Contemporary Reviews in Cardiovascular Medicine
Nonatherosclerotic Arterial Disorders of the
Lower Extremities
Ido Weinberg, MD; Michael R. Jaff, DO
A therosclerotic peripheral artery disease (PAD) is com-
mon, estimated to affect 4.3% to 29% of the adult
population.1,2 PAD is an important syndrome to identify
promptly because it is associated with an increased risk of
premature myocardial infarction, stroke, and all-cause mor-
tality.3 The public has limited appreciation for the disorder
and its associated risks, making awareness of this disorder a
high priority.4 Conversely, nonatherosclerotic artery diseases
of the lower extremities (nonatherosclerotic PAD [NAPADs])
represent a heterogeneous group of uncommon conditions
(Figure 1). Given the frequency of symptoms of leg discom-
fort, these disorders must also be considered in the differen-
tial diagnosis of patients who may not have the classic profile
of atherosclerosis. Although each condition has distinctive
pathophysiology, clinical manifestations, treatment, and
prognosis, NAPAD also has unifying characteristics. Further-
more, left undiagnosed or mismanaged, these conditions may
result in seriously adverse outcomes that may otherwise have
been avoided or minimized.
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When Should NAPAD Be Suspected?
Patients with symptoms of exertional limb discomfort or
physical examination findings suggestive of lower-extremity
arterial ischemia may have PAD; however, it is important to
differentiate between PAD and NAPAD. Given the uncom-
mon nature of NAPAD, the differential diagnosis is unfamil-
iar to most clinicians. PAD is the most common arterial cause
of lower-extremity symptoms and therefore must be consid-
ered the leading diagnosis. Clues suggesting that symptoms
are due to PAD include the appropriate patient age, the
presence of associated cardiovascular risk factors (diabetes
mellitus, tobacco abuse, hypercholesterolemia, hyperten-
sion5,6), clinical manifestations of atherosclerosis in other
vascular beds (myocardial infarction, ischemic stroke), char-
acteristic physical findings, and a typical appearance on
imaging studies. Leg discomfort in patients with PAD as
described by the Rose criteria is a deep, cramp-like achiness
in the calf7 after a consistent amount of exertion that is often
stable over time.8 However, it has been shown that most
patients with lower-extremity PAD do not provide the classic
history.2 In a combined cohort of 3629 subjects, although as
many as 56% of those without PAD (defined as a normal
ankle brachial index at rest) had exertional leg symptoms,
From the Section of Vascular Medicine, Division of Cardiovascular Medicine and the Vascular Center, Massachusetts General Hospital, Boston, MA.
Correspondence to Michael R. Jaff, DO, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114. E-mail mjaff@partners.org
(Circulation. 2012;126:213-222.)
© 2012 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
213
classic symptoms of calf claudication were associated with
lower ankle brachial index values.9 Furthermore, the absence
of exertional leg symptoms reduces the likelihood for mod-
erate to severe PAD.10 Although no study has directly
compared the utility of the physical examination in discerning
between PAD and NAPAD, the following physical findings
were found to be suggestive, yet not pathognomonic, of PAD:
symmetrically diminished pulses, a bruit over an affected
artery, cool or atrophic skin, and nail changes. Elevation
pallor, dependent rubor, skin ulcerations, and symmetrical
ischemic neuropathy are more typical of advanced cases of
PAD.10 Normal pulses do not exclude the presence of PAD.
The angiographic pattern of atherosclerotic PAD is charac-
terized by vessel wall calcification,11 multivessel involve-
ment, a mixture of focal and diffuse lesions,6 and association
with typical ostial and proximal artery locations.12
A constellation of patient history, physical examination
findings, and the results of specific diagnostic tests may
prompt the suspicion for NAPAD. Examples include a
competitive cyclist who notes leg fatigue with extreme
exertion (iliac artery endofibrosis) or a high school soccer
player who can no longer compete because of severe limb
discomfort (popliteal entrapment syndrome). Lack of aware-
ness of these alternative diagnoses may delay appropriate
treatment and result in progressive disability. The clues to
discern between PAD and NAPAD are highlighted in Table 1. A
diagnostic approach to patients with leg pain with exertion is
presented in Figure 2.
Nonatherosclerotic Arterial Causes of
Lower-Limb Discomfort
Intermittent claudication (IC) is defined as reproducible
fatigue, discomfort, or pain that occurs in specific limb
muscle groups during effort resulting from exercise-induced
ischemia.5 Atherosclerosis is by far the most common cause
of IC, and it is much more common in the lower extremity
than the upper extremity. Nonatherosclerotic causes of leg
discomfort can be divided into vascular and nonvascular
conditions (Table 2). Although the minority of patients with
IC provide a classic history of calf muscle tightness with
walking that is promptly relieved by stopping the activity and
resting,13 a nonatherosclerotic origin for IC should be sus-
pected in patients who are young, have no other manifesta-
DOI: 10.1161/CIRCULATIONAHA.111.060335
 214 Circulation July 10, 2012
tions of atherosclerosis, and who have a paucity of athero-
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sclerotic risk factors. Additionally, when a patient presents
with a condition known to cause nonatherosclerotic IC (ie,
thromboangiitis obliterans [TAO]), lower-extremity arterial
involvement should be actively considered. Furthermore, in
cases when there is a discrepancy between symptoms and
imaging, the possibility of an alternative diagnosis other than
atherosclerosis should be entertained. Here, we review the
specific unique manifestations of popliteal artery entrapment,
cystic adventitial disease (CAD) of the popliteal artery,
endofibrosis of the iliac artery, fibromuscular dysplasia
(FMD), arteritis, idiopathic midaortic syndrome, and TAO, all
representing vascular, nonatherosclerotic causes of IC. Features
of these conditions are summarized in Tables 3 and 4.
Popliteal Artery Entrapment Syndrome
Popliteal artery entrapment syndrome (PAES) results from
pressure exerted on the popliteal artery by muscles or
ligaments within or surrounding the popliteal fossa.14 There
are 6 types of PAES, largely determined by the structures that
entrap the artery (types I–IV; Figure 315). Rarely, the vein is
also involved (type V). A sixth type has been described in
which the symptoms are functional, a result of a hypertro-
phied medial head of the gastrocnemius muscle (type VI).16
Symptoms of PAES range from pain, paresthesias, and cold
feet after exercise to ischemic rest pain and tissue necrosis. A
recent review of the published literature regarding PAES
found IC to be the most common presenting symptom.17
Progressive limb ischemia is an uncommon presentation and
more typical of undiagnosed cases in which arterial degener-
ation and poststenotic aneurysmal dilatation with emboliza-
Figure 1. Examples of various types of
lower-extremity peripheral artery dis-
ease. A, Halo sign caused by artery wall
edema, typical of vasculitis. B, Com-
puted tomographic angiography recon-
struction of lower extremities revealing
diffuse arterial calcification, typical of
atherosclerosis. C, Angiography reveal-
ing transient occlusion of the popliteal
artery on active plantar flexion (right),
consistent with popliteal artery entrap-
ment. D, Typical beaded appearance of
the medial fibroplasia type of fibromus-
cular dysplasia (FMD) in the right exter-
nal iliac artery. Note the associated an-
eurysms of the common iliac arteries,
potentially representing aneurysms asso-
ciated with FMD or combined athero-
sclerosis and FMD.
tion occur. In longstanding cases, well-developed arterial
collaterals may actually result in milder symptoms. Bilateral
symptoms have been described, prompting the need for
investigation of both limbs regardless of whether symptoms
are unilateral or bilateral.17,18 Entrapment of the popliteal vein
results in leg swelling, heaviness, varicosities, nocturnal calf
cramping, and even deep vein thrombosis.19
Findings of anatomic entrapment are not uncommon. In 1
postmortem study, anatomic abnormalities of the popliteal
fossa were found in 3 of 86 subjects (3.5%).20 Ultrasono-
graphic evidence for popliteal artery occlusion with provoc-
ative maneuvers has been described in as many of 80% of
tested asymptomatic individuals.17 Clinically evident PAES
is rare, described in as few as 33 of ⬇20 000 (0.165%) Greek
military recruits.21 Nonetheless, it is a cause of disabling limb
symptoms in young individuals presenting with IC, often
described more in men than in women.18
The diagnosis of PAES is suggested by demonstration of
popliteal artery compression on active pedal plantar flexion
against resistance. This is manifested by a decrease in the
intensity of the pulse examination or with loss of the
continuous-wave Doppler signal during provocative maneu-
vers while a probe is placed over the distal tibial arteries.
Pulse-volume recordings and segmental pressures should be
measured at rest with the knee extended and the ankle in the
neutral, dorsiflexed, and plantarflexed positions. Exercise
treadmill studies may also be helpful by demonstrating
diminished limb arterial pressure after exercise in the symp-
tomatic limb. Arterial duplex ultrasonography may demon-
strate abnormalities when performed in these provocative
positions.22 In a series of 16 healthy volunteers, popliteal
 Weinberg and Jaff
Table 1. When to Suspect Nonatherosclerotic Peripheral
Artery Disease in a Patient With Lower-Extremity Symptoms
Characteristic Comment
Claudication Most patients with claudication caused by PAD
chracteristics present with reproducible symptoms
Claudication symptoms from atherosclerosis
typically resolve within several minutes of stopping
activity, and occur after a fixed amount of exertion
Symptoms typically occur sooner on an incline
Symptoms only during extreme exertion are not
typical of PAD
Age ⬍50 y PAD prevalence rises with age and is less common
before 50 y of age
Lack of PAD is a marker of systemic atherosclerosis
cardiovascular risk
Tobacco abuse and diabetes mellitus represent the
factors
strongest risk factors for PAD
Sudden onset, rapid Claudication symptoms from atherosclerosis are
progression, or typically stable over time
waxing and waning
An exception is acute limb ischemia resulting from
pattern
systemic embolism
Associated Symptoms associated with NAPAD include fever,
symptoms malaise, weight loss, upper-extremity claudication,
atypical ulcerations, rash suspicious for systemic
vasculitis, and superficial venous thrombosis
Elevated inflammatory markers or hematologic
abnormalities are more typical of NAPAD
Known systemic If a patient with lower-extremity symptoms has a
illness that may known diagnosis of a potential cause of NAPAD (eg,
cause NAPAD FMD), lower-extremity involvement should be
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entertained
Physical findings The Allen’s test is abnormal
not typical for Pedal pulse intensity is affected by knee flexion
atherosclerosis
A discrepancy in brachial artery blood pressure or
radial-femoral pulse delay exists in a young patient
There is evidence of isolated distal arterial disease
Imaging findings Atherosclerotic lesions are typically variable in
atypical of length and associated with arterial calcifications
atherosclerosis Atherosclerotic lesions are usually present in
several vascular beds such as the coronary,
cerebrovascular, renal, and aorta
Atherosclerotic lesions are most often
ostial/proximal in location
PAD indicates peripheral artery disease; NAPAD, nonatherosclerotic PAD;
and FMD, fibromuscular dysplasia.
artery compression was demonstrated in 84% of limbs on
active plantar flexion,23 highlighting the potential for false-
positive results. For this reason, dynamic computerized to-
mographic arteriography or magnetic resonance arteriogra-
phy may be helpful to confirm the diagnosis. Computerized
tomographic arteriography and magnetic resonance arteriog-
raphy also demonstrate the causative structures resulting in
entrapment of the vascular structures. Data on the utility of
these tests are limited to small series.24
Treatment of PAES types I through V is by surgical relief
of the entrapment by resection or translocation of the com-
pressing elements. In the case of functional PAES (type VI),
part of the medial head of the gastrocnemius muscle is
resected or translocated to relieve pressure on the vascular
Nonatherosclerotic Vascular Disease 215
structures.16 Prompt therapy should be offered because of the
progressive nature of the disorder. If the disease is advanced,
arterial reconstruction or surgical bypass of an occlusion or
aneurysm, preferably with a venous autologous graft, may be
required.
Cystic Adventitial Disease (CAD) of the
Lower-Extremity Arteries
Cystic adventitial disease (CAD) is a rare cause of IC,
typically found in middle-aged men and affecting mainly the
popliteal artery.25 Bilateral disease has been described,26 as
has CAD in other locations such as the external iliac,
femoral,27 radial, or ulnar arteries.26 Symptoms are caused by
compression of the arterial lumen by a cystic collection of
mucinous material inside the adventitia of the artery.28
Various theories have been proposed for the origin of CAD,
including a systemic disorder, repetitive trauma, and a per-
sistent embryonic synovial track.29
Classically, limb pain will linger for as long as 20 minutes
on cessation of activity, as opposed to the rapid relief that
most patients with PAD-associated limb discomfort experi-
ence. CAD-related IC may wax and wane or even disappear
for as long as several months, just to reappear without any
clear inciting event.30 Acute limb ischemia secondary to
arterial compression and thrombosis has also been de-
scribed.31 The diagnosis is suspected when pedal pulses
disappear with passive knee flexion (Ishikawa sign)26 and
occasionally with exercise32 and is confirmed with imaging,
typically magnetic resonance imaging.33 Conventional an-
giography may not represent the gold standard diagnostic
modality for CAD in that it may only demonstrate compres-
sion of the arterial lumen (hourglass sign or scimitar sign)
without further characterization of the underlying origin.25
There are no uniform recommendations for the treatment
of CAD. Image-guided aspiration, surgical resection followed
by autologous venous interposition graft, and adventitial
resection have been described.29,32 Percutaneous transluminal
angioplasty has not been found to be useful. Data on
long-term surveillance are lacking; however, recurrence is
possible, thereby prompting the need for prospective
surveillance.32
Endofibrosis of the Iliac Artery
Endofibrosis of the iliac artery is a rare cause of arterial
stenosis, reported most often in highly functioning and
competitive cyclists34 and highly functioning runners.35 It is
thought to result from repetitive trauma, predominantly of the
external iliac artery. Symptoms include IC and a sensation of
swelling or paresthesia in the proximal lower limb at the time
of maximal exertion.36 Physical examination may be normal
at rest, although a bruit may be heard over the ipsilateral
pelvic fossa or inguinal region.37 Diagnostic imaging should
include pre-exercise and postexercise ankle pressure determi-
nation with maximal, symptom-limiting treadmill exercise.
Further imaging with duplex ultrasonography and contrast
angiography,36 preferably when the leg is flexed at the hip in
the cycling position, will reveal concentric stenosis and often
lengthening of the affected iliac artery. Intravascular ultra-
sound has been reported to aid in the diagnosis, in addition to
 216 Circulation July 10, 2012

Figure 2. Diagnostic approach to

patients with leg pain with exertion.
NAPAD indicates nonatherosclerotic pe-
ripheral artery disease; PVR, pulse-
volume recording; DUS, duplex ultra-
sonography; CTA, computed
tomographic angiography; and MRA,
magnetic resonance angiography.

intra-arterial translesional pressure gradients. Although no
large-scale trials exist to guide treatment, most report surgical
revascularization with patch angioplasty or interposition
grafts. More recently, endovascular therapy with percutane-
ous transluminal angioplasty and stent deployment have
demonstrated efficacy.35
Fibromuscular Dysplasia
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Although less common, FMD may affect the iliac,43
femoral, or popliteal arteries. Lower-extremity involvement
may result in IC, microemboli, or (rarely) critical limb
ischemia via dissection or rupture of the artery.22,44 FMD is
divided into several types according to which arterial layer is
affected and by the arteriographic pattern of disease: medial
fibroplasia, intimal fibroplasia, and adventitial (periarterial)

hyperplasia. Medial fibroplasia is the most common type,

FMD is a noninflammatory, nonatherosclerotic arterial dis-
ease38 that occurs most commonly in women 20 to 60 years
of age. FMD has been described in men, children, and the
elderly.39 The true prevalence of FMD is unknown; however,
in a series of potential renal donors40 and from incidental
findings on imaging, it is not rare.41 The clinical manifesta-
tions of FMD depend on its arterial distribution. The renal
arteries are affected in 75% and the extracranial carotid
arteries in 70% of patients with FMD.38,42 FMD may be
asymptomatic and incidentally discovered when imaging is
performed for other reasons.
Table 2. Differential Diagnosis of Intermittent Claudication
Condition
Vascular Atherosclerosis
Popliteal artery entrapment syndrome
Cystic adventitial disease of the popliteal artery
Iliac artery endofibrosis
Fibromuscular dysplasia
Venous claudication
Large- and medium-vessel vasculitis
Nonvascular Chronic exertional compartment syndrome
Arthritis (lumbosacral spine, hip or knee)
Peripheral neuropathy
Hamstring muscle tightness
Symptomatic popliteal (Baker) cyst
Plantar fasciitis
making up 80% to 90% of cases in the renal arteries. It is
characterized by intra-arterial fibrotic webs that give rise to a
beaded appearance on imaging studies in which the beads are
larger than the lumen of the artery. Thus, the diagnosis relies
on a combination of clinical and imaging findings. Duplex
ultrasonography, magnetic resonance arteriography, and
computerized tomographic arteriography can all identify
FMD and assess aneurysm formation, but none is as accurate
as angiography45 or intravascular ultrasonography.46 The
scope of imaging should accommodate the fact that FMD
may involve several vascular beds. Thus, patients with
extracranial FMD should be screened for intracranial aneu-
rysms and for renal involvement, especially if they are
hypertensive.47 The differential diagnosis of FMD includes
atherosclerosis, systemic vasculitis, segmental arterial me-
diolysis,48 and arterial aneurysms and dissections from other
causes (eg, genetic collagen disorders). It should be noted that
in older individuals FMD and atherosclerosis may occur
simultaneously (see Figure 1). Treatment of FMD depends
on the presentation and extent of arterial involvement.
Asymptomatic patients are usually empirically prescribed
aspirin. Despite a lack of high-quality data, relying on
experience from treatment of renal arteries and on case
reports on the iliac arteries49 in which percutaneous
transluminal angioplasty has proved to be successful in
patients with FMD,50 it is recommended as first-line
therapy for patients with debilitating symptoms related to
lower-extremity artery involvement. Of the 10 case reports
in the literature on spontaneous iliac artery dissection in
 Weinberg and Jaff Nonatherosclerotic Vascular Disease 217

Table 3. Comparison of Clinical Characteristics of Lower-Extremity Atherosclerosis and Nonatherosclerotic Peripheral Artery Disease
Large- and
Popliteal Medium-Vessel
Atherosclerosis Entrapment Cystic Adventitial Disease Vasculitis Midaortic Syndrome Endofibrosis FMD Buerger Disease

Clinical characteristics
Age of onset Typically ⬎50 y Teenagers and 4th–5th decade 2 Peaks: young Children and young Young, physically Variable Typically ⬍50 y
young adults adults adults active adults presentation
(Takayasu/Behcet)
and elderly
(giant-cell arteritis)
Sex predominance Male⬎female None Male⬎female Female⬎male in Insufficient data None Female⬎male Male⬎female
Takayasu
Symptom trigger Reproducible, often Exercise is a Variable onset, may wax Symptoms may Claudication is rare; Often extremely Variable Often constant
stable over time; typical trigger and wane exacerbate with the severity of aortic strenuous activity
walking on incline active vasculitis narrowing dictates
produces earlier and abate with symptom severity
symptoms treatment or
become chronic in
the fibrotic stage
of disease
Time to symptom Several minutes unless Several minutes Up to 20 min Symptoms may be Symptoms may be Symptoms resolve Symptoms may Symptoms may
resolution on rest critical limb ischemia unless rest pain constant or resolve constant or resolve after activity be constant or be constant or
in which case rest pain and tissue after several after several resolve after resolve after
may be persistent, necrosis minutes as in minutes as in several minutes several minutes
particularly at night develop in atherosclerosis atherosclerosis
neglected cases
Additional Other vascular beds None None Fever, night Hypertension in a None Extracranial Superficial vein
symptoms typically affected, sweats, weight child or teen is the carotid artery thrombosis, tissue
specifically coronary loss, malaise, most common and renal necrosis
and cerebral arthralgia, renal presenting circulation is
failure, symptoms typical
hematologic
abnormalities,
TIA/CVA; oral or
genital ulcerations
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and uveitis
suggest Behcet
Other clinical clues Atherosclerotic risk None None Asian or Latin None History of None Tobacco or
factors and specifically descent competitive sports, marijuana abuse
tobacco abuse often cycling
Physical Diminished pulses, Popliteal pulse Popliteal and distal pulses Diminished Pulse delay between Can be normal; may Can be normal; Tobacco stains,
examination bruits, elevation pallor diminished with disappear with knee brachial or radial the radial and hear bruit in bruit may be digital ischemia,
and dependent rubor; forced plantar flexion (Ishikawa sign) pulse; bruit over femoral arteries ipsilateral pelvis after heard over the abnormal Allen
in critical limb flexion the subclavian, activity femoral artery test
ischemia, nonhealing carotid, mesenteric and over the
ulcers over bony or renal arteries; carotid and renal
prominences or distal pulse delay arteries
aspects of toes between the radial
and femoral
arteries
Treatment Atherosclerosis risk Early surgical Aspiration or resection of Immunomodulating Surgery is most Surgical bypass; Antiplatelets; Avoidance of
factor modification, repair of cysts agents; common; endovascular repair endovascular or tobacco and
consider endovascular anatomic endovascular and endovascular has been described surgical nicotine products
and surgical treatment abnormality surgical treatments approach advocated approach for
preferred are reserved for as bridge complications
complications

FMD indicates fibromuscular dysplasia; TIA/CVA, transient ischemic attack/cerebrovascular accident.

patients with FMD, all patients were treated surgically population, significantly lower than the reported incidence of
with prosthetic or vein graft.44 3.3 per 1 million in Japan.52 Criteria for the diagnosis of TA
include young age, claudication of ⬎1 extremity (classically
Medium- and Large-Vessel Vasculitis an upper extremity), a diminished brachial pulse, asystolic
Several large- and medium-vessel vasculitides have been
blood pressure difference of ⬎10 mm Hg between the bra-
described to affect the lower extremities. These include
chial arteries, a bruit over at least 1 subclavian artery, and
Takayasu arteritis (TA), giant-cell arteritis (GCA), and Beh-
imaging evidence of long segments of tapering stenosis of the
cet disease. TA is a large-vessel vasculitis that typically, but
aorta or one of its large branches.53 In contrast to PAD, IC
not exclusively, affects young women of Asian or Latin
resulting from TA is much more common in the upper
descent.51 An analysis of a large nationwide database in the
extremity than the lower extremity.
United Kingdom revealed a prevalence of 0.8 per 1 million
 218 Circulation July 10, 2012

Table 4. Comparison of Imaging and Laboratory Characteristics of Lower-Extremity Atherosclerosis and Nonatherosclerotic
Peripheral Artery Disease
Large- and
Popliteal Medium-Vessel
Atherosclerosis Entrapment Cystic Adventitial Disease Vasculitis Midaortic Syndrome Endofibrosis FMD Buerger Disease

Imaging characteristics
Noninvasive Physiologic testing Popliteal None Periarterial edema Reduced ABI Physiological testing Arterial beading Asymmetric
imaging should be performed at Doppler signal (halo sign) should be performed may be seen in digital waveforms
rest and with exercise diminished with after intense activity the distal renal
with exercise; on DUS, forced plantar (eg, running, cycling) or distal
there is varied lesion flexion extracranial
lengths from to diffuse; carotid arteries
lesions associated with
calcification
CTA/MR Multiple vascular bed Studies in the MRI may show adventitial Long segments of Abdominal aortic Redundant external Arterial beading Atherosclerosis
involvement, varied neutral position, fluid collections that can arterial narrowing narrowing iliac arteries may be may also be
lesion lengths, flexion, and appear to be confluent (macaroni sign), visualized present
calcifications, irregular extension are with the synovium typical distribution;
plaque necessary for arteritis may be
the diagnosis identified
Angiography As CTA/MR Runoff may Not the modality of Long segments of Variable infraisthmic As CTA/MR As CTA/MR Abnormal palmar
disappear with choice; hourglass or arterial narrowing aortic narrowing; arch, corkscrew
plantar flexion scimitar signs in a typical renal artery ostium collaterals
distribution involvement
Distribution Multiple vascular beds Isolated to the Most commonly isolated Aortic arch and Abdominal aorta External iliac arteries Most common in Distal disease
popliteal fossa to the popliteal fossa but great vessels or the renal and precedes proximal
can appear in other midaortic extracranial disease
locations syndrome carotid artery
(Takayasu); distribution
temporal arteries
Laboratory characteristics
Elevated Not typical Not typical Not typical Typical, but not Not typical in the Not typical Not typical Not typical
inflammatory essential, during idiopathic form
markers active phase
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FMD indicates fibromuscular dysplasia; DUS, duplex ultrasound; ABI, ankle brachial index; CTA, computed tomographic angiography; and MR, magnetic resonance.

GCA, a granulomatous arteritis of medium- and large-sized Figure 1).65,66 Long segments of smooth narrowing or
arteries, represents a component of a spectrum of arteritides aneurysmal dilatation may be visualized with computer-
along with TA.54 It is a disease of adults ⬎50 years of age. Its ized tomographic arteriography or magnetic resonance
prevalence is estimated to be 15 to 33 per 100 000 popula- arteriography.67 Additional testing with positron emission
tion.55 It is characterized by new-onset headache, scalp tomography to demonstrate uptake of fluorodeoxy-D-
tenderness, jaw claudication, and in advanced cases, visual glucose in the arterial wall may prompt the diagnosis even
disturbance.56 Lower-extremity involvement has been de- before visible anatomic arterial changes occur. However,
scribed in GCA.54 Although typically affecting the aortic arch uptake may remain visible long after treatment has been
and the great vessels, TA may also result in a midaortic initiated,68 and 2 small studies comparing positron emis-
variant. This variant causes abdominal aortic coarctation, sion tomographic computed tomography with clinical and
resulting in renovascular hypertension, IC, or both.57 In an laboratory assessment of disease activity have yielded
analysis of 58 patients with this variant of TA and renovas- conflicting results.69,70
cular hypertension in India, it has been found to be equally Treatment of vasculitides includes managing inflammation
common in men and women.58 In a retrospective analysis of and treating arterial complications (ie, stenosis, occlusion,
272 patients with TA spanning 50 years, 41 (⬇15%) were aneurysm).60,71 While the disease is active, IC may respond to
found to have IC.59 treatment with antiinflammatory agents, including corticoste-
Finally, Behcet disease is a multisystem vasculitis that roids, methotrexate, azathioprine, and cyclophosphamide.
affects both arteries and veins. When present, large-artery The effects of tocilizumab, an interleukin-6 inhibitor, have
involvement is the most typical and may result in both not been described specifically for the treatment of lower-
aneurysmal dilatation and, less commonly, stenosis or artery extremity ischemia associated with GCA, although it has
occlusion.60 Lower-extremity involvement has also been been used in the treatment of both TA and GCA.72 In contrast,
described in the iliac, femoral, popliteal, and posterior tibial in the fibrotic stages of the disease, endovascular or surgical
arteries.61,62 Isolated infrainguinal involvement is distinctly intervention may be necessary to correct the underlying
unusual. obstruction to flow or to exclude aneurysms.57 Surgical
Inflammatory markers are typically, yet not necessarily, options in TA include aortoiliac and aortofemoral bypass.59,73
elevated in the active stages of both TA and GCA.54,63 Duplex Aneurysm repair in patients with Behcet disease has been
ultrasonography may demonstrate long segments of arterial complicated by disease recurrence despite antiinflammatory
narrowing (macaroni sign)64 or vessel wall edema (halo sign; treatment in 2 retrospective series.62,74
 Weinberg and Jaff
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Idiopathic Midaortic Syndrome
Midaortic syndrome refers to narrowing of the subisthmic
aorta.75 It is a form of aortic coarctation most probably arising
from an embryonic developmental disorder. This should be
differentiated from involvement of the abdominal aorta in
large-vessel vasculitis. The diagnosis is commonly made in
children and young adults. It can affect the suprarenal, renal,
or infrarenal segments of the abdominal aorta. Involvement of
the renal artery origins is typical and may result in renovas-
cular hypertension. IC has been described, albeit rarely.76 In
a retrospective series of a mixed population of 16 patients
with idiopathic and secondary midaortic syndrome, 2 present-
ed with IC.76 In another retrospective series of 17 patients,
most of whom did not have elevated inflammatory markers,
only 3 had lower-extremity symptoms, although in 4 patients
a substantial blood pressure gradient could be measured
between the arms and the legs.77 Treatment of midaortic
syndrome has classically been surgery. Recurrence with
percutaneous transluminal angioplasty is said to be high
owing to extensive aortic involvement and significant elastic
recoil and has been proposed as a bridge to surgery. High-
radial-strength balloon-expandable stents, either bare or cov-
ered with a fabric material, may represent an effective
primary modality for therapy.
TAO (Buerger Disease)
TAO is a segmental inflammatory condition that affects small
and medium arteries, veins, and nerves.78 TAO is a disease of
Nonatherosclerotic Vascular Disease 219
Figure 3. The 4 most common types of
popliteal vascular entrapment (types
I–IV). Reprinted from Pillai15 with permis-
sion from the publisher. © Copyright,
2008, Elsevier.
young people, typically ⬍50 years of age, who abuse to-
bacco, most classically in the form of cigarettes. Atheroscle-
rotic risk factors other than smoking are commonly absent.
Clinical manifestations of TAO include pain in a digit or
extremity, digital ischemia, Raynaud phenomenon, distal
digital ulcerations, and extremity claudication. As TAO
progresses, it may progress to extremity gangrene and ampu-
tation. TAO is a clinical diagnosis. Commonly, ⬎2 extrem-
ities are involved, sometimes subclinically, wherein patients
without obvious upper-extremity involvement have an abnor-
mal Allen test. In a retrospective series of 112 patients, 61
(72%) had lower-extremity ischemic ulcerations.79
Physical examination must include a thorough vascular
examination with particular attention to pulses, bruits, and
assessment of the ankle brachial index. An Allen test should
be performed to demonstrate arterial involvement of the
upper extremity even if asymptomatic. Markers of inflamma-
tion and autoantibodies are usually absent and are assayed to
exclude alternative diagnoses. Anti-endothelial antibodies,
not routinely measured, have been described in Buerger
disease.80 Imaging studies should be used to identify the
distribution of vascular involvement when TAO is suspected,
demonstrating normal proximal arteries. Proximal sources of
emboli should be excluded, typically with transthoracic and
transesophageal echocardiography. Although computerized
tomographic arteriography and magnetic resonance arteriog-
raphy may be helpful in excluding atherosclerosis, diagnostic
arteriography is often needed to demonstrate the distal in-
 220 Circulation July 10, 2012
volvement of arteries and the usual absence of atherosclerotic
lesions.81 A typical presentation is that of segmental arterial
occlusion and corkscrew collaterals (Martorell sign). How-
ever, contrary to popular belief, corkscrew collaterals are not
pathognomonic for TAO. Biopsy, usually reserved for atyp-
ical cases, demonstrates a highly cellular thrombus with
relative sparing of the vessel walls. Features distinguishing it
from atherosclerosis include disease distribution, involve-
ment of both the upper and lower extremities, associated
superficial venous thrombosis, a paucity of atherosclerotic
risk factors, and normal proximal large arteries.
The cornerstone of treatment is tobacco cessation. Com-
plete abstinence is crucial because a reduction in tobacco
exposure does not prevent progressive tissue necrosis and
limb loss. Tobacco cessation has been supplemented by
various adjuvant therapies. Intravenous alprostadil, a stable
prostacyclin analog, has been compared with aspirin in a
prospective, double-blind, randomized trial of 133 subjects
with TAO and critical limb ischemia.82 Fifty-eight of the 68
patients (85%) who received alprostadil showed response to
treatment as measured by ulcer healing and pain reduction
compared with 11 of 65 patients (17%) who received aspirin
alone at 21 to 28 days (P⬍0.05). Another prospective,
double-blind, randomized, placebo-controlled trial examined
the effect of 2 doses of oral iloprost on ulcer healing, pain,
and amputation-free survival in 319 patients with TAO.83
Patients were treated for 8 weeks and followed up for 6
months. Only patients receiving low-dose iloprost experi-
enced greater pain relief (63% versus 49%; P⫽0.02). Other
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vasodilators such as calcium channel antagonists, peripheral
␣-blockade, and sildenafil have not been formally evaluated
in TAO. The results of surgical venous bypass grafts for the
treatment of TAO-related lower-extremity ischemia have
been reported. In a retrospective study of 71 venous graft
bypass procedures in 61 patients, of whom 38 also underwent
sympathectomy,81 the mean follow-up was 62.6 months.
There were 14 early failures and 24 late failures, and the
primary, assisted primary, and secondary patency rates at 5
years were 48%, 58%, and 62.5% and at 10 years were 43%,
52.1%, and 56.3%, respectively. Other treatments that have
been attempted include bosentan,84 spinal cord stimulation,85
and intermittent pneumatic compression.86 In a pilot study,
vascular endothelial growth factor was injected intramuscu-
larly into 7 limbs of patients with critical limb ischemia who
also fulfilled the diagnostic criteria for TAO, resulting in
ulcer healing in 5 and resolution of rest pain in 2.87 Imaging
studies revealed improved collateral blood flow in all treated
legs. Finally, lumbar sympathectomy and periarterial sympa-
thectomy have also been described with various degrees of
success.
Conclusions
The most common vascular cause for exertional limb discom-
fort is PAD resulting from atherosclerosis. However, alterna-
tive diagnoses must be considered for patients without the
classic risk factors for atherosclerosis and those without
evidence of atherosclerosis involving other vascular beds.
NAPAD can be caused by extrinsic arterial compression
(PAES), abnormalities in the artery wall (CAD, FMD),
inflammatory states (TA), and tobacco-related disorders
(TAO). A thorough understanding of these disorders will
allow prompt and appropriate diagnosis and treatment. The
practicing cardiovascular specialist must have a high index of
suspicion for these diagnoses.
Disclosures
Dr Jaff is a board member of VIVA Physicians, a 501c3 not-for-
profit education and research organization. Dr Weinberg reports no
conflicts.
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KEY WORDS: atherosclerosis 䡲 peripheral arterial disease 䡲 lower extremity