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Epidemiology, risk factors, and natural history of peripheral

artery disease
Authors: Linda Harris, MD, FACS, Maciej Dryjski, MD, PhD, FACS
Section Editors: Joseph L Mills, Sr, MD, John F Eidt, MD
Deputy Editor: Kathryn A Collins, MD, PhD, FACS

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Mar 2019. | This topic last updated: Oct 10, 2018.

INTRODUCTION

Atherosclerosis is a systemic disease of the large and medium-sized arteries causing luminal
narrowing (focal or diffuse) as a result of the accumulation of lipid and fibrous material between the
intimal and medial layers of the vessel. Atherosclerosis of the noncardiac vessels is defined as
peripheral artery disease (PAD). An ankle-brachial index (ABI) ≤0.90 is sensitive and specific for
arterial stenosis/occlusion and diagnostic for PAD [1].

Although other disease processes can lead to narrowing of the arteries (eg, inflammation,
thrombosis) and symptoms of arterial insufficiency, PAD is by far the most prevalent etiology. The
lower extremity vessels are affected more commonly than the upper extremity vessels.

Ischemic symptoms result when there is an imbalance between the supply and demand for blood
flow. The clinical manifestations of PAD depend upon the location and severity of arterial stenosis or
occlusion, and range from mild extremity pain with activity (ie, claudication) to limb-threatening
ischemia. For patients found to have asymptomatic PAD, the natural history is relatively benign;
however, for those patients with PAD who continue to smoke or have diabetes or renal insufficiency,
the clinical manifestations can progress rapidly and unpredictably.

The epidemiology, risk factors, and natural history of peripheral artery disease are reviewed here. The
clinical manifestations and management of peripheral artery disease are discussed elsewhere. (See
"Clinical features and diagnosis of lower extremity peripheral artery disease" and "Management of
claudication due to peripheral artery disease".)
EPIDEMIOLOGY AND RISK FACTORS

The worldwide prevalence of lower extremity peripheral artery disease (PAD) is between 3 and 12
percent [2-8]. In 2010, 202 million people around the world were living with PAD [9]. In Europe and
North America, an estimated 27 million individuals are affected with approximately 413,000 inpatient
admissions annually attributed to PAD [2]. The majority of individuals with PAD (70 percent) live in
low/middle income regions of the world, including 55 million individuals in southeast Asia and 46
million in the Western Pacific Region [9]. The number of individuals with PAD increased by 29 percent
in low/middle income regions and 13 percent in high income regions from 2000 to 2010 compared
with the preceding decade [9].

In a study that included over 3 million participants in Life Line screening (LLS, Independence, Ohio) in
the United States, PAD was present in 3.6 percent [10]. PAD is more prevalent in older individuals,
certain ethnic populations, families with atherosclerosis, and in those with risk factors for
cardiovascular disease.

Risk factors that favor the development of PAD are similar to those that promote the development of
coronary heart disease (CHD) [11-14]. However, the Scottish Heart Health Extended Cohort identified
some risk factor differences [15]. Among over 15,000 men and women aged 30 to 75 years who were
free of PAD or CHD and followed for 15 to 25 years, 19.7 percent developed CHD and 3.2 percent
developed PAD. PAD and CHD shared seven of the nine of the ASSIGN risk score variables,
including age, gender, family history, socioeconomic status, diabetes mellitus, tobacco smoking, and
systolic blood pressure, and four biomarkers (N-terminal pro b-type natriuretic peptide [NT-pro-BNP],
cotinine, high-sensitivity C-reactive protein, and cystatin-C). For PAD, markers associated with
inflammation and tobacco smoking predominated, while total cholesterol and body mass were less
important. The highest ranked adjusted hazard ratios in PAD were age, high-sensitivity C-reactive
protein, systolic blood pressure, expired carbon monoxide, cotinine, socioeconomic status, and
lipoprotein(a). Diabetes mellitus was also an important risk factor but not the most common cause of
PAD. These identified differences in risk factors for PAD versus CHD may indicate subtle differences
in pathophysiology.

The American College of Cardiology/American Heart Association (ACC/AHA) guidelines on PAD have
identified the risk groups below, which are associated with an increased prevalence of PAD and
earlier onset of symptomatic PAD [4,6,8]. These include:

● Age ≥70 years

● Age 50 to 69 years with a history of smoking or diabetes

 ● Age 40 to 49 with diabetes and at least one other risk factor for atherosclerosis

● Leg symptoms suggestive of claudication with exertion or ischemic pain at rest

● Abnormal lower extremity pulse examination

● Known atherosclerosis at other sites (eg, coronary, carotid, renal artery disease)

Several large studies have evaluated the incidence and prevalence of these factors, alone or
together, in patients with PAD.

● The Health Professionals Follow-up Study tracked 44,985 men in the United States without a
history of cardiovascular disease at baseline for a median follow-up of 24.2 years (1986 to 2011)
[16]. There were 537 cases of incident PAD defined as limb amputation or revascularization,
angiogram reporting vascular obstruction ≥50 percent, ankle-brachial index (ABI) <0.90, or
physician-diagnosed PAD. Each risk factor (smoking, hypertension, hypercholesterolemia, type 2
diabetes) was significantly and independently associated with a higher risk of PAD after
adjustment for the other three risk factors, and confounders. Men without any of the four risk
factors had a lower risk of PAD compared with all other men in the cohort (hazard ratio [HR] 0.23,
95% CI 0.14-0.36). The age-adjusted incidence rates (cases per 100,000 person-years) were 9
for no risk factors, 23 for one risk factor, 47 for two risk factors, 92 for three risk factors, and 186
for four risk factors. The population-attributable risk for PAD associated with these four risk
factors was 75 percent.

● Similarly, a study evaluating data from the United States National Health and Nutrition
Examination Survey (NHANES) determined the cumulative effects of known risk factors for
peripheral artery disease [17]. Risk factors for PAD used in the model included age, gender,
race/ethnicity, hypertension, diabetes, chronic kidney disease, and smoking. The likelihood of
PAD increased with each additional risk factor present. With one risk factor present relative to no
risk factors, the risk for PAD was not significant (odds ratio [OR] 1.5, 95% CI 0.9-2.6). For two
risk factors, the risk for PAD was nearly quadrupled (OR 3.7, 95% CI 2.3-6.1), and for three risk
factors the risk was increased 10-fold (OR 10.2, 95% CI 6.4-16.3). Smoking was the single factor
associated with the highest risk for PAD. Non-Hispanic blacks and women, who had the highest
prevalence rates, were particularly sensitive to this cumulative effect. A higher prevalence of
current smoking among women and non-Hispanic blacks may explain the excessive risk of PAD
in these populations.

● An epidemiologic model based upon a systematic review of the prevalence of PAD (defined as
an ABI ≤0.90) around the world was used to compare predicted PAD prevalence in three high
income and five low/middle income World Health Organization (WHO) regions [9]. Smoking,
 diabetes, hypertension, and hypercholesterolemia were important risk factors in high and
low/middle income regions. Sex-specific prevalence increased with age for both sexes (eg, for
men, 5.4 percent, 45 to 49 years; 18.8 percent, 86 to 89 years).

• Prevalence in men was lower in low/middle income regions than in high income regions (eg,
2.9 versus 5.4 percent for men 45 to 49 years; 14.9 versus 18.8 percent for men 85 to 89
years).

• Prevalence was higher in women, especially at younger ages in low/middle income regions
(6.31 versus 5.3 percent for women 45 to 49 years; 15.2 versus 18.4 percent for women 85
to 89 years).

● In the PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program
study that included 6979 subjects, the prevalence of PAD in individuals at high risk for PAD (50 to
69 years of age and diabetes mellitus or >10 pack-year history of smoking, or >70 years of age)
was 29 percent [12]. Of these, 13 percent had PAD only, and 16 percent had evidence of PAD
and coronary artery disease (CAD).

Age — The prevalence of PAD increases progressively with age, beginning after age 40 [11,18-23].
As a result, PAD is a growing clinical problem in the United States and other developed countries due
to an aging population. (See "Overview of established risk factors for cardiovascular disease", section
on 'Age and gender'.)

Individuals over 70 are at a significantly increased risk for PAD due to age alone [24], while risk for
those who are younger is due to other factors, most commonly cigarette smoking [25]. However, only
half of aged patients are symptomatic from lower extremity PAD, often because of other comorbidities
that limit mobility, such as arthritis, cardiac disease, and pulmonary disease [26].

The relationship between PAD prevalence and age was illustrated in the NHANES study [11,25]. The
prevalence of PAD (ABI ≤0.90, either lower extremity) was:

● 0.9 percent between the ages of 40 and 49

● 2.5 percent between the ages of 50 and 59
● 4.7 percent between the ages of 60 and 69
● 14.5 percent age 70 and older
● 23.2 percent for those over 80

Traditional risk factors for PAD may be absent in patients older than 80 years, particularly those with
infrapopliteal disease [27].
Gender — Gender-related differences in the risk for cardiovascular disease have been described.
(See "Overview of established risk factors for cardiovascular disease", section on 'Age and gender'.)

PAD is cited historically as more prevalent in men overall compared with women. However, the
population-based prevalence of PAD in women has not been fully evaluated. In population studies,
the prevalence of PAD in women is at least as high as that of men across all age groups but
increases to a greater extent in women after age 70 compared with men of the same age [28-32]. In a
review of 133,750 women and 71,996 men who underwent voluntary screening for PAD (ie, Lifeline),
women were significantly more likely to have ABI ≤0.9 (4.1 versus 2.6 percent) [33]. In a large review,
incident cardiovascular disease varied by type of presentation (eg, myocardial infarction, transient
ischemic attack, peripheral artery disease, abdominal aortic aneurysm), age, and gender [34]. The
risk difference between men and women for an initial presentation of peripheral artery disease was
most pronounced for men aged 50 to 59, with a twofold increase compared with women.

In a population study of individuals 60 to 90 years of age in Sweden, women had a higher prevalence
of PAD compared with men, when ABI only was used to diagnose PAD (asymptomatic: 12.6 versus
9.4 percent). In this study, the prevalence of severe limb ischemia was higher in women compared
with men (1.5 versus 0.8 percent) [35]. Similar results were found in a retrospective review of 231
consecutive patients diagnosed with PAD following referral to a vascular laboratory [30]. The
prevalence of severe limb ischemia was 13.2 percent in women and 4.3 percent in men. The
difference was likely related to the significantly higher incidence of hypercholesterolemia (88.2 versus
73 percent), metabolic syndrome (78 versus 43 percent), and diabetes (67.6 versus 42.9 percent)
found in the female patients.

Whether there is any effect of hormone replacement therapy in postmenopausal women on the
development of PAD is largely unknown. One study of 847,982 postmenopausal women found that in
spite of an increased prevalence of several atherosclerotic risk factors among women who used
hormone replacement therapy, they were significantly less likely to have PAD (3.3 versus 4.1 percent)
[36]. The benefits and risks of hormone replacement therapy are discussed in detail elsewhere. (See
"Menopausal hormone therapy: Benefits and risks".)

Ethnicity — Ethnic-related differences in prevalence rates of PAD and for risk factors known to be
associated with PAD have been identified. The prevalence of PAD is higher in African Americans than
non-Hispanic whites [11,37-39]. The difference does not appear to be completely explained by
differences in the prevalence of risk factors for atherosclerosis [40]. African and Hispanic Americans
have higher rates of diabetes and hypertension, whereas Caucasians are more likely to have
hypercholesterolemia [31].
The NHANES study found an increased prevalence of PAD for African Americans (men and women),
and also Hispanic-American women compared with non-Hispanic Caucasian Americans (19.2 and
19.3 percent, respectively, versus 15.6 percent) [11].

Similarly, in the San Diego Population Study, a survey of 2343 randomly selected participants, African
Americans had a significantly higher prevalence of PAD (7.8 versus 4.9 percent) compared with non-
Hispanic whites [38]. In this study, PAD was defined as an ABI ≤0.90, an abnormal Doppler
waveform, or prior revascularization for PAD. Although African Americans had significantly higher
rates of diabetes, hypertension, and greater body mass index, the increased risk for PAD was
maintained after adjustment for these and other variables. Hispanic and Asian Americans had
somewhat lower rates of PAD than non-Hispanic whites, but the difference was not significant. In a
multiethnic Asian (Chinese, Malays, and Indians) population study from Singapore, PAD was present
in 4.3 percent of the population, and a high ABI >1.4 was rare [41]. A systematic review identified 14
studies comparing prevalence between South Asians and white Europeans and found a significantly
lower risk of PAD in South Asians with coronary artery disease (OR 0.47, 95% CI 0.39-0.56) and
diabetes (OR 0.44, 95% CI 0.30-0.63) [42].

Family history and genetic factors — Patients with a family history of cardiovascular disease
appear to be at increased risk, although the relative contributions of genetics and environmental
factors are not fully elucidated but continue to be an active area of investigation. (See "Overview of
established risk factors for cardiovascular disease", section on 'Family history' and "Overview of
possible risk factors for cardiovascular disease", section on 'Genetic markers'.)

The risk of PAD is increased in families identified with early-onset atherosclerosis, but no single
genetic marker has been identified for PAD in this population [43]. Patients with early-onset
atherosclerosis are a separate subgroup distinct from patients with familial hypercholesterolemia,
which is discussed elsewhere [44,45]. (See 'Early-onset atherosclerosis' below.)

Atherosclerotic disease likely results from numerous genes interacting with each other and the
environment [46]. Studies that have investigated heritable factors in the development of PAD include
family and twin studies, ankle-brachial index variance analysis, and gene studies [43-45,47-53].

Several studies have found that 20 to 50 percent of the variance in ABI can be explained by genetic
factors [47-49]. However, in spite of finding such correlations, investigators of the National Heart,
Lung, and Blood Institute Twin study found no significant difference in the prevalence of PAD for
identical (monozygotic) compared with fraternal (dizygotic) twins (33 versus 31 percent) [47]. In
contrast, a study using data from the Swedish Twin Registry and the national patient discharge
registry found that traditional cardiovascular risk factors were significantly more prevalent in twins with
PAD compared with those without PAD [50]. Concordances and correlations were higher in
monozygotic compared with dizygotic twins, suggesting genetic influences in PAD. The risk of PAD
for persons whose twin had PAD was significantly increased compared with persons whose twin did
not have PAD (OR 17.7, 95% CI 11.7-26.6 for monozygotic twins; OR 5.7, 95% CI 4.1-7.9 for
dizygotic twins). Genetic effects accounted for 58 percent of the phenotypic variance among the
twins, and nonshared environmental effects accounted for approximately 42 percent.

A case control study that compared 2296 patients with PAD with 4390 controls found that a family
history of PAD was present significantly more often in patients with PAD than in controls even after
adjusting for conventional risk factors (OR 1.97, 95% CI 1.60-2.42) [54]. The association was stronger
in younger subjects (age <68 years), and a greater number of affected relatives with PAD was also
more strongly associated with PAD.

A meta-analysis of possible genetic susceptibility to PAD found no strong supportive evidence for
most genetic polymorphisms but did identify three genes that may be important variants (IL6-174
G/C, ICAM1 1462 A/G, and CHRNA3 831C/T) [51]. In one genotyping study, a discovery meta-
analysis found a strong association between rs10757269 on chromosome 9 near CDKN2B and ABI
[55].

The chromosome 9p21 (Chr9p21) locus, identified in 2007, was first associated with coronary artery
disease and myocardial infarction, but it may have a more general role in vascular pathology [56].
Additional associations have been demonstrated for carotid artery plaque and plaque progression,
peripheral artery disease, and aneurysmal disease. (See "Epidemiology, risk factors, pathogenesis,
and natural history of abdominal aortic aneurysm".)

Smoking — Cigarette smoking correlates significantly with cardiovascular disease. The mechanism
by which cigarette smoke promotes the development and progression of atherosclerosis is not clearly
understood, but its effects include endothelial damage, arterial smooth muscle proliferation,
thrombophilia, inflammation, increased sympathetic tone, and other metabolic abnormalities [57-61].
In the NHANES study, the risk for PAD was increased in active cigarette smokers, but no association
was found for other forms of tobacco exposure [25]. On average, a diagnosis of PAD is made
approximately a decade sooner in cigarette smokers than in nonsmokers [62].

A systematic review that included 55 original studies performed in North America, South America,
Europe, Australia, and Africa assessed the magnitude of increased risk of PAD in current smokers
relative to never smokers (OR 2.71, 95% CI 2.28-3.21), and ex-smokers relative to never smokers
(OR 1.67, 95% CI 1.43-1.81) [63]. Most studies (47/55) used ABI to define PAD; the remainder used
symptoms of claudication. The Erfurt Male Cohort (ERFORT) Study, which followed 1160 men aged
40 to 59 years every five years, also associated smoking with an increased risk of incident
intermittent claudication (hazard ratio [HR] 2.20, 95% CI 1.24-3.92) [64]. In another study, ongoing
cigarette smoking was associated with the largest decline in ABI compared with other risk factors
[65].

Smoking appears to be a more powerful risk factor for PAD than for CAD [63,66,67]. In the Edinburgh
Artery Study, the adjusted relative risk for PAD in heavy smokers compared with nonsmokers was
2.72 (95% CI 1.13-6.53), but lower for CHD at 1.61 (95% CI 0.91-2.85) [66,67]. A separate meta-
analysis evaluating the risk of CHD in smokers identified a relative risk of 1.72 for men and 1.92 in
women [68].

A significant relationship between cigarette dose and risk for PAD has been reported [12,14,69]. In
the PARTNERS program study discussed above, patients aged 50 to 69 years of age with a history of
cigarette smoking more than 10 pack-years or a history of diabetes had an incidence of PAD similar
to those ≥70 years of age [12]. The Framingham Heart Study found that the risk for developing
claudication was directly related to the number of cigarettes smoked, with a 1.4-fold risk increase for
every 10 cigarettes smoked per day [14]. In another study, the hazard ratio for PAD was 2.52 (95% CI
1.49-4.25) for 10 pack-years, 6.75 (95% CI 4.33-10.52) for 10 to 29 pack-years, and 11.09 (95% CI
6.94-17.72) for ≥30 pack-years [69]. A greater number of pack-years of smoking is also associated
with increasing disease severity, negative effects on the patency of vascular reconstruction, and an
increased risk of amputation and cardiovascular mortality following revascularization [62]. Passive
exposure to smoke appears to increase vascular endothelial inflammation and may increase the risk
for atherosclerotic plaque development in children and adults [70]. (See "Secondhand smoke
exposure: Effects in adults", section on 'Cardiovascular disease and stroke' and "Secondhand smoke
exposure: Effects in children", section on 'Atherogenesis'.)

Smoking cessation decreases morbidity related to PAD; however, risk of progression of PAD is
significantly greater in former smokers compared with never smokers [69,71,72]. The Edinburgh
Arterial Study found a decreased risk of claudication for patients who stopped smoking compared
with those who continued to smoke [73]. Smoking cessation is also associated with a decreased risk
of graft failure following lower extremity bypass surgery [74]. These effects are limited if the patient
reduces cigarette consumption rather than eliminating smoking altogether [75]. Because the effect of
smoking cessation on quality of life and survival is not immediately evident, patients require a high
level of support to initiate and maintain smoking cessation [76,77]. (See "Overview of smoking
cessation management in adults".)

Hypertension — Hypertension is strongly associated with the development of atherosclerosis in men

and women. (See "Overview of established risk factors for cardiovascular disease", section on
'Hypertension'.)
In the United States, the prevalence of hypertension in adults is approximately 30 percent [78].
However, among those with an abnormal ankle-brachial index, the prevalence of hypertension in the
Rotterdam Study was 60 percent [79]. The risk of developing symptoms of PAD, such as intermittent
claudication, in those with hypertension was twice that of those without hypertension in the
Framingham study [14,80]. The NHANES study found that hypertensive patients also have an even
higher prevalence of asymptomatic PAD [11] and, further, that patients with PAD were less likely to
have antihypertensive treatment compared with those who have other forms of cardiovascular
disease [81]. The association between hypertension and PAD among patients older than 60 years of
age was particularly strong in those with untreated and poorly controlled hypertension [18].

In a cohort of over 1.25 million patients aged 30 years or older without baseline cardiovascular
disease, including 20 percent with baseline treated hypertension, the associations of several
cardiovascular diseases, including PAD with systolic hypertension, diastolic hypertension, or both,
were studied [82]. PAD had the strongest association of all cardiovascular diseases with pulse
pressure (HR 1.23, 95% CI 1.20-1.27]). In another large database review that included over 4.2
million individuals, a 20 mmHg higher than usual systolic blood pressure was associated with a 63
percent higher risk of peripheral artery disease (OR 1.62, 95% CI 1.59-1.66) [83].

Hypertension together with smoking is a major factor for progression of PAD in patients with diabetes
mellitus, but there is no evidence that adequate control of hypertension impacts disease progression
[84]. (See 'Natural history and progression of PAD' below.)

Diabetes — Diabetes is a coronary artery disease risk equivalent. Patients with diabetes have more
advanced arterial disease at initial diagnosis and poorer outcomes than nondiabetic patients [85,86].
(See "Overview of established risk factors for cardiovascular disease", section on 'Diabetes mellitus'.)

The NHANES study found an increased risk for PAD in patients with diabetes (OR 2.71, 95% CI 1.03-
7.12), a level of risk exceeded only by smokers (OR 4.46, 95% CI 2.25-8.84) [11]. A prospective
cohort study with more than 20 years follow-up found an increased risk of death (HR 2.9, 95% CI 1.3-
4.0) for patients with diabetes and PAD, compared with those without diabetes [87]. (See "Overview
of peripheral artery disease in patients with diabetes mellitus".)

Poor glycemic control also incrementally increases the risk of atherosclerosis. A systematic review
identified 13 studies evaluating hyperglycemia and cardiovascular risk, and found a 26 percent
increase in risk for every 1 percent increase in HbA1c [88].

Diabetes also increased the risk for developing symptomatic PAD (OR 2.6) in the Framingham Heart
Study, which followed subjects for 38 years [14]. The effect of diabetes on graft patency has varied
between studies, with the majority finding no difference in patency rates [89,90]. However,
retrospective reviews have reported increased mortality and amputation in patients with diabetes
[91,92]. In one study, the mortality rate for patients with diabetes following aortic or lower extremity
revascularization was 9.6 percent compared with 2.2 percent for those without diabetes [92].
Although the risk of amputation in patients with diabetes is related to the severity of PAD, infection
and neuropathy are also contributing factors.

While alcohol use has typically been associated with a protective effect, one review found that heavy
alcohol use in patients with type II diabetes was associated with an increased risk for lower extremity
PAD (OR 6.25, 95% CI 1.78-22.65) [93]. The increased risk remained after adjusting for all other
factors, including smoking, body mass index, and sex. A dose-response relationship was also found
between prolonged alcohol consumption and PAD.

Chronic kidney disease — Many guidelines do not specifically identify chronic kidney disease
(CKD) as a risk factor for PAD. However, an association between PAD and CKD is being recognized
and reported with increasing frequency. While an increased risk has generally been recognized for
patients with severely reduced renal function, a growing number of studies have suggested an
increased risk for even mild to moderately reduced renal function [94-96]. CKD is considered a
coronary heart disease risk equivalent. (See "Chronic kidney disease and coronary heart disease"
and "Overview of established risk factors for cardiovascular disease" and "Lower extremity peripheral
artery disease in patients with chronic kidney disease".)

Metabolic syndrome — Metabolic syndrome (a constellation of obesity, hypercholesterolemia,

hypertension, and insulin resistance) is associated with increased risk for cardiovascular disease.
(See "Overview of established risk factors for cardiovascular disease", section on 'Metabolic
syndrome'.)

The following studies illustrate the relationship between metabolic syndrome and PAD:

● In a cross-sectional study, 60 percent of patients with PAD also had metabolic syndrome, but the
metabolic syndrome score did not significantly correlate with the extent of disease [97].

● In the Second Manifestations of Arterial Disease (SMART) study, patients with metabolic
syndrome had a higher incidence of vascular events (vascular death, stroke, myocardial
infarction) compared with patients with PAD and no metabolic syndrome (15 versus 8 percent)
[98].

● A prospective cohort study that followed 27,111 women without baseline cardiovascular disease
over an average of 13.3 years found that women with metabolic syndrome had a 62 percent
increased risk for future symptomatic PAD compared with those without metabolic syndrome [99].

Hyperlipidemia — Patients with certain lipid and lipoprotein abnormalities [eg, total cholesterol, low-
density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein (a)] have an increased risk for
cardiovascular disease, and adverse long-term cardiovascular outcomes. (See "Overview of
established risk factors for cardiovascular disease", section on 'Lipids and lipoproteins' and
"Lipoprotein(a) and cardiovascular disease".)

Patients with PAD are more likely to have increased levels of triglycerides and/or cholesterol,
lipoprotein (a), apolipoprotein B, and very low density lipoprotein, compared with patients without PAD
[100-102]. Conversely, the levels of high density lipoprotein (HDL) cholesterol and apolipoprotein A-I
and A-II levels, the "protective" lipoproteins, are lower in these patients [103].

Lipoprotein (a) is a significant independent risk factor for PAD. Lipoprotein (a) is genetically
determined and controlled by a single gene locus. In the Québec Cardiovascular Study, the risk of
intermittent claudication was doubled in men with higher concentrations of plasma lipoprotein (a)
[104-106]. Patients with premature PAD have lipoprotein (a) levels that are fourfold higher than
controls [107]. Lipoprotein (a) levels vary between ethnic populations, with otherwise healthy African
Americans having levels that are almost twice those of Caucasians [108].

In the Framingham study, a fasting cholesterol level >7 mmol/L (270 mg/dL) was associated with a
doubling of the incidence of intermittent claudication; for each 40 mg/dL increase in total serum
cholesterol, the odds of developing symptomatic PAD increased by 1.2 [14]. In the Physicians Health
Study, the ratio of total to HDL cholesterol was the best independent predictor of occurrence of PAD
[109].

Treatment of hyperlipidemia may decrease the risk of progression of PAD and the incidence of
intermittent claudication. In the Heart Protection Study, the cholesterol lowering agent simvastatin
decreased overall mortality by 12 percent, and vascular mortality by 17 percent [110].

Heavy metal exposure — Excess exposure to heavy metals (arsenic, lead, cadmium, mercury) is
associated with incident cardiovascular disease and increased cardiovascular mortality [111-114]. The
risk for PAD specifically has been studied for arsenic, cadmium, and lead [115-118]. There are no
data as to whether treatment of any of these heavy metal exposures alters PAD risks.

In a review using data from the NHANES, after adjusting for known risk factors, comparing the
highest with lowest quartiles, the risk for PAD trended higher for cadmium (OR 2.82, 95% CI 1.36-
5.85) and for lead (OR 2.88, 95% CI 0.87-9.47) [116].

In later prospective cohort studies in a Native-American population, increased exposure to arsenic or

cadmium was independently associated with incident PAD [118,119]. In one of these studies, arsenic
methylation increased the risk for noncompressible vessels (ABI >1.4; HR 2.04, 95% CI 1.02-3.41);
however, there was no association for ABI <0.9 [119]. Urine cadmium was also significantly
associated with PAD (ABI <0.9) after adjusting for cardiovascular risk factors including smoking status
(HR 1.96, 1.32 to 2.81 for the highest versus lowest tertile) [118].

In a separate systematic review that included a diverse population, high arsenic exposure was
associated with PAD (pooled relative risk [RR] 2.17, 95% CI 1.47-3.20) and also with coronary heart
disease (pooled RR 1.89, 95% CI 1.33-2.69) [120]. High arsenic levels may also increase
homocysteine levels. (See 'Homocysteine' below.)

Homocysteine — Homocysteine was one of the earliest biomarkers to be studied in association with
the development of atherosclerosis [121]. Elevated homocysteine is associated with earlier-onset
atherosclerosis and is present in up to 40 percent of patients with PAD [122]. Homocysteine is
thought to promote smooth muscle proliferation, increase arterial wall inflammation, and increase
levels of plasminogen activator inhibitor. Homocysteine also interferes with nitric oxide released by
endothelial cells. Excess homocysteine leads to vessel thickening, luminal stenosis, and thrombus
formation.

Although a more rapid progression of PAD in patients with increased homocysteine has been
described in some studies [43,123], this finding is not uniform [39]. However, no study has shown that
homocysteine-lowering therapy reduces PAD progression or improves outcomes [124].

Other biomarkers — Other biomarkers are increasingly being studied as a means to identify those at
higher risk for development of atherosclerosis. Based on the Scottish Heart Health Extended Cohort
study, N-terminal pro b-type natriuretic peptide [NT-pro-BNP], cotinine, high-sensitivity C-reactive
protein, and cystatin-C are risk factors for PAD [15]. Biomarker risk factors for PAD were not entirely
consistent with those for CHD. For PAD, high-sensitivity C-reactive protein, indicative of inflammatory
state, and expired carbon monoxide and cotinine, associated with tobacco abuse, as well as
lipoprotein (a), were associated with higher rates of PAD development. (See "Overview of possible
risk factors for cardiovascular disease", section on 'Vitamins, antioxidants and homocysteine'.)

Tissue plasminogen activator activity appears to be associated with asymptomatic lower extremity
arterial disease [125]. In a study of subjects previously unknown to have PAD, tissue plasminogen
activator activity at baseline and at the 10-year follow-up significantly predicted the presence of
sign(s) of PAD (OR 1.78, 95% CI 1.02-3.10). Age, hypertension, and HbA1c were also independent
risk factors in this study for development of PAD at 10 years.

HIV infection — The mechanisms by which HIV might increase atherogenesis are unclear but may
be related to endothelial dysfunction, platelet activation, and increased inflammation.

Among over 90,000 participants in the Veterans Aging Cohort Study, the rate of incident PAD events
per 1000 person-years was significantly higher among HIV-positive compared with HIV-negative
veterans (11.9 versus 9.9 percent). The risk was highest among those with time-updated HIV viral
load >500 copies/mL and CD4 cell counts <200 cells/mm3 [126]. It is important to note that incident
PAD events were defined based upon the reported diagnosis codes, rather than based upon ankle-
brachial indices. Also, since this study was almost exclusively men, it is not possible to determine
whether HIV in women confers the same risk.

ANATOMIC PATTERNS OF DISEASE

Atherosclerotic disease tends to be well localized and usually occurs in the proximal or mid portions
of the arterial bed. Less commonly, however, the disease can occur more distally. Among the various
vascular beds, atherosclerotic disease appears to follow patterns, which may also have a bearing on
the natural history and progression of disease.

Asymptomatic — Subclinical atherosclerosis is prevalent in asymptomatic middle-aged individuals.

The Progression of Early Subclinical Atherosclerosis (PESA) study evaluated the presence,
distribution, and extent of subclinical atherosclerosis in 4184 asymptomatic participants aged 40 to 54
years using carotid, abdominal, and iliofemoral artery ultrasound and noncontrast coronary artery
computed tomography (CT) [127]. Subclinical atherosclerosis was present in 63 percent of
participants (71 percent of men, 48 percent of women). Nearly one-half of the participants were
classified as having intermediate or generalized disease. Plaques were most common in the
iliofemoral arteries (44 percent), followed by the carotid arteries (31 percent) and aorta (25 percent),
whereas coronary artery calcification was present in 18 percent. Most participants with a high
Framingham Heart Study (FHS) risk had subclinical disease, but extensive atherosclerosis was also
seen in low-risk individuals. A second study that also used arterial ultrasound and noncontrast
coronary CT identified atherosclerotic plaques in 72 percent of middle-aged men, which were most
common in femoral arteries (54 percent), coronary arteries (38 percent), and carotid arteries (34
percent) [128].

In a study of whole body magnetic resonance (MR) angiography with contrast among 1531
asymptomatic participants (577 men, median age of cohort 53.5 years) at low-to-intermediate risk for
cardiovascular disease, 747 (50 percent) demonstrated disease in one or more vessels [129]. The
coronary arteries were not assessed. Vascular stenoses were distributed throughout the body with no
localized distribution, with approximately 3.5 percent of the arteries in the neck (eg, carotids and
vertebrals), torso (eg, abdominal aorta, iliac), and extremities (eg, femoral, popliteal) demonstrating
stenoses of >50 percent. While imaging is typically not necessary or indicated clinically to assess
asymptomatic patients, this study does demonstrate prevalence of disease in a low-to-intermediate
risk group.
Symptomatic — In addition to the vascular bed that is producing symptoms, patients with
symptomatic disease are at risk for developing additional lesions in the same or other vascular beds,
which underscores the need for ongoing follow-up. (See "Overview of lower extremity peripheral
artery disease", section on 'Postprocedure surveillance'.)

A review of 13,827 patients admitted at a single institution over a 40-year period (1948 to 1983)
identified five major patterns of symptomatic atherosclerotic disease [130,131]:

● Type I: The coronary arterial bed (32 percent, mean age 55, 84 percent male)
● Type II: The major branches of the aortic arch (eg, carotid, subclavian) (17 percent, mean age
62, 65 percent male)
● Type III: The visceral arterial branches of the abdominal aorta (3 percent, mean age 49.4, 60
percent male)
● Type IV: The abdominal aorta and lower extremity arteries (42 percent, mean age 59, 80 percent
male)
● Type V: A combination of two or more of these categories occurring simultaneously (6 percent,
mean age 61, 73 percent male)

Important findings of this classic study included:

● Disease of the aorta and lower extremity arteries was the most prevalent, followed by coronary
heart disease. By contrast, visceral vessel disease and combined patterns were the least
prevalent.

● The onset of symptomatic disease varied with the arterial bed affected. Patients with coronary
heart disease and visceral artery disease presented at a younger age compared with those in the
other categories.

● Rates of disease progression varied with arterial bed. More rapid progression of disease
occurred most frequently in those with aortic arch branch disease and visceral artery disease.
Gender did not influence the rate of progression; however, the risk for recurrence or progression
of disease in the same category and in a new category was significantly greater in younger
patients. In most other studies evaluating the natural progression of disease of the aorta and
lower extremities, symptoms tend to remain stable [132]. Patients who continue to smoke
cigarettes and those with diabetes mellitus are generally at the highest risk for progression of
disease. (See 'Natural history and progression of PAD' below.)

● Disease of the abdominal aorta and lower extremity arteries had the highest incidence of
developing disease in a new category, whereas those with coronary heart disease had the lowest
incidence. The association between coronary heart disease and extracranial atherosclerotic
 carotid disease is well known. In one retrospective review, the severity of carotid artery stenosis
significantly correlated with the extent of coronary heart disease [133]. Atherosclerotic disease of
the renal artery branches is relatively common in patients with aortic disease, estimated at 22 to
59 percent of patients [134-136].

● Patients initially diagnosed with aortic arch branch disease had a greater tendency to develop
disease of the abdominal aorta and lower extremity arteries, and vice versa. In more modern
series, among patients with disease of the aorta and lower extremity arteries, a hemodynamically
significant carotid lesion is present in 12 to 25 percent of patients [137-139]. The Atherosclerosis
Risk in Communities (ARIC) study [140] and the Edinburgh Artery Study [141] documented an
increased risk of stroke in these patients.

In the lower extremity, patterns of atherosclerotic disease have also been described [142,143].
Femoropopliteal disease is the most common anatomic location, occurring in approximately 50
percent in retrospective reviews [144-146]. However, among those with earlier-onset disease, the
aortoiliac segment appears to be more commonly affected. However, atherosclerotic lower extremity
arterial disease is a multisegmental disease in approximately two-thirds of symptomatic patients
[145,147]. Patients with aortoiliac disease are likely to have disease involving the femoral and tibial
vessels as well. Among patients with diabetes, more distal disease affecting the tibial vessels
predominates [142].

NATURAL HISTORY AND PROGRESSION OF PAD

The clinical manifestations of PAD depend upon the location and severity of arterial stenosis or
occlusion and range from mild extremity pain with activity (eg, claudication) to limb-threatening
ischemia. Most patients with asymptomatic PAD have a benign course; however, clinical
manifestations can develop or progress rapidly and unpredictably in those with PAD who continue to
smoke, or those with concomitant diabetes or renal insufficiency.

The factors that predict progression of PAD were evaluated in a longitudinal study involving 403
patients using a standard questionnaire, clinical examination, ankle-to-brachial index (ABI), and the
toe-brachial index (TBI) over a mean follow-up of 4.6 years [65]. The following findings were noted:

● Among patients with follow-up ABI decrements exceeding 0.3 (the study author's definition of
progression), significant risk factors after adjustment included current cigarette smoking (hazard
ratio [HR] 3.2, 95% CI 1.51-6.8), ratio of total cholesterol to high-density lipoprotein (HDL)
cholesterol (per unit) (HR 1.35, 95% CI 1.05-1.73), elevated high-sensitivity C-reactive protein
(per 1 mg/L) (HR 1.37, 95% CI 0.99-1.90), and elevated lipoprotein (a) (per 1 mg/dL) (HR 1.37,
95% CI 1.03-1.82).
 ● Diabetes, hypertension, triglycerides, homocysteine, and body mass index (BMI) were not
significant for large vessel disease progression as measured by changes in ABI.

● Among patients with a significant decrement in TBI (decrement exceeding 0.27), diabetes was
the only significant predictor of progression.

Similar findings were noted in the National Health and Nutrition Examination Survey (NHANES) [11]
and Multi-Ethnic Study of Atherosclerosis (MESA) studies discussed above [39]. In the NHANES
study, the risk of PAD was significantly increased in current smokers and patients with diabetes,
hypertension, and hyperlipidemia. Other significant risk factors for PAD were black race and
decreased renal function. Each of these factors were also independently predictive of PAD
progression, and many had synergistic effects. (See 'Epidemiology and risk factors' above.)

In a systematic review of observational studies, increasing age, male sex, smoking, and concurrent
cardiovascular disease were all predictors of disease progression [148]. During follow-up (ranging
from 1 to 13 years), approximately 7 percent of asymptomatic PAD patients progressed to
claudication, and 21 percent of claudication patients were diagnosed as having critical limb ischemia,
with 4 to 27 percent undergoing amputations. However, with respect to gender, a population cohort
study did not identify any significant differences in the composite risk of major adverse cardiovascular
events for women with PAD compared with men, although men may be at increased risk for adverse
limb events compared with women [149].

Asymptomatic PAD — Most patients with PAD are unaware of their disease. Fewer than 50 percent
of PAD patients and approximately 30 percent of their physicians are aware that PAD is present [7].

PAD is a strong predictor of adverse cardiovascular outcomes [150]. The annual cardiovascular event
rate is 5 to 7 percent for patients with PAD [2]. In the AGATHA study, patients with PAD in one
vascular bed had a 35 percent chance of having disease in at least one other territory, and 50 percent
had cerebrovascular or coronary heart disease [151]. There was a 2 to 3 percent nonfatal myocardial
infarction rate, and a twofold to threefold increase in the occurrence of angina compared with age-
matched controls. Asymptomatic PAD is also a risk factor for increased mortality [73,150,152], and
mortality associated with asymptomatic and symptomatic PAD may not differ [150]. Even mild
asymptomatic PAD increases the risk of cardiovascular death [73]. For each decrement of 0.1 in ABI,
mortality increases approximately 13 percent [153]. The increased risk is due to cardiovascular
causes but also includes nonvascular etiologies, most of which are neoplasms related to smoking.
Clearly, identifying patients with asymptomatic PAD is important to institute risk factor modification to
reduce adverse cardiovascular outcomes. Screening asymptomatic patients for PAD is discussed
elsewhere. (See "Screening for lower extremity peripheral artery disease".)
The risk of progression from asymptomatic PAD to ischemic symptoms that require intervention is
generally low but may be underestimated. PAD progression as measured by ABI is similar for
asymptomatic and symptomatic patients. The decline in ABI closely relates to the initial value of ABI
upon initial diagnosis; a more rapid decline is seen in patients with lower initial ABI values [152]. One
study of 117 patients found a 30 percent progressive decline in ABI [87]. Another study that focused
on functional capacity found a greater decrease over time for those with abnormal ABI, despite a lack
of symptoms, compared with those with normal ABI over a two-year time period [26]. In a systematic
review, the cumulative incidence over five years for progression from asymptomatic PAD patients to
intermittent claudication was 7 percent [148].

In the Framingham Heart Study, 381 men and women were followed for 38 years [14]. The risk of
developing intermittent claudication in asymptomatic patients was increased in patients with elevated
serum cholesterol (odds ratio increase of 1.2 for each 40 mg/dL [1 mmol/L] elevation), cigarette
smoking (odds ratio increase 1.4 for each 10 cigarettes smoked per day), moderate hypertension
(odds ratio increase 1.5 for mild and 2.2 for moderate hypertension), and diabetes mellitus (odds ratio
2.6) [14]. In patients with diabetes, 28 percent of patients had progression of disease, regardless of
symptoms [87]. Other studies have also demonstrated a decline in ABI over time that is not
necessarily associated with the development of symptoms. On the other hand, the Edinburgh Artery
study found no change in ABI over five years in asymptomatic patients [73].

Intermittent claudication — The most common symptom among patients with PAD is intermittent
claudication, which is a reproducible pain with ambulation that is relieved with rest. Intermittent
claudication is discussed in more detail elsewhere. (See "Clinical features and diagnosis of lower
extremity peripheral artery disease".)

The natural history of intermittent claudication is characterized by slow symptom progression. Critical
limb ischemia (ischemic rest pain, tissue loss) seldom occurs. In a long-term study of 1244 patients
with intermittent claudication, predictors of progression to critical ischemia included diabetes, a lower
initial ankle-brachial index, and greater number of pack-years of smoking [154]. Based upon several
population studies, the estimated risk of major amputation in patients with intermittent claudication is
approximately 7 percent over a five-year period and 12 percent over a 10-year period [155].

The American College of Cardiology/American Heart Association (ACC/AHA) guidelines on PAD

(2005, updated 2011) estimated the following rates of limb and cardiovascular outcomes at five years
in patients with intermittent claudication [4,6,8]:

● Stable claudication in 70 to 80 percent

● Worsening claudication in 10 to 20 percent

 ● Critical limb ischemia in 1 to 2 percent

● Nonfatal myocardial infarction or stroke in 20 percent

● Death in 15 to 30 percent (75 percent due to cardiovascular causes)

Intermittent claudication as a manifestation of PAD is a strong marker for generalized atherosclerosis

and other cardiovascular and cerebrovascular morbidity and mortality [156-158]. In older studies, the
5- and 10-year mortality rates among patients with intermittent claudication were 30 to 42, and 50 to
65 percent, respectively [159,160]. In a later study that compared all-cause and cardiovascular
mortality in patients with and without PAD, all-cause and cardiovascular mortality at five years for
patients with PAD was 19 and 7.3 percent in asymptomatic patients, and 24 and 7.7 percent in
symptomatic patients, a difference that was not significant between these groups, but significantly
greater compared with patients without PAD for whom all-cause and cardiovascular mortality was 9.5
and 2.4 percent, respectively [150].

The degree of impairment in symptomatic patients may also predict mortality. In a study that identified
1048 men and women with and without PAD, lower baseline walking impairment questionnaire (WIQ)
stair-climbing scores were associated with a higher risk of all-cause and cardiovascular mortality
compared with the higher WIQ stair-climbing scores (hazard ratio 1.7, 95% CI 1.08-2.66 and 3.11,
95% CI, 1.3-7.5, respectively) [161]. However, lower WIQ speed or distance scores did not increase
risk for all-cause or cardiovascular mortality among the PAD participants.

The importance of PAD as a marker for coexistent coronary artery disease cannot be overstated. The
association between cardiovascular disease and symptomatic PAD has been noted in many studies.
Patients with intermittent claudication also have a relative increase in the incidence of tumor and
tumor-associated death, probably due to a high prevalence of smoking [162].

In addition to high morbidity and mortality, patients with intermittent claudication have a poor quality of
life and high rates of depression [163,164]. The adverse impact of intermittent claudication on the
patient's physical and emotional well-being appears to be directly related to walking ability [165].

Critical limb ischemia — Critical limb ischemia is manifest as ischemic rest pain or with tissue loss
such as skin ulceration or gangrene in 1 to 2 percent of patients with symptomatic PAD. The clinical
manifestations of critical limb ischemia are discussed in detail elsewhere.

The natural history of untreated critical limb ischemia is difficult to elucidate since almost all patients
undergo medical management to prolong survival, and in the era of endovascular therapies, most will
undergo some form of intervention attempting limb salvage. In a systematic review, the five-year
cumulative incidence of patients with claudication that deteriorated or progressed to critical limb
ischemia was 21 percent [148].
Risk factors that increase the risk for critical limb ischemia include diabetes (fourfold risk), smoking
(threefold risk), and hypercholesterolemia (twofold risk) [65,154].

Patients with critical limb ischemia are at immediate risk for limb loss. Amputation rates remain high
at 25 percent, and long-term survival is poor. Nearly 25 percent of patients presenting with critical
limb ischemia will suffer a cardiovascular death within one year of their initial diagnosis [12,166]. In
one review, only 50 percent of patients presenting with critical limb ischemia were alive with both
limbs intact at the end of one year [12]. In studies of patients with nonreconstructible disease, 40
percent of patients with critical limb ischemia underwent amputation within six months, and 20
percent died within the same time period [2].

Limb salvage and long-term survival are significantly worse in patients with diabetes and those who
continue to smoke [167].

Progression of disease in selected populations — Patients with early-onset atherosclerosis,

diabetes, or end-stage renal disease have a higher risk for progression of PAD and worse prognosis.

Early-onset atherosclerosis — Early-onset atherosclerosis, or premature atherosclerosis, is

defined as PAD presenting prior to 50 years of age. Patients with early-onset atherosclerosis are
more frequently male, are active smokers, have diabetes, and more often present with critical limb
ischemia [168]. A defect in coagulation or fibrinolysis is identified in up to 75 percent of patients with
early-onset atherosclerosis [169-171]. In one study, 30 percent had hypercoagulable states, and 47
percent had platelet aggregation defects [169].

Outcomes are poor in this group of PAD patients.

● One review identified an 8 percent risk of transient ischemic attack, 9 percent risk of stroke, and
60 percent risk of coronary artery disease [43]. Surgery was undertaken for critical limb ischemia
in 62 percent of patients, and 38 percent demonstrated further progression of disease following
revascularization.

● Late amputation rates were significantly higher in a study of patients with early-onset
atherosclerosis compared with an older cohort of control patients (17 percent versus 3.9 percent)
[168]. Nearly half of the early-onset atherosclerosis patients underwent contralateral amputation
within two years.

● Mortality rates for younger patients with PAD are higher than for older patients, but the difference
has not been found to be significant [168,172]. However, compared with age-matched controls,
patients with early-onset atherosclerosis demonstrate significantly higher mortality (26 versus 1.7
percent) [168]. In another review, 32 percent of younger patients undergoing major amputation
died within one year of surgery; 20 percent died within five years [172].
 Diabetes — Diabetes is associated with a higher prevalence of PAD, and increased risk for
adverse outcomes [173]. In the Prevention Of Progression Of Arterial Disease and Diabetes
(POPADAD) trial, 16 percent of 1276 asymptomatic patients with diabetes and PAD progressed to
intermittent claudication, 3 percent to critical limb ischemia, and 1.6 percent to a major amputation
rate at six years [174]. Medical therapies (aspirin or antioxidants) had no influence on these numbers.
(See "Overview of peripheral artery disease in patients with diabetes mellitus".)

Chronic kidney disease — Peripheral artery disease is common among patients with end-stage
renal disease and is associated with a poor prognosis. Even mild-to-moderate chronic kidney disease
increases the risk of incident PAD, with a strong association between albuminuria and amputation.
Moreover, patients with end-stage renal disease are at increased risk for vascular calcification, which
independently increases the risk of cardiovascular morbidity and mortality. PAD in this population is
discussed elsewhere. (See "Lower extremity peripheral artery disease in patients with chronic kidney
disease".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Occlusive carotid, aortic, and
peripheral atherosclerotic disease".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The
Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and
they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read
materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for patients
who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-
mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Peripheral artery disease and claudication (The Basics)")
 ● Beyond the Basics topics (see "Patient education: Peripheral artery disease and claudication
(Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● The prevalence of peripheral artery disease (PAD) increases progressively with age, beginning
after age 40. As a result, PAD is growing as a clinical problem due to the aging population in the
United States and other developed countries. As such, a standard review during the examination
of older patients should always include questions related to a history of walking impairment,
extremity pain with ambulation, and the presence of nonhealing wounds. (See 'Introduction'
above.)

● Risk factors for peripheral artery disease are similar to those that promote the development of
coronary atherosclerosis (ie, smoking, hypertension, hyperlipidemia, diabetes, and metabolic
syndrome). Other factors include age, gender, ethnicity, family history and genetic influences,
and possibly homocysteinemia. The American College of Cardiology/American Heart Association
(ACC/AHA) guidelines on PAD identified the following groups at risk for lower extremity PAD (see
'Epidemiology and risk factors' above):

• Age ≥70 years

• Age 50 to 69 years with a history of smoking or diabetes

• Age 40 to 49 with diabetes and at least one other risk factor for atherosclerosis

• Leg symptoms suggestive of claudication with exertion or ischemic pain at rest

• Abnormal lower extremity pulse examination

• Known atherosclerosis at other sites (eg, coronary, carotid, renal artery disease)

● The prevalence of PAD increases progressively with age, beginning after age 40. Individuals
over 70 are at a significantly increased risk for PAD due to age alone, while the risk for younger
individuals is due to other factors, most commonly cigarette smoking. Early-onset
atherosclerosis, or premature atherosclerosis, is defined as PAD presenting prior to 50 years of
age. Patients with early-onset atherosclerosis more often present with critical limb ischemia and
have poor overall outcomes. (See 'Age' above and 'Early-onset atherosclerosis' above.)

● Gender- and ethnic-related differences in prevalence of PAD have been documented. PAD is
cited historically as more prevalent in men overall compared with women. However, the
population-based prevalence of PAD in women has not been fully evaluated. The prevalence of
 PAD in women is at least as high as that of men across all age groups but increases to a greater
extent in women after age 70 compared with men of the same age, African Americans having a
higher prevalence of PAD than non-Hispanic whites, and Hispanics and Asians having a
somewhat lower rate of PAD than non-Hispanic whites. (See 'Gender' above and 'Ethnicity'
above.)

● The natural history of peripheral artery disease in patients who present initially as asymptomatic
or with mild to moderate intermittent claudication is relatively benign. Of those with intermittent
claudication, 70 to 80 percent have stable claudication, 10 to 20 percent develop worsened
claudication, and only approximately 1 to 2 percent progress to critical limb ischemia. The
prognosis for limb loss or survival is significantly worse in those with early-onset atherosclerosis,
patients with diabetes or end-stage renal disease, and for those who continue to smoke. (See
'Natural history and progression of PAD' above.)

ACKNOWLEDGMENT

We are saddened by the death of Emile R Mohler, III, MD, who passed away in October 2017.
UpToDate wishes to acknowledge Dr. Mohler's work as our Section Editor for Vascular Medicine.

Use of UpToDate is subject to the Subscription and License Agreement.

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Topic 15210 Version 16.0

Contributor Disclosures
Linda Harris, MD, FACS Nothing to disclose Maciej Dryjski, MD, PhD, FACS Grant/Research/Clinical Trial
Support: Gore [Thoracic aortic aneurysm (Abdominal and thoracic endograft)]; Terumo Aortic [Thoracic aortic
aneurysm (Thoracic endograft)]. Joseph L Mills, Sr, MD Grant/Research/Clinical Trial Support: Voyager Trial
[Peripheral artery disease (Rivoxaraban)]. Consultant/Advisory Boards: Innomed [Peripheral artery disease
(Femoral artery stent)]. Equity Ownership/Stock Options: NangioTx [Peripheral artery disease (Self-assembling
nanotubules)]. Other Financial Interest: Elsevier; Rutherford [Vascular surgery (Rutherford and Comprehensive
Vascular and Endovascular Surgery textbooks)]. John F Eidt, MD Nothing to disclose Kathryn A Collins, MD,
PhD, FACS Nothing to disclose

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