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The Zena and
MichaelA. Wiener
Cardiovascular Institute
& Marie-José and
HenryR. Kravis
Cardiovascular Health
Center, Mount Sinai
School of Medicine,
One Gustave L. Levy
Place, Box 1033, New
York, NY 10029-6574,
USA (J. F. Lau,
M.D.Weinberg,
J.W.Olin).
Correspondence to:
J. W. Olin
jeffrey.olin@
msnyuhealth.org
Peripheral artery disease. Part 1: clinical
evaluation and noninvasive diagnosis
Joe F. Lau, Mitchell D. Weinberg and Jeffrey W. Olin
Abstract | Peripheral artery disease (PAD) is a marker of systemic atherosclerosis. Most patients with PAD
also have concomitant coronary arter y disease (CAD), and a large burden of morbidity and mortality in patients
with PAD is related to myocardial infarction, ischemic stroke, and cardiovascular death. PAD patients without
clinical evidence of CAD have the same relative risk of death from cardiac or cerebrovascular causes as
those diagnosed with prior CAD, consistent with the systemic nature of the disease. The same risk factors
that contribute to CAD and cerebrovascular disease also lead to the development of PAD. Because of the
high prevalence of asymptomatic disease and because only a small percentage of PAD patients present with
classic claudication, PAD is frequently underdiagnosed and thus undertreated. Health care providers may have
difficulty differentiating PAD from other diseases affecting the limb, such as arthritis, spinal stenosis or venous
disease. In Part 1 of this Review, we explain the epidemiology of and risk factors for PAD, and discuss the
clinical presentation and diagnostic evaluation of patients with this condition.
Lau, J. F. etal. Nat. Rev. Cardiol. advance online publication 31 May 2011; doi:10.1038/nrcardio.2011.66
Introduction
For the purposes of this Review, the definition of peripheral
artery disease (PAD) is atherosclerosis of the aorta, and the
iliac and lower extremity arteries. PAD is a manifestation
Competing interests
J. W. Olin declares associations with the following companies:
Bristol-Myers Squibb, Genzyme, Merck & Co., and Sanofi–
Aventis. See the article online for full details of the relationships.
J. F. Lau, M. D. Weinberg, the journal Chief Editor B. Mearns and
CME questions author C. P. Vega declare no competing interests.
Continuing Medical Education online
This activity has been planned and implemented in accordance
with the Essential Areas and policies of the Accreditation Council
for Continuing Medical Education through the joint sponsorship of
Medscape, LLC and Nature Publishing Group. Medscape, LLC is
accredited by the ACCME to provide continuing medical education
for physicians.
Medscape, LLC designates this Journal-based CME activity for
a maximum of 1 AMA PRA Category 1 Credit(s)TM. Physicians
should claim only the credit commensurate with the extent of
their participation in the activity.
All other clinicians completing this activity will be issued a
certificate of participation. To participate in this journal CME
activity: (1) review the learning objectives and author disclosures;
(2) study the education content; (3) take the post-test and/or
complete the evaluation at http://www.medscape.org/journal/
nrcardio; (4) view/print certificate.
Released: 31 May 2011; Expires: 31 May 2012
Learning objectives
Upon completion of this activity, participants should be able to:
1 Analyze the epidemiology of PAD.
2 Evaluate risk factors for PAD.
3 Describe the clinical presentation of PAD.
4 Apply imaging studies for PAD effectively.
of systemic atherosclerosis and is, therefore, associated
with substantial morbidity and mortality.1–2 The major‑
ity of patients with PAD also have concomitant coronary
artery disease (CAD), and a large burden of morbidity and
mortality in patients with PAD is related to myo cardial
infarction (MI), ischemic stroke, or cardio vascular death.1
Indeed, in a series of 1,000 coronary angiograms of patients
who were under consideration for vascular surgery for
abdominal aortic aneurysm (n = 263), carotid artery disease
(n = 295), or PAD (n = 381) only 8% demonstrated normal
coronary arteries.3 Also note worthy is that patients with
PAD but no clinical evidence of CAD have the same rela‑
tive risk of death from cardiac or cerebrovascular causes as
those whose main diagnosis is CAD, which is consistent
with the systemic nature of the disease.1,4 Furthermore,
PAD is associ ated with depression, a profound reduction in
functional capacity (as measured by 6‑min walk distance,
4‑m fast‑walking velocity, and performance on a series of
tests that measure balance and mobility), and overall poor
quality of life.5–6 Notably, patients with PAD who already
exhibit the greatest declining functional performance as
measured by these tests (lowest tertile) possess the great‑
est risk for loss of mobility, and have the highest risk for
all‑cause and cardiovascular mortality.7
The same risk factors that contribute to CAD and
cerebro vascular disease, such as advancing age, hyper‑
tension, hyperlipidemia, diabetes mellitus, and a current
or prior history of smoking, also lead to the development
of PAD.8 Additional risk factors that have been associated
with PAD include chronic kidney disease,9 low serum
25‑hydroxy‑vitamin D levels,10,11 and the presence of
several inflammatory biomarkers, such as homocysteine,
C‑reactive protein (CRP), beta‑2‑microglobulin, and
cystatin C.12,13 PAD is underdiagnosed owing to the lack
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of education about PAD during medical school and post‑
graduate medical training, and the high prevalence of
asymptomatic disease.4 Excellent noninvasive imaging
modalities are available to assist the clinician in the diagnosis
and management of PAD.
In Part 1 of this Review, we focus on the epidemiology
of and risk factors for PAD, and the clinical presentation
and diagnostic evaluation of patients with this condition. In
Part2,14 we cover the medical and endovascular manage ment
of these patients.
Epidemiology
An estimated 27million people in Western Europe and
North America, including 8–10million Americans, have
PAD. This figure represents approximately 16% of the total
population of both the USA and Western Europe aged
over 55years.15 Approximately 10–35% of patients with
PAD present with classic claudication and 20–40% have
atypical leg pain.1 Nearly 50% of all patients with PAD are
asymptomatic and PAD is only detected by measuring
the ankle–brachial index (ABI), which is the ratio of the
highest systolic blood pressure (SBP) in the dorsalis pedis
or posterior tibial arteries of each leg to that of the highest
SBP in the brachial artery of each arm.1,16–18
The 5‑year rate of nonfatal cardiovascular events
(including MI and stroke) among patients with sympto‑
matic PAD is ~20%; mortality ranges from 15–30%
(Figure1).1,18 Of those who develop critical limb ischemia
(1–2%), as many as 25% will ultimately require amputa‑
tions and annual mortality among these patients has
been reported to be as high as 25%.19 A poorer 6‑min
walk performance and slower walking speed in treadmill
exercise tests are predictors of increased all‑cause and
cardio vascular mortality of patients with PAD,20 even
after adjustment for confounding variables, such as ABI
andcomorbidities.21
ABI as a prognostic tool
ABI has been validated as a predictive marker for future
cardiovascular events, and has been shown to enhance the
prognostic capabilities of the Framingham risk score.2,4,22–30
Key points
■Most patients with peripheral artery disease (PAD) also have concomitant
coronary artery disease; morbidity and mortality in patients with PAD are often
related to myocardial infarction and ischemic stroke
■Risk factors for coronary artery and extracranial cerebrovascular disease
also promote the development of PAD; smoking and diabetes mellitus are
particularly prevalent among patients with PAD
■Only a small percentage of patients with PAD present with classic Rose
claudication, as approximately 70–90% have atypical leg symptoms or are
asymptomatic
■The ankle–brachial index remains the initial noninvasive diagnostic tool of
choice for PAD screening, with 95% sensitivity and 99% specificity
■Segmental limb pressures, pulse–volume recordings, and exercise treadmill
testing can help localize the diseased arterial segment(s), and provide
information about the functional limitations of the patient
■Duplex ultrasound can identify the site, extent, and severity of PAD from the
aorta to the feet
Among participants of the Cardiovascular Health Study,
who were aged 65years or older and had no previously
known cardiovascular disease, total and cardiovascular
mortality after 6years of follow‑up was higher in those
with an initial ABI <0.9 when compared with those with
normal (1.0–1.4) ABI (all‑cause mortality: 25.4% versus
8.7%; cardiovascular mortality: 6.9% versus 1.7%).2 These
differences between the two groups were statistically
signifi cant. A decline in ABI within this population also
correlated with the increased prevalence of modifiable risk
factors, such as tobacco use, hypertension, and dia betes.31
In the Strong Heart Study,32 a population‑based study of
American Indians aged 45–74years, cardio vascular mortal‑
ity over an 8‑year follow‑up period was significantly higher
in subjects with an initial ABI <0.9 or >1.4 when com‑
pared with counter parts with normal ABIs. The U‑shaped
association between ABI and cardiovascular mortality
correlated with the increased prevalence of diabetes and
hyper tension in both low and high ABI groups. Both high
(>1.4 or noncompressible) and low ABIs (<0.9) have been
closely associated with chronic kidney disease, suggesting
that arterial stiffness could be an important mechanism
for PAD in patients with this disease.33 Indeed, large‑scale
syste matic reviews affirmed the high specificity of the ABI
to predict future cardiovascular outcomes.34,35
Risk factors
The risk factors that contribute to atherosclerosis in
the carotid and coronary arteries also contribute to the
develop ment of PAD. Several population studies and
observational analyses have identified major risk factors for
PAD, such as increasing age, African‑American or Hispanic
ethnicity, current or past tobacco use, and the presence of
diabetes, dyslipidemia, hypertension, and chronic kidney
disease.4,36–39 Of these risk factors, smoking and diabetes
pose the greatest risk for the development and progression
of PAD (Figure2).40,41
Age
Multiple studies have demonstrated that the prevalence of
PAD increases with age.4,36,37,39 Long‑term follow‑up data
from the Framingham Heart Study (FHS) revealed that
the prevalence of PAD increases significantly after the age
of 65years. From the FHS, which determined the inci‑
dence of PAD on the basis of symptoms of claudication,
the annual incidence of claudication has been determined
to be 6 per 10,000 in men and 3 per 10,000 in women
within the 30–44years age group. Concordant with the
increased prevalence of PAD in older patients, the inci‑
dence of claudication increased to 61 per 10,000 in men
and 54 per 10,000 in women aged 65–74years.42 In the
Health and Nutrition Examination Survey (NHANES),37
the prevalence of PAD among individuals aged older than
70years was more than threefold higher than those aged
40–70years (14.5% versus 4.3%).
Ethnicity
Several observational population studies have demon‑
strated that the prevalence of PAD is greatest among
African‑American and Hispanic populations.4,37,43,44
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In NHANES,37 African Americans had a 2.4‑fold higher
risk of developing PAD than non‑Hispanic white partici‑
pants. The higher risk of PAD was maintained after
adjustment for traditional risk factors (such as diabetes,
hyper tension, and obesity) and several biomarkers.37,44
Similarly, in the Multi‑Ethnic Study of Atherosclerosis
(MESA)45 cohort, the prevalence of PAD varied greatly
among different ethnic groups, with the highest preva‑
lence of PAD found in African‑American men and
women. The prevalence of PAD was lowest among
Hispanic womenand Chinese men.45 Across all ethnic
groups, McDermott andcolleagues demonstrated inverse
relationships between ABI and measures of subclinical
atherosclerosis (carotid intimal–media thickness and
coronary artery calcium [CAC] scores), although the
strength of these associ ations varied between ethnic
groups.45 Again, the ethnic propensities remained even
after analyses were adjusted for traditional cardiovascular
risk factors.
Smoking
Tobacco use correlates with the development and pro‑
gression of PAD. Smoking appears to be more strongly
associated with PAD than with CAD.46 Smokers develop
symptoms of PAD almost a decade earlier when compared
with nonsmokers.47–49 Patients with PAD, who continue
to smoke, have a much higher risk of progressing to
critical limb ischemia, and are twice as likely to develop
compli cations requiring amputation.49 In patients with
lower extremity bypass grafts, smoking is associated witha
threefold increase in graft failure.50 Most importantly,
smoking cessation can effectively lower the risk of develop‑
ing PAD, and in patients who already have this condition
can reduce the severity of limb symptoms, decrease the
likelihood of amputation, and improve survival.51
Diabetes
In the PAD Awareness, Risk, and Treatment: New
Resources for Survival (PARTNERS) study,2 nearly one‑
third of individuals with PAD had concomitant diabetes.
Approximately 20% of patients with symptomatic PAD
participating in the FHS had diabetes, but this figure is
likely to be an underestimate given the higher numbers of
individuals with asymptomatic PAD.36 In the NHANES
study, 26% of patients with PAD (defined as having an ABI
of <0.90) also had diabetes.37 In MESA, 26% of women
and 28% of men with an ABI <0.90 had concomitant dia‑
betes.45 Insulin resistance has also been validated as an
independent predictor of PAD.52
The 5‑year mortality can be twice as high in patients with
diabetes and symptomatic PAD when compared with those
who do not have diabetes.18,53 This increased risk of death
appears to be related to the higher prevalence of risk factors
and comorbidities, such as tobacco use, hyper tension,
Figure 1 | Clinical presentation, natural history, and outcomes in patients with atherosclerotic PAD. Abbreviations:
CV, cardiovascular; MI, myocardial infarction; PAD, peripheral artery disease. Permission obtained from Wolters Kluwer
Health © Weitz, J.I. etal. Diagnosis and treatment of chronic arterial insufficiency of the lower extremities: a critical review.
Circulation 94 (11), 3026–3049 (1996).
Natural history of atherosclerotic lower extremity PAD syndromes
PAD population (50 years and older)
Initial clinical presentation
Asymptomatic PAD
20–50%
Progressive functional
impairment
Atypical leg pain
40–50%
5-year outcomes
Limb morbidity CV morbidity and mortality
Claudication
10–35%
Critical limb ischemia
1–2%
Amputation
25%
CV mortality
25%
Stable claudication
70–80%
Worsening claudication
10–20%
Critical limb ischemia
1–2%
Nonfatal cardiovascular event
(MI or stroke) 20%
Mortality
15–30%
CV causes
75%
Non-CV causes
25%
Alive with two limbs
50%
1-year outcomes
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and dyslipidemia among patients with diabetes.54 Among
patients with PAD and diabetes, the infrapopliteal arteries
are most likely to be affected.55–57 Patients with diabetes
have impaired pain perception resulting from associ‑
ated neuro pathic disease and are, therefore, more likely
to present late with more severe clinical manifestations,
including ischemic ulcerations and gangrene, than patients
without diabetes.53 As a result, they are at an increased risk
of develop ing critical limb ischemia and amputations.58
In fact, in one series, the presence of concomitant dia‑
betes inpatients with PAD was associ ated with a 15‑fold
increased risk of lower extremity amputation.59
Dyslipidemia
Dyslipidemia is a well‑established risk factor for PAD. A
high percentage of individuals with known PAD within
the NHANES (60%) and PARTNERS (77%) study popula‑
tions also had dyslipidemia.4,37 Patients with PAD typically
exhibit a decreased level of HDL cholesterol and elevated
triglyceride levels, which is similar to the pattern seen in
those with metabolic syndrome.46
In the National Cholesterol Education Program Adult
Treatment Panel III guidelines, PAD has been classified as
a ‘CAD equivalent’ because it carries a risk for major coro‑
nary events equal to that of established CAD.60,61 Therefore,
in the ACC and AHA guidelines for the management of
patients with PAD, the recommend target level for trigly‑
cerides is <150 mg/dl (<1.7 mmol/l) and the target level for
LDL cholesterol is <100 mg/dl (<2.59 mmol/l), or <70 mg/dl
(<1.81 mmol/l) for those patients deemed to have addi‑
tional cardiovascular risk factors.1 However, because
PAD is associated with a higher cardiovascular event rate
than known CAD, it makes intuitive sense to attempt to
achieve LDL‑cholesterol concentrations below 70 mg/dl
(1.81 mmol/l).62 In other words, every patient with PAD
should be considered to have the highest risk for CAD.63
Hypertension
The Seventh Report of the Joint National Committee
on Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure (JNC7) also deemed PAD to carry
an equiva lent risk to CAD.64 Approximately 2–5% of all
patients with hypertension also have claudication.43 Multiple
population studies have confirmed a strong association
between hypertension and PAD. In the Cardiovascular
Health Study,43 38% of patients with a normal ABI had
hypertension, while the number increased to 52% in those
with an ABI <0.9. In NHANES,37 74% of participants with
PAD also had hypertension, whereas in PARTNERS,4 92%
of patients with PAD were hypertensive. Similarly, in the
FHS, a twofold increase in the risk of developing claudi‑
cation among patients with hypertension was reported.36
Although the increased risk for PAD among patients with
hypertension is not as strong as that for tobacco use, dia‑
betes, and advanced age, blood‑pressure control should
remain a top priority for clinicians.
Cardiovascular morbidity and mortality are increased
among patients with hypertension and PAD when com‑
pared with those with PAD and no hypertension, mostly
owing to an increased risk of stroke and MI.54 In prospec‑
tive observational study of older adults (aged ≥60years;
mean age 72years; 57% women) with systolic hyper‑
tension performed over 4years, a low ABI (<0.90) was
associated with a twofold to threefold increase in total
and cardiovascular mortality, even after adjustment for
potential confounding variables.65
Chronic kidney disease
Patients with chronic kidney disease, particularly those
with end‑stage renal disease, have an increased prevalence
of PAD when compared with those with normal renal
function.19,66,67 In these patients, severe complications of
PAD, such as critical limb ischemia and amputation, are
more frequent.68,69 O’Hare and colleagues estimated that
24% of the NHANES37 population aged 40years or older
with renal insufficiency (estimated glomerular filtration
rate [GFR] <60 ml/min/1.73 m2) also had PAD, on the basis
of an ABI <0.90.19 By contrast, only 3.7% of those indivi‑
duals with normal kidney function had an ABI <0.90.19
The association between PAD and chronic kidney disease
was independent of diabetes, hypertension, and advanced
age.19 Moreover, a different study of the NHANES37 data
identified that microalbuminuria (as defined by a urinary
albumin/creatinine ratio ≥30 mg/g), in combination with
renal insufficiency was particularly useful in identifying
a subpopulation of patients with chronic kidney disease,
who had a much higher prevalence of PAD than those
with neither or just one of these two risk factors.9
Vitamin D
A growing body of evidence suggests that low 25‑hydroxy‑
vitaminD levels can have a negative impact on cardio‑
vascular health.70,71 A subanalysis of NHANES37 data
identified that low serum 25‑hydroxy‑vitaminD levels
Figure 2 | Risk factors for the development of peripheral
artery disease. Reprinted from J.Vasc. Surg. 45 (1),
Norgren,L. etal. Inter-Society Consensus for the
management of peripheral arterial disease (TASC II).
S5–S67 © 2007 with permission from Elsevier.
12
Odds ratio
34
Male gender
Age (per 10 years)
Diabetes
Smoking
Hypertension
Dyslipidemia
Hyperhomocysteinemia
Race
(Asian/hispanic/
black vs white)
C-reactive protein
Renal insufciency
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(<30 ng/ml) were associated with a higher prevalence
of PAD.10 The racial differences in serum 25‑hydroxy‑
vitaminD levels have been hypothesized to be an addi‑
tional reason for there being excess PAD risk in African
Americans, even after controlling for traditional cardio‑
vascular risk factors.72 Furthermore, low serum vitaminD
levels have already been associated with traditional risk
factors that are associated with increased PAD risk,
such as diabetes, hypertension, and obesity.72 Whether
vitaminD supplementation decreases adverse cardio‑
vascular outcomes and PAD risk remains unclear, and
further investigations are warranted.
Biomarkers and genetic factors
The pathophysiological mechanisms underlying CAD are
similar to those of PAD; both conditions are the mani‑
festation of systemic atherosclerosis involving the func‑
tional dysregulation of mediators of inflammatory and
oxidative stress (including monocytes, macrophages,
B and Tlympho cytes), platelets, endothelial cells, and
vascular smooth muscle cells. Accordingly, higher levels
of several biomarkers, such as high‑sensitivity CRP, inter‑
leukin (IL)‑6, and homocysteine, have been independently
associated with the increased incidence of PAD,73,74 and
portend for poor cardiovascular outcomes.75 Data from
the Physicians’ Health Study and the NHANES cohort
indicate that elevated CRP levels are associated with a
twofold increase in the risk of developing PAD.76,77
Elevated levels of various biomarkers, such as homo‑
cysteine, D‑dimer, and lipoprotein(a), have been indepen‑
dently associated with PAD. Hyperhomocysteinemia is
associated with premature atherosclerosis and seems to be
more‑strongly associated with PAD than with CAD.74,78 An
elevated homocysteine level is also associated with signifi‑
cantly higher 1‑year cardiovascular and vascular mortality
when present with concomitant PAD, in comparison to
those who do not have PAD and have homocysteine levels
within the normal range.75,79 Furthermore, even higher bio‑
marker levels (including CRP, IL‑6, D‑dimer, and homo‑
cysteine) have been identified in individuals with PAD who
are physically inactive (as demonstrated by poorer 6‑min
walk test performance) when compared to those with
PAD, who fared better;80,81 the levels seem to be reversed
by exercise.82
One candidate biomarker for PAD that emerged from a
proteomic screening is beta2 microglobulin, a component
of the major histocompatibility complex classI proteins
involved in the regulation of immune and inflammatory
pathways. Cooke and Wilson reported that this marker
was elevated in patients with PAD and correlated with
the severity of disease independent of other risk factors.34
Another potential PAD biomarker is cystatin C, an inhibi‑
tor of lysosomal proteinases, implicated in its ability to
predict risk of death, development of cardio vascular
events,35 and chronic kidney disease in the elderly.32 Both
beta‑2‑microglobulin and cystatin C, along with CRP
and fasting blood glucose levels, were subsequently com‑
bined into a panel of biomarkers to provide greater accu‑
racy of classification and improved PAD risk assessment
than could be obtained with individual biomarkers.12,13,83
Among the biomarkers tested, elevated levels of beta‑
2‑microglobulin and cystatin C had the highest corre‑
lation with the ABI—even more so than traditional risk
factors, such as increased age, tobacco use, and presence
of diabetes.12
Although the potential for genetic susceptibility to
PAD has been supported by observations from numerous
case‑controlled studies,83 a ‘gene for PAD’ has not yet been
identi fied. High‑throughput genome‑wide association
studies have been used with modest success thus far.83
Table 1 | Differential diagnoses for lower extremity discomfort
Condition Location of pain or
discomfort
Symptoms Onset relative
to exercise
Effect of rest Effect of body position Other features
Classic
claudication
Calf, thigh, hip or
buttock muscles
(rarely foot)
Cramping, aching,
fatigue, tightness,
weakness, heaviness,
burning, or pain
After same degree
of exercise
Relieved by
standing within
2–5 min
None Reproducible
Nerve root
compression
(for example
herniated disc)
Radiates down leg,
usually posteriorly.
Might radiate to hip,
groin, or buttock
Sharp, lancinating,
boring pain
Soon, if not
immediately, after
onset. Sometimes not
related to exercise
Not quickly
relieved (can be
present at rest)
Relief can be aided by
adjusting back position,
sitting, or lying down
History of back
pain
Spinal stenosis Hip, thigh, buttocks,
and/or calf
Motor weakness or
radiated pain is more
common than back pain.
Similar characteristics to
vascular claudication
Can occur after
walking or with
standing. Distance
to reproduce pain
is variable
Relieved only by
stopping with
position change
Relief by lumbar spine
exion (sitting, lying down,
or stooping forward). It
can take 15–30 min for
complete relief
Frequent history
of back problems,
provoked by
intra-abdominal
pressure
Hip arthritis Hip, thigh, and/or
buttocks
Aching discomfort,
usually hip and gluteal
pain
After variable degree
of exercise. Can occur
with standing alone
Not quickly
relieved (can be
present at rest)
More comfortable sitting
with weight off legs
Variable, can be
related to activity
level or weather
changes
Venous
claudication
Entire leg, usually
worse in thigh and
groin
Tight, bursting pain During walking Subsides slowly.
It can take
15–30 min for
complete relief
Relief hastened by leg
elevation
History of
iliofemoral DVT,
signs of venous
congestion, edema
Abbreviation: DVT, deep vein thrombosis. Reprinted from J. Vasc. Surg. 31 (1), Dormandy, J.A. & Rutherford, R.B. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic
Inter-Society Consensus (TASC). S56–S62 © 2000 with permission from Elsevier.
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Diagnostic evaluation
Presentation and differential diagnosis
Only a small percentage of patients with PAD will present
with classic Rose claudication; between 70% and 90%
have atypical leg symptoms or are asymptomatic.1,17
Differentiating between classic claudication or leg symp‑
toms caused by PAD and those that result from other
medical conditions can be a challenge, and a detailed
patient history and physical examination facilitates the
diagnostic process (Table1). A detailed history should
include a full assessment of whether patients have pre‑
existing risk factors (such as tobacco usage, hypertension,
diabetes, or dyslipidemia) that increase their risk for the
development of atherosclerotic PAD.
The clinician should ask patients if they experience
‘discomfort’ when they walk, as some patients might not
describe their symptoms as ‘pain’. Patients with claudication
can experience discomfort, pain, burning, cramping, heavi‑
ness, tightness, or fatigue in their buttock, hip, thigh, calf,
or arch of the foot. Symptoms occur with exercise (usually
walking), and are typically relieved within 2–5 min after
ceasing to walk. In classic claudication, the distance the
patient can walk before developing discomfort does not
change considerably from day to day (Table1).17,36,84
The location of the symptoms experienced by patients
can give clues as to the position of the diseased arterial
segment. Patients with aortoiliac occlusive disease might
describe power failure (the feeling of total fatigue from the
waist down and the inability to continue moving forward),
or buttock, hip, or thigh claudication. Patients with superfi‑
cial femoral artery disease might experience claudication in
thecalf. Those with infrapopliteal disease note discomfort
in the calf or in the arch of the foot. If multilevel disease
is present, the patient usually experiences claudication
proximal to the most distal arterial segment involved.
The symptoms of claudication caused by vascular disease
can easily be confused with those of pseudoclaudication
owing to spinal stenosis or other nerve root compression
(Table1). However, symptoms caused by pseudoclaudi‑
cation differ in that the walk distance to symptom onset
can vary considerably, and the patient might need to sit
down, bend over, or change body positions to achieve
symptom relief. In addition, the patient might not be able
to walk again for another 15–30 min. Patients with spinal
stenosis can experience discomfort simply by standing,
which never occurs in the presence of vascular claudi‑
cation. Pain at rest, or the presence of ischemic ulcerations
on the feet or toes, indicates that PAD has progressed from
claudication to critical limb ischemia. In this situation,
the limb is in jeopardy and revascularization should be
urgently performed.
Physical examination
Every patient with suspected PAD should undergo a
complete cardiovascular examination, including palpa‑
tion of the foot pulses and auscultation for bruits over
the subclavian and carotid arteries, abdominal aorta, and
femoral arteries. In addition, an attempt should be made to
palpate the abdominal aorta for the presence of an aneur‑
ysm. The femoral, popliteal, dorsalis pedis, and posterior
tibial arteries should be palpated and recorded as normal,
diminished, or absent. If the femoral or popliteal artery is
enlarged, further investigation to rule out aneurysms might
be n eces sary.
In patients with advanced PAD and acute or chronic
critical limb ischemia, the extremities might be cool and
one might observe pallor on elevation; rubor depends on
venous filling time, which can be delayed in these patients.
Poor hair and toenail growth are not sensitive or specific
findings indicating PAD.85 If the patient has diabetes
and PAD, indications of peripheral neuropathy might be
present, such as diminished or absent deep tendon reflexes,
absence of pain, impaired vibratory sensation and prop‑
rioception, or the presence of abnormal callus formation
Figure 3 | Diagnostic algorithm for the patient with suspected PAD. Abbreviations: ABI, ankle–brachial index;
PAD,peripheral artery disease; PVR, pulse volume recordings.
Normal resting ABI
■ If history and exam are atypical
for PAD, consider other causes of
leg discomfort
■ Perform exercise ABI
Post-exercise ABI is abnormal (<0.9)
Options
■ Duplex ultrasound (stenosis vs
occlusion), length of disease
■ If endovascular therapy considered,
CT, MRI or catheter angiogram
Normal post-exercise ABI with
reproduction of symptoms
The paient does not have PAD
Aortoiliac disease is suspected
■ CT angiogram or MR angiogram
■ Duplex ultrasound if issues with
contrast administration
Stent if aortoiliac disease is conrmed
and patient is symptomatic
Infrainguinal disease is suspected
■ Trial of medical therapy (4–6
months)
■ CT angiogram, MR angiogram
or duplex if medical therapy fails
Abnormal resting ABI (<0.9)
The patient does have PAD: localize
disease with segmental pressures
and PVRs or duplex ultrasound
Leg discomfort with exercise
■ History and physical examination
■ Ankle brachial index (ABI)
ABI >1.4 (calcied blood vessels)
Perform toe–brachial index
■ ≥0.7 normal
■ <0.7 abnormal
Further investigation based on symptoms
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on the feet. Removal of the patient’s shoes at every office
visit is important to examine for ischemic or neurotrophic
ulcerations, abnormal callus formation, and the presence of
athlete’s foot, which can be a potential source of infection.
Diagnostic tests
Good history‑taking and a thorough physical examination
can help establish the diagnosis of PAD, but further objec‑
tive testing is often required. Physiological information
about limb perfusion can be obtained from nonimaging
methods, such as measurement of the ABI, segmental limb
pressures, or pulse–volume waveform analysis. Imaging
methods, such as duplex ultrasonography, CT angio‑
graphy (CTA) and magnetic resonance angiography
(MRA) provide detailed anatomical, but little functional,
information on limb perfusion. A diagnostic algorithm for
the evaluation of patients with suspected PAD is outlined
in Figure3.
ABI
In patients who present for an initial evaluation of PAD,
the ABI remains the easiest, most cost‑effective initial test
to screen for PAD, and can be readily performed in an
office with a manual blood‑pressure cuff and a handheld
continuous wave Doppler ultrasound device (Figure4).
The ABI has 95% sensitivity and 99% specificity for the
detection of PAD.1,2 In PAD, SBP distal to an obstructive
arterial lesion is reduced, resulting in a decrease in SBP
at the ankle relative to the brachial SBP, and thus a ratio
below 1.0. An ABI <1.0 generally correlates with the sever‑
ity of disease.86–88 Although an ABI of less than 0.9 is the
most‑commonly used value to denote PAD, it should be
recognized that individuals with an ABI between 0.90–0.99
have higher cardiovascular and all‑cause mortality31,39 and
are at an increased risk of developing progressive func‑
tional decline, as defined by an increased loss of mobility81
compared with individuals who have an ABI of 1.00–1.20.
A reduction in ABI generally correlates with severity of
disease.86–88An ABI <0.4 indicates advanced disease and
might be associated with pain at rest, ischemic ulcerations,
and gangrene.1
In patients with noncompressible calcified arteries, such
as those of advanced‑stage age, or with diabetes or end‑
stage renal disease, the ABI might not be accurate and can
result in elevated values above 1.4. Under these circum‑
stances, the toe–brachial index, which is the ratio of toe to
brachial SBP, should be used. A value above 0.7 indicates a
normal toe–brachial index.33
Segmental limb pressures
After PAD has been diagnosed by measurement of the ABI,
the patient should be referred to a vascular laboratory or
imaging center for further characterization of the disease.
Segmental limb pressure evaluation can help to identify
the anatomic location and severity of lower extremity arte‑
rial disease by comparing SBP measurements at the upper
and lower thighs, calf, and ankles. SBP is obtained with a
pneumatic cuff system and a handheld continuous‑wave
Doppler ultrasound device, which is placed over the dorsa‑
lis pedis or posterior tibial artery (Figure5). The difference
in pressures between two adjacent limb segments, and
between the two extremities at the same level, is typically
less than 20 mmHg. A pressure drop greater than 20 mmHg
implies the presence of an obstructive lesion between the
two measured segments.89 SBP increases more distally than
proximally, owing to higher peripheral resistance and dif‑
ferences in compliance between central and peripheral
arteries; therefore, the proximal thigh SBP is expected to
be 20–30 mmHg higher than the brachial SBP. Successive
pressure drops greater than 20 mmHg in two adjacent limb
segments should lead to suspicion of multilevel disease.
In patients with ischemic ulcerations, an ankle SBP of
<50 mmHg is associated with poor ulcer healing.90,91 As
with the ABI, testing segmental limb pressures might not
be accurate in patients with noncompressible arteries where
the SBP cannot be abolished by pneumatic cuff inflation.
Treadmill exercise testing
McDermott and associates have clearly demonstrated that
even asymptomatic patients with PAD have poorer func‑
tional performance (manifesting in slower walking speed,
poorer balance, slower arising from a chair, and fewer miles
walked per week), poorer quality of life, smaller calf muscle
area, and a higher proportion of calf muscle fat than age‑
matched, sedentary, asymptomatic individuals without
PAD.20 In patients with normal or mildly reduced ABI, but
with leg symptoms suggestive of claudication, ABI and
segmental pressures obtained before and after treadmill
exercise can help establish the diagnosis (Figure5). For
example, with 50–60% stenosis of the aorta or iliac arter‑
ies, the resting ankle pressure and ABI might be normal.
However, during exercise, such as walking, the arterioles in
the lower extremities dilate. Because of the stenosis, only a
160
Right arm
pressure
120
Left arm
pressure
Pressure:
40 PT
80 DP
Pressure:
120 PT
80 DP
ABi Severity of disease
Above 0.90 Normal
0.71–0.90 Mild
0.41–0.70 Moderate
0.00–0.40 Severe
Right ABI
80/160
=
0.50 Left ABI
120/160
=
0.75
Figure 4 | Measuring the ankle–brachial index using a hand-held continuous wave
Doppler device. The ABI is the ratio of the highest SBP in the dorsalis pedis or
posterior tibial arteries of each leg to that of the highest SBP in the brachial artery
of each arm. A normal resting ABI value is between 0.9–1.4; a value below 0.9
indicates PAD. Abbreviations: ABI, ankle–brachial index; DP, dorsalis pedis;
PT, posterior tibial; SBP, systolic blood pressure.
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limited amount of blood is delivered to the dilated arterio‑
lar bed, leading to a reduction in the ankle SBP, often with
an increase in the brachial SBP and, therefore, a reduction
in the ABI.
Exercise testing is helpful in differentiating claudication
from pseudoclaudication in patients with exertional leg
complaints. By having a patient walk on a treadmill, the
clinician can objectively reproduce the physiological condi‑
tions that lead to claudication, gauge walk time, and thus
determine the presence and extent of functional impair‑
ment. A patient without PAD should be able to complete a
standard treadmill exercise protocol (typically 2 miles per
hour at a 12% incline for 5 min), with either no change or
a slight increase in ankle SBP. A normal exercise test rules
out the presence of PAD, provided that the patient walks
for long enough to develop their typical leg symptoms. A
drop in ankle SBP after exercise of more than 20 mmHg,
and slow recovery to resting pressures, are highly indicative
of hemodynamically important disease.92 In patients who
develop leg, hip, buttock, or back discomfort, but whose
ankle SBP does not drop, the underlying etiology is likely
to be something other than ischemia. In those with estab‑
lished PAD, a comparison of a patient’s performance on
the treadmill before and after treatment can be helpful in
determining the success of therapy.
Pulse volume recordings
As with segmental limb pressure measurements, segmen‑
tal pulse volume recordings also provide objective physio‑
logical information on limb perfusion; these two tests are
usually performed together (Table1). Pulsatile volume
changes occur in the lower extremities during diastole and
systole, and correlate directly with arterial flow. The same
pneumatic cuffs used to measure segmental limb pressures
can also detect slight increases in arterial volume caused by
each pulsation during systole. Pressure transducers detect
the slight changes in arterial volume and provide plethymo‑
graphic tracings for interpretation. A normal pulse volume
recording waveform is similar to an arterial pulse tracing,
typified by a characteristic rapid systolic peak followed by
a rapid down stroke, with a prominent dicrotic notch in the
middle of the downslope. The dicrotic notch diminishes in
patients with mild PAD, whereas the entire waveform has
a lower amplitude and widened waveform in severe cases
of the disease (Figure5).93,94
Continuous wave Doppler ultrasonography
Specialized vascular laboratories also apply continuous
wave Doppler ultrasonography to help characterize PAD
anatomy. The velocity waveforms of arterial blood flow,
which are obtained by moving a Doppler ultrasound
device along the arterial branches of the lower extremities,
can help localize hemodynamically obstructive lesions. A
normal Doppler waveform in the lower extremities has
acharacteristic triphasic pattern, composed primarily
ofa systolic forward‑flow phase, a late‑systolic reverse‑
flow phase, and a smaller, diastolic forward‑flow phase.89
The finding of a normal triphasic waveform at the
common femoral artery virtually excludes the presence
of a proximal stenosis of more than 50%. In cases of mild‑
to‑ moderatestenosis, the waveform becomes biphasic,
with loss of the reverse‑flow phase and, in the presence
of severe stenosis, appears monophasic with an isolated
forward systolic waveform with diminished amplitude
Duplex ultrasonography
Duplex ultrasonography, which comprises real‑time bright‑
ness (B‑mode/gray scale) imaging and color pulsed‑wave
Doppler ultrasonography, provides both anatomical and
functional information about the arterial segments under
investigation (Table2). The sensitivity and specificity of
duplex ultrasonography for the detection of substantial
lesions is high (92% and 97%, respectively).95 For total
Figure 5 | Segmental blood pressure, ABI, and PVRs at rest and after exercise. The
tracings display PVRs taken at the thigh, calf, ankle, metatarsal, and toe. The
lowest diagram depicts an ankle PVR after exercise. The ABIs at rest are 0.80 on
the right and 1.16 on the left. The patient walked on a treadmill for 3 min20 sec.
The exercise was ended because of right calf pain. The ABIs after exercise are
0.45 on the right and 0.76 on the left. The right ankle pressure is 98 mmHg at rest
and decreases to 65 mmHg with exercise. The left ankle pressure is 141 mmHg at
rest and decreases to 108 mmHg with exercise. The brachial artery systolic
pressure is 122 mmHg at rest and augments to 143 mmHg with exercise. Note the
pressure drop between the right thigh and the right calf, and the lack of
augmentation of the right calf pulse volume waveform, which are consistent with
right superficial femoral artery or popliteal artery disease. The left side was
normal at rest but the decrease in ankle pressure after exercise indicates that
there is peripheral artery disease in the left leg as well. The location of disease
cannot be determined on the left. Abbreviations: ABI, ankle–brachial index;
DP, dorsalis pedis; PT, posterior tibial; PVRs, pulse volume recordings.
Thigh
Gain 10% Amp: 16
mm
Calf
Gain 10% Amp: 16
mm
Ankle
Gain 10% Amp: 18
mm
Metatarsal
Gain 10% Amp: 5
mm
Digit
Gain 20% Amp: 3
mm
Ankle (after exercise)
Gain 10% Amp: 14
mm
Thigh
Right leg Brachial blood pressure
Segmental blood pressure
Segment/Brachial index
122 117
ABi
(at rest)
0.80 1.16
Left leg
Gain 10%
138
1.14
Amp: 16
mm
Calf
Gain 10% Amp: 40
mm
Ankle
Gain 10% Amp: 25
mm
Metatarsal
Gain 10% Amp: 10
mm
Digit
Gain 20% Amp: 10
mm
Ankle (after exercise)
Gain 10% Amp: 24
mm
156
1.28
107
0.88
149
1.22
98 (PT)
0.80
141 (PT)
1.16
98 (DP)
0.80
136 (DP)
1.11
ABi
(after excercise)
0.45 0.76
65 (PT) 108 (PT)
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occlusions, sensitivity (95%) and specificity (99%) are
even better.95 B‑mode imaging permits visual resolution of
arterial wall layers and characterization of atherosclerotic
plaques by gray‑scale imaging. The density of the plaque
can be quantified by measuring the gray‑scale median.96,97
Pulsed‑wave Doppler ultrasonography adds physio logical
information not provided by B‑mode imaging because
it provides flow velocities in vessels and across stenotic
lesions. Color Doppler ultrasonography complements
the information obtained by B‑mode and pulsed‑wave
Doppler ultrasonography, as it visualizes moving blood
and detectsturbulence.98
The degree of arterial disease in the lower extremi‑
ties is often classified into four categories—‘normal’ (0%
stenosis), ‘1–49% stenosis’, ‘50–99% stenosis’, and ‘total
occlusion’ (100% stenosis). Some laboratories further dif‑
ferentiate between ‘50–74% stenosis’ and ‘75–99% steno‑
sis’. In our vascular laboratory, we use the wide range of
50–99% because determining with precision the exact
degree of stenosis is difficult, since the infrainguinal
arteries are small. Diagnostic criteria for a hemodynami‑
cally important ‘50–99% stenosis’ require that the peak
systolic velocity is double at the lesion when compared
with a more‑proximal segment, and that it is greater than
Table 2 | Noninvasive and invasive vascular diagnostic tools: benefits and limitations
Diagnostic Test Benefits Limitations
Ankle–brachial
indices
Quick, cost-effective method to screen for PAD
Can be used in postintervention surveillance
Might not be accurate in patients with noncompressible
arteries (for example, those with diabetes, renal failure,
orat advanced age)
Toe–brachial
indices
Quick, cost-effective method to screen for PAD
Mostly used to assess toe perfusion when small-vessel arterial disease
issuspected or present
Can be used in subjects with noncompressible arteries
Requires small cuffs
Accuracy highly operator-dependent
Segmental
pressure
examination
Can be used to establish diagnosis of PAD
Provides anatomic localization in lower-extremity disease
Can provide information to predict limb survival and wound healing
Postintervention surveillance
Might not be accurate in patients with noncompressible
arteries (for example, those with diabetes, renal failure,
orat advanced age)
Pulse-volume
recording
Can be used to establish diagnosis of PAD
Can provide information to predict outcome in critical limb ischemia and risk
ofamputation
Postintervention surveillance
Provides only a qualitative measure of perfusion
Less accurate in distal arterial segments
Can be abnormal in patients with low cardiac output
Less accurate than other noninvasive tests in providing
arterial anatomic location of PAD
Duplex
ultrasound
Can be used to establish diagnosis of PAD
Provides anatomic localization
Denes severity of arterial stenoses
Can be used to help select suitable candidates for endovascular or
surgicalrevascularization
Postintervention surveillance
Cost-effective
Less accurate in aortoiliac segments, owing to obesity
orbowel gas
Dense arterial calcication can limit diagnostic accuracy
Sensitivity is diminished for detection of additional
stenosis downstream from a proximal stenosis
Treadmill
exercise testing
(with ABI before
and after
exercise)
Helps to differentiate claudication from pseudoclaudication in subjects with
exertional leg symptoms
Useful to diagnose PAD when resting ABI is normal
Provides objective physiologic information regarding symptomatic limitations
Helps to individualize regimen for those starting therapeutic exercise training
Can provide objective data regarding functional response to therapy
Requires treadmill and staff familiar with exercise
trainingprotocols
Magnetic
resonance
angiography
Denes anatomy and presence of signicant stenoses
Can be used to help select suitable candidates for endovascular
or surgicalrevascularization
Helpful in providing soft-tissue diagnostic information that may be associated
with PAD (such as aneurysms, popliteal entrapment, cystic adventitial disease)
Can overestimate degree of stenosis
Cannot be used in patients with contraindications to MRA
(for example, pacemakers, debrillators, intravascular or
intracranial metallic stents, clips, coils, and other devices)
Patients with estimated GFR <30 ml/min/1.73 m2 should
not be exposed to gadolinium contrast agents
Multidetector
computed
tomographic
angiography
Denes anatomy and presence of signicant stenoses
Can be used to help select suitable candidates for endovascular
or surgicalrevascularization
Can be useful for follow-up after stent or surgical revascularization (ultrasound
is preferred)
Helpful in providing soft-tissue diagnostic information that may be associated
with PAD (such as aneurysms, popliteal entrapment; cystic adventitial disease)
Metal clips, stents, and prostheses do not cause signicant artifacts
Faster scan times compared with MRA
Requires iodinated contrast, and therefore might be limited
in patients with signicant renal insufciency
Requires ionizing radiation
Catheter-based
angiography
Angiography was previously the denitive method in anatomic evaluation
beforeplanned revascularization
Advances in CTA and contrast-enhanced MRA are now preferred
diagnosticmethods
Contrast angiography performed during endovascular procedures
Associated with small complication risk of bleeding,
infections, vascular access complications,
atheroembolism, contrast agent allergy and
contrastnephropathy
Abbreviations: ABI, ankle–brachial index; CTA, CT angiography; GFR, glomerular filtration rate; MRA, magnetic resonance angiography; PAD, peripheral artery disease. Reprinted with Permission
Circulation, 2006; 113: e463–e465 © 2006 American Heart Association, Inc.
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200 cm/s, with evidence of turbulence demonstrated by
color Doppler ultra sonography (Figure6).95,99
Duplex ultrasonography is particularly useful in assessing
patients with PAD, for several reasons. Firstly, to determine
if a hemodynamically important lesion is present when the
data from segmental limb pressure measurement and pulse
volume recording are ambiguous. Secondly, to demonstrate
the anatomy of the disease (to distinguish stenosis from
occlusion, to measure the length of the occlusion, or to
assess the status of collateral vessels such as the profunda
femoral artery) so that the patient can be counseled on the
likelihood of a successful and durable result with endo‑
vascular or surgical revascularization. Thirdly, for sur‑
veillance after endovascular or surgical revascularization
procedures. However, duplex ultrasonography has limited
utility in providing the detail necessary for assessment of
the most distal, smallest vessels, such as those in the foot.
CT angiography
Multidetector CTA provides rapid, noninvasive assessment
of the peripheral arterial vasculature (Table2). Within
the past several years, technical improvements in spatial
and temporal resolution, with multirow CT scanners as
standard equipment at most institutions, have markedly
improved image quality and decreased acquisition times,
resulting in thinner section scans over larger anatomical
territories. CTA for patients with PAD has a sensitivity of
95% and specificity of 96%.100–103 Owing to improvements
in image acquisition and postprocessing techniques, CTA
scans can now provide detailed information about vascu‑
lar anatomy noninvasively during the workup of a patient
with suspected PAD (Figure7).
CTA has several advantages over conventional angio‑
graphy. Through volumetric acquisition, arterial vascu‑
lature can be evaluated from multiple angles and planes
after a single round of data acquisition. CTA also pro‑
vides soft‑tissue details, which are useful in defining
pathologies outside the vessel lumen, such as throm‑
bosed aneurysms, dissections, wall‑thickening in
large arteryvascu litis, cystic adventitial disease, and
popliteal artery entrapmentsyndrome.104
Optimizing contrast agent administration during image
acquisition is an important step in CTA. Different injection
protocols have been established for the various anato mical
regions of interest, while keeping in mind that contrast
agent transit time from the superficial venous site to the
peripheral arteries varies among patients (depending on
cardiac output), and can thus require adjustments. The
raw axial images that are obtained undergo software post‑
processing to produce three‑dimensional (3D) images
of the vasculature, similar in spatial resolution to those
obtained during catheter‑based digital subtraction angio‑
graphy. For the visualization and analysis of lower extrem‑
ity arterial stenoses, several different image postprocessing
techniques are currently used—‘multi‑planar reconstruc‑
tion’, ‘maximum‑intensity projections’, ‘volume‑ rendering
technique’ and, to a lesser degree, ‘shaded‑surface display’.
Most 3D workstations can also reformat images using
‘curved multi planar reconstruction’, which visualizes the
entire length of a vessel of interest in one plane. These
postprocessing methods, when used in combination, allow
manipulation of raw data to optimize resolution of vessel
lesions.100 Clearly, however, the ultimate diagnosis should
come from the raw data (axial images) and not from the
angiographic reformatting of the data, because the process
of reformatting can sometimes lead to the generation of
composite images that contain artifacts that might be
misread as intraluminal stenoses.
Figure 6 | Duplex ultrasonography of a left superficial femoral artery after stent
implantation. Note that the flow velocity in the stent (peak systolic velocity 325 cm/s)
is markedly increased and the color flow through the stent (in red) is reduced,
indicating a severe stenosis. The spectral waveform also demonstrates the presence
of a seagull bruit (yellow arrow), which also signifies that the stenosis is quite severe.
The in-stent restenosis is caused by substantial intimal hyperplasia (white arrows).
PS 336.4
cm/s
PS 52.8
cm/s
Seagull
L SFA M STENT
–49
cm/s
–5 –4 –3 –2 –1 –0
AC 60
300
200
100
cm/s
–100
400
Figure 7 | CTA of a patient with PAD. a | CTA image of the abdominal aorta, renal
arteries, and iliac arteries. There is no stenosis in the aortoiliac segment.
However, marked calcium deposition (white areas) is present in the aorta, renal
arteries, and iliac arteries. b | CTA image of the iliofemoral arteries. Severe, focal
stenosis (arrow) is present in the right mid-to-distal superficial femoral artery.
Abbreviation: CTA, CT angiography.
ab
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Multidetector CTA has been shown to be as accurate
as digital subtraction angiography in all anatomical seg‑
ments of the lower extremity arteries, although accuracy is
diminished in the setting of heavy calcification.100,102,105–107
Dual‑energy CT combines CT density values from two
synchronous CT scans set at two different X‑ray tube volt‑
ages. This technique achieves greater tissue differentiation
than normal CT and could overcome imaging problems
associated with calcified vessels.108,109
Magnetic resonance arteriography
MRA was initially performed without contrast enhance‑
ment using time‑of‑flight imaging techniques. This tech‑
nique was hampered by small imaging volumes, prolonged
acquisition times, and patient motion artifacts. Resolution
of retrograde arterial flow in collateral and reconstituted
vessels distal to stenotic lesions was also difficult with
time‑of‑flight imaging.110 Many of these limitations have
been overcome by the use of contrast‑enhanced MRA,
which exploits the T1‑shortening effects of gadolinium‑
based contrast agents and has become the standard MRA
method for imaging of the peripheral arteries. In a system‑
atic review, Collins etal. reported that contrast‑enhanced
MRA had high diagnostic accuracy, with a sensitivity of
95% and a specificity of 97% to detect hemodynamically
important stenoses (Figure8).111
Newer, highfield 3 Tesla MRA machines, dedicated coils,
and new image‑reconstruction algorithms have combined to
further shorten image acquisition time and improve spatial
resolution. In a typical contrast‑enhanced MRA study of the
lower extremities, a peripherally administered intra venous
bolus or constant infusion of gadolinium is sequentially
chased down over three ‘stations’ or arterial segments: the
aortoiliac segment, the femoral‑popliteal segment, and
the infrapopliteal segment (Figure3).110,112,113 Because this
three‑station, moving‑table, single‑bolus, chasing method
can produce unwanted venous enhancement in the distal
tibial arteries, various hybrid image‑acquisition and
contrast‑ timing techniques have been developed to avoid
this problem. In hybrid imaging, the distal tibial‑ peroneal
trunk is imaged first in multiple phases using a small con‑
trast bolus, followed by imaging of the more‑ proximal
two stations using a second, larger contrast bolus. These
methods are often helpful in resolving the extent of distal
vessel obstruction, particularly in patients with small‑ vessel
disease or limb‑threatening ischemia.110,112 Abdominal MRA
is also now frequently used to evaluate the abdominal aorta
and its branches, including the renal arteries.
Exposure to gadolinium‑based contrast agents in the
setting of renal failure has been associated with nephro‑
genic systemic fibrosis, a rare dermopathy that involves
fibrosis of the joints, eyes, and internal organs.114,115
Although the incidence of nephrogenic systemic fibrosis
is exceedingly rare,116 current recommendations advise
against administering gadolinium contrast to indivi duals
with a GFR below 30 ml/min/1.73 m2, or to those with
acute renal failure or acute deterioration of chronic renal
failure.114,115 Noncontrast, flow‑sensitive imaging sequences
are being developed and might circumvent the need for
contrast agents in the future.112
Digital subtraction angiography
With the greater availability of improved, noninva‑
sive vascular imaging modalities, the routine use of
catheter‑based angiography as a primary diagnostic
approach has diminished. Nevertheless, catheter‑based
angio graphy can allow for selective visualization of spe‑
cific vessels without motion artifacts. This technique
Figure 8 | 3Tesla gadolinium-enhanced MRA of a patient with PAD.
a | MRA image from the descending thoracic aorta to the feet. Note the aortoiliac
segment demonstrates no significant stenosis. b | Amplification of the iliofemoral
segment. The superficial femoral artery (double-ended arrow) is severely stenosed
on the right and occluded on the left. The distal superficial femoral artery
reconstitutes via robust collaterals from the profunda femoral artery (small arrows).
c | Amplification of the popliteal and tibial segment. A single-vessel run-off via the
anterior tibial artery is present in both legs (double-ended arrow). Abbreviation:
MRA, magnetic resonance angiography, PAD, peripheral artery disease.
a
c
b
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Review criteria
The NCBI PubMed database was searched for full-text,
English language papers that appeared in the literature
since 1980, with the exception of several earlier articles
that were included for historical relevance. Search terms
included “peripheral artery disease”, “claudication”,
“noninvasive imaging”, “risk factors”, “ankle-brachial
index”, “magnetic resonance angiography”, and
“computed tomographic angiography.”
can also provide direct functional information via
pressure gradients or imaging of vessel endothelium
and athero matous plaques through the application of
intravascularultrasound.
Choice of imaging technique
Once noninvasive testing (ABI measurement and pulse
volume recording, with or without exercise) has docu‑
mented the presence and severity of PAD, an imaging test
will provide detailed anatomical information and offer a
visual roadmap for possible future interventions. Table2
provides a summary of the benefits and limitations of
each diagnostic test.117
In the presence of aortoiliac disease, or once a deci‑
sion has been made to consider percutaneous or surgi‑
cal revasculari zation, performing either MRA or CTA as
the first imaging technique is reasonable. In addition to
considering the benefits and limitations of either imaging
modality, the choice between CTA and MRA relies ulti‑
mately on physician and patient preferences, and on the
level of expertise at the imaging center. Patients with
medical devices, claustrophobia, or those who cannot
tolerate lying flat for an extended period of time, should
undergo CTA. The caveat is that small calcified vessels
cannot be adequately visualized with standard CTA,
although dual‑energy CTA is anticipated to circumvent
this obstacle in the future. On the other hand, the clinician
should also note that MRA tends to overestimate stenoses
in small vessels, but spares the patient from exposure
to ionizing radiation that comes with CTA. Proceeding
directly with catheter‑based angio graphy might also be
considered, particularly when the likelihood of an endo‑
vascular intervention is high, or when the use of contrast
agents has to be limited.
When infrainguinal disease is suspected, ultrasono‑
graphy of the lower extremity artery as the first imaging
study is reasonable. Ultrasonography provides accu‑
rate information on the location, length, and severity of
stenoses, or whether an occlusion is present. Taking into
consideration the combination of the velocity of blood
flow, the appearance on gray scale, and color Doppler
ultrasonography, allows for an accurate assessment of the
hemodynamic severity of a given lesion. A good arterial
ultrasonography will be able to detect hemodynamically
significant lesions from the aorta to the ankle.
Conclusions
Individuals with PAD are at increased risk of MI, stroke,
and cardiovascular death, owing to the high prevalence
of concomitant coronary and cerebrovascular disease in
these patients. The clinical manifestations and differential
diagnosis of PAD can be quite varied, and due diligence
is required to sort through clinical entities that can dis‑
tract from the actual diagnoses. Diagnostic algorithms
can provide an organized approach tor assessment of the
patient with suspected PAD. Once PAD has been diag‑
nosed, the primary goals are to improve symptoms and
quality of life, and to decrease cardiovascular morbid‑
ity and mortality with risk factor control and optimal
medical management.
There have been enormous advances in the understand‑
ing of the cardiovascular consequences of PAD. In addition,
noninvasive imaging has improved considerably over the
past decade, so much so, that catheter based angiography
is rarely necessary for diagnostic purposes only. CTA and
MRA provide all the necessary detail to allow the clinician
to visualize the anatomy and determine which therapeutic
approaches are feasible for an individual patient.
An important advance in the diagnostic aspects of PAD
would be for the development of an imaging test that would
also provide physiological information about blood flow
and oxygen delivery to the muscles and tissues. As it stands
now, there are physiological tests (ABI, PVR and segmen‑
tal pressures) that provide no detailed information about
the anatomy, and imaging tests (duplex ultrasound, CTA,
MRA, catheter based angiography) that provide an excel‑
lent assessment of the anatomy but limited assessment of
blood flow or oxygen delivery. Future research should focus
on diagnostic methods that would provide both anatomic
and physiological information, thus helping the clinician
determine the best course of therapy for a patient.
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Acknowledgments
C.P. Vega, University of California, Irvine, CA, is the
author of and is solely responsible for the content of
the learning objectives, questions and answers of the
Medscape, LLC-accredited continuing medical
education activity associated with this article.
Author contributions
J.F. Lau researched the data, J.F. Lau and J.W. Olin
wrote the article, and all authors contributed
substantially to the discussion of content, reviewed,
and edited the manuscript before submission.
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