Lower extremity peripheral arterial disease (LEPAD) is a major cause of poor quality of life, disability, and significant morbidity and mortality in the United States.^{1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17} In this chapter, LEPAD is used to refer to any arterial disease affecting the lower extremity, including occlusive, aneursymal, and vasculitic disease states. Even when asymptomatic, LEPAD has been shown to decrease mobility and bone mineral density^8,9,12,18; leads to foot ulcers and amputations^8,19; and be a strong predictor of subsequent cardiovascular (CV) disease, nonfatal CV events (e.g., myocardial infarction and stroke), and mortality.^6,10,20 Standard therapy for LEPAD should include antiplatelet therapy and be directed at control of risk factors including smoking cessation, lipid management, strict diabetic therapy, and control of blood pressure²¹ in attempts to stop progression of the systemic atherosclerotic process. Current therapy on symptomatic disease includes exercise therapy, antiplatelet medications, and a variety of percutaneous interventional and surgical procedures. Therefore, early diagnosis and appropriate therapy for LEPAD can significant improve quality of life and decrease significant morbidity and CV mortality.

This chapter will attempt to concisely

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  review the epidemiology and determined risk factors of LEPAD,

  
  
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  discuss the embryologic development and subsequent normal and variant anatomic features of LE vasculature,

  
  
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  summarize the classification and grading schemata for LEPAD,

  
  
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  discuss the pathophysiology underlying LEPAD and limb ischemia,

  
  
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  review the common and uncommon etiologies of LEPAD,

  
  
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  discuss the typical clinical presentation, physical examination findings, and natural history of LEPAD,

  
  
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  summarize the various diagnostic modalities for LEPAD,

  
  
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  review the medical and nonpharmacologic therapies for LEPAD,

  
  
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  discuss the percutaneous and surgical revascularization procedures for LEPAD and outline the appropriate clinical indications for use of each therapy,

  
  
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  discuss more specific therapy for critical limb ischemia (CLI), and

  
  
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  summarize the current investigations and future directions in the treatment of LEPAD.

Prevalence

It is without question that LEPAD is a common disease process affecting a significant portion of the adult population. There are a reported 413 000 discharges per year with chronic peripheral arterial disease (PAD), 88 000 inpatient lower extremity arteriographies, and nearly 30 000 discharges involving patients who had undergone embolectomy or thrombectomy of the lower limb arterial vasculature.²² Numerous epidemiologic studies have been performed in attempts to accurately quantify the prevalence of LEPAD in the adult population and although these studies have reported a variety of rates, most experts and consensus statements agree that up to 12 million individuals in the United States are affected by PAD. The variability found in these numerous studies evaluating LEPAD is widely attributable to the differing clinical presentations (namely asymptomatic individuals), clinical definitions, diagnostic modalities, or specific patient subpopulations used in each study.

The Framingham Heart Study was the first to address the prevalence of LEPAD in a large population sample in 1948. The initial and long-term follow-up data, which based the diagnosis of LEPAD exclusively on intermittent claudication symptoms, reported the prevalence of LEPAD to be 7.3%. In addition, this study was the first to report the incidence of LEPAD was higher in the elderly, a finding which has been consistently reproduced. However, their data suggesting a higher incidence in males has not been as well validated.^16,23,24 However, the overall prevalence rates reported in this cohort study is a gross underestimate, since LEPAD often may present in asymptomatic forms that can only be detected via noninvasive or invasive imaging. Therefore, more recent studies have used other modalities to diagnosis LEPAD in further attempt investigate the prevalence of LEPAD in the general and specific patient populations. These studies have revealed a number of epidemiologic characteristics and disease comorbid risk factors that result in a higher prevalence in certain patient populations.

One such study attempted to elucidate the prevalence of large-vessel and small-vessel LEPAD in a small population. Their assessment involved traditional questionnaires, physical examination, and noninvasive testing (segmental blood pressure, flow velocity, postocclusive reactive hyperemia, and pulse reappearance half-time). Results revealed a nearly 12% and 16% prevalence of large- and small-vessel lower extremity disease, respectively. Interestingly, the prevalence of large-vessel disease, but not isolated small-vessel disease, was significantly correlated with patients who were male and older than 60 years of age. These results demonstrate a significant fivefold underestimate of LEPAD when compared to symptoms of claudication, but a twofold overestimate of LEPAD when compared to pulse abnormalities on physical examination.¹⁴

A national, community-based PAD detection program (PARTNERS) used 350 local primary care sites to identify patients who were deemed higher risk for PAD: Age more than 70 years, or age more than 50 years with a history of diabetes and/or tobacco abuse. Findings revealed a 29% incidence of PAD, defined as an ankle–brachial index (ABI) less than 0.9.¹³ Similarly, a European population study evaluating more than 7000 patients, found nearly a 20% frequency of LEPAD in patients 55 years and older, with nearly 60% frequency in men elder than 85 years of age.^13,16

Interestingly, in nearly all of the patients diagnosed by abnormal ABIs or other noninvasive imaging in these studies, only 1% to 22% of the patients had self-reported claudication or symptoms by Rose questionnaire.^{13,16,25,26,27,28,29} This strongly supports the notion that most patients with LEPAD remain either asymptomatic, have limited their activities to avoid claudication symptoms, are limited by other comorbid conditions, or simply attritibute their symptoms to their increasing age. Yet, it is important to note that nearly 10% of these “asymptomatic” patients have advanced PAD with severe obstruction to blood flow,¹⁷ and all carry an increased risk of future CV events.^{14,16,17,30,31}

Risk Factors

Numerous risk factors for the development of LEPAD have been identified (Figure 33-1). And since the vast majority of LEPAD is caused by occlusive atherosclerotic disease, risk factors for the development and/or progression of LEPAD are nearly identical to those which can lead to cardiac and cerebrovascular atherosclerotic disease.²¹ The strongest correlations exist with elderly age and variably male gender (as discussed above). Other comorbidities including tobacco abuse, diabetes mellitus, hypertension, and hyperlipidemia and the relative risk—each of these relays onto the development of LEPAD are discussed below (Figure 33-1). Also, the coexistence of these risk factors relates synergistic effects on the development of LEPAD—one study reported a relative risk increase of 2.3 to 3.3 to 6.3 in patients with one, two, or three risk factors (tobacco abuse, hypertension, and diabetes) present, respectively.³²

Tobacco Abuse

The association between smoking and PAD and subsequent claudication symptoms was first described in 1911.³³ Tobacco abuse is a strong predictor of the development and progression of LEPAD¹⁵ as studies have reported a two- to sixfold risk of development of LEPAD compared to nonsmokers.^{5,16,34,35,36} In fact, tobacco abuse has been demonstrated to have a significantly higher relative risk for the development of PAD compared with the traditional atherosclerotic risk factors.³⁴ Also, there is a strong, dose-dependent (i.e., number of packs per day and number of pack-years smoked) predictor of the development of LEPAD, risk of amputation, peripheral graft occlusion, and mortality.^33,37,38,39

Diabetes

Numerous epidemiologic studies have reported a strong association between diabetes and an increased prevalence of PAD.^40,41 Specifically, studies have reported that for every 1% increase in hemoglobin A1C levels, there is an associated 26% increased risk of PAD.⁴² Even patients with insulin resistance (and not diabetes) carry an increased risk of PAD.⁴³ Moreover, other studies have demonstrated a two- to fourfold higher prevalence of LEPAD (defined as ABI <0.9) in patients with diagnosed diabetes.^{7,15,16,44,45,46} A large cohort study reported that 30.3% of patients with diabetes also had previously known or newly diagnosed PAD.¹³ PAD in diabetic patients is more aggressive, with early large vessel involvement in addition to standard microangiopathy.³³ Also, patients with longstanding diabetes are more likely to have more severe LEPAD^47,48 and suffer from claudication symptoms.³³ In addition, moderate-to-severe PAD in diabetic patients may be asymptomatic because of diabetic peripheral neuropathy.¹² Thus, the risk of a diabetic patient to develop LEPAD and possibly chronic CLI is correlated to the severity and duration of the diabetes.^46,49 Diabetic patients who develop LEPAD have a nearly 10-fold increased risk for need to undergo a major amputation as compared to nondiabetic patients with LEPAD.^{47,50,51,52,53,54}

Hypertension

Chronically elevated blood pressure results in increased shear stress against the vessel wall and causes subsequent endothelial damage. This disrupted endothelium acts as a nidus for inflammation, platelet adhesion, and cholesterol deposition (i.e., the atherosclerotic process). Therefore, it is not surprising that the majority of epidemiologic studies evaluating LEPAD have reported a strong, independent association between the presence of systolic hypertension and LEPAD.^{36,55,56,57,58,59} Specifically, patients with a diagnosis of hypertension carry a 1.50 to 2.20 odds ratio of having or developing LEPAD compared to nonhypertensives. In addition, the presence of hypertension increased the risk of the development of claudication symptoms claudication up to fourfold, and the risk was proportional to the severity of hypertensive disease.³⁵

Hyperlipidemia

Since the underlying cause of the vast majority of LEPAD is atherosclerosis, it is logic that hyperlipidemia predisposes a patient to the development and/or progression of LEPAD. However, extensive epidemiologic research in this area has proved inconsistent results. The majority of initial trials provided evidence that elevated total cholesterol levels was associated with an increased risk of developing LEPAD.^34,58,59,60 Specifically, the incidence of LEPAD increases by 5% to 10% for each 10 mg/dL rise in total cholesterol.^23,60 Other trials have reported that high-density lipoprotein (HDL) cholesterol is protective against the development of LEPAD.^61,62,63 Therefore, a measure to combine these values (e.g., non-HDL cholesterol and a total to HDL cholesterol ratio) have reported patients in this highest quartile having nearly four times the claudication risk than those patients in the lowest quartile.^36,64 In addition, further studies have confirmed elevated low-density lipoprotein (LDL) levels to be associated with LEPAD and the development of claudication symptoms.^{16,23,34,45,65} In addition, one study reported patients with PAD had significantly higher levels of VLDL cholesterol, IDL cholesterol, triglycerides, VLDL triglycerides, and IDL triglycerides.⁶³ However, evidence to support isolated hypertriglyceridemia as a risk factor for LEPAD is conflicting,^{66,67,68,69,70} as most studies report a nonsignificant relationship following multivariate analysis.^34,71

Homocysteinemia

Homocysteine (Hcy), an amino acid, is determined by both genetic and dietary factors and has been proven to have thrombotic and arteriosclerotic properties⁷² via direct toxicity to the endothelium, increasing DNA synthesis in vascular smooth muscles, and causing oxidation of LDL.^72,73,74 In addition, previous studies have shown that elevated levels of serum Hcy appear to act as an independent predictor for PAD. Another study compared peak serum Hcy levels following a standard methionine loading test in normal subjects and in patients with known early PAD (diagnosed prior to 55 years of age). In this study, hyperhomocystenemia was detected in 28% of patients with known early PAD and in none of the normal subjects.⁷⁵ More specifically, a case–control study which defined hyperhomocysteinemia as a fasting Hcy level greater than 12 μmol/L or greater than 38 μmol/L 6 hours postmethionine load (dose of 100 mg/kg). The relative risk for a patient with only an elevated fasting Hcy, only elevated postload Hcy level, or both was 1.6, 1.5, and 2.5, respectively.^76,77 This risk factor has been shown to be more significant in patients with noninsulin dependent diabetes.⁷⁸ Additionally, a thorough meta-analysis reported that hyperhomocysteinemia’s effect on the development of PAD was independent of serum cholesterol, diabetes mellitus, smoking, or hypertension.^72,76

A prospective study following 351 patients with symptomatic LEPAD or cerebrovascular disease who were followed more than a 3-year period reported an increased risk of all-cause mortality, death from CV causes, and progression of coronary heart disease.⁷⁹ Although a more recent study suggested that elevated levels of serum Hcy did not predict progression of large- or small-vessel LEPAD.⁸⁰ In addition, patients with elevated serum Hcy levels who undergo lower extremity revasclurazation procedures are more likely to have failure of their vascular intervention.⁸¹

C-reactive Protein

Previous research^82,83 have shown that low-grade inflammation and therefore elevated inflammatory markers (e.g., C-reactive protein [CRP]) are present in patients with atherosclerotic disease is coronary and cerebral vascular beds. But more recently, a prospective study evaluated apparently healthy males with baseline serum CRP levels who subsequently developed symptoms of intermittent claudication or necessitated revascularization during a 60-month follow-up period. The findings support that patients who developed symptomatic LEPAD had significantly higher baseline CRP levels (1.4 vs. 0.99 mg/L), and the risk of developing symptomatic LEPAD increased with each increasing quartile of baseline serum CRP level (e.g., highest quartile had relative risk of 4.1 vs. patients who remained asymptomatic). The predictive value of CRP levels was independent of presence of hyperlipidemia, hypertension, and/or diabetes.⁸³ A more recent study suggested that an elevated level of serum hsCRP is predictive of progression of large-vessel (as evidenced by a decline in ABI measurements), but not small-vessel LEPAD.⁸⁰

Ethnicity

Until recently, it has been difficult to assess any correlation with ethnicity and the risk of development of LEPAD since most previous large trials and registries involved non-Hispanic white patients. However, in more recent trials that have had larger percentages of minority patients, it is apparent that non-Hispanic blacks have an increased rate of LEPAD when compared to non-Hispanic whites.^7,84 Specifically, studies have reported that black race is associated with a greater than twofold risk of developing PAD.^44,85,86,87 This relationship persisted after multivariable analysis was made for traditional atherosclerotic risk factors, such as hypertension and diabetes.⁸⁸ In addition, there appears to be an increased risk of developing PAD in Mexican Americans when compared to non-Hispanic whites.^7,84

On the other hand, other studies have reported other ethnic groups (e.g., Hispanics, Asians, Native Americans) as having a lower prevalence of PAD when compared to non-Hispanic white patients.^88,89,90,91 Therefore, studies to assess the relationship between ethnicity and nontraditional atherosclerotic risk factors (e.g., various markers of inflammation) with the development of LEPAD.

Specific High Risk Groups

In addition to disease comorbidities, specific patient populations have been found to have extremely high rates of LEPAD. These subpopulations include patients who are hospitalized with known CAD (40%)⁹¹; or have known abdominal aortic aneurysms⁹² (46%), chronic renal insufficiency (27%),⁹³ or previous renal or cardiac transplantation.^94,95

Genetic Influence and Protective Risk Factors

Although previous studies, including the Framingham Heart Study, have clearly shown a genetic component to the development of coronary artery disease, there has been no objective evidence correlating a positive family history of LEPAD as a risk factor for the development of LEPAD.³³ On the other hand, few patient characteristics have been elucidated that appear to incur a protective effect on the development of LEPAD and/or symptoms of claudication. The positive protective factors include regular physical activity⁹⁶ and moderate alcohol intake.⁹⁷

Coexistence with Coronary Artery, Carotid Artery, and Renal Artery Disease

Since atherosclerosis is the major underlying disease process of LEPAD, CAD, carotid artery disease, and renal artery disease, it is intuitive that patients diagnosed with one of these disease processes have a significantly higher risk for coexistence of another of these conditions. In general, patients with LEPAD are two- to four-times more likely to have underlying CAD or carotid artery disease than those patients that do not have LEPAD⁹⁸ (Figure 33-2). A prospective study, completed in a long-term health care facility, revealed a 33% to 58% prevalence of coexistence of symptomatic coronary artery disease, PAD, and/or atherothrombotic brain infarctions in their patient population.⁸⁴ Another study suggest that in patients with known LEPAD, angiographically proven coronary heart disease can be seen in up to 90%.^99,100 Similar studies have reported more than one-fourth of patients undergoing coronary angiography prior to elective LEPAD revascularization surgery have severe triple-vessel coronary artery disease.¹⁰¹ Furthermore, an autopsy study which evaluated the coronary arteries in elderly patients (mean age 63 years) who had undergone amputation of at least one lower extremity because of severe LEPAD revealed that 92% of subjects had severe atherosclerotic narrowing (>75% of CSA) of at least one major epicardial vessels.¹⁰² Although the association is less dramatic, it appears that in patients with known LEPAD, carotid artery disease is seen in up to 25% of patients.^33,102 However, these patients rarely have any history of clinically significant cerebrovascular events (less than 5%).³³

In addition, a smaller study of patients undergoing elective aortoiliac surgery revealed nearly 40% of patients showed >60% stenosis in one or both renal arteries as assessed by renal duplex scanning. These patients were more likely to have significant renal artery stenosis if the planned aortoiliac surgery was secondary to obstructive arterial disease rather than abdominal aortic aneurysm (43% vs. 29%), or had an ABI less than 0.5 (73% coprevalence rate).¹⁰³ Although not yet supported by clinical data, some suggest that in patients with PAD, the presence of significant renal artery stenosis portends a higher mortality rate³³ (Table 33-1).

Embryology

Early in development, the embryologic dorsal aorta develops three sets of branches, including the (dorsal and ventral) intersegmental arteries which give rise to vasculature of the head, neck, body wall, vertebral column, and limbs. The median sacral artery is the small continuation of the dorsal aorta beyond the bifurcation at the iliac arteries. The fifth intersegmental artery which becomes the lumbar and lateral sacral arteries, together with an axial artery that develops along the central axis of the limb, supply blood to each leg limb bud. This original axial artery, which develops as a continuation of the internal iliac artery, terminates into a plexus where it joins the femoral artery. The axial artery, then progressively degenerates and is represented in the adult only as a small sciatic (ischiatic), inferior gluteal, popliteal, and distal section of the peroneal artery. Thereafter, the majority of the limb blood supply is derived from the external iliac artery. For instance, the obturator artery, tibial arteries, and proximal part of the popliteal artery develop much later in utero¹⁰⁴ (Figure 33-3).

In vast majority of patients with normal arterial anatomy, the abdominal aorta bifurcates into the common iliac arteries at the level of the fourth and fifth lumbar vertebrae (Figure 33-4). Each common iliac artery travels laterally and caudally and gives rise to small branches to the peritoneum, lumbar musculature, ureters, and occasionally iliolumbar or accessory renal arteries. The common iliac artery terminates by dividing into the hypogastric and external iliac artery, the latter supplying blood to the lower extremity. The hypogastric artery provides blood to the pelvis, buttocks, genitalia, and medial thigh. In addition, the common iliac gives rise to small branches to the peritoneum, lumbar musculature, ureters, and occasionally iliolumbar or accessory renal arteries (Figures 33-5 and 33-6). In addition, there is an extensive collateral circulation present involving the iliac and pelvic vasculature (Figure 33-7).

The external iliac artery courses to the inguinal ligament and becomes the common femoral artery (CFA) just distal to the lateral circumflex and inferior epigastric arteries. The first portion of the CFA, which is enclosed in a fibrous sheath (i.e., the femoral sheath), subsequently divides into the deep profunda femoral artery (PFA) and the superficial femoral artery (SFA) (Figures 33-8, 33-9 and 33-10). From its posterolateral origin at the CFA, the PFA travels deep behind the adductor longus and adductor magnus, feeding blood to the posterior thigh musculature and acts as an important source of collateral flow to the distal vessels. More specifically, the PFA gives off the lateral and medial femoral circumflex, perforating and muscular arteries.

As the SFA courses along the upper third and middle part of the thigh, it is contained in the femoral triangle (Scarpa’s triangle) and adductor canal (Hunter’s canal), respectively. Major branches of the SFA include the superficial epigastric, superficial iliac circumflex, superficial and deep external pudendal, and various muscular branches. The SFA ends as it passes into the adductor canal and becomes the popliteal artery. In turn, the popliteal artery gives off blood supply to numerous cutaneous, muscular (to the posterior thigh and lower leg musculature), and genicular arterial branches (Figure 33-11). At the lower border of the popliteus muscle, the popliteal artery divides into the anterior tibial artery and tibioperoneal, which further divides into the peroneal and posterior tibial (PT) arteries. Also, surrounding the knee is a complex network of vessels that constitutes a superficial and deep plexus (Figure 33-12).

For the majority of its course, the anterior tibial artery travels along the interosseous membrane supplying the front of the leg via the tibial recurrent, fibular, maelleolar, and more muscular artery branches (Figure 33-13). At the lower part of the leg, the anterior tibial artery lies along the tibia and becomes the dorsalis pedis artery. In contrast, the majority of the blood supply to posterior lower leg musculature arises from the PT artery. As the PT artery travels on the tibial side of the leg to the posterior aspect of the ankle, it gives rise to several branches including malleolar, medial calcaneal, muscular, and the peroneal artery. The peroneal artery travels down the medial side of the fibula and terminates into lateral calcaneal branches.

The majority of the blood supply to the foot is from the dorsalis pedis artery, peroneal artery, and the distal branches of the PT artery (Figure 33-14). Initially, the anterior tibial artery gives rise to the anterior (medial and lateral) malleolar arteries that arise above the ankle and travel through the sides of the ankle, and anastomose distally with the (medial and lateral) plantar arteries (Figure 33-15). Also, the dorsalis pedis artery branches include the tarsal (medial and lateral), arcuate, and deep plantar arteries. The tarsal arteries provide blood supply to the medial and lateral borders of the foot, and anastomose distally with the branches of the malleolar and lateral plantar arteries. The arcuate artery gives off the second, third, and fourth dorsal metatarsal arteries and subsequent digital branches. The dorsalis pedis terminates into the bifurcation of the first dorsal metatarsal and deep plantar artery (Figure 33-16). These arteries mainly supply the halux and sole of the foot, respectively. Lastly, the PT artery gives rise to the calcaneal arteries (supplying the heel) and nutrient artery (supplying the navicular bone). The PT ends at the takeoff of the medial and lateral plantar arteries. The smaller medial plantar artery courses toward the base of the halux and supplies blood flow to the halux and musculature on the medial portion of the foot. On the other hand, the lateral plantar artery tranverses laterally to join with the deep plantar branch of the dorsalis pedis artery (the plantar arch). This artery acts as the major blood supply of the lateral foot musculature; second, third, and fourth metatarsals; and digits.¹⁰⁵

Variant Anatomy

Minor alterations in the above described anatomy; considered merely normal variants, occur in the general population. For example, the level of aortic bifurcation varies and may be seen below the level of the iliac crest. Levels of bifurcation and relative lengths of the each of the described arteries can vary. Cases have been reported of patients with absence of the CFA, SFA, and/or PFA¹⁰⁶; duplication of the SFA and/or PFA¹⁰⁷; SFA bifurcation again after the origin of the PFA; or the popliteal artery trifurcating directly into the anterior tibial, PT, and peroneal artery¹⁰⁶ (Figure 33-17). Also, there appears to be a clear association with some chromosomal abnormality syndromes (e.g., disorganization-like syndrome, campomelic syndrome, congenital abnormalities of the lower limb) and abnormalities in lower leg vasculature.^108,109,110 Other rare causes of LEPAD include gelatinous dystrophy, Leriche-Fontaine aneursymal dystrophy, and anterior tibial hypoplasia.¹¹¹

Persistence of Sciatic (Ischiatic) Artery

The sciatic artery is an embryologic continuation of the internal iliac artery into the popliteal–tibial arteries. In early embryologic development, it serves as the major source of blood supply to the lower limb bud. In normal embryologic development, the sciatic artery involutes once the femoral arteries form and provide the majority of blood to the lower extremity.¹¹² Normal adult remnants of the proximal sciatic artery are the proximal portions of the anterior and superior gluteal arteries, the artery to the sciatic nerve, and the popliteal and peroneal arteries^112,113 (Figure 33-18). However, in less than 0.5% of adults, the embryologic sciatic artery persists. In most cases, this occurs when the femoral arterial vasculature (specifically, the SFA) fails to develop properly.¹¹² In these patients, the persistent sciatic artery (PSA) may continue to be the major blood supply to the lower extremity as a continuation from the internal iliac artery to the popliteal artery.^114,115,116 Five types of PSA anomalies have been described in attempt to better compare outcomes from different centers: Type I—complete PSA with continuity from the internal iliac to the popliteal artery with the femoral system ending as the saphenous artery; Type II—complete PSA associated with aplastic external iliac and femoral arteries and normal superficial femoral and popliteal arteries; Type III—incomplete PSA with the femoral system ending as the saphenous and sural arteries; Type IV—incomplete PSA with hypoplasia of the sciatic artery in the thigh with the femoral system as the dominant supply to the lower extremity; and Type V—incomplete PSA with hypoplasia of both the femoral and the sciatic arteries with limb atrophy.¹¹⁷ Of more clinical importance, there is an estimated 44% incidence of aneurysmal dilatation in these persistent sciatic arteries.¹¹⁵ Other vascular findings that can be seen in conjunction with persistent sciatic arteries include abnormal iliac and hypogastric arteries,^118,119,120 and various venous anomalies.^{119,120,121,122}

Most commonly, a PSA is an incidental finding. However, patients with this disorder may present with abnormal lower extremity pulses, claudication, sciatic pain (via compression of the adjacent sciatic nerve), a pulsatile mass in the buttocks, or rupture.^{115,118,122,123,124} Diagnosis can be readily made by ultrasound, computed tomography (CT), magnetic resonance imaging, or angiography. Treatment is not necessary for asymptomatic patients with persistent sciatic arteries. However, aneursymal sciatic arteries should be occluded by surgical ligation or transcatheter embolization in attempts to prevent distal embolization or rupture.¹¹² In select patients, bypass revascularization from an adequate proximal (femoral) artery to the distal limb vasculature may be necessary.^116,125,126

There are two major schemes to characterize PAD: The Fontaine and Rutherford Classifications. The severity of a patient’s disease process is based on symptoms, evidence of tissue damage, and/or tissue loss. The Fontaine classification includes four stages (Table 33-2). Fontaine I represents asymptomatic individuals; Stages IIa and IIb describe individuals with mild and moderate claudication, respectively; Stage III includes patients with ischemic rest pain; and patients with ischemic ulcerations or gangrene are classified as Fontaine Stage IV. Similarly, the newer Rutherford classification divides PAD into five grades (0-IV), which include six categories: Rutherford Grade 0 represents asymptomatic individuals; Grade I signifies claudication symptoms of varying severity; Grade II describes patients with ischemic rest pain; and Grades III and IV include patients with tissue loss, ulceration, or gangrene.^33,127

The most common cause of LEPAD is systemic, atherosclerotic disease. However, LEPAD may also be caused by degenerative disorders that affect arterial wall structure and subsequent dilation⁹⁹ including Marfan syndrome, Ehlers-Danlos syndrome (EDS), and cystic medical necrosis. The disorders that lead to thromboembolic phenomenon or inflammatory changes, in the vessel wall, may also lead LEPAD (Table 33-3).

Atherosclerosis

The most common cause of asymptomatic and symptomatic LEPAD is atherosclerosis. Studies have shown that this disease is a complex, chronic, active immunoinflammatory and fibroproliferative process. The atherosclerotic plaques begin with macrophages and cholesterol deposition into intact, but leaky endothelium. These complexes become oxidized and, in turn, become proinflammatory, prothrombotic, and chemotaxic via the MMP, tissue factor and further macrophage recruitment. This inflammatory process promotes further cholesterol deposition and plaque formation. The process continues as smooth muscle cell proliferation occurs in attempt to heal and repair arterial injury. This fibroproliferative process may thicken the plaque’s cap, but also may become voluminous and result in symptomatic stenosis.^127,128 These plaques may continue to remain stable or become unstable, the latter often referred to as “vulnerable” plaques. These vulnerable plaques have been defined to have a (1) thin fibrous cap, (2) necrotic; lipid rich core, and (3) dense macrophage infiltration.¹²⁹ Once a vulnerable plaque ruptures, circulating platelets adhere to the necrotic core and monocytes secrete tissue factor promoting thrombosis or embolization.¹

Patients with (and without) underlying atherosclerosis may present with an embolic phenomenon that leads to symptoms of LEPAD. Patients with known atherosclerosis are prone to cholesterol plaque rupture and subsequent thrombosis or distal atheroembolization resulting in thrombosis. Other conditions (e.g., primary prothrombotic diseases, atrial fibrillation, prosthetic valves, aneurysmal disease, ventricular thrombus, or endocarditis) predispose patients to an embolic event that may affect large or medium-sized arterial vessels.⁹⁹ Embolic events may classically appear on angiography with multiple filling defects, filling defects at bifurcations, meniscus sign, and/or lack of collateral or notable atherosclerotic disease.³³

Abdominal Coarctation of the Aorta

Claudication secondary to abdominal (infrarenal) coarctation of the aorta with/without severe hypoplasia of the aortoiliac femoral arterial system has been reported.^{130,131,132,133,134} Typically, these patients present with hypertension, cardiac failure, claudication, or decreased lower extremity pulses.^{130,131,133,134,135} Diagnosis can be confirmed with contrast aortography and standard treatment is surgical bypass revascularization.

Aneurysmal Disease and Acute Dissection

Diseases of the arterial wall (e.g., atherosclerosis, connective tissue disorders, trauma, nonspecific inflammatory changes, etc.) can lead to local weakening and subsequent aneurysm formation. In the case of atherosclerosis, the exact mechanism of aneurysm formation is unknown. Although it is likely because of a combination of compromise of oxygen and nutrients to the media and aortic wall shear stress from hypertension. This scenario leads to ischemic injury to the media producing local weakening and damage (to the media and elastic membrane) to the vessel wall. Subsequently, this weakening allows dilatation of the aorta that (based on Laplace’s law) results in further wall tension stress and further dilatation of the vessel lumen. This process may be accentuated by an active inflammatory and proteolytic process. Also, these aneursymal lesions are predisposed to dissection that may cause distal ischemia via rupture or lumen occlusion.

In addition, as a result of nonlaminar flow through the aneursymal segment, blood stasis may occur predisposing the patient to lumen thrombus formation. This thrombus material may embolize distally and produce ischemic symptoms.

Aneurysmal disease can be seen in any arterial vascular bed. Most commonly, it affects the aorta with and without combination with more distal peripheral arterial beds. The most commonly occurring peripheral arterial aneurysms are popliteal artery aneurysms (PAAs), which account for up to 85% of all peripheral arterial aneurysms, and are most often because of underlying atherosclerosis.¹³⁵ These aneurysms, defined when the artery is greater than 1.5 cm, are often bilateral and associated with abdominal aortic aneurysms.¹³⁶ These aneurysms may be asymptomatic if small, but also may present as symptomatic disease (e.g., claudication/rest pain or leg pain/numbness as a result of mass effect and compression). PAAs may present with acute limb ischemia caused by acute vessel thrombosis (Figure 33-19), distal embolization or rupture—all historically carrying a high rate of limb loss.¹³⁷

In contrast, aneurysms involving the CFA are rare but also are a marker of possibly aneurismal disease elsewhere (Figure 33-20). Common femoral artery aneurysms (CFAA) can be classified anatomically as Type I, in which the aneurysm ends before the bifurcation of the CFA into the superficial femoral and profunda femoris arteries, and Type II, in which the aneurysm involves the orifice of the profunda femoris artery.

However, aneursymal disease isolated to the iliac system (IIAA) can be seen in 2% to 7% of patients affected with intra-abdominal aneurysms. Of note, these isolated iliac aneurysms are mostly asymptomatic but do carry a high rate of rupture, embolization, thrombosis, compression of adjacent structures, and significant operative mortality.^138,139

Connective Tissue Disorders

Ehlers-Danlos Syndrome

EDS is a disorder consisting of nine distinct subtypes, all of which are characterized by abnormal collagen and subsequent hyperelasticity of the skin and hypermobile joints. The diagnosis of EDS is based on the clinical presentation: Patients typically present in the third decade with hyperplastic and fragile skin, hypermobile joints, or spontaneous rupture of arteries in the legs with ensuing ecchymosis.^{140,141,142,143} Currently, there is no specific therapy for patients with EDS. Since patients with Type IV and IX (Menkes’ Syndrome) have been found to have an increased risk of arterial aneurysm formation and possible arterial (e.g., popliteal, femoral, iliac, and aorta) dissection or rupture, it would be prudent for these patients to undergo serial ultrasound evaluations for early detection of aneurysm formation. However, surgical repair of detected aneurysms may be complicated by the increased friability of tissues and pseudoaneursym formation.^144,145,146

Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum is a rare, inherited connective tissue disorder that results in abnormal elastic fibers. Pseudoxanthoma elasticum most commonly presents in the second to fourth decade of life¹⁴⁷ with symptoms related to elastic degeneration of the skin, eyes, gastrointestinal system, or arteries (18% present with intermittent claudication).^148,149,150 All arterial beds may be affected and is manifested as progressive luminal narrowing with severe arterial calcification that may lead to complete occlusion.^148,149,150 Treatment consists of avoidance of dietary calcium and standard (albeit often extensive) revascularization interventions for only symptomatic stenosis.¹⁵¹

Fibromuscular Dysplasia

Fibromuscular dysplasia (FMD) is a disease affecting medium- and small-sized arteries. It is most commonly seen affecting the renal or carotid arterial vasculature, although there have been reports of isolated abnormalities of the iliac and lower limb vasculature.¹⁵² Histologic examination most often reveals medial dysplasia with or without fibrosis of the elastic membrane in the diseased vessel wall. Specifically in isolated cases of lower limb vasculature, the abnormality has been theorized to be attributable to arteritis, previous thigh injury, or thromboembolic events with recanalization of the artery.¹⁵² Diagnosis can be made by angiography revealing a classic “string of beads” appearance reflecting diseased, thickened fibromuscular ridges adjacent to thin, less involved arterial wall segments. Treatment consists of PTA or surgical revascularization for symptomatic patients. In addition, these patients presenting with FMD of the lower extremity should be routinely screened for similar disease in the carotid and renal vasculature.

Adventitial Cystic Disease

Cystic adventitial disease, whereas intramural mucin-containing cysts occur between the media and adventitial layers of the vessel wall, has been reported to cause claudication. This condition more commonly affects the popliteal and femoral artery, and presents as sudden calf claudication aggravated by knee flexion.^153,154 However, this condition was first described affecting the external iliac artery.¹⁵⁵ Diagnosis can be made using Doppler ultrasound, CT, or MR. Also, contrast angiography may depict a smooth, curvilinear stenosis (scimitar sign) or hour-glass narrowing. Treatment may include cyst evacuation or aspiration, patch angioplasty, or surgical resection with vein bypass.^154,156,157

Vasculitis

Vasculitides consist of a large, variable group of chronic inflammatory disorders that result in damage to the blood vessel structure. These conditions result in a reduced peripheral blood flow caused by endothelial dysfunction and/or vascular obstructions.¹⁵⁸ A broad range of vasculitic disease states exists, since any vessel type, vessel size, and vascular bed can be affected. (Of note, limb ischemia may develop acutely with inflammatory processes such as HIV arteriopathy).³³

Thromboangiitis Obliterans

Thromboangiitis obliterans (TO or Buerger disease) is an inflammatory disorder resulting in stenosis and obstruction of medium- and small-sized vessels in the distal arms and legs. The disease typically affects young Asian males (although women and the elderly have been reported) with heavy tobacco use. Although the underlying pathophysiology of TO is unclear, it is suggested that it may be an autoimmune reaction against a component of tobacco. Histologic examination reveals leukocyte and fibroblast infiltration leading to perivascular fibrosis and recanalization. Also, endothelin-1, a potent vasoconstrictor, may be elevated in patients with TO.^159,160,161 Patients with TO often present with claudication or ischemic rest pain in the hand or foot. In more severe cases, ulcerations and gangrene of the fingers and toes may occur.

Diagnosis is supported by angiography depicting smooth, tapering segmental lesions in the distal vasculature and/or classic “corkscrew” appearance of arteries resulting from vascular damage at sites of occlusions (Figure 33-21). In contrast to other vasculitidis, TO does not affect arteries outside the limb vasculature (e.g., visceral, pulmonary, renal, cerebral vasculature). To date, there has been no data to support the benefit for use of antiplatelet, anticoagulant, or anti-inflammatory medications in these patients. The only effective treatment for Buerger disease is immediate and complete cessation of tobacco use. Results with sympathectomy to control the vasospastic component of the disorder has been have been suboptimal. In end-stage patients, attempts with omentopexy (pedicled omental transplantation) to the affected limb to avoid amputation have been promising with nearly 85% limb-salvage rates.^162,163

Takayasu Arteritis

Most commonly, Takayasu’s arteritis (TA) affects the aortic arch and its branches (large- and medium-sized vessels) of young women. The underlying pathophysiology of TA is unclear, but immunopathogenic mechanisms have been suggested. Histologic examination suggests a panarteritis with inflammatory infiltrates, occasional giant cells, marked intimal proliferation and fibrosis, scarring of the media, and degeneration of the elastic lamina.¹⁶⁴ Affected patients may complain of fever, fatigue or be noted to have new-onset hypertension, aortic insufficiency, or suffer a cerebrovascular event. In severe cases, patients may present with arm and/or leg claudication. Often, these patients will have evidence of arterial occlusive disease on physical examination with appreciable bruits and significantly dimished (or absent) peripheral pulses. Diagnosis can be confirmed by ultrasound and MR (evidenced by thickening of the aortic wall) or contrast angiography (revealing stenosis, poststenotic dilatation, aneurysm formation and occlusion of the aorta with possible involvement of its major branches). Most patients respond to prednisone therapy, but methotrexate may be useful. Additional revascularization via endovascular or surgical bypass revascularization also may be needed for significant stenosis.

Giant Cell Arteritis

Giant cell arteritis (GCA or temporal arteritis) is the most common adult type of vasculitis that occurs almost exclusively in the elderly population. This disorder typically affects the carotid artery and its branches, but may affect any large- or medium-sized artery, including, but rarely, the lower extremities. Nearly half of GCA patients are found to have polymyalgia rheumatica. Classic presenting symptoms include headache or scalp tenderness, jaw claudication, proximal muscle pain, fever or blurred vision. If severe and left untreated, it may progress to blindness. The underlying mechanism of this disease is unknown, but likely related to an autoimmune reaction or elevated levels of endothelin-1, a potent vasoconstrictor.^159,160,161 Histologic examination reveals a panarteritis with leukocyte infiltrates in the vessel wall with frequent giant cell formation. Diagnosis is made the clinical scenario, elevated sedimentation rate, and confirmed by biopsy of the temporal (affected) artery. The current treatment for TA is prednisone therapy. Smaller studies have reported response to therapy with methotrexate and tumor necrosis factor blockers.

Behcet Disease

Behcet disease, presumed to be immune mediated, presents typically as a triad of mouth ulcers, genital ulcers, and eye inflammation. But, in less common instances, it may include a panarteritis affecting even the limb arteries. Vascular symptoms include claudication or a lower extremity mass that can be as a result of aneursymal formation or occlusion of an affected arterial bed. The underlying histopathology reveals fragmentation of the vessel wall’s elastic fibers, degeneration of vasa vasorum with perivascular round cell infiltrate.^165,166 Diagnosis can be made with CT or angiography. Treatment usually includes immune-mediated medications and possible surgical resection and/or bypass revascularization. However, surgical repair is complicated by the diseased delicate vessel walls, which predispose the patient to pseudoaneurysm at the site of anastomosis or thrombosis of the bypass grafts.^{166,167,168,169}

Other Etiologies

Vasospastic (Raynaud) Disease

Abnormal peripheral vasospasm, first described by Maurice Raynaud in 1862,¹⁷⁰ is often caused by increased vascular tone in response to cold or emotional stimuli. Classic presentation occurs in three phases: First, the digits main arterial branches constrict resulting in paleness, numbness, pain or parasthesias; second, the digits become cyanotic and become purple or black in appearance; and third, the blood flow is reestablished with postischemic hyperemia and the digits appear purple. The pathophysiology of this condition is unclear, although many believe it is a result of endothelial dysfunction. The abnormal vascular tone may be a primary (Raynaud disease) or secondary phenomenon (usually because of an underlying collagen vascular disease). The diagnosis of Raynaud disease is entirely based on clinical presentation and there are no laboratory or imaging tests needed for confirmation (although some may be done to rule out other etiologies). Treatment for Raynaud disease includes avoidance of sudden cold exposure, cessation of tobacco use, and avoidance of sympathomimetic medications (e.g., decongestatnts, amphetamies, etc.). Cases that are more resistant may be treated with calcium channel blockers, other vasodilators, sympatholytic agents, and prostaglandins.

Pernio (Chilbain’s Disease)

Similar in clinical presentation to Raynaud disease, pernio is an inflammatory condition characterized by raised red and blue, pruritic lesions located on the pretibial area and toes. In severe cases, these lesions may blister or ulcerate. Typically, these lesions last less than 3 weeks. Pernio is caused by an abnormal vasomotor tone response to cold exposure, and therefore most likely to present in the spring and autumn (during cold, damp conditions). Pernio may be idiopathic or secondary to an underlying disorder (e.g., chronic myelomonocytic leukemia, macroglobulinemia, cyroglobulinemia, antiphospholipid antibody syndrome, or anorexia nervosa). A variant of pernio is chilblain lupus erythematosus that manifests as similar lesions over the dorsal interphalangeal joints. These patients often have abnormal serology (antinuclear antibody and/or rheumatoid factor) and a small proportion progress to develop systemic lupus. Diagnosis can be confirmed by lesion biopsy revealing dermal edema, perivascular lymphocytic infiltrate (“fluffy edema” of vessel walls) and epidermal spongiosis or necrosis. Treatment consists of keeping affected areas warm and dry. Several other studies have suggested that vasodilator medications, such as calcium channel blockers, or ultraviolet light therapy may have clinical benefit in treating and preventing episodes.

Ergot Toxicity

Rare cases of claudication and digital ischemia may be secondary to ergot toxicity (e.g., St. Anthony’s fire), most commonly seen in younger females being treated with ergot derivatives for migraines. Typical symptoms are a result of an acute vasospastic episode initially occurring in the SFA and progressing distally.^171,172,173 Diagnosis can be made with contrast angiography which classically reveals diffuse and segmental vasospasm seen as a smooth narrowing of the vessels.¹⁷⁴ Treatment includes discontinuation of smoking, caffeine intake or any other offending ergot product. Additional vasodilator therapy (nitroprusside or nifedipine) may be necessary in severe or refractory cases.

Popliteal Artery Entrapment Syndrome

First described in 1879, the popliteal artery entrapment syndrome is a rare anatomic abnormality (0.2%–3% of adults) consisting of an anomalous popliteal artery, which courses around the gastrocnemius muscle, resulting in intermittent vascular compression (i.e., entrapment) between the muscle and medial femoral condyle.^175,176,177 The compression can lead to vessel wall fibrosis, stenosis, thrombosis, aneurismal dilatation, and distal microembolization.¹⁷⁵ This abnormality is caused by abnormal embryologic development of the gastrocnemius and popliteal artery (although cases have been reported following femoropopliteal bypass surgery because of the similar misplacement of the venous graft.¹⁷⁵ Based on Insua’s classification, there are four variants of this entrapment syndrome, but most cases are secondary to an abnormal course of the popliteal artery or abnormal insertion site of the medial head of the gastrocnemius.¹⁷⁸ In rare cases, acquired entrapment syndrome may occur following surgical procedures.^{175,177,178,179,180}

Although a rare entity, history of sudden, unilateral calf claudication with parathesia and numbness while walking—but not running—in a young, athletic male should raise the clinician’s suspicion of this disorder. Diagnosis should be confirmed by angiography (performed with leg straight and in flexion), or more recently, by CT of the popliteal fossa.¹⁷⁵ The treatment of choice is surgical release of the gastrocnemius muscle, grafting of the damaged artery with a vein graft resulting in normal blood flow to the lower limb.^175,181

In addition, there are several case reports of other muscular or surrounding (e.g., Baker’s cyst, bony prominence, or venous aneurysm) structures constricting or compressing large arteries. For example, adductor canal compression syndrome occurs in cases where an abnormal band of tissue, originating from the adductor magnus muscle, courses across the SFA. Patients with this abnormality often are asymptomatic, but may have claudication with exercise as a result of the compression of the artery within the adductor canal. This condition may result in arterial damage and thrombotic events and can be treated with surgical ligation of the compressing tissue bands.¹⁸² Other case reports have described the passage of the femoral artery through the sartorius muscle.¹⁸³

Iliac Artery Entrapment Syndrome

Similarly, patients with external iliac endofibrosis (iliac artery compression) may complain of leg pain with exercise—most commonly with high-performance cycling. Initial reports suggested the leg pain was as a result of the compression of the iliac artery at the inguinal ligament (because of the position of a cyclist).^184,185 Others suggest the symptoms that occur with exercise are secondary to marked intimal thickening and subsequent significant stenosis. Treatment of symptomatic patients may be PTA/stent, surgical endarterectomy, or surgical bypass revascularization.¹⁸⁵

Pseudoocclusion

Some patients who present with symptoms of lifestyle limiting claudication or ischemic pain and undergo angiography are not found to have severely stenotic or occlusive lesions. Instead, these patients are found to have symptoms as a result of the external compression of arteries. For example, intermittent popliteal occlusion can occur with marked extension of the knee with or without plantar flexion.^186,187 In more rare instances, popliteal artery compression can occur with the knee in neutral position. Pseudoocclusion of the popliteal artery must be differentiated from popliteal entrapment syndrome that also often occurs with only extreme dorsal flexion of the ankle. Evidence that might suggest pseudoocclusion as a cause of the symptoms includes normal angiographic appearance with change in position (e.g., knee flexed) (Figure 33-22), angiographic appearance out of proportion to an ABI measurement, lack of contralateral disease or collateral circulation. Patients with pseudoocclusion, and therefore proven normal arterial anatomy, should not undergo mechanical intervention.¹⁸⁸

Miscellaneous

Other causes of LEPAD include trauma (including iatrogenic), pseudoanueryms (PSA), and arteriovenous fistulas (AVF). A pseudoaneursym is a contained disruption of the intimal and medial layers of a vessel wall. A PA may result from blunt trauma,¹⁸⁹ an iatrogenic cause (e.g., arterial puncture), or dehiscence of a surgical anastomosis. Patients with PA located in the lower limb vasculature may remain asymptomatic or complain of swelling, a pulsatile mass, parasthesias, localized pain, or claudication. Symptomatic PA may be successfully treated with ultrasound-guided compression, thrombin injection, endovascular ligation or stent implantation, or via open surgical repair. In addition, these PA may become complicated by infection, most commonly by Staphlyococcus. Patients with infected PA most often present following a percutaneous arterial access or synthetic graft bypass revascularization procedure and require surgical excision and bypass revascularization with (commonly) the superficial femoropopliteal vein.¹⁹⁰

Arteriovenous fistulas (AVF) are abnormal communications between an artery and vein, which bypasses the capillary bed. These defects may be congenital or acquired (as a complication to cardiac catheterization, etc.). Other reports have presented patients presenting with claudication because of the spontaneous arteriovenous fistulas of the lower extremities.¹⁹¹ AVFs may be asymptomatic, but can present as a pulsatile mass that may result in chronic venous insufficiency and/or distal ischemia. Duplex ultrasound or angiography can confirm the diagnosis. Treatment of large/symptomatic AVFs include surgical excision.

Other modes of trauma injury include penetrating injuries, gunshot wounds or blunt trauma. Patients with traumatic vascular injury may present either hemodynamically stable or unstable. Diagnosis can be made on physical examination (e.g., evidence of distal ischemia, absent or diminished peripheral pulses, or expanding hematoma) or by preoperative angiography. These patients should be treated with surgical bypass revascularization (utilizing saphenous vein or PTFE grafts) or arteriorrhaphy.¹⁹²

Asymptomatic

The overwhelming percentage of patients with LEPAD are asymptomatic. On the basis of previous data, nearly 90% of all PAD patients would be missed if ABI testing was reserved only for patients with classic claudication symptoms.¹⁹³ Therefore, further objective evaluation of high-risk asymptomatic patients is necessary.

Claudication

The most common presenting symptom in patients with LEPAD are atypical symptoms. However, intermittent claudication, defined as pain in the leg musculature with ambulation which is relieved by a short rest, is the earliest and most common classic presenting symptom in patients with LEPAD affecting 2% to 5% of the Unites States population older than 55 years,^21,33 with prevalence of claudication symptoms increasing with age.³³ However, the rates of reported intermittent claudication by patients greatly underestimates the prevalence of LEPAD in the general population (Figure 33-23). This is likely a result of many elderly patients who are unable to walk far enough to experience claudication symptoms caused by other comorbidities including congestive heart failure, chronic obstructive pulmonary disease, and/or osteoarthritis. Yet, less than 25% of patients with claudication will have significant progression of their disease.¹⁹⁴ This stabilization of the disease process may be as a result of the development of collateral vessels, metabolic adaptation of ischemic muscle, or change in the patient’s behavioral or activity patterns.³³ It is important to realize that not all subjective complaints of leg pain is claudication. Therefore, it is imperative for the clinician to have a thorough understanding of the various causes of leg discomfort (Table 33-3).

Critical Limb Ischemia

CLI, defined as pain that occurs at rest in the affected limb or impending limb loss, is secondary to a severe reduction of blood flow in the affected tissue bed.⁹⁹ These patients have tissue perfusion that is inadequate to maintain the resting metabolic needs of the affected limb. In a patient presenting with limb ischemia, it is mandatory that the clinician quickly determine if the disease process is acute or chronic CLI because the diagnostic methodology, therapeutic regimen, and prognosis for each is strikingly different. In general, chronic ischemic disease is defined as the presence of symptoms for more than 2 weeks.³³

Chronic CLI

The most common symptoms of chronic CLI are rest pain, ischemic ulcers and gangrene. Rest pain as a result of severe, chronic tissue ischemia is most often located in the forefoot or toes and is not easily attenuated by standard analgesics. Since the discomfort is often worsened when the patient is supine or when the limb is elevated, it is very common for the patient to complain of the symptoms at night or while sleeping. On the other hand, ischemic ulcers often originate in patients with an ABI <0.3, T_cPO₂ <40%, ankle pressures <50 mm Hg, and/or toe pressures <30 mm Hg. These ulcers are most commonly seen at the site of nonhealing minor trauma sites and may lead to osteomyelitis. These ulcers are most often dry, painful, and are located at sites of local pressure (e.g., lateral malleolus, metatarsal heads, and distal aspects of toes). Lastly, gangrene occurs when the arterial blood supply is unable to meet the metabolic needs of resting tissue.¹⁹⁵ It is typified by cyanotic, anesthetic tissue and can either characterized as “dry” or “wet.” Dry gangrene appears hard and most often occurs in the distal toes, with clear demarcation between healthy and necrotic tissue. In contrast, wet gangrene appears moist, swollen and may blister and carries a more severe prognosis.

Most CLI is secondary due severe atherosclerotic disease, but may be due to by a variety of diverse etiologies. But, when caused by atherosclerotic disease, CLI is a sign of severe, diffuse, or multisegmental disease.⁹⁹ Additional factors that contribute to the development and progression of CLI include diabetes, heart failure, infection, skin breakdown, or skin/tissue injury.⁹⁹ Therefore, the clinician must understand the likelihood of concomitant severe coronary and cerebrovascular disease and the subsequent greater risk of CV ischemic events^{6,13,196,197,198} when determining the appropriate treatment strategy for a patient with CLI.

Acute CLI

Acute ischemia of the lower extremity can result from thrombosis of a preexisting atherosclerotic lesion or more commonly from an acute embolic event (Figure 33-24). It may present as either a focal event because of embolic disease or a diffuse ischemic event secondary to an abrupt occlusion of a previously stenotic area.¹⁹⁹ The size and consequently the level of obstruction of the embolus generally dictate the patients’ symptoms, clinical signs, and the anatomic territory at risk. A more proximal obstruction by the embolus leads to a larger territory at risk, but usually a less severe presentation of ischemia because of collaterals. Patients who have embolization to the small digital end arterioles, quite often present with ischemic (“blue”) toes that are extremely painful.

When acute limb ischemia presents as a diffuse process, the patient may experience an abrupt onset of pain, coolness, numbness and paralysis of the affected limb. In the majority of cases, acute limb ischemia is secondary to thrombosis of a ruptured atherosclerotic (e.g., “vulnerable”) plaque, thrombosis of a previously placed bypass graft, or embolization to the lower extremity from a cardiac or proximal aneursymal source^99,200 (although less commonly from a paradoxical or tumor embolus). When acute limb ischemia is a result of thrombosis of an existing plaque, the thrombosis tends to propogate proximally in the artery, up to the previous major side branch. In addition, there may be distal propogation of the thrombosis as a result of the resultant low flow state. During an embolic event, the subsequent occlusion often occurs at a branch point in the arterial tree.⁹⁹

Acute limb ischemia caused by embolization is most likely to present as sudden, severe, pain in the affected limb. In comparison, acute limb ischemia caused by thrombosis may present more gradually. In either case, the pain often is less dependant on position and localized than that of CLI. Associated signs and symptoms of acute limb ischemia are the six P’s: Pain, paralysis, paresthesias, pulselessness, pallor, and polar (cold). Typically, the line of transition in temperature or color is one limb segment below the level of occlusion. Common findings of early ischemia include loss of light touch sensation, 2-point discrimination, proprioception, and vibratory perception. Findings of motor dysfunction or pain on passive movement is indicative of advanced ischemia and impending limb loss.⁹⁹ However, it is important to note that in patients with previous neurosensory defects (such as diabetic neuropathy), pain may not be present. Also, pedal pulses may be normal in cases of microembolization.

Blue Toe Syndrome

Focal acute limb ischemic events are characterized by a sudden appearance of a cold, painful forefoot/toe in the presence or absence of strong pedal pulses. In addition, there may be evidence of petechaie or cyanosis on the soles of the ischemic foot. The “blue toe syndrome (BTS)” often suggests embolic showering from a proximal atherosclerotic lesion.

Classically, patients with BTS have dusky or bluish demarcated lesions on one or multiple toes (occasionally bilaterally) in the presence of pedal pulses. In addition, there may be evidence of petechaie or cyanosis on the soles of the ischemic foot. Cholesterol emboli incite an intense inflammatory reaction and when coupled with embolization to the renal parenchyma can lead to acute renal failure, elevated sedimentation rate with hypocomplementemia, plasma and urinary eosinophilia, a urine sediment with modest proteinuria, and livedo reticularis.

BTS can develop either spontaneously or secondary to plaque disruption during trauma, angiography/catheterization, intra-aortic balloon pump counterpulsation, or (cardio) vascular surgery. The source of embolization is often a proximal atherosclerotic plaque, but may include proximal aneurysms (e.g., abdominal aortic aneurysm (AAA) or popliteal artery aneurysms). Since it appears that the underlying lesions that result in BTS may be multiple and can be found at various levels in the arterial tree, it can be difficult to determine the exact source of embolization. Avoiding further manipulation of the aorta is advised and hence, noninvasive diagnostic tests (e.g., Magnetic resonance angiography [MRA], CT-A, duplex) are advocated as first line.

Although, it is not possible to consistently determine the severity or extent of acute limb ischemia, a classification scheme has been constructed in attempts to further detail this disease process (Table 33-4).

Natural History

The natural history of patients with LEPAD has been well documented in previous studies. Patients with asymptomatic LEPAD or claudication symptoms may clinically improve, stabilize or deteriorate with possible ensuing revascularization and/or amputation (Figure 33-25). Initial studies which investigated the natural history of LEPAD reported that only 25% of these patients will significantly deteriorate, but only 7% and 12% patients requiring a major amputation at 5 and 10 years, respectively.¹⁹⁴ More recent studies confirm that the majority of patients with asymptomatic, but objectively defined LEPAD (per abnormal ABI or angiography), will not have any limiting claudication symptoms at 5 years.³³ In addition, these studies report an improved rate of major amputation of 2% at 5 years,^33,194 which likely is attributable to the current availability of more limb-salvage techniques. This small subset of patients, most often deteriorate within the first year of diagnosis compared to the years thereafter. Also, it appears that patients with an ABI <0.5 or ankle pressure <60 mm Hg have an increased risk for amputation than those patients that do not. Interestingly, studies suggest that the presence of symptoms do not indicate a higher risk of disease progression.³³ Also, patients with diabetes mellitus, tobacco abuse, or severely abnormal ABI (less than 0.5) were more likely to have progressive LEPAD.^{50,51,201,202}

In patients with critical leg ischemia, it is difficult to accurately define the natural history of the disease process since most patients will undergo a revascularization procedure. However, the overall prognosis is grim. In patients who develop chronic limb ischemia, the risk of major amputation is greater than 10% in a 3-month follow-up period²⁰³ and approximately 40% will lose their limb within 6 months.^204,205,206 One large cohort study involving patients suffering from CLI (defined as rest ischemic pain, ulceration and/or gangrene), 1 and 2 years mortality rates neared 22% and 33%, respectively, and was not altered by surgical revascularization procedures.²⁰³ Additional research has suggested that more than 80% of patients who present with CLI will be dead within 10 years.^204,205,206

Risks

Several short and long-term cohort studies have shown significant risk of CV morbidity and increased mortality rates in patients with LEPAD. However, these patients are more commonly afflicted by the consequences of the underlying systemic atherosclerotic process (e.g., myocardial infarction, stroke, incident congestive heart failure) than by progression of the LEPAD. CAD is the most common cause of death among these patients, accounting for approximately 50% of their mortality. In addition, patients with known PAD have an increased risk of anginal symptoms and a 2% to 3% annual incidence of nonfatal myocardial infarction Other catastrophic vascular events, namely stroke or ruptured abdominal aneurysms, account for 20% to 30% of the remaining deaths.³³

Interestingly, the severity of the LEPAD infers a greater risk of CV morbidity and mortality: Analysis of studies report a statistically significant increase in mortality with each 0.1 decrement in the ABI⁴⁴ (Figure 33-26). In so much, that an ABI less than 0.5 confers more than a fivefold increase in nonfatal CV events,²⁰⁷ and an ABI less than 0.4 predicts a nearly 70% mortality at 10 years.²⁰⁸

Patients with large-vessel LEPAD (as defined in various studies by ABI < 0.9, abnormal segmental blood pressures, abnormal image findings or flow velocity by Doppler ultrasound) have a relative risk of approximately 3.0 for all-cause mortality, 6.0 for CV death, and nearly 7.0 for death related to coronary heart disease compared to patients without LEPAD more than a 10-year period.⁶ Several other studies confirmed this data in various patient subgroups including patients with advanced age⁴⁴ and hypertension.²⁰ More specifically, patients with symptomatic large-vessel LEPAD are at a 15-fold increase in CV and coronary heart disease-related deaths.⁶

Similar studies have reported that LEPAD patients have been shown to have an increased risk of angina, coronary artery bypass graft surgery, congestive heart failure, and nonfatal or fatal myocardial infarction.^{196,20,209,210,211,212,213,214,215,216,217} In addition, LEPAD predicts increased mortality in these patients with acute myocardial infarction^218,219,220 or undergoing percutaneous coronary intervention,²²¹ or coronary artery bypass graft surgery.²²² Also, patients with LEPAD are at increased risk for TIA,¹⁹⁶ nonfatal stroke,²²³ and worse outcomes once a cerebrovascular event occurs.²²⁴

The clinician can initiate an appropriate, focused work-up only after a thorough understanding of the patient’s subjective complaints, medical history, and physical examination. However, the history and standard physical examination alone have a very low accuracy in the diagnosis of LEPAD. Therefore, many patients require more objective measures of LEPAD be used (Table 33-5).

Clinical History and Standard Questionnairres

The vast majority of patients with LEPAD are asymptomatic. The lack of symptoms is most likely because of either mild, nonflow limiting obstructive disease, or a sedentary lifestyle which does not induce ischemic symptoms. The most common presenting symptom of LEPAD is intermittent claudication. Other clinical presentations include atypical leg pain, ischemic ulcers, or chronic and acute limb ischemia (see above). Important aspects of any reported symptoms include the timing, symmetry (i.e., symptoms in the contralateral limb), use of potentially vasospastic medications, abuse of nonprescription drugs (especially tobacco), and occupational exposures.

Also, one must closely review the comorbid medical conditions that the patient has been, and maybe even has not been, diagnosed with previously. Specifically, one must ascertain if the patient has a known history of atherosclerosis in another vascular bed (e.g., coronary, carotid, or renal). Additionally, a prior history of atrial fibrillation or flutter, severe left ventricular dysfunction, aortic plaqueing, aneursymal disease, or intracardiac shunts (e.g., patent foramen ovale or atrial septal defect)⁹⁹ raises the probability that thromboembolic disease may be a culprit of any lower extremity symptoms. Other constitutional symptoms, such as fever, weight loss, night sweats, malaise, arthralgias, and myalgias may be indicative of an inflammatory vasculitic process. Any previously diagnosed hematologic, rheumatologic, or malignant diseases raises the suspicion for vasospasm, vasculititis, or hypercoaguable conditions.

In addition to obtaining a standard medical history, the clinician may find a standardized questionnaire to help elucidate symptoms of claudication or LEPAD. Presently, three standardized forms originally created to assess and standardize patients’ symptoms in previous trials regarding LEPAD can be effectively used in clinical practice: The Rose and Edinburgh questionnaires. The Rose questionnaire, developed in 1962, has been shown only to correctly identify 10% patients with an abnormal ABI.²⁰ In addition, numerous epidemiologic studies have shown only moderately sensitivity (∼65%) but high specificity (90%–100%) in detecting intermittent claudication.¹⁹⁶ Therefore, in efforts to improve upon the questionnaire’s diagnostic accuracy, the Edinburgh claudication questionnaire (ECQ) was created as a modification of the Rose questionnaire in 1962. In an initial small study of 300 patients, the ECQ had a reported sensitivity of 91% and sensitivity of 99% in the diagnosis of intermittent claudication.²²⁵ Thirdly, the San Diego Claudication Questionnaire was developed in order to further evaluate leg-specific symptoms and evaluate thigh, buttock and calf pain.⁵⁵