recoil and remodeling are eliminated, and thrombosis followed by intimal hyperplasia is the main contributor to in-stent restenosis (51).

Endovascular stents were introduced to help resolve the problems of residual stenosis, elastic recoil, flow-limiting arterial dissection, and to improve patency rates after balloon angioplasty. The response of a vessel to a stent is dependent on the stent design, length, composition, delivery system, and deployment technique (51

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