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Exercise in Peripheral Arterial Disease
Atherosclerotic lower extremity peripheral arterial disease (PAD) represents one of the most common manifestations of systemic atherosclerosis and is known to affect approximately 5% of the adult population and more than 20% of patients older than 70 years. As for any atherosclerotic disease, key clinical goals include preserving life and limb, which are best accomplished by creating individualized treatment programs supported by evidence-based clinical care guidelines that encompass the translation of best science into clinical practice.
Current evidence-based guidelines recognize five clinical syndromes that define the presentation of patients with lower extremity PAD. These syndromes encompass patients who are asymptomatic (or who could not express a concise symptom limitation, even though most such patients are objectively limited); who experience atypical leg pain, defined as limb discomfort that is present at both rest and with exercise, and that includes impediments to ambulatory function that are, in part, nonvascular in origin; who have classic claudication, which is present in only 8% to 12% of the total population of patients with PAD; who have acute critical limb ischemia; and who experience chronic critical limb ischemia.
Past care pathways and national health care reimbursement schemes were rarely based on an accurate understanding of the patients’ health or the symptom burden of PAD. Thus, negligible resources have been applied to preventing PAD in healthy populations and to preventing its progression in asymptomatic patients. Current care guidelines provide no pathways that define an effective approach to improve outcomes in patients with atypical leg pain. Such patients are often relegated to a challenging attempt to deliver care that might focus on lumbar spine disease; hip, knee, and ankle arthritis; neuropathy; and deconditioning. Most current vascular specialists internationally receive training in revascularization, but not didactic or clinical training in the biology of leg function, and they do not receive mentorship in delivering effective behavioral therapies to improve leg ambulatory function.
Any lower extremity PAD health system based on revascularization alone cannot fully address patient autonomy and treatment preference, might not fully balance clinical risk and benefit, and likely cannot achieve the mandate to offer an economically sustainable health care delivery approach to a common disease.
Systemic Diseases Always Require Systemic Care
Patients with PAD have systemic atherosclerosis and they have risk factors for progressive atherosclerosis and major ischemic events (e.g., heart attack, stroke, death) that are similar to those for patients with coronary artery disease (CAD). Low health-related quality of life is defined, in large part, by the limitation in functional status. Functional status is defined by the ability of the patient to perform independent ambulation, and it is usually best defined with objective treadmill testing. Quality of life is defined by a more complex interplay of functional status and leg symptoms on the perceived ability of the patient to accomplish key life goals. Patients with PAD are characterized by a very low functional status and variable impact on health-related quality of life. Community-derived patients with PAD were assessed in the Peripheral Arterial Disease Awareness, Risk, and Treatment (PARTNERS) program, in which the impact of PAD on quality of life was prospectively measured, demonstrating that health-related quality of life was as low or lower in all PAD patients compared to patients with other cardiovascular diseases, such as CAD and/or stroke.
As each nation provides resources to preserve health (prevention), to lower suffering (quality-of-life interventions), and lower mortality, the role of intervention for PAD claudication provides an example of where central improvements must occur. Current estimates of the United States health economic cost of PAD care suggest that more than $21 billion is now expended annually, and much of this cost is associated with invasive procedures. The annual medical cost to Medicare for PAD patients is estimated to be at least 5% higher than for other cardiovascular diseases. Unfortunately, there is little evidence that this expenditure prevents PAD, improves quality of life, or decreases amputation or death on a population scale.
An evidence-based, guideline-supported approach to the treatment of claudication in both individual patients and populations would, therefore, include the use of each proven intervention (supervised exercise, claudication pharmacotherapies, and revascularization) in alignment with the science establishing their efficacy and the mandate to include the choice of the individual patient. This approach should be undertaken in a population-sustainable manner. Exercise interventions are effective, safe, and cost-effective, and they protect the autonomy of the patient with PAD.
Efficacy of Exercise Training
The benefit of exercise training to improve claudication symptoms in patients with PAD was recognized as early as 1966. This database of efficacy and safety has continued to strengthen every decade through 2013. Several observational studies of patients who had claudication and who were offered access to therapeutic exercise training programs have consistently demonstrated improvements in both pain-free and maximum walking distances, with an associated improvement in quality of life.
The 1995 claudication exercise meta-analysis by Gardner and colleagues included 18 nonrandomized and three randomized clinical trials. This meta-analysis revealed that exercise training was associated with a 179% increase in pain-free walking distance and a 122% increase in maximum walking distance.
The most recent 2008 Cochrane Collaboration systematic review included 22 randomized trials of exercise versus usual care, medical intervention, or surgical intervention in 1200 participants with stable claudication and provided an analysis of efficacy for variable periods of follow-up that spanned 2 weeks to 2 years. Improvements in functional capacity were achieved despite the lack of change of measured ankle-to-brachial index (ABI) values between the groups. Exercise training improved maximal walking time by a mean of 5.12 minutes and achieved an overall improvement in walking ability of approximately 50% to 200% compared with patients not offered such care. Pain-free walking distance improved by 82 meters and maximum walking distance by 113 meters, and these improvements were durable for at least 2 years.
Such improvements in pain-free and maximal walking distances have been reproducibly achieved whether the treatment effect has been assessed in randomized or nonrandomized trials. This improvement is one of exercise science’s most consistent proven outcomes and is unambiguous, consistently achieved, reproducible in every health system studied, and observed regardless of PAD anatomy, PAD severity (e.g., baseline ABI), or baseline functional status.
As for any behavioral, pharmacologic, or invasive therapy, there is a well-defined dose–response relation that predicts clinical benefit. The benefit of exercise training for PAD has usually been observed to require training sessions that last more than 30 minutes and occur at least 2 or 3 times per week. Beneficial responses are observed as early as 1 month, are consistently increased at 3 months, and continue to improve for at least 6 months after the exercise program has begun. Despite persistent clinical anecdotes, there is no scientific or clinical experiential evidence that functional gains diminish at the conclusion of the supervised phase of an exercise program.
Science and Mechanisms of Exercise Benefit
The leg is a complex end-organ whose function is not defined by arterial anatomy alone. Excellent ambulatory function is plastic and can be achieved by way of its effects on muscle function, neurologic function, arterial perfusion, and orthopedic and podiatric function. Every health professional who has observed the impact of hospital-based deconditioning is aware that limb function markedly changes (declines and improves) in patients with normal leg blood flow, as it also does in patients with severe PAD.
Blood Flow
In normal adults, the common femoral artery blood flow measured at rest by a dye dilution technique is approximately 500 mL/min and can decrease at rest to 300 mL/min in patients with claudication. During exercise, leg blood flow in healthy persons can increase 30-fold to the working lower extremity muscles, but in patients with PAD this blood flow might not increase beyond two to three times basal flow rates. This supply-and-demand mismatch is only one cause of ischemic claudication symptoms. Other causes coexist, such as muscle deconditioning, denervation, and loss of skeletal myocytes, which also contribute to the inability to sustain functional performance.
In animal studies, limb blood flow can return to baseline within a year after femoral artery ligation owing to the development of robust collaterals. Such collaterals also occur in patients with PAD, but collateral flow does not support normal exercise perfusion. Exercise training does not cause either conduit artery blood flow or collateral circulation flow to increase to normal levels. This strongly demonstrates that other mechanism(s) of action underpin the dramatic improvement of symptoms and walking distance. In response to training, flow may be preferentially shunted from minimally active muscles (low oxygen-extraction rate) to exercising muscles (high oxygen-extraction rate). What is proved is that improvement in major conduit artery blood flow is not a prerequisite for the success of an exercise program for PAD patients.
Change in Muscle Metabolism
Skeletal muscle function depends on a continuous supply of adenosine triphosphate (ATP), which serves as an immediately available form of energy. The ATP stored in muscle is sufficient for only a short period of activity, and much larger amounts of energy are stored as creatine phosphate, which can be rapidly converted to ATP ( Figure 1 ) . During rest or light exercise, skeletal muscles use fatty acids as the main source of energy. These can only be used by the oxidative processes in the mitochondria. Increasing the exercise intensity leads to glycolysis of carbohydrate. When compared with glucose, fatty acid oxidation generates more ATP, but at a higher oxygen cost.
Trained adaptation after endurance training is manifested by the ability to use fatty acids more effectively, as demonstrated by trained athletes. In patients with PAD, aerobic generation of ATP becomes inadequate and anaerobic metabolism predominates. This results in an increase in lactic acid production and depletion of ATP and creatine phosphate, leading to pain, a slower recovery of high-energy phosphate substrate in the muscles, poor physical tolerance of exercise, and a prolonged recovery time.
There are two types of skeletal muscle fibers: type I and type II. Type I fibers have more mitochondria and higher oxidative capacity and are specialized for sustained activity such as walking or distance running. These muscle fibers require an uninterrupted blood flow to supply the large amounts of ATP that can be produced only by oxidative (aerobic) metabolism. For type II fibers, on the other hand, a limited supply of ATP can be generated from phosphocreatine and by anaerobic glycolysis and do not depend on oxidative metabolism. Thus, in these fibers the rate of energy expenditure can exceed that of energy production, with an associated oxygen debt and lactic acid production. Some studies have suggested a more preferential loss of type II fibers in patients with severe PAD that leads to a higher concentration of type I fibers than type II.
Chronic ischemia also affects other specialized cells such as those of the peripheral nervous system. In most patients with mild to moderate disease, changes caused by denervation and reinnervation are seen in both motor and sensory nerves, as reflected by the fact that 88% of patients with claudication have sensory impairment and 56% have motor weakness, with detrimental effects on walking biomechanics.
Patients with PAD have an increase in oxidative enzymes such as citrate synthase and cytochrome oxidase in the calf muscles, which is reversed following vascular bypass procedures. In animal studies, hypoxia per se does not induce an increase in the metabolic capacity of muscles; a combination of hypoxia and physical activity is required to stimulate enzyme production. Patients with claudication who exercise infrequently and athletes who stop training share the same histological findings. The requirement for ATP in patients with claudication is twice as high as in normal controls for a standard workload. This metabolic inefficiency is supported by the finding of an accumulation of acylcarnitine, a marker of muscle metabolic rate. Therefore, inefficient muscle function is produced by a multiplicity of proven mechanisms, regardless of blood flow.
Inflammation and Muscle Injury
Atherosclerosis is a chronic inflammatory disease, and ischemia contributes to local muscle inflammation. Patients with claudication can experience repeated episodes of low-grade inflammation. Furthermore, the resting phase can promote an inflammation that is more severe than the initial insult, owing to a process of reperfusion injury. The exercise associated with training to improve claudication results in activation of the inflammation cascade. Although this process could, in theory, have deleterious effects, none are observed over the long term.
Patients with PAD have higher neutrophil counts in the venous blood of the affected limb, higher complement levels, and free oxygen radicals that could cause damage to the vascular endothelium. These inflammatory effects represent systemic disease, because increased endothelial permeability and microalbuminuria have been observed in the glomeruli of patients with PAD. The urinary albumin loss is accentuated by exercise in a manner that is not observed in healthy persons, and this observation may be reversed by revascularization. However, exercise-trained PAD patients manifest an attenuation of the post-exercise albumin excretion that is not observed in control subjects. In adequately trained patients with PAD, the level of albuminuria, C-reactive protein, serum amyloid A protein, blood viscosity, and red blood cell filterability all significantly improve.
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