Epidemiology, risk factors, and natural history of peripheral artery disease Authors Linda Harris, MD, FACS Maciej

Dryjski, MD Section Editors Joseph L Mills, Sr, MD John F Eidt, MD Emile R Mohler III, MD Deputy Editor Kathryn A Collins, MD, PhD, FACS Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2013. | This topic last updated: sep 26, 2012. 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 (picture 1). 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, diagnosis, and natural history of lower extremity peripheral artery disease" and "Medical management of claudication".) EPIDEMIOLOGY AND RISK FACTORS The worldwide prevalence of lower extremity peripheral artery disease (PAD) is between 3 to 12 percent [2-8]. In Europe and North America, an estimated 27 million individuals are affected with approximately 413,000 inpatient admissions annually attributed to PAD [2]. 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 [9]. Of these, 13 percent had PAD only, and 16 percent had evidence of PAD and coronary artery disease (CAD). PAD is more prevalent in older individuals, men, certain ethnic populations, families with atherosclerosis, and in those with risk factors for cardiovascular disease. Risk factors that favor the development of peripheral artery disease (PAD) are similar to those that promote the development of coronary atherosclerosis and include smoking, hypertension, diabetes, hyperlipidemia, homocysteinemia, and metabolic syndrome [9-12]. Risk factors for peripheral artery disease are similar to those that promote the development of coronary atherosclerosis (ie, smoking, hypertension, hyperlipidemia, diabetes). The American College of Cardiology/American Heart Association (ACC/AHA) guidelines on PAD identified the following groups at risk for lower extremity PAD [4,6,8]:

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)

An increased prevalence of PAD and earlier onset of symptomatic PAD are associated with these risk factors, which are reviewed below, focusing on PAD, and reviewed in detail elsewhere with respect to coronary heart disease. (See "Overview of the risk equivalents and established risk factors for cardiovascular disease".) 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 [13]. Risk factors for PAD used in the model included age, gender, race/ethnicity, hypertension, diabetes, chronic kidney disease, and smoking. The highest prevalence of PAD was among elderly, non-Hispanic Blacks and women; the higher prevalence of current smokers among women and non-Hispanic Blacks may explain this excessive risk of PAD in these populations. The likelihood of PAD increased with each additional risk factor present. Smoking was the single factor associated with the highest risk for PAD. 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 2.36.1) and for three risk factors the risk was increased 10-fold (OR 10.2, 95% CI 6.4-16.3). Non-Hispanic Blacks and women were particularly sensitive to this cumulative effect. Age The prevalence of PAD increases progressively with age, beginning after age 40 [10,14-19]. 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 the risk equivalents and 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, while risk for those who are younger is due to other factors, most commonly cigarette smoking [20]. 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 [21]. The relationship between PAD prevalence and age was illustrated in the National Health and Nutrition Examination Survey (NHANES) [10,20]. The prevalence of PAD (anklebrachial index [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

Gender Gender-related differences in the risk for cardiovascular disease have been described. (See "Overview of the risk equivalents and established risk factors for cardiovascular disease", section on 'Age and gender'.) Peripheral artery disease (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 [22-26]. 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) [27]. Similar results were found in a retrospective review of 231 consecutive patients diagnosed with PAD following referral to a vascular laboratory [24]. 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 percent versus 73 percent), metabolic syndrome (78 percent versus 43 percent), and diabetes (67.6 percent versus 42.9 percent) found in the female patients. 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 [10,28,29]. The difference does not appear to be completely explained by differences in the prevalence of risk factors for atherosclerosis [30]. African and Hispanic Americans have higher rates of diabetes and hypertension, whereas Caucasians are more likely to have hypercholesterolemia [25]. The National Health and Nutrition Examination Survey (NHANES) 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) [10].

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 [29]. In this study, PAD was defined as an ankle-brachial index (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 multi-ethnic 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 [31]. 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 the risk equivalents and established risk factors for cardiovascular disease", section on 'Family history' and "Overview of the 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 [32]. Patients with early onset atherosclerosis are a separate subgroup distinct from patients with familial hypercholesterolemia, which is discussed elsewhere [33,34]. (See 'Early-onset atherosclerosis' below.) Atherosclerotic disease likely results from numerous genes interacting with each other and the environment [35]. Studies that have investigated heritable factors in the development of peripheral artery disease (PAD), include family and twin studies, ankle-brachial index variance analysis, and gene studies [32-34,36-42]. Several studies have found that 20 to 50 percent of the variance in ankle-brachial index (ABI) can be explained by genetic factors [36-38]. However, in spite of finding such a correlation, 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 percent versus 31 percent). 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 [39]. 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 (odds ratio [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 about 42 percent.

A metaanalysis 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) [40]. 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 [43]. 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 [44-48]. (See "Cardiovascular risk of smoking and benefits of smoking cessation", section on 'Smoking and atherosclerosis'.) Smoking appears to be a more powerful risk factor for PAD than for CAD. In the Edinburgh Artery Study, the adjusted relative risk for heavy smokers compared with nonsmokers was 2.72 (95% CI 1.13-6.53) for PAD, but lower at 1.61, (95% CI 0.91-2.85) for CAD [49]. On average, a diagnosis of PAD is made about a decade sooner in smokers than in nonsmokers [50]. The National Health and Nutrition Examination Survey (NHANES) found an increased risk of PAD in patients who were active cigarette smokers (odds ratio 3.39, 95% CI 2.58-4.46) [20]. No association was found for other forms of tobacco exposure. 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 [9]. In another study, ongoing cigarette smoking was associated with the largest decline in ABI compared with other risk factors [51]. 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 [12]. 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 [50]. Smoking cessation decreases morbidity related to PAD; however, risk of progression of PAD is significantly greater in former smokers compared with never-smokers [52-54]. The Edinburgh Arterial Study found a decreased risk of claudication for patients who stopped smoking compared with those who continued to smoke [55]. Smoking cessation is also associated with a decreased risk of graft failure following lower extremity bypass surgery [56]. These effects are limited if the patient reduces cigarette consumption rather than

eliminating smoking altogether [57]. 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 [58,59]. (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 the risk equivalents and established risk factors for cardiovascular disease", section on 'Hypertension'.) In the United States, the prevalence of hypertension in adults is about 30 percent [60]. However, among those with an abnormal ankle-brachial index, the prevalence of hypertension in the Rotterdam Study was 60 percent [61]. 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 [12,62]. The National Health and Nutrition Examination Survey (NHANES) study found that hypertensive patients also have an even higher prevalence of asymptomatic PAD [10], and, further, that patients with PAD were less likely to have antihypertensive treatment compared with those who have other forms of cardiovascular disease [63]. 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 [14]. 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 [64]. (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 [65,66]. (See "Overview of the risk equivalents and established risk factors for cardiovascular disease", section on 'Diabetes mellitus'.) The NHANES study found an increased risk for PAD in patients with diabetes (odds ratio [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) [10]. A prospective cohort study with more than 20 years follow-up found an increased risk of death (hazard ratio 2.9, 95% CI 1.3-4.0) for patients with diabetes and PAD, compared with those without diabetes [67]. 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 [68]. Diabetes also increased the risk for developing symptomatic PAD (OR 2.6) in the Framingham Heart Study, which followed subjects for 38 years [12]. The effect of diabetes on graft patency has varied between studies, with the majority finding no difference in patency rates [69,70]. However, retrospective reviews have reported increased mortality and amputation in patients with diabetes [71,72]. 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 [72]. Although the risk of amputation

in patients with diabetes is related to the severity of PAD, infection and neuropathy are also contributing factors. Hyperlipidemia Patients with certain lipid and lipoprotein abnormalities [eg, total cholesterol, LDL, triglycerides, lipoprotein (a)] have an increased risk for cardiovascular disease, and adverse long-term cardiovascular outcomes. (See "Overview of the risk equivalents and 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 [73-75]. 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 [76]. Lipoprotein (a) is a significant independent risk factor for PAD. Lipoprotein (a) is genetically determined and controlled by a single gene locus. In the Qubec Cardiovascular Study, the risk of intermittent claudication was doubled in men with higher concentrations of plasma lipoprotein (a) [77-79]. Patients with premature PAD have lipoprotein (a) levels that are fourfold higher than controls [80]. Lipoprotein (a) levels vary between ethnic populations, with otherwise healthy African Americans having levels that are almost twice those of Caucasians [81]. 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 [12]. In the Physicians Health Study, the ratio of total to high-density lipoprotein (HDL) cholesterol was the best independent predictor of occurrence of PAD [82]. 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 [83]. Metabolic syndrome Metabolic syndrome (a constellation of obesity, hypercholesterolemia, hypertension, and insulin resistance) is associated with increased risk for cardiovascular disease. (See "Overview of the risk equivalents and 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 [84]. 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 percent versus 8 percent) [85]. 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 [86].

Homocysteinemia High levels of homocysteine are associated with earlier onset atherosclerosis and have been found in up to 41 percent of patients with PAD [87]. (See "Overview of the possible risk factors for cardiovascular disease", section on 'Vitamins, antioxidants and homocysteine'.) 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 [88]. Excess homocysteine leads to vessel thickening, luminal stenosis and thrombus formation. A more rapid progression of PAD in patients with increased homocysteine has been described in some studies [32,89], but not others [90]. However, although increased homocysteine levels are associated with an increased risk for developing PAD and more rapid progression of PAD, no study has shown that homocysteine lowering therapy reduces PAD progression or improves outcomes. 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-tobrachial index (ABI), and the toe-brachial index (TBI) over a mean follow-up of 4.6 years [51]. The following findings were noted:

Among patients with follow-up ABI decrements exceeding 0.3 (the authors 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 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 NHANES [10], and Multi-Ethnic Study of Atherosclerosis (MESA) studies discussed above [90]. In the NHANES study, the risk of PAD is significantly increased in current smokers, patients with diabetes, hypertension, and hyperlipidemia. Other significant risk factors for PAD are black race and decreased renal function. Each of these factors are also independently predictive of PAD progression, and many have synergistic effects. (See 'Epidemiology and risk factors' above.) Asymptomatic PAD Most patients with PAD are unaware of their disease. Fewer than 50 percent of PAD patients and about 30 percent of their physicians are aware that PAD is present [7]. PAD is a strong predictor of adverse cardiovascular outcomes [91]. 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 [92]. 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 [55,91,93], and mortality associated with asymptomatic and symptomatic PAD may not differ [91]. Even mild asymptomatic PAD increases the risk of cardiovascular death [55]. For each decrement of 0.1 in ABI, mortality increases about 13 percent [94]. 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. 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 [93]. One study of 117 patients found a 30 percent progressive decline in ABI [67]. 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 [21]. In the Framingham Heart Study, 381 men and women were followed for 38 years [12]. 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) [12]. In patients with diabetes, 28 percent of patients had progression of disease, regardless of symptoms [67]. 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 ankle-brachial index (ABI) over five years in asymptomatic patients [55].

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, diagnosis, and natural history 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 [95]. 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 [96]. The 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 [9799]. 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 [100,101]. In a more recent 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 [91]. 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) [102]. However, lower WIQ speed or distance scores did not increase risk for all-cause or CVD 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 [103].

In addition to high morbidity and mortality, patients with intermittent claudication have a poor quality of life and high rates of depression [104,105]. The adverse impact of intermittent claudication on the patients physical and emotional well-being appears to be directly related to walking ability [106]. 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. (See "Clinical manifestations and evaluation of chronic critical limb ischemia".) 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 intervention attempting limb salvage. Risk factors that increase the risk for critical limb ischemia include diabetes (fourfold risk), smoking (threefold risk), and hypercholesterolemia (twofold risk) [51,95]. 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 [9,107] 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 [9]. 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 [108]. 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 [109]. A defect in coagulation or fibrinolysis is identified in up to 75 percent of patients with early-onset atherosclerosis [110-112]. In one study, 30 percent had hypercoagulable states, and 47 percent had platelet aggregation defects [110]. 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 [32]. 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 earlyonset atherosclerosis compared with an older cohort of control patients (17 percent versus 3.9 percent) [109]. 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 [109,113]. However, compared with age-matched controls, patients with early-onset atherosclerosis demonstrate significantly higher mortality (26 versus 1.7 percent) [109]. In another review, 32 percent of younger patients undergoing major amputation died within one year of surgery; 20 percent died within five years [113].

Diabetes Diabetes is associated with a higher prevalence of PAD, and increased risk for adverse outcomes [114]. 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 [115]. Medical therapies (aspirin or antioxidants) had no influence on these numbers. End-stage renal disease Peripheral artery disease is common among patients with endstage renal disease and is associated with a poor prognosis. PAD in this population is discussed elsewhere. (See "Lower extremity peripheral artery disease in end-stage renal 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 information: Peripheral artery disease and claudication (The Basics)") Beyond the Basics topics (see "Patient information: 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 about 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.)

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REFERENCES

1. Creager MA, Belkin M, Bluth EI, et al. 2012 ACCF/AHA/ACR/SCAI/SIR/STS/SVM/SVN/SVS Key data elements and definitions for peripheral atherosclerotic vascular disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Data Standards (Writing Committee to develop Clinical Data Standards for peripheral atherosclerotic vascular disease). J Am Coll Cardiol 2012; 59:294. 2. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007; 45 Suppl S:S5. 3. Olin JW, Sealove BA. Peripheral artery disease: current insight into the disease and its diagnosis and management. Mayo Clin Proc 2010; 85:678. 4. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease) endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic InterSociety Consensus; and Vascular Disease Foundation. J Am Coll Cardiol 2006; 47:1239. 5. European Stroke Organisation, Tendera M, Aboyans V, et al. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J 2011; 32:2851. 6. 2011 WRITING GROUP MEMBERS, 2005 WRITING COMMITTEE MEMBERS, ACCF/AHA TASK FORCE MEMBERS. 2011 ACCF/AHA Focused Update of the Guideline for the Management of patients with peripheral artery disease (Updating the 2005 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2011; 124:2020. 7. Novo S. Classification, epidemiology, risk factors, and natural history of peripheral arterial disease. Diabetes Obes Metab 2002; 4 Suppl 2:S1. 8. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung,

and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006; 113:e463. 9. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001; 286:1317. 10. Selvin E, Erlinger TP. Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999-2000. Circulation 2004; 110:738. 11. Smith SC Jr, Milani RV, Arnett DK, et al. Atherosclerotic Vascular Disease Conference: Writing Group II: risk factors. Circulation 2004; 109:2613. 12. Murabito JM, D'Agostino RB, Silbershatz H, Wilson WF. Intermittent claudication. A risk profile from The Framingham Heart Study. Circulation 1997; 96:44. 13. Eraso LH, Fukaya E, Mohler ER 3rd, et al. Peripheral arterial disease, prevalence and cumulative risk factor profile analysis. Eur J Prev Cardiol 2012. 14. Ostchega Y, Paulose-Ram R, Dillon CF, et al. Prevalence of peripheral arterial disease and risk factors in persons aged 60 and older: data from the National Health and Nutrition Examination Survey 1999-2004. J Am Geriatr Soc 2007; 55:583. 15. Reeder BA, Liu L, Horlick L. Sociodemographic variation in the prevalence of cardiovascular disease. Can J Cardiol 1996; 12:271. 16. Criqui MH, Fronek A, Barrett-Connor E, et al. The prevalence of peripheral arterial disease in a defined population. Circulation 1985; 71:510. 17. Murabito JM, Evans JC, Nieto K, et al. Prevalence and clinical correlates of peripheral arterial disease in the Framingham Offspring Study. Am Heart J 2002; 143:961. 18. Pasternak RC, Criqui MH, Benjamin EJ, et al. Atherosclerotic Vascular Disease Conference: Writing Group I: epidemiology. Circulation 2004; 109:2605. 19. Krger K, Stang A, Kondratieva J, et al. Prevalence of peripheral arterial disease results of the Heinz Nixdorf recall study. Eur J Epidemiol 2006; 21:279. 20. Agarwal S. The association of active and passive smoking with peripheral arterial disease: results from NHANES 1999-2004. Angiology 2009; 60:335. 21. McDermott MM, Greenland P, Liu K, et al. Sex differences in peripheral arterial disease: leg symptoms and physical functioning. J Am Geriatr Soc 2003; 51:222. 22. Newman AB, Siscovick DS, Manolio TA, et al. Ankle-arm index as a marker of atherosclerosis in the Cardiovascular Health Study. Cardiovascular Heart Study (CHS) Collaborative Research Group. Circulation 1993; 88:837. 23. Hirsch AT, Allison MA, Gomes AS, et al. A call to action: women and peripheral artery disease: a scientific statement from the American Heart Association. Circulation 2012; 125:1449. 24. Brevetti G, Bucur R, Balbarini A, et al. Women and peripheral arterial disease: same disease, different issues. J Cardiovasc Med (Hagerstown) 2008; 9:382. 25. Meadows TA, Bhatt DL, Hirsch AT, et al. Ethnic differences in the prevalence and treatment of cardiovascular risk factors in US outpatients with peripheral arterial disease: insights from the reduction of atherothrombosis for continued health (REACH) registry. Am Heart J 2009; 158:1038. 26. Allison MA, Ho E, Denenberg JO, et al. Ethnic-specific prevalence of peripheral arterial disease in the United States. Am J Prev Med 2007; 32:328.

27. Sigvant B, Wiberg-Hedman K, Bergqvist D, et al. A population-based study of peripheral arterial disease prevalence with special focus on critical limb ischemia and sex differences. J Vasc Surg 2007; 45:1185. 28. Golomb BA, Dang TT, Criqui MH. Peripheral arterial disease: morbidity and mortality implications. Circulation 2006; 114:688. 29. Criqui MH, Vargas V, Denenberg JO, et al. Ethnicity and peripheral arterial disease: the San Diego Population Study. Circulation 2005; 112:2703. 30. Kullo IJ, Bailey KR, Kardia SL, et al. Ethnic differences in peripheral arterial disease in the NHLBI Genetic Epidemiology Network of Arteriopathy (GENOA) study. Vasc Med 2003; 8:237. 31. Subramaniam T, Nang EE, Lim SC, et al. Distribution of ankle--brachial index and the risk factors of peripheral artery disease in a multi-ethnic Asian population. Vasc Med 2011; 16:87. 32. Valentine RJ, Myers SI, Inman MH, et al. Late outcome of amputees with premature atherosclerosis. Surgery 1996; 119:487. 33. Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment. Atherosclerosis 2012; 223:262. 34. Bender R, Bell DA, Hooper AJ, et al. Screening for familial hypercholesterolaemia. Pathology 2012; 44:122. 35. Leeper NJ, Kullo IJ, Cooke JP. Genetics of peripheral artery disease. Circulation 2012; 125:3220. 36. Carmelli D, Fabsitz RR, Swan GE, et al. Contribution of genetic and environmental influences to ankle-brachial blood pressure index in the NHLBI Twin Study. National Heart, Lung, and Blood Institute. Am J Epidemiol 2000; 151:452. 37. Kullo IJ, Turner ST, Kardia SL, et al. A genome-wide linkage scan for anklebrachial index in African American and non-Hispanic white subjects participating in the GENOA study. Atherosclerosis 2006; 187:433. 38. Murabito JM, Guo CY, Fox CS, D'Agostino RB. Heritability of the ankle-brachial index: the Framingham Offspring study. Am J Epidemiol 2006; 164:963. 39. Wahlgren CM, Magnusson PK. Genetic influences on peripheral arterial disease in a twin population. Arterioscler Thromb Vasc Biol 2011; 31:678. 40. Zintzaras E, Zdoukopoulos N. A field synopsis and meta-analysis of genetic association studies in peripheral arterial disease: The CUMAGAS-PAD database. Am J Epidemiol 2009; 170:1. 41. Allison MA, Peralta CA, Wassel CL, et al. Genetic ancestry and lower extremity peripheral artery disease in the Multi-Ethnic Study of Atherosclerosis. Vasc Med 2010; 15:351. 42. Prushik SG, Farber A, Gona P, et al. Parental intermittent claudication as risk factor for claudication in adults. Am J Cardiol 2012; 109:736. 43. Holdt LM, Teupser D. Recent studies of the human chromosome 9p21 locus, which is associated with atherosclerosis in human populations. Arterioscler Thromb Vasc Biol 2012; 32:196. 44. Rahman MM, Laher I. Structural and functional alteration of blood vessels caused by cigarette smoking: an overview of molecular mechanisms. Curr Vasc Pharmacol 2007; 5:276. 45. Carty CS, Huribal M, Marsan BU, et al. Nicotine and its metabolite cotinine are mitogenic for human vascular smooth muscle cells. J Vasc Surg 1997; 25:682.

46. Leone A. Smoking, haemostatic factors, and cardiovascular risk. Curr Pharm Des 2007; 13:1661. 47. Chelland Campbell S, Moffatt RJ, Stamford BA. Smoking and smoking cessation -the relationship between cardiovascular disease and lipoprotein metabolism: a review. Atherosclerosis 2008; 201:225. 48. Narkiewicz K, van de Borne PJ, Hausberg M, et al. Cigarette smoking increases sympathetic outflow in humans. Circulation 1998; 98:528. 49. Price JF, Mowbray PI, Lee AJ, et al. Relationship between smoking and cardiovascular risk factors in the development of peripheral arterial disease and coronary artery disease: Edinburgh Artery Study. Eur Heart J 1999; 20:344. 50. Powell JT, Greenhalgh RM. Continued smoking and the results of vascular reconstruction. Br J Surg 1994; 81:1242. 51. Aboyans V, Criqui MH, Denenberg JO, et al. Risk factors for progression of peripheral arterial disease in large and small vessels. Circulation 2006; 113:2623. 52. Howard G, Wagenknecht LE, Burke GL, et al. Cigarette smoking and progression of atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) Study. JAMA 1998; 279:119. 53. Fowler B, Jamrozik K, Norman P, Allen Y. Prevalence of peripheral arterial disease: persistence of excess risk in former smokers. Aust N Z J Public Health 2002; 26:219. 54. Conen D, Everett BM, Kurth T, et al. Smoking, smoking cessation, [corrected] and risk for symptomatic peripheral artery disease in women: a cohort study. Ann Intern Med 2011; 154:719. 55. Fowkes FG, Housley E, Cawood EH, et al. Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. Int J Epidemiol 1991; 20:384. 56. Willigendael EM, Teijink JA, Bartelink ML, et al. Smoking and the patency of lower extremity bypass grafts: a meta-analysis. J Vasc Surg 2005; 42:67. 57. Noike H, Nakamura K, Sugiyama Y, et al. Changes in cardio-ankle vascular index in smoking cessation. J Atheroscler Thromb 2010; 17:517. 58. Jonason T, Bergstrm R. Cessation of smoking in patients with intermittent claudication. Effects on the risk of peripheral vascular complications, myocardial infarction and mortality. Acta Med Scand 1987; 221:253. 59. Hoogwegt MT, Hoeks SE, Pedersen SS, et al. Smoking cessation has no influence on quality of life in patients with peripheral arterial disease 5 years post-vascular surgery. Eur J Vasc Endovasc Surg 2010; 40:355. 60. Ong KL, Cheung BM, Man YB, et al. Prevalence, awareness, treatment, and control of hypertension among United States adults 1999-2004. Hypertension 2007; 49:69. 61. Meijer WT, Hoes AW, Rutgers D, et al. Peripheral arterial disease in the elderly: The Rotterdam Study. Arterioscler Thromb Vasc Biol 1998; 18:185. 62. Kannel WB, McGee DL. Update on some epidemiologic features of intermittent claudication: the Framingham Study. J Am Geriatr Soc 1985; 33:13. 63. Selvin E, Hirsch AT. Contemporary risk factor control and walking dysfunction in individuals with peripheral arterial disease: NHANES 1999-2004. Atherosclerosis 2008; 201:425.

64. Palumbo PJ, O'Fallon WM, Osmundson PJ, et al. Progression of peripheral occlusive arterial disease in diabetes mellitus. What factors are predictive? Arch Intern Med 1991; 151:717. 65. Jude EB, Oyibo SO, Chalmers N, Boulton AJ. Peripheral arterial disease in diabetic and nondiabetic patients: a comparison of severity and outcome. Diabetes Care 2001; 24:1433. 66. Bund M, Muoz L, Prez C, et al. Asymptomatic peripheral arterial disease in type 2 diabetes patients: a 10-year follow-up study of the utility of the ankle brachial index as a prognostic marker of cardiovascular disease. Ann Vasc Surg 2010; 24:985. 67. Leibson CL, Ransom JE, Olson W, et al. Peripheral arterial disease, diabetes, and mortality. Diabetes Care 2004; 27:2843. 68. Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004; 141:421. 69. Weiss JS, Sumpio BE. Review of prevalence and outcome of vascular disease in patients with diabetes mellitus. Eur J Vasc Endovasc Surg 2006; 31:143. 70. Komai H, Obitsu Y, Shigematsu H. Diabetes and old age could affect long-term patency of paramalleolar distal bypass for peripheral arterial disease in Japanese patients. Circ J 2011; 75:2460. 71. Dosluoglu HH, Lall P, Nader ND, et al. Insulin use is associated with poor limb salvage and survival in diabetic patients with chronic limb ischemia. J Vasc Surg 2010; 51:1178. 72. Mellire D, Berrahal D, Desgranges P, et al. Influence of diabetes on revascularisation procedures of the aorta and lower limb arteries: early results. Eur J Vasc Endovasc Surg 1999; 17:438. 73. Vitale E, Zuliani G, Baroni L, et al. Lipoprotein abnormalities in patients with extra-coronary arteriosclerosis. Atherosclerosis 1990; 81:95. 74. Greenhalgh RM, Rosengarten DS, Mervart I, et al. Serum lipids and lipoproteins in peripheral vascular disease. Lancet 1971; 2:947. 75. Vogelberg KH, Berchtold P, Berger H, et al. Primary hyperlipoproteinemias as risk factors in peripheral artery disease documented by arteriography. Atherosclerosis 1975; 22:271. 76. Bradby GV, Valente AJ, Walton KW. Serum high-density lipoproteins in peripheral vascular disease. Lancet 1978; 2:1271. 77. Cantin B, Moorjani S, Dagenais GR, Lupien PJ. Lipoprotein(a) distribution in a French Canadian population and its relation to intermittent claudication (the Qubec Cardiovascular Study). Am J Cardiol 1995; 75:1224. 78. Banerjee AK, Pearson J, Gilliland EL, et al. A six year prospective study of fibrinogen and other risk factors associated with mortality in stable claudicants. Thromb Haemost 1992; 68:261. 79. Lowe GD, Fowkes FG, Dawes J, et al. Blood viscosity, fibrinogen, and activation of coagulation and leukocytes in peripheral arterial disease and the normal population in the Edinburgh Artery Study. Circulation 1993; 87:1915. 80. Valentine RJ, Grayburn PA, Vega GL, Grundy SM. Lp(a) lipoprotein is an independent, discriminating risk factor for premature peripheral atherosclerosis among white men. Arch Intern Med 1994; 154:801.

81. Guyton JR, Dahlen GH, Patsch W, et al. Relationship of plasma lipoprotein Lp(a) levels to race and to apolipoprotein B. Arteriosclerosis 1985; 5:265. 82. Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA 2001; 285:2481. 83. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360:23. 84. Maksimovic M, Vlajinac H, Radak D, et al. Relationship between peripheral arterial disease and metabolic syndrome. Angiology 2009; 60:546. 85. Vlek AL, van der Graaf Y, Sluman MA, et al. Metabolic syndrome and vascular risk in patients with peripheral arterial occlusive disease. J Vasc Surg 2009; 50:61. 86. Conen D, Rexrode KM, Creager MA, et al. Metabolic syndrome, inflammation, and risk of symptomatic peripheral artery disease in women: a prospective study. Circulation 2009; 120:1041. 87. Asfar S, Safar HA. Homocysteine levels and peripheral arterial occlusive disease: a prospective cohort study and review of the literature. J Cardiovasc Surg (Torino) 2007; 48:601. 88. Cacciapuoti F. Hyper-homocysteinemia: a novel risk factor or a powerful marker for cardiovascular diseases? Pathogenetic and therapeutical uncertainties. J Thromb Thrombolysis 2011; 32:82. 89. Taylor SM. Current status of heroic limb salvage for critical limb ischemia. Am Surg 2008; 74:275. 90. Allison MA, Cushman M, Solomon C, et al. Ethnicity and risk factors for change in the ankle-brachial index: the Multi-Ethnic Study of Atherosclerosis. J Vasc Surg 2009; 50:1049. 91. Diehm C, Allenberg JR, Pittrow D, et al. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation 2009; 120:2053. 92. Fowkes FG, Low LP, Tuta S, et al. Ankle-brachial index and extent of atherothrombosis in 8891 patients with or at risk of vascular disease: results of the international AGATHA study. Eur Heart J 2006; 27:1861. 93. Nicoloff AD, Taylor LM Jr, Sexton GJ, et al. Relationship between site of initial symptoms and subsequent progression of disease in a prospective study of atherosclerosis progression in patients receiving long-term treatment for symptomatic peripheral arterial disease. J Vasc Surg 2002; 35:38. 94. Leibson, CL, Ransom, JE, Olson, W, et al. Peripheral arterial disease, diabetes, and mortality. Available on-line at: http://care.diabetesjournals.org/content/27/12/2843.full (Accessed on December 09, 2010). 95. Aquino R, Johnnides C, Makaroun M, et al. Natural history of claudication: longterm serial follow-up study of 1244 claudicants. J Vasc Surg 2001; 34:962. 96. Dormandy JA, Rutherford RB. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Consensus (TASC). J Vasc Surg 2000; 31:S1.

97. Leng GC, Fowkes FG, Lee AJ, et al. Use of ankle brachial pressure index to predict cardiovascular events and death: a cohort study. BMJ 1996; 313:1440. 98. O'Hare AM, Katz R, Shlipak MG, et al. Mortality and cardiovascular risk across the ankle-arm index spectrum: results from the Cardiovascular Health Study. Circulation 2006; 113:388. 99. Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992; 326:381. 100. Muluk SC, Muluk VS, Kelley ME, et al. Outcome events in patients with claudication: a 15-year study in 2777 patients. J Vasc Surg 2001; 33:251. 101. Dormandy J, Heeck L, Vig S. Intermittent claudication: a condition with underrated risks. Semin Vasc Surg 1999; 12:96. 102. Jain A, Liu K, Ferrucci L, et al. The Walking Impairment Questionnaire stair-climbing score predicts mortality in men and women with peripheral arterial disease. J Vasc Surg 2012; 55:1662. 103. Taute BM, Thommes S, Taute R, et al. Long-term outcome of patients with mild intermittent claudication under secondary prevention. Vasa 2009; 38:346. 104. McDermott MM, Greenland P, Guralnik JM, et al. Depressive symptoms and lower extremity functioning in men and women with peripheral arterial disease. J Gen Intern Med 2003; 18:461. 105. Regensteiner JG, Hiatt WR, Coll JR, et al. The impact of peripheral arterial disease on health-related quality of life in the Peripheral Arterial Disease Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) Program. Vasc Med 2008; 13:15. 106. Izquierdo-Porrera AM, Gardner AW, Bradham DD, et al. Relationship between objective measures of peripheral arterial disease severity to self-reported quality of life in older adults with intermittent claudication. J Vasc Surg 2005; 41:625. 107. Wolfe JH, Wyatt MG. Critical and subcritical ischaemia. Eur J Vasc Endovasc Surg 1997; 13:578. 108. Ouriel K. Peripheral arterial disease. Lancet 2001; 358:1257. 109. Harris LM, Peer R, Curl GR, et al. Long-term follow-up of patients with early atherosclerosis. J Vasc Surg 1996; 23:576. 110. Eldrup-Jorgensen J, Flanigan DP, Brace L, et al. Hypercoagulable states and lower limb ischemia in young adults. J Vasc Surg 1989; 9:334. 111. Aronson DC, Ruys T, van Bockel JH, et al. A prospective survey of risk factors in young adults with arterial occlusive disease. Eur J Vasc Surg 1989; 3:227. 112. Johnson EJ, Prentice CR, Parapia LA. Premature arterial disease associated with familial antithrombin III deficiency. Thromb Haemost 1990; 63:13. 113. Hansen ME, Valentine RJ, McIntire DD, et al. Age-related differences in the distribution of peripheral atherosclerosis: when is atherosclerosis truly premature? Surgery 1995; 118:834. 114. Britton KA, Mukamal KJ, Ix JH, et al. Insulin resistance and incident peripheral artery disease in the Cardiovascular Health Study. Vasc Med 2012; 17:85.