Exercise Rehabilitation in Peripheral Artery Disease: Functional Impact and Mechanisms of Benefits

In the United States, 8 million adults have peripheral arterial disease (PAD), a number that is likely to escalate as the population ages.^1–3 Lower extremity PAD is a component of systemic atherosclerosis and confers a markedly heightened risk of cardiovascular morbidity and mortality.^4–7 It is now established that PAD accelerates functional decline leading to physical disability.^8,9 Exercise therapy combined with comprehensive secondary prevention has the potential to benefit patients with PAD by preserving or improving functional capacity and reducing cardiovascular events. Accordingly, this review will address the relation between exercise intolerance and outcomes in patients with PAD; the effects of exercise training in PAD, and the many possible mechanisms of benefit; and the potential role of comprehensive secondary prevention programs in these patients.

PAD as a Marker of Cardiovascular Risk

Traditionally PAD has been viewed as a disease of the lower extremities typified by intermittent claudication. Studies now have demonstrated the malignant cardiovascular course of PAD even in the absence of claudication. The presence of PAD can be readily identified by the ankle-brachial index (ABI), a simple test comparing systolic blood pressure measured in the arm and in the ankle by Doppler.^10–12 Among patients with a low ABI (defined as ≤0.90) detected in both population-based and high risk primary care cohorts, only 10–15% have intermittent claudication.^13–15 The international ABI Collaboration patient-level meta-analysis of over 48,000 individuals found that a low ABI predicted a doubling of 10 year risk of mortality, cardiovascular mortality, and major coronary events at all levels of Framingham Risk Score.⁴ Importantly, the German Epidemiologic Study on Ankle Brachial index recently reported that asymptomatic individuals with PAD identified in a primary care screening program had similarly elevated 5-year risk of morbidity and mortality compared to symptomatic PAD patients.¹⁶ As has been reviewed elsewhere, the use of ABI testing to detect PAD in asymptomatic patients remains controversial^17,18; however, an ABI screening strategy to identify individuals at risk for cardiovascular events and functional decline would allow institution of secondary prevention measures including exercise therapy. Thus, the clinical significance of PAD derives not only from limb symptoms and functional impairment but as a marker of cardiovascular risk.

Functional disability in PAD

Several lines of evidence support the presence of pervasive functional alterations in PAD (see Figure 1). In the past, reduced walking capacity was identified as a consequence of intermittent claudication, the hallmark symptom of PAD. While a minority of patients with PAD experience classic claudication, up to 50% describe atypical leg symptoms that interfere with mobility.^13,14 Importantly, PAD limits exercise capacity and hastens physical decline, even in the absence of reported leg symptoms.^19–21 Asymptomatic patients, and patients with atypical symptoms who have PAD, experience progressive functional impairment and an increased risk of becoming unable to walk for 6 minutes compared to individuals without PAD.^9,22 The physical limitations in asymptomatic patients may reflect self-imposed activity restriction to prevent the occurrence of symptoms.

Figure 1.

Functional consequences of PAD. PAD is characterized by atherosclerotic lesions that limit blood flow manifest as reduced ankle brachial index. Patients with PAD have diminished functional capacity across the spectrum of leg symptoms. Functional impairment has clinical impact including progression to disability and increasing cardiovascular risk. Exercise training has the potential to interrupt functional decline. Further studies are needed to evaluate the impact of exercise training on long-term cardiovascular events in PAD patients.

Impaired walking ability has several important clinical implications. Patients with PAD have markedly reduced health- related quality of life and higher prevalence of depression which is largely related to leg symptoms.^23,24 Diminished physical activity in daily life predicts higher overall mortality in PAD.^25,26 Functional measures including the 6-minute walk test and treadmill walking time have been associated with increased mortality and risk of cardiovascular events in PAD.^27–31 Together these findings suggest that interventions that augment exercise performance in PAD may have wide-ranging health benefits.

Effects of Exercise Training on Functional Status in PAD

Supervised exercise programs have been recommended as first line therapy for treatment of claudication.^32–34 Recent evidence demonstrates benefits of exercise training even among those patients with PAD who do not have claudication.³⁵ Exercise programs combined with risk factor modification offer the possibility of altering the clinical trajectory of PAD. The goals of comprehensive prevention strategies including exercise are threefold: 1) to reduce limb symptoms; 2) to improve exercise capacity and prevent or lessen physical disability; and 3) to decrease the occurrence of cardiovascular events.

Exercise training markedly improves walking ability in PAD patients with intermittent claudication. A meta-analysis performed in 1995 that included uncontrolled trials suggested clinical efficacy of exercise in ameliorating claudication symptoms indicating that supervised exercise increased pain-free walking distance by 180%.³⁶ A rigorous systematic review including only controlled clinical trials encompassing 22 studies with over 1200 participants conducted by the Cochrane group in 2008 compared supervised exercise programs to usual care in the treatment of claudication.³⁷ Exercise produced clinically relevant increases in walking time (5 minutes) and walking distance (>100 meters). While all studies show exercise-related improvements in treadmill based measures, the degree of benefit varies across studies and individuals. Differences in exercise intensity as well as adherence to exercise programs may account for the observed variability in treatment effect. The magnitude of functional benefit derived from exercise training exceeds that observed in drug therapy trials with both pentoxifylline and cilostazol;³⁸ however, there are limited data that directly compare the two treatment modalities. Improvements in treadmill performance appear to translate to improved physical activity and quality of life. In randomized trials of exercise rehabilitation in patients with claudication, exercise has been shown to increase daily activity levels measured by accelerometer³⁹, and patient perceived health-related quality of life.^40,41 Increased physical activity may translate to slower functional decline and potentially to reduced cardiovascular risk.^25,42,43

Limited controlled data are available comparing revascularization with exercise training for intermittent claudication. In a single randomized trial, both exercise training and lower limb bypass surgery improved maximal walking distance to a similar degree at one year.⁴⁴A second study indicated greater walking distance at one year in a combined surgical and endovascular revascularization group compared to an exercise trained group; however, the compliance with exercise training was poor with less than 2/3 of assigned patients completing the exercise program.⁴⁵In a study performed more than 20 years ago, exercise training induced a greater increase in walking distance compared to angioplasty particularly in patients with superficial femoral artery lesions.⁴⁶However, a more contemporary trial showed greater benefit of endovascular therapy compared to supervised exercise training at 6 months but no difference at one year.⁴⁷ The Claudication: Exercise vs. Endoluminal Revascularization (CLEVER) study is an ongoing National Institutes of Health funded multi-center randomized trial comparing medical therapy, stenting, and exercise training in patients with claudication and aortoiliac obstructive disease.^48,49 The results from this important study using contemporary endovascular and exercise training techniques are anticipated to provide additional information that may guide choices about optimal therapy to improve functional outcomes in PAD patients.

Exercise training has been incorporated into current guidelines for the management of PAD. Multiple societal guidelines including American College of Cardiology/American Heart Association 2005 Practice Guidelines for the Management of Patients with Peripheral Arterial Disease, American Association of Cardiovascular and Pulmonary Rehabilitation 2004 Guidelines for Cardiac Rehabilitation and Secondary Prevention Programs, Inter-society Consensus for the Management of PAD (TASC II), and American College of Sports Medicine 2010 Guidelines for Exercise Testing and Prescription all recommend supervised exercise training in the treatment of claudication symptoms in PAD.^{33 34 50,51}

A recent seminal study extends the therapeutic impact of exercise training to the larger population of PAD patients without classic claudication symptoms. McDermott and colleagues conducted a randomized trial of supervised treadmill exercise compared to strength training and usual care in 156 PAD patients.³⁵ The symptom pattern corresponded to the observed distribution in clinical practice: 18% had claudication and 82% had atypical symptoms or were asymptomatic. At 6 months, patients in the treadmill exercise group increased exercise performance as evidenced by a longer 6 minute walk distance (+20.9m) compared to a decline in the control group (−15m). Lower extremity resistance training improved leg strength as well as maximum treadmill walking time without an increase in 6-minute walk distance. Both treadmill and resistance exercise training improved physical functioning- associated quality of life measures. However, increases in exercise tolerance in both training groups were not associated with a change in daily physical activity as measured by accelerometer. Perhaps additional behavioral interventions are needed to attain such increases. Thus, the findings support 1) recommending supervised exercise programs for all patients with PAD regardless of symptom status; and 2) the notion that exercise training can interrupt functional deterioration in PAD.

Mechanisms of Functional Impairment and Benefits of Exercise in PAD

Multiple mechanisms contribute to reduced exercise capacity in PAD. Atherosclerotic disease exists in the presence of pathophysiologic processes that together may contribute to impaired walking ability. Similarly, the functional benefits of exercise are likely attributable to amelioration of diverse maladaptive responses. Potential mechanisms are outlined in Table 1 and the available evidence supporting the role of arterial obstruction, endothelial dysfunction, altered skeletal muscle phenotype including mitochondrial dysfunction, and inflammatory activation in limiting exercise ability in PAD is discussed in this section. Exercise has the potential to reverse these pathologic events and thereby interrupt the clinical course toward disability.

Table 1.

Potential Mechanisms of Functional Impairment and Benefits of Exercise in PAD

Pathophysiologic Process	Functional Consequence	Effect of Exercise
Arterial Obstruction	Reduced blood flow	Minimal increase in collateral flow
Endothelial Dysfunction	Decreased vasodilator function	Improved nitric oxide-dependent vasodilation
	Increased arterial stiffness
	Impaired hyperemic response
	Impaired arterial remodeling
	Increased inflammatory activation
Mitochondrial Dysfunction	Impaired energy production	Improved mitochondrial energetics
	Impaired oxygen utilization	Increase in mitochondrial biogenesis in animal models
	Increased reactive oxygen species
	Reduced skeletal muscle content
Inflammatory Activation	Adverse skeletal muscle remodeling	Decreased markers of systemic inflammation
	Increased atherosclerotic progression

Arterial obstruction and blood flow limitation

Functional limitation in PAD traditionally has been ascribed to diminished blood flow induced by arterial obstruction from atherosclerotic stenoses. Typical intermittent claudication could theoretically be attributed to ischemia induced by an oxygen demand and supply imbalance. Certainly, fixed atherosclerotic lesions reflected in a diminished ankle-brachial index are the precipitating event that leads to functional abnormalities in PAD. However, multiple findings indicate that the pathophysiology of functional decline in PAD and the improvement with exercise is more complex.

The association between the severity of arterial obstruction and function status in PAD is inconsistent. Compared with individuals with normal ABI, patients with PAD have reduced self-reported and measured walking ability.^8,52 Select studies have demonstrated a moderate association between ABI and walking distance among PAD patients,^53–56 while others have reported no association of ABI with functional measures.^57,58 Similarly, calf blood flow measured with a magnetic resonance based technique was shown to be only modestly associated with walking distance (unadjusted r= 0.3, p<0.01).⁵⁹ In contrast, calf blood flow assessed by plethysmography did not correlate with baseline treadmill walking time or the subsequent 3-month change in walking time in an intervention study.⁵⁷ In an observational, longitudinal study of 676 individuals with and without PAD, the presence of an abnormal ABI predicted a greater decline walking measures at two years, thus confirming the clinical relevance of PAD to functional outcomes.⁹ However, the relation between severity of ABI reduction and functional decline in PAD patients remains ill-defined. Overall, the lack of consistency in the prior studies suggests that there are additional factors beyond anatomic disease that contribute to development of functional impairment in PAD.

Theoretically, enhanced distal blood flow due to vascular adaptations could underlie the benefits of exercise therapy in PAD. In animal models of arterial insufficiency, available evidence indicates that exercise training augments peripheral arterial supply.^60–63 Restoration of blood flow after arterial occlusion involves multiple complex processes that produce vascular growth.⁶⁴ Tissue ischemia in the underperfused muscle induces growth factors, including vascular endothelial growth factor and hypoxia inducible factor-1alpha, leading to angiogenesis.^65,66 Recent studies demonstrate that exercise stimulates gains in collateral blood flow after femoral occlusion in rodent models through collateral enlargement.^60,67,68 Collateral growth induced by exercise reflects vascular structural remodeling, a process that depends on both growth factor activity and increased nitric oxide bioavailability via shear stress stimulation of endothelial nitric oxide synthase.^60,67,69

In contrast, studies in patients with PAD have not convincingly demonstrated that exercise training produces clinically relevant gains in peripheral blood flow. Maximal hyperemic blood flow increased in some ^{70 71,72}but not all exercise training studies^73,74. In addition, an association between the increase in blood flow and walking time has not been shown.⁷⁰ In a trial comparing surgical revascularization to exercise training, the change in maximal calf blood flow after exercise at 13 month follow-up was not associated with the change in walking distance.⁴⁴ In a study of angioplasty compared to exercise, angioplasty produced an immediate increase in ABI whereas exercise-training improved walking time after a longer time period with more sustained efficacy.⁴⁶ The results of this study indicate a divergence between improvements in arterial flow and functional parameters with exercise intervention. Several factors may explain the apparent contradiction between the animal and human studies. Patients with PAD typically have multi-level disease of the vascular tree that may impede sufficient collateral growth. Concomitant endothelial dysfunction may inhibit shear-stress mediated vascular remodeling in PAD patients.^75,76 Finally, it remains possible that more sophisticated measures of collateral flow are required to detect exercise-mediated changes in humans. However, a recent meta-analysis of 7 exercise training studies demonstrated no change in the resting ABI, a cumulative measure of blood supply to the lower extremity.³⁷ Taken together, the studies in PAD patients indicate that an anatomic model of increased blood supply does not appear to account for the functional benefits of exercise.

Disruption of endothelial function

Functional limitations in PAD likely reflect an integration of abnormal vascular function with severity of arterial obstruction. Normal vascular function depends on a healthy endothelium that elaborates vasoprotective factors including nitric oxide to regulate arterial flow.⁷⁷ Reduced nitric oxide bioavailability in the skeletal muscle microcirculation diminishes the hyperemic flow response to ischemia and may impede augmentation of blood flow during exercise in PAD. ^{78 79} As has been observed in coronary arteries, endothelial dysfunction could also lead to peripheral arterial vasoconstriction and limit vasodilator responses to flow, which would tend to exacerbate blood flow limitation during exercise.^80–82

Consistent with these potential links between vascular function and functional status, a number of studies have demonstrated impaired endothelial vasodilator responses in PAD. Patients with PAD have attenuated flow-mediated dilation of the brachial artery as well as reduced acetylcholine-induced vasodilation, both consistent with the loss of nitric oxide activity.^83–86 In a cross-sectional study, greater physical activity during daily life was associated with greater brachial artery flow-mediated dilation in 111 patients with PAD, supporting a relation between functional status and vascular function.⁸⁷ Importantly, vascular dysfunction has been observed in the brachial artery of PAD patients indicating the presence of systemic endothelial abnormalities induced by cardiovascular risk factors and inflammation.^88,89 Vascular stiffness measures including pulse pressure and augmentation index that depend in part on nitric oxide bioavailability have also been associated with walking time.⁹⁰ The question of whether endothelial dysfunction contributes to functional decline over time in PAD has not been evaluated.

Two studies have demonstrated an improvement in endothelial function with exercise training in PAD. A supervised exercise program increased endothelium-dependent flow-mediated dilation of the brachial artery by 65% in 19 elderly patients with intermittent claudication.⁹¹ In this small study, no correlation was observed between gains in walking time and vasomotor function. In the randomized trial comparing treadmill exercise to lower extremity strength training and to usual care in PAD discussed above, McDermott and colleagues evaluated the effect of each exercise regimen on flow-mediated dilation of the brachial artery. Treadmill exercise but not lower extremity strength training augmented flow-mediated dilation consistent with improvement in endothelial health.³⁵ The lack of improvement in endothelial function with resistance training contrasts with a recent randomized trial in patients following myocardial infarction, and suggests that further study is needed to clarify the impact of strength training on endothelial function.⁹² The ability of exercise to reverse endothelial dysfunction may reflect sustained increases in shear-stress that stimulate nitric oxide bioactivity.⁹³ A study in coronary disease patients showed that exercise rehabilitation induced favorable effects on coronary endothelial function associated with increased endothelial nitric oxide synthase expression and activation.⁹⁴ As impaired endothelial function predicts higher risk for cardiovascular events among patients with PAD,^76,95 the exercise-induced improvement in vasodilator function may have the potential to reduce cardiovascular risk.

Altered skeletal muscle phenotype and mitochondrial dysfunction

It is increasingly clear that vascular obstruction has adverse consequences on the distal skeletal muscle tissue in PAD. Metabolic dysfunction at the skeletal muscle level superimposed on compromised blood flow has the potential to magnify physical limitation. Episodic ischemia in concert with chronically low physical activity levels alters skeletal muscle phenotype in PAD patients.⁹⁶ Imaging studies demonstrate gross structural changes in calf muscle tissue including reduced overall area, decreased muscle density, and increased fat content.^20,97 At the cellular level, there is evidence of increased muscle apoptosis, reduced type I fibers, and reduced capillary density.^98,99

Altered skeletal muscle energetics in PAD has been linked to mitochondrial dysfunction. Intermediate metabolites of substrate oxidation, including acylcarnitines, accumulate in the blood and muscle of PAD patients and are consistent with impaired metabolism at the mitochondrial level.¹⁰⁰ Whereas muscle mitochondrial content is higher, aberrant mitochondrial function impedes energy production and favors reactive oxygen species generation.^101–104 Abnormal mitochondrial function may interfere with skeletal muscle oxygen utilization and accelerate endothelial damage.^105,106 Further studies are needed to elucidate the contribution of mitochondrial abnormalities to vascular dysfunction in PAD.

Growing evidence relates adverse skeletal muscle changes, including mitochondrial dysfunction, to functional impairment in PAD.¹⁰⁷ Decreased calf muscle area and lower type I fiber content are associated with impairments in functional performance measures.^97,99 Abnormal mitochondrial function evidenced by delayed phosphocreatine recovery on magnetic resonance spectroscopy, has been shown to be associated with treadmill exercise time, though not with 6 minute walk distance.⁵⁹ The level of muscle acylcarnitine accumulation appears related to exercise intolerance.¹⁰⁰ In a prospective study, PAD patients with adverse calf muscle characteristics including higher calf muscle fat and lower calf muscle density had a heightened risk of functional decline over two years.¹⁰⁸

Exercise training has the potential to enhance skeletal muscle metabolism and mitochondrial function. In experimental models of ischemia, peroxisome-proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α), a key regulator of mitochondrial biogenesis, is critical to blood vessel recovery.¹⁰⁹ Interestingly, exercise-induced capillary growth in skeletal muscle also depends on PGC-1α, suggesting a connection between mitochondrial function and exercise adaptations relevant to PAD.¹¹⁰ Higher levels of physical activity in daily life are related to more favorable calf muscle traits, an association that is likely bidirectional.¹¹¹ In PAD patients, exercise training has been shown to restore carnitine metabolism in association with improved treadmill walking.^70,103 Whether exercise training improves mitochondrial energy production or calf muscle characteristics in PAD remains to be evaluated.

Inflammatory Activation

Chronic inflammation participates in the atherosclerotic process. Systemic markers of inflammation including C-reactive protein and soluble intracellular adhesion molecule-1 (sICAM-1) increase the risk of developing PAD.^112,113 Higher levels of inflammation are associated with disease progression and with adverse cardiac and lower extremity outcomes.^114–116 Inflammation may accelerate functional impairment in PAD by favoring plaque growth and inducing skeletal muscle injury. In addition, endothelial inflammatory activation reduces nitric oxide bioavailability and may impede vasodilatory function during exercise.¹¹⁷

A number of studies have assessed associations of functional measures and inflammation in PAD. Higher levels of inflammatory markers including C-reactive protein, interleukin 6, and soluble vascular cellular adhesion molecule-1 (sVCAM-1) are related to poorer walking ability in PAD patients.^118,119 Systemic inflammation may also impair functional status through adverse skeletal muscle remodeling. Multiple inflammatory markers were associated with lower calf muscle area and higher calf muscle fat content in a computed tomography study.¹²⁰ In longitudinal follow-up, both higher levels of inflammatory markers and an increase in C-reactive protein have been shown to predict functional decline among individuals with PAD.¹²¹

Physical activity may have favorable effects in PAD by suppressing inflammatory activation. Extensive epidemiologic data demonstrate lower inflammatory marker levels in individuals who participate in regular physical activity compared to those who are sedentary.¹²² Similarly in PAD, physical activity has an inverse association with C-reactive protein, IL-6, fibrinogen, sICAM-1, and sVCAM-1.¹²³ While, acute bouts of exercise increase inflammatory markers in claudicants, chronic exercise training appears to curb inflammation.¹²⁴ A 3-month exercise program ameliorated neutrophil activation after treadmill exercise in 46 PAD patients with claudication. ¹²⁵ Whether reduced inflammation produced by chronic exercise training underlies increased walking ability and translates to decreased events remains to be determined.

Exercise Rehabilitation Programs for PAD

Clinical studies have defined the optimal methods for implementing exercise training in PAD. Supervised exercise programs appear to deliver a greater improvement in functional measures compared to unsupervised training. A Cochrane review in 2006 of 8 small randomized trials with a total of 319 participants concluded that supervised exercise training was superior to non-supervised exercise, and yielded a 150m greater improvement in walking time.¹²⁶ The American College of Cardiology/American Heart Association 2005 Practice Guidelines for the Management of Patients with Peripheral Arterial Disease provide a Class I recommendation for supervised exercise training, but only a Class IIb recommendation for unsupervised training. They note that there is limited supporting symptom-based evidence for simply advising patients to walk more independently,³³ although increased daily physical activity may have other health benefits.¹²⁷ The differences between supervised and unsupervised training may be related to better patient adherence and greater intensity of treadmill exercise compared to normal walking. Results from the ongoing National Institute on Aging randomized controlled trial of home-based versus supervised exercise for people with claudication promise to provide further information on this important area.¹²⁸

Supervised exercise programs commence with a baseline assessment of functional status. The American Heart Association and the American College of Cardiology, the American College of Sports Medicine, and the American Association of Cardiovascular and Pulmonary Rehabilitation all recommend an exercise treadmill test prior to exercise training in order to evaluate walking capacity and to assess the degree of exercise limitation (Class I; level of evidence B).^33,50,51 However, some patients may have symptoms that are so limiting as to preclude the performance of an exercise test. As PAD patients frequently have co-existent coronary artery disease, exercise testing may identify potential cardiovascular complications including exercise - related ischemia and arrhythmias. It should be noted that exercise stress testing may have reduced sensitivity for ischemic chest pain or arrhythmias in PAD patients as the leg symptoms may limit ability to achieve adequate cardiac workload.¹²⁹ Exercise testing protocols, including individualized ramp protocols, that begin at low workrates and have low workrate increments per stage may be useful among patients with severe claudication symptoms. Treadmill testing serves as a guide to tailor initial exercise intensity levels. While the data are sparse, adverse event rates are low, but not absent during exercise training.³⁵ As patients walk farther and at higher intensity levels, cardiac signs and symptoms may be unmasked.

Exercise training using treadmill walking has been used most frequently in clinical trials.¹²⁶ The treadmill walking exercise prescription for patients with PAD and symptoms of intermittent claudication is outlined in Table 2.⁴⁸ Patients with leg symptoms are instructed exercise to mild to moderate pain (3–4 of 5 on the claudication scale) and then stop. When claudication has resolved, the patient begins walking on the treadmill again.⁴⁸PAD patients without intermittent claudication should follow the exercise prescription for patients with cardiovascular disease as outlined in Table 3, where exercise intensity is guided by exercise tolerance test using heart rate reserve or oxygen uptake reserve.^50,51In all patients with PAD, treadmill walking exercise is the preferred modality, but supplemental exercise using other exercise modalities including resistance training as recommended for patients with cardiovascular disease (Table 3) may be of additional benefit.^50,130

Table 2.

Exercise Prescription for Supervised Endurance Training in PAD Patients with Intermittent Claudication

Endurance Training
Frequency:	3–5 d·wk−1	Modality:
		Treadmill walking
Intensity:	Exercise at a given workrate at which the patient experiences the onset of claudication; continue walking until the patient has an ischemic leg pain symptom score of mild-moderate (3–4 out of maximum 5 points); then stop until pain completely subsides; resume exercise again at similar intensity; repeat rest/exercise bouts. Progress to a higher workrate when the patient is able to walk for 8 minute bouts without the need to stop for leg symptoms.
Duration:	Total exercise time (including rest periods) should equal 50 min·day−1

Adapted From Reference⁴⁸

Table 3.

Exercise Prescription for Endurance and Resistance Training for Patients with Cardiovascular Disease

Endurance Training
Frequency:	3–5 d·wk−1	Modality:
		For patients with intermittent claudication symptoms see Table 2
		Treadmill walking Stairclimber Stationary Cycle Arm Cycle Ergometry Rowing Swimming
Intensity:	40 – <60% heart rate reserve + resting HR or 40 – <60% VO2 reserve + resting VO2
Duration:	30–60 min·day−1
Resistance Training
Frequency:	≥2–3 d·wk−1	All Major Muscle Groups
		Arms/Shoulders:
Intensity:	1–3sets of 8–15 RM for muscle group	Biceps curl Triceps extension Overhead press Lateral raises
		Chest/back:
		Bench press Lateral pull down /pull-ups Bent-over / Seated row
		Legs:
		Leg extensions, curls, press Adductor / Abductor

Modalities listed above are not all inclusive.

HR = heart rate

Maximum HR= peak HR on exercise test

HRR = heart rate reserve = (peak-resting HR)

RM = maximum number of times a load can be lifted before fatigue

VO₂ = measured oxygen uptake

VO₂ reserve = (peak VO₂-resting VO₂)

Adapted from References50,130

Several studies have investigated alternate exercise training approaches. Arm ergometry exercise increases walking performance in patients with claudication and may be an appropriate exercise modality especially in patients with difficulty perform treadmill walking including patients with prior leg amputation.^131–133 Polestriding has also been shown to have efficacy in increasing walking performance in claudicants.^{134 135} Low intensity exercise and painfree walking have both been shown to increase walking time in small studies.^{136,137 138}

Patients can be gradually transitioned to independent, unsupervised exercise over time, if independent exercise is deemed safe by the program staff and if the patient understands the basic principles of self –monitoring, as outlined in detail in elsewhere.^50,51 At the completion of the supervised training program, patients should be given a home exercise prescription to maintain activity levels, as it is expected that exercise training should be continued as a life-long activity. However, as yet, the benefits of home exercise in patients with PAD remain unproven. Patients should be encouraged to contact the exercise program staff or their physician for any questions or concerns that they may have, and to periodically update the exercise prescription.

Barriers to Exercise Training in PAD

While there are a number of barriers that restrict or prevent patients with PAD from participation in supervised exercise programs, a major impediment is the lack of coverage for such programs by medical insurance. In 2001, the proven clinical efficacy of exercise in the treatment of claudication resulted in the creation of a Current Procedural Terminology Code (CPT 93,668) for PAD Rehabilitation. However, both Medicare and most private insurers still do not provide exercise training for PAD as a covered benefit. It is important to note that the lack of insurance coverage is incongruent with the clear clinical efficacy of exercise training in PAD. At this time, many patient and professional groups continue to advocate for expanded coverage to include PAD as a primary qualifying diagnosis. Patients who have a concurrent eligible cardiac condition may qualify for exercise rehabilitation on this basis. Additional patient and physician related factors may limit the use of supervised exercise including: physician referral; patient willingness to participate; availability of programs; time constraints and logistical issues; and medical co-morbidities. Patients with foot ulcers or rest pain, or those who are planned to undergo revascularization should defer exercise training until their condition has been treated and stabilized.

Comprehensive Vascular Rehabilitation and Secondary Prevention Programs in PAD

Comprehensive cardiovascular rehabilitation that includes exercise training is a model for expanded delivery of secondary prevention in PAD.^43,130Prevention strategies have potential to improve cardiovascular health for patients with PAD and the medical therapy of PAD has been reviewed elsewhere.^38,139We have included a brief discussion of secondary prevention therapies here to emphasize the potential benefit of a multifaceted exercise-based intervention to improve risk profile in PAD patients. As outlined in Table 4, multiple interventions to reduce cardiovascular risk have proven efficacy in PAD.^38,139 Even among patients with clinically identified PAD, utilization of guideline-based risk factor interventions remains low in comparison to patients with coronary artery disease.^{33,34,140,141} In a meta-analysis of over 30,000 PAD patients described in studies between 1999 and 2008, there was low penetration of optimal therapies including only 63% of patients on antiplatelet agents and 45% on lipid-lowering medications.¹⁴² Amongst PAD patients undergoing vascular surgery, only 41% achieved guideline-based medication therapy, while the use of recommended therapies was associated with reduced 3 year mortality.¹⁴³ Implementation of secondary prevention in PAD is vital to mitigating the high cardiovascular risk in this population. Accordingly patients with PAD may derive additional favorable effects from exercise training combined with comprehensive risk reduction interventions. Cardiac rehabilitation programs serve as a coordinating center for the implementation of secondary prevention therapies in patients with coronary artery disease, and could readily assimilate patients with PAD. The American Heart Association/American Association of Cardiovascular and Pulmonary Rehabilitation Core Components of Cardiac Rehabilitation/Secondary Prevention Programs outline the comprehensive nature of such programs with the ultimate goal of reducing physical disability and cardiovascular risk, while restoring optimal physical, psychological and social functioning. Such programs integrate exercise into the overall treatment plan that includes lipid management, blood pressure control, smoking cessation, nutrition education and weight reduction, diabetes treatment and psychosocial intervention.¹³⁰ Using this multifaceted approach, cardiac rehabilitation/secondary prevention programs have been associated with up to a 56% improvement in survival among patients after myocardial infarction and a 28% reduction in risk of recurrent myocardial infarction.¹⁴⁴ Such benefits are seen despite age, gender and ethnic background.¹⁴⁵ Furthermore, the benefits of such programs appear to be dose-related in that patients who attend 36 sessions have a 14%, 22% and 47% lower risk of mortality than those who attended 24 sessions, 12 sessions and 1 session, respectively.¹⁴⁶ However, no study has yet been conducted to evaluate the effect of exercise rehabilitation in PAD patients on mortality. Nonetheless, given the elevated cardiovascular risk and the proven benefit of multiple secondary prevention measures in PAD patients, it is reasonable to anticipate analogous reductions in risk among those who actively participate in comprehensive rehabilitation.

Table 4.

Secondary Prevention to Reduce Cardiovascular Events in PAD

Lipid-lowering therapy	Treatment with statin for all PAD patients to target LDL cholesterol<100mg/dl
	Target LDL cholesterol < 70mg/dl for high risk patients
Hypertension Treatment	Treat to target blood pressure <140/90mmHg (<130/80mmHg for patients with diabetes or chronic kidney disease)
	Consider ACE inhibitor in hypertensive patients
	Use of beta-blockers is not contraindicated in PAD
Smoking Cessation	Provide comprehensive smoking intervention program
	Consider pharmacotherapy to support smoking cessation
Antiplatelet Therapy	Treat with aspirin 75–325mg or clopidogrel 75mg
	Treat with aspirin+thienopyridine in patients with acute coronary syndrome or coronary or peripheral stent

LDL: low-density lipoprotein, ACE: angiotensin converting enzyme

Adapted from American College of Cardiology/American Heart Association 2005 Practice Guidelines for the Management of Patients with Peripheral Arterial Disease (33)