Rehabilitation of, and the Effects of Exercise on Peripheral Arterial Diseases

Disease/Disorder

Definition

Peripheral arterial disease (PAD), the third most common manifestation of atherosclerosis, is an atherosclerotic occlusive and thromboembolic pathophysiologic process that narrows and obstructs the arterial lumens. It is more prevalent in the lower extremity than the upper extremities, including the aortoiliac, femoropopliteal, and infrapopliteal arteries.­^1,2

Etiology

PAD primarily arises from atherosclerosis causing insufficient tissue perfusion. Other less common non-atherosclerotic causes are congenital anatomical variations within and external to the vessel wall (i.e., persistent sciatic artery), autoimmune diseases (i.e., vasculitis), collagen vascular disease (i.e., Ehlers-Danlos Syndrome), hereditary or acquired aneurysmal diseases (i.e., fibromuscular dysplasia), radiotherapy, vasospastic agents (i.e., cocaine), tumor invasion, or trauma.³  

Epidemiology including risk factors and primary prevention

The worldwide prevalence of PAD in 2015 for age > 25 years was 5.56%, which is approximately 236.62 million, an increase of 17.10% from 2010.¹

Risk factors include the following^1,2,4

• Smoking – most important modifiable risk factor
• Dyslipidemia
• Diabetes
• Obesity
• Hypertension
• Family history and genetic factors
• Chronic kidney disease
• Advanced age
• High homocysteine levels

The American College of Cardiology (ACC)/American Heart Association (AHA) classified the following groups at a higher risk²

• Age ≥ 65 years
• Age 50 to 64 years with history of smoking and diabetes
• Age <50 years with diabetes and at least 1 other risk factor for atherosclerosis
• Known atherosclerosis at other sites (e.g., coronary, carotid, subclavian, renal, mesenteric artery stenosis, or abdominal aortic aneurysm)

Hence, primary prevention includes physical activity, dietary modifications, smoking cessation, as well as blood pressure, cholesterol, and diabetes control.

Patho-anatomy/physiology

PAD has a complex pathophysiology that involves multiple cells, proteins, and pathways. The key cells to the development of athero-thrombosis are vascular endothelial cells, vascular smooth muscle cells, fibroblasts, platelets, resident stem cells, pericytes, and inflammatory cells. In patients with PAD, the vascular remodeling, inflammation, and apoptotic pathway responses that promote angiogenesis and arteriogenesis to increase blood supply to compensate for ischemia are ineffective. This leads to inadequate tissue perfusion, endothelial dysfunction, chronic inflammation, and high oxidative stress. These changes then progress to mitochondrial injury, free radical generation, muscle fiber damage, myofiber degeneration, fibrosis, and tissue damage, which could present as gangrene.⁵

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

It can be difficult to predict the progression of PAD, as its clinical presentation varies. Patients may experience classical symptoms of intermittent claudication, atypical symptoms (such as leg pain unrelated to exercise) or be asymptomatic.⁶

For patients with classical symptoms, the two most commonly used classification systems are the Fontaine Classification and the Rutherford Classification^6,7

Fontaine Classification

Rutherford Classification

Patients with the aforementioned risk factors are at higher risk of disease progression with worse prognosis. PAD can limit function, such as reducing the distance walked during a 6-minute walking test (6MWT). Shorter 6MWT has been associated with greater likelihood of disease progression, increased risk of mobility loss, and major adverse cardiovascular events.⁶

Specific secondary or associated conditions and complications

Complications of PAD^9,10

• Acute limb ischemia – sudden drop in blood flow
• Critical limb ischemia – chronic poor blood flow
• Ulceration
• Severe Infection
• Amputation
• Heart attack
• Stroke
• Erectile dysfunction
• Blood clots
• Functional impairment
• Decreased quality of life  

Inactivity and Disease Progression

The effects of exercise in the peripheral artery disease patient population can be further understood by evaluating the detrimental effects of physical inactivity on peripheral vasculature in humans. Recent studies have shown that uninterrupted prolonged sitting and short-term inactivity impairs endothelial function, causes arterial structural changes, predominantly in lower body vasculature. Proposed mechanisms of these changes include modulation of shear stress, inflammatory and vascular biomarkers.¹¹

Essentials of Assessment

History

Conduct a comprehensive medical history and review of symptoms to evaluate for exertional leg symptoms: claudication, walking impairments, atypical non-joint related lower extremity symptoms, ischemic rest pain, and nonhealing wounds. It is also important to ask about the common PAD risk factors as noted above.^2,12 

Physical examination

A thorough vascular exam is necessary^2,12

• Palpate for any abnormal upper and lower extremity pulses (e.g., brachial, radial, femoral, popliteal, dorsalis pedis, and posterior tibial)
• Auscultate for audible bruits
• Inspect the legs and feet for non-healing wounds, gangrene, elevation pallor, dependent rubor, delayed capillary refill, hair distribution, and coolness of temperature

Functional assessment

PAD may significantly affect patients’ functional independence and quality of life. Therefore, it is important to evaluate the patient’s level of assistance to perform activities of daily living and independent activities of daily living on initial exam. As their mobility can also be compromised, it is key to assess for patient’s gait and ability to ambulate a certain distance without pain as well as their endurance level.¹⁰

Laboratory studies

Laboratory studies are not used to diagnose PAD, but they are helpful to detect associated risk factors such as hemoglobin A1c, lipid profiles, and renal function.

Imaging

Not recommended for PAD patients who are asymptomatic or patients who are not candidates for revascularization as it will not likely change management. These patients should still consider multimodal, conservative management for PAD with their physicians as discussed later below.

For symptomatic patients who are considered for revascularization, the following imaging modalities are helpful to determine the anatomical location and severity of disease.^2,12

• Duplex (Doppler) ultrasound – Safe and inexpensive with the ability to distinguish between occlusion and stenosis but has a lower spatial resolution. Its pressure gradients and pulse volume waveforms used with ankle-brachial index measurements (as defined below) can distinguish isolated aortoiliac PAD from femoropopliteal PAD and below-the-knee PAD.
• Computed tomography angiography (CTA) – Better spatial resolution, but arterial calcification limits the interpretation especially below the knee. There is also a risk of contrast-induced nephropathy, exposure to radiation, and anaphylaxis from the iodine contrast.
• Magnetic resonance angiography (MRA) – Superior spatial resolution where images are not degraded by calcified vessels. Some patients cannot tolerate the length of scanning time. Gadolinium contrasts are also contraindicated for advanced renal disease due to risk of nephrogenic systemic sclerosis.
• Invasive angiography – For patients with chronic limb ischemia or patients with lifestyle limiting claudication with an inadequate response to guideline-directed management and therapy.

Supplemental assessment tools

History and exam findings of PAD need to be confirmed with the diagnostic testing of ankle-brachial index (ABI). The resting ABI is the initial and only test required to establish the diagnosis. The ABI is a simple, non-invasive exam that measures the systolic blood pressure (BP) of bilateral arms (brachial arteries) and ankles (dorsalis pedis, or posterior tibial arteries) in the supine position with the Doppler. The ABI is calculated by dividing the higher dorsalis pedis pressure or posterior tibial pressure by the higher right or left brachial pressure.

Resting ABI is reported as abnormal (ABI ≤0.90), which signifies PAD; borderline (ABI 0.91 – 0.99); normal (ABI 1.00 – 1.40); non-compressible (ABI >1.40).

When ABI >1.40, the toe-brachial index (TBI) is measured for suspected PAD. The TBI is the ratio of systolic BP of the great toe to the higher of the brachial artery pressures. Abnormal TBI is <0.70 and is diagnostic of PAD.

Table 1: ABI Value Interpretation & Recommendations¹³

If patients have exertional on-joint related leg symptoms but have normal or borderline resting ABI, exercise treadmill ABI testing is recommended. A ≥20% decrease in ABI after exercise is diagnostic for PAD. An alternative to treadmill testing is the pedal plantar flexion test.^2,12

If amputation of the lower extremity is indicated, transcutaneous oxygen pressure (TcPO) significantly predicts healing. It provides a way to evaluate skin perfusion and cutaneous healing at a specific level. An optimal value of TcPO 38 mmHg while in a supine position had a sensitivity and specificity of 71% for predicting healing or failure. TcPO should be used to better determine the correct amputation level; however, it should not be used in isolation.¹⁴

Coexisting medical conditions

The prognosis of PAD varies by stage. There is greater functional impairment, faster functional decline, and increased rates of mobility loss compared to those without PAD.¹⁵ The disease is progressive and patients with ABI ≤0.9 have a 3-fold increased risk of all-cause mortality and cardiovascular mortality in both men and women. The risk of myocardial infarction (MI) and stroke among PAD patients is comparable to the risk of these events in patients with coronary artery disease.¹⁶ Compared to men, women are more likely to have acute MI, longer hospital stays, and requiring rehabilitation or nursing home care.¹⁷

Modifiable risk factors

Active smoking and second-hand exposure to tobacco smoke plays a significant role as an environmental variable in the progression of PAD. Studies have found that tobacco smoke alters the epigenetic state.^18,19 Therefore, it is strongly advised to quit smoking and continue ongoing restrictions of smoke exposure in public, at work, and at home.²

Social role and social support system

Intermittent claudication and ischemic ulcers can be very painful, affecting quality of life, mobility, and functional level of independence. There is a sense of burden, powerlessness, social isolation, and compromised independence.²⁰ There are studies showing association of depression with PAD.²¹ As patients become more debilitated, they will require assistance and support that may include social security disability insurance. PAD is listed under the Cardiovascular System Impairments Category (medical listing 4.12).

The role of social determinants

PAD is often underdiagnosed and undertreated, which is further complicated by health disparities stemming from social determinants of health and structural racism. For example, studies have shown that Black Americans have a higher prevalence of PAD and are less likely to be treated for conditions that increase the risk of developing PAD. Healthcare providers should consider social determinants of health and implicit bias when evaluating and managing patients for PAD.²² 

Impact on participation

Professional and work life may be impaired because of claudication pain and ischemic wounds. This leads to reduced walking capacity and impaired mobility leading to limited exercise and a sedentary lifestyle. Asymptomatic patients or those with atypical symptoms also experience progressive functional impairment.²³

Rehabilitation Management and Treatments

Available or current treatment guidelines

A comprehensive approach should be taken to reduce symptoms, improve exercise capacity, decrease physical disability, and prevent cardiovascular events.¹² This can include several types of intervention: pharmacotherapy, health behavior changes, surgical interventions, and cardiac rehabilitation including supervised exercise.²⁴

Table 2: Pharmacotherapy for management of PAD^2,12

Health behavior changes²

• Smoking cessation – the most important modifiable risk
• Glycemic control – management of diabetes mellitus
• Annual influenza vaccine – general primary prevention to decrease risk of illness and subsequent debility that can impact physical activity
• Proper foot care to avoid lower extremity wounds – daily feet inspection, wear proper shoes and socks, avoid barefoot walking

Surgical interventions²⁵

• Endovascular procedures
  • Balloon angioplasty – plain balloon, specialized balloon, drug-coated
  • Stent placement – bare metal, drug-eluting, covered stent
  • Atherectomy – plaque removal
• Open surgical procedures
  • Endarterectomy
  • Bypass grafting – autogenous, prosthetic

Endovascular revascularization procedures and/or surgery are reserved for PAD that causes lifestyle limiting claudication, hemodynamically significant aortoiliac occlusive disease, or has been unresponsive to conservative measures.²

Studies have shown that compared to medical therapy alone, percutaneous angioplasty plus supervised exercise therapy outperformed other treatment strategies, with a maximum walking distance gain of 290 m (95% credible interval, p < 0.001).²⁶

Cardiac rehabilitation

Cardiac rehabilitation (CR) is a comprehensive program to provide patients with personalized exercise plans and help patients manage risk factors for cardiovascular disease.^24,27 It includes management of weight, blood pressure, lipid levels, and diabetes along with counseling on tobacco cessation, psychosocial factors, and physical activity. Supervised exercise therapy, which CR provides, is highly recommended by the American Heart Association and American College of Cardiology (AHA/ACC) for patients with PAD,² although it is contraindicated in patients who have an acute arterial occlusion or have chronic limb ischemia with infection.²⁸ Resistance training programs for the lower extremities have been shown to improve muscle endurance and strength, which translates to improved daily function including stair-climbing and greater 6MWT distances.^24,29

A systematic review to evaluate the effect of supervised exercise training on cardiovascular risk factors of intermittent claudication showed that exercise reduced systolic blood pressure by 5.8 mmHg, whereas all other cardiovascular (CV ) risk factors (body weight, body mass index, diastolic blood pressure, and blood lipids) remained statistically unaltered. This study recommends further evaluation through high quality RCTs which include an assessment of CV risk factors to determine the effect of exercise therapy in the secondary prevention of CV disease of intermittent claudication patients.³⁰

Prehabilitation

Pre-rehabilitation (or prehabilitation) can be an effective tool for PAD patients to improve function and quality of life. This has been studied in patients with severe life-limiting intermittent claudication or previous failed bypass attempts to delay or spare the need for surgery. Typically this is a 12-week program consisting of outpatient therapy, home exercise programs, nutritional counseling, smoking cessation, and psychosocial resources. A multimodal approach to prehabilitation in the PAD patient can significantly improve their quality of life and help these patients maintain these behavioral changes through forming better habits and daily routine.³¹

Resistance Training

Resistance training was shown to clinically improve treadmill and flat ground walking ability in older patients with peripheral artery disease. The level of intensity correlated with the degree of improvement in this patient population. Formal resistance training exercise programs should be implemented in peripheral artery disease rehabilitation.³²

It has been shown that there was a greater effect on initial claudication distance with 24-week resistance training interventions showing larger effects compared to 12-week interventions in both middle aged and elderly populations with PAD.³³

Table 3: 2017 Medicare Coverage for supervised exercise therapy (SET)³⁴

CR is often underutilized for multiple reasons including cost and travel barriers, disparities in healthcare, and low physician referral.²⁷

Upper Extremity PAD and Exercise

PAD is present in both upper extremities and lower extremities, however, there have been limited studies examining the effects of exercise on upper extremity PAD. When present in the upper extremity, PAD can cause impaired endothelial function in the brachial artery. It was hypothesized that blood flow and vasodilation are impaired during upper extremity exercise similar to lower extremity exercise due to PAD. A cross sectional study was performed, examining 21 subjects with upper extremity PAD compared to 16 healthy age-matched control subjects performing mild-intensity and moderate-intensity handgrip exercise and the effects of inorganic nitrate supplementation. This study showed that blood flow limitation and exaggerated pressor response to moderate-intensity forearm exercise in patients with upper extremity PAD are improved with 8 weeks of inorganic nitrate supplementation. It was shown that the inorganic nitrate supplementation helped boost nitric oxide bioavailability, improving exercise blood flow and pressor responses during exercise.⁴²

At different disease stages

Acute PAD may result from acute compartment syndrome, rupture, thrombosis, or embolus of an atherosclerotic plaque. Immediate angiography to confirm location of occlusion and collateral flow is essential. Embolectomy, thrombolysis, and bypass surgery are options for treatment. Of the patients, 20% to 30% with acute arterial occlusion require amputation within the first 30 days.³

For chronic PAD, supervised claudication rehabilitation is superior to unsupervised training: Begin at 15 min/session increasing to 45-50 minutes/session of treadmill or track walking at least 3 times per week for minimum of 12 weeks. Initial workload is set to speeds that is near maximal claudication within 3 to 5 minutes followed by rest periods as needed. The patient should resume walking when claudication subsides. It is expected to markedly improve walking ability, with results of increased speed, duration, distance, and decreased claudication symptoms. If there are cardiac signs, exercise should stop. Home-based exercise with behavioral change techniques is also an effective alternative for patients unwilling or unable to attend the 3 times a week supervised exercise session.¹⁵

Individuals with professional and lifestyle limitations caused by PAD that are not responding to conservative treatments can be considered for endovascular interventions (e.g., percutaneous transluminal angioplasty [PTA]). PTA with or without stent insertion is the primary nonsurgical method for dilating vascular occlusions.

Similarly, candidates for surgery have intermittent claudication that inhibits daily activities, rest pain, and gangrene. Surgery options include thromboendarterectomy, revascularization, and as a last resort, amputation.²

Coordination of care

A multidisciplinary approach with communication between the primary care physician, physiatrist, vascular surgeon, general surgeon (if amputation is a consideration), and the claudication rehabilitation program is essential. This should include addressing modifications for cardiovascular risk factors, pharmacologic and exercise claudication management, lifestyle modifications, and patient-family education.

Patient & family education

Patients and their family should be educated on PAD, importance of risk factor modification, lifestyle changes, and a rehabilitation exercise program. Referral to support group services should be offered.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Early detection and diagnosis of PAD is important for better prognosis. Diagnosis with history, physical examination, and ABI measurement is the standard of care. Treatment of mild PAD includes aggressive risk factor modification, smoking cessation, an exercise rehabilitation program, antiplatelet drugs, and cilostazol as needed for claudication symptoms. PTA or surgical bypass are options in PAD that is not responsive to conservative measures with a possibility of amputation in necrotic, septic, or limb-threatening ischemia.

Cutting Edge/Emerging and Unique Concepts and Practice

Inorganic nitrate supplements

PAD has a pressor (elevated blood pressure) response during lower and upper extremity exercises. Emerging evidence suggests inorganic nitrate supplements can boost nitric oxide bioavailability, which could improve blood flow and pressor response during exercise.³⁵

Technology for exercise therapies

Mobile health technology, including smartphone applications and wireless devices (such as pedometers), has been shown to improve functional outcomes when used to aid in home-based exercise therapy and supervised exercise therapy; however, research in this technology is new and subsequently limited.^36,37

Supervised exercise therapy has been recommended as first line management for intermittent claudication, a common symptom in peripheral artery disease patients. Recent evidence has shown the effectiveness of using external wearable activity monitors (WAM) for a more structured monitoring system of home exercise. There are two PAD-specific apps (TrackPAD and Movn) that have been developed to assess patients’ activity during exercise therapy. These apps incorporate coaching and patient specific elements such as PAD education, self-regulation, goal setting, feedback, claudication reminders and action planning.³⁸

Supervised Exercise Therapy Vs Home Based Exercises

Supervised exercise programs have been shown to be effective in improving walking distance in patients with intermittent claudication, however participation rates have been suboptimal and recently have been significantly affected by the Coronavirus pandemic. If supervised exercise programs are unavailable, home exercise programs are recommended. In order to elicit maximum benefit home exercise programs should be structured, incorporating wearable technology and PAD specific app monitoring for data analysis, feedback, and ongoing patient education.³⁹

Alternative Exercise Modalities

All patients with intermittent claudication should receive an initial treatment of cardiovascular risk modification, lifestyle coaching, and supervised exercise therapy which often consists of treadmill or track walking. If these are unavailable to the patient, alternative modes of exercise therapy have been reported to yield comparable results to walking. One study showed that cycling, lower-extremity resistance training, upper-arm ergometry, Nordic walking and combinations of exercise modes to be considered as an alternative, although further evidence is recommended at this time.⁴⁰

Heat Therapy

Heat therapy has recently emerged as a novel treatment option for attenuating the progression of PAD. Heat therapies are effective at stimulating the cardiovascular system, which has been shown to lead to beneficial adaptations that may ultimately reduce fatigue during walking in patients with peripheral arterial disease. It has been shown that full-body heating has similar effect to exercise in attenuating the progression of PAD through improving blood flow distally through collateral blood vessels, decreasing vascular resistance, and increasing distribution of anti-inflammatory cytokines. These processes are thought to ultimately impede the development of plantar ulcers and decreases claudication symptoms.⁴¹

Gaps in the Evidence-Based Knowledge

Improvement in walking distance, duration, and decrease of symptomatology of PAD with exercise has been established. However, the exact mechanism of improvement is not well understood. It is thought that muscles are conditioned to work by extracting more blood, which increases collateral vessel formation. Further research is recommended to be able to provide evidence-based guidelines related to exercise in the PAD patient.

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Original Version of the Topic

Marlis Gonzalez-Fernandez, MD, PhD, Tiffany Vu, DO. Rehabilitation of and the effects of exercise on peripheral arterial diseases. 9/20/2014

Previous Revision(s) of the Topic

Cheng-Chuan Chiang, DO, Marlis Gonzalez-Fernandez, MD, PhD. Rehabilitation of, and the Effects of Exercise on Peripheral Arterial Diseases. 12/29/2020

Author Disclosure

Toquynh Vu, DO
Nothing to Disclose

Sean Furlong, DO
Nothing to Disclose

Prateek Grover, MD PhD MHA
Nothing to Disclose