Peripheral Arterial Disease: Effects on Skeletal Muscle

By Scherer, Susan A

ABSTRACT

Peripheral arterial disease (PAD) is considered a manifestation of atherosclerosis primarily affecting the arteries of the lower extremity. Many patients with PAD have symptoms of intermittent claudication IC (PAD-IC) in which pain occurs in the affected muscle during walking and is relieved by rest. Intermittent claudication is associated with decreased walking ability and decreased physical function particularly in activities that require walking. Historically, PAD has been diagnosed, quantified, and managed primarily on blood flow measurements. A growing body of research suggests that changes in peripheral muscle metabolism are part of the disease and can be altered with physical activity. This has implications for physical therapy related exercise interventions with this group of patients. This paper will review findings relating to abnormalities of muscle structure and function related to PAD, examine potential physiologic abnormalities that contribute to decreased walking ability, and summarize results of exercise training on muscle structure and function.

Key Words: muscle metabolism, blood flow, muscle structure, physical activity, exercise training

INTRODUCTION

Peripheral arterial disease (PAD) is a manifestation of atherosclerotic disease. Atherosclerosis limits arterial diameter by deposition of fibro-fatty plaque, thereby reducing blood flow. Patients may have PAD with or without symptoms; however, when symptoms occur they are usually intermittent in nature and correlated with activity or exercise intensity. The primary symptom of PAD is called intermittent claudication (IC), described as a cramping pain, usually in the calves, that occurs with walking and resolves with rest. The symptoms of IC are reproducible, occurring each time with the same amount of muscle work. Symptoms of IC significantly limit walking ability and have a negative effect on physical function and quality of life.1,2 The limitation in blood flow contributes to exercise limitations seen in PAD-IC, however, a growing body of research suggests that changes in peripheral muscle metabolism are part of the disease and can be altered with physical activity.3 It is significant that increasing blood flow via vascular surgery does not fully reverse the condition of PAD-IC.4 Other factors, such as peripheral muscle metabolism likely contribute significantly to exercise limitations. This paper will review findings relating to abnormalities of muscle structure and function related to PAD, examine potential physiologic abnormalities that contribute to decreased walking ability, and summarize results of exercise training on muscle structure and function.

SCOPE OF THE PROBLEM

Peripheral arterial disease may be symptomatic or asymptomatic. The prevalence of PAD in adults has been reported to be 8.4 million, while the prevalence of symptomatic disease, measured by IC is approximately 3.3 million.1 Symptoms are related to older age, the amount of activity attempted to perform, and severity of disease.5 Peripheral arterial disease is seen as a manifestation of atherosclerosis, demonstrated as an increased incidence of PAD among individuals with atherosclerotic coronary or cerebral disease.6 There is recent emphasis on the need to diagnose PAD early and in primary care practices.6,7 The American Heart Association and American College of Cardiology (AHA-ACC) guidelines indicate that efforts should be made to identify individuals with PAD, even if asymptomatic. This includes history, examination, and measurement of ankle-brachial index (ABI), for the purpose of managing the increased CV risk that occurs with all forms of atherosclerosis.8 Given the current prevalence of PAD and the increased effort on diagnosing this condition, it is likely that physical therapists will encounter patients with PAD.

Peripheral arterial disease is classified as an impairment in blood flow, as defined by abnormal systolic artery pressure in the lower extremities. The ankle-brachial index (ABI), a ratio of ankle to arm systolic pressure with the patient supine, is the primary diagnostic tool used to screen for and categorize the severity of PAD. An ABI of less than or equal to 0.90 at rest is considered diagnostic of PAD.9 The lower systolic pressure in the lower extremities leads to decreased blood flow either at rest or during exercise. Generally, the blood flow is less during exercise due to the constrictive effect of muscle contraction on blood flow. A drop of 20% in the ABI after exercise can be used to diagnose PAD in individuals who are at risk for PAD but have a normal ABI at rest.8,10 Physical therapists should become familiar with this test since it is easy to administer and sensitive for PAD. There is good reproducibility of this test following training, even among physical therapy students11 and less experienced clinicians.12

IMPORTANCE TO PHYSICAL THERAPY

Peripheral arterial disease has negative effects on patient’s physical performance, demonstrated by slower walking speeds, decreased walking distance, and decreased physical performance.2,13,14 It is necessary for physical therapists to differentiate whether the intermittent leg pain in patients is due to vascular (PAD) or neurologic claudication (spinal stenosis). Utilizing ABI allows physical therapists to differentiate vascular from neurologic claudication and develop an appropriate plan of care. If the claudication pain is linked to peripheral arterial disease, it is essential that physical therapists understand the effects of PAD on the peripheral muscle, in order to adequately design an effective plan of care.

PAD AS A PERIPHERAL MUSCLE PROBLEM

In PAD, while decreased blood flow does contribute to exercise limitation, blood flow appears to explain only a portion of the variability in exercise. The current view of PAD also includes the premise that muscle metabolic dysfunction and abnormalities in muscle structure or function also contribute significantly to walking limitations.3 There are conflicting reports of the relationship of low blood flow on walking ability. In a study by Hiatt et al, blood flow, as measured by ABI explained only 10% of the variation in walking time.15 McDermott demonstrated a correlation of PAD severity, measured by lower ABI, and slower walking speeds and shorter 6-minute walk distances.16 Despite this association, McDermott suggests that the relationship is due to PAD impaired functioning of both Type I and Type II lower extremity muscle fibers.16

Vascular surgery improves blood flow and ABI, but is less effective than exercise training in improving walking ability in long-term evaluations.4 Exercise training improves walking performance, and may improve blood flow, but the increased blood flow generally is not correlated to increase in peak walk time.17 Finally, metabolic interventions, such as glucose and carnitine18 improve walking ability. This information, taken together, suggests that the metabolic function of the muscle is a significant determinant of walking ability in persons with PAD.

One could also argue that PAD is a central cardiovascular problem, that is, walking ability is limited primarily by the oxygen delivery systems such as heart rate and blood pressure. Literature suggests that peak oxygen consumption in patients with PAD is approximately 50% of normal for age, in the range of 4 METS19 or 18.1 ml/kg/min.15 While this might indicate that exercise limitations are central and cardiovascular in nature, in these studies, patients stopped exercise due to leg pain, and did not reach age-predicted target heart rates or ventilatory exchange ratios that are indicative of maximal aerobic capacity. This implies that the exercise limitations seen in PAD are peripheral rather than central.

ALTERATIONS IN MUSCLE STRUCTURE AND FUNCTION

Abnormal muscle structure exists in patients with PAD. England et al20 demonstrated histologic evidence of muscle denvervation, evidenced by an increase in angular fibers and a grouping of fiber types in the ischemic muscles. Patients with PAD also demonstrate abnormalities of cross sectional muscle area, muscle fiber type incongruence, and capillary density. Compared to activity-matched, same age controls, patients with PAD have smaller cross sectional areas of both Type I and Type II muscle fibers in the gastrocnemius muscle.21,22 Smaller muscle fibers can cause decreased force production, thus affecting walking performance. There is also a change in fiber type expression with a greater percentage of Type II fibers (fast twitch) and a lesser percentage of Type I (slow twitch- endurance) fibers as compared to controls.22 Fewer aerobic muscle fibers may mean decreased endurance, and the predominance of Type II fibers also indicates a limitation of exercise endurance related to fiber type.

Neurophysiologic function also appears to be abnormal in muscles affected by PAD. England et al20 demonstrated that in the gastrocnemius muscles of patients with unilateral PAD, the mean duration of motor unit action potentials (MUAP) measured by electromyography was greater in ischemic legs compared to nonischemic legs and control subjects. This finding indicates repeated ischemic injury to motor nerves. Others have demonstrated that motor conduction velocit\y and amplitude of the nerves affected by PAD were decreased.23,24

Increased capillary density has also been demonstrated in the affected muscles of people with PAD.22 This increase in capillary may indicate a positive adaptation to decreased blood flow, and may actually contribute to increased exercise performance.

There appears to be a link between these muscle structure changes and muscle performance in patients with PAD. Regensteiner et al21 and McDermott14 suggest a relationship between muscle cross sectional area and gastrocnemius strength in patients with PAD. McDermott et al24 found an association between PAD, nerve conduction velocity, and reduced leg power. Muscle fiber type appears to be associated with walking tolerance as well.25

CHANGES AT THE CELLULAR LEVEL

In addition to structural and functional changes at the level of the muscle and nerve in patients with PAD, changes in cellular/ metabolic structure and function also exist. Normally, exercise training increases muscle mitochondrial content, which contributes to increased oxidative capacity. We would hypothesize that since PAD limits walking, a detraining effect would be seen in muscle metabolism. However, the literature is controversial on this point, with some laboratories demonstrating an increase in mitochondrial content in patients with PAD.26-29 This finding is hypothesized to be a beneficial adaptation to decreased blood flow. Although mitochondrial content may be high, the ability of the mitochondria to produce ATP appears to be slowed in the muscles affected by PAD.30-32

An alternative explanation for changes in metabolic function is based on the pattern of mitochondrial DNA expression. Normally, there is a regulation of both nuclear and mitochondrial DNA expression that allows for appropriate amounts of each type DNA. In PAD, there is increased expression of a nuclear coded metabolic enzyme (citrate synthase) as compared to a mitochondrial enzyme (cytochrome oxidase).33-34 The overall increase in enzyme expression is more than expected in sedentary individuals. Furthermore, this pattern of mitochondrial DNA expression resembles those found in other mitochondrial diseases, indicating that metabolic dysfunction is a key component of PAD.

There are also changes in substances considered metabolic intermediates, or those that assist in muscle metabolism. Normally, oxidative phosphorylation is considered efficient when fuels are converted to usable energy. In PAD, substrates in the intermediate pathways of oxidation accumulate and are not completely metabolized. For example, L-carnitine is a substance that transports fatty acids into the mitochondria for beta-oxidation. In PAD, these acylcarnitines accumulate in plasma and muscle, implying that the metabolism is not complete. In addition, muscle carnitine accumulation is associated with low exercise capacity,35 and exercise capacity increases when patients with PAD are given doses of carnitine substances to improve muscle metabolism.36 In these studies, the control group consisted of sedentary controls, indicating that the differences seen are due to PAD, rather than inactivity.

Other metabolic changes in muscle include impairment in specific segments of the electron transport chain, as well as abnormalities in oxidation. Mitochondrial respiration can be quantified by measuring the level of adenosine diphosphate (ADP). Peripheral arterial disease is characterized by decreased available ADP and decreased oxidation.33 Changes in ADP are rare and usually found in mitochondrial myopathies. Considering all information, these abnormalities in muscle metabolism and electron transport partially explain reduced PAD exercise performance and walking time, and appear to be part of the pathophysiology of PAD.

ALTERATIONS IN OXYGEN CONSUMPTION AND KINETICS

In individuals without pathology, as exercise workloads increase, oxygen consumption increases and matches the workload. In PAD, the oxygen kinetics are slowed, taking longer for oxygen to reach a steady state as compared to age-matched sedentary controls.37 This metabolic inertia hypothesis suggests that the limitation in exercise performance is determined by the kinetics of skeletal muscle oxygen utilization, rather than overall aerobic capacity.3,38 In summary, the factors which contribute to decreased physical function and low exercise performance in PAD include decreased blood flow, abnormalities in muscle structure and function, mitochondrial dysfunction, and metabolic inertia. Thus, PAD is associated with significant abnormalities in peripheral muscle as well as decreased blood flow. The relative change in emphasis away from blood flow towards metabolic abnormalities leads to a greater importance of exercise training in the management of patients with PAD.

EFFECTS OF AEROBIC EXERCISE TRAINING

Although surgery may be effective at increasing blood flow, and medications may provide some relief of symptoms, the current best practice recommendations for patient with symptomatic PAD state that exercise training is the most effective intervention for increasing walking ability.8,39,40 Supervised exercise programs that include walking universally improve both pain-free and absolute walking time. Recommended frequency of exercise is 3 times per week for 30 to 45 minutes of total exercise for a duration of 20 weeks.39,40 Improvement in walking ability is seen when exercise intensity includes walking until the onset of pain as well as past the pain free threshold, then resting until pain subsides.40,41 Greater increases in walking time are seen with exercise programs than any medication or surgical procedures.39 In addition, exercise training has demonstrated an improvement in physical functioning as measured by the physical functioning scale of the Medical Outcomes Study Short-form 36.42,43

EFFECTS OF WALKING PROGRAMS ON MUSCLE METABOLISM

Exercise training produces consistent improvement in walking ability, and many of the improvements appear to be in muscle metabolism (peripheral adaptations) while blood flow does not change significantly in some studies, or does not correlate with the degree of walking improvement.44,46 In normal individuals, exercise training stimulates an increase in mitochondria or change in mitochondria expression.47 Related changes are seen after training in patients with PAD, in that training decreases the accumulation of metabolic intermediates, such as plasma and muscle acylcarnitine content, and these changes are correlated with the degree of improvement.29 Other training studies are more difficult to interpret due to differences in which metabolic intermediates are measured.29 The training studies also support the idea that peripheral skeletal muscle alterations account for some limitations in exercise performance.

Exercise training with walking (exercise specificity) offers the best opportunity for improvement in both peripheral muscle function and overall physical function. Exercise training appears to improve physical function through the cellular effects in the skeletal muscle. Ischemic muscle tissue appears to be able to improve muscle metabolism with exercise training.48 The training parameters are well established and provide universal improvement for patients. This view that skeletal muscle metabolism contributes significantly to exercise intolerance in people with PAD, leads to additional questions about other types of training that may improve physical function in this group of individuals.

RESISTANCE TRAINING

Since skeletal muscle abnormalities are evident in patients with PAD, a specific muscle resistance training program might improve physical function as effectively as walking training, but with less pain. Hiatt et al performed a study of strength training versus walking training in subjects with PAD.49 The 29 subjects were randomized to either treadmill (TM), strength, or control groups. The 12 weeks of training was performed 3 times per week. The TM group performed 60 minutes of intermittent walking and the strength training group performed 50 minutes of exercise including 6 repetitions of a 6 repetition-maximum for lower extremity muscle groups including gastrocnemius-soleus, anterior tibialis, hamstrings, quadriceps, and gluteus medius and maximus. Peak walking time increased more with the TM group (+ 74%) than the strength group (+ 36%). The increases in strength were not associated with muscle fiber hypertrophy. The conclusion was that muscle strength was not a major determinant of the training response,49 although the specificity and intensity of training may also have influenced the results. McGuigan et al50 provides some additional evidence of muscle strength training effects in patients with PAD. Subjects with PAD participated in a resistance training program 3 days per week for 24 weeks, while a nonexercising control group performed no exercise. Subjects trained with weights at progressively increasing load of 8 to 15 repetition maximum including lower exercises such as the leg press, calf raises, leg extensions and curls, and upper extremity exercises including bench and shoulder press as well as abdominal crunches. The training group demonstrated significantly decreased percentage of fibers that expressed myosin heavy chain (MHC) Type II b. The training group also increased both Type I and Type II fiber areas as well as increased capillary density, while there were no significant changes in fiber type in the control group.50 This study demonstrates that resistance training results in increased muscle strength as well as improved muscle structural changes, however does not address the effect of strength training on walking performance.

Strength training using a variety of intensities and repetitions has been inadequately studied to date. While strength training may be beneficial in improving muscle strength, it is difficult to determine the optimal intensity \and frequency of strength training. Muscle strength or power has been associated with physical function in people with PAD,24 so a resistance training program may have positive results in regard to physical function. Strength training is primarily beneficial in increasing strength, but less effective than walking training (endurance) on increasing endurance as to be expected with specificity of training. The effects of strength training on walking distance appear to be weak.

UPPER EXTREMITY VS. LOWER EXTREMITY TRAINING

It is unclear as to whether the improvement in walking performance after exercise training is due to improved physiology in the lower extremity muscles in PAD or to an overall increase in cardiovascular capacity. One study investigated the role of increased cardiovascular capacity by testing upper vs. lower limb exercise on walking distance.51 The 67 patients with PAD were randomized to upper or lower limb training twice weekly for 6 weeks. The groups were not significantly different in disease status or walking parameters. Work intensity was at maximum workload, performed as interval training of 2 minutes work/2 minutes rest for a total work time of 20 minutes. Positive cardiovascular training effects, measured by mean arm and leg power output on the cycle ergometer test, were seen in both training groups. While maximal walking distance was not different between the two groups, pain- free walking distance increased more in the upper extremity group (122% vs 93% p < .001). No data was provided on muscle structural or metabolic changes. This study is interesting in that it demonstrates a novel approach to exercise in the patient with lower extremity pain that limits exercise. However, the findings suggest a cardiovascular training effect rather than the peripheral hypothesis presented throughout this paper. Incorporating a training method to improve overall aerobic capacity with exercise training that improves peripheral function may lead to greater improvements in physical function.

IMPLICATIONS FOR PHYSICAL THERAPISTS

Walking training has been studied extensively and has been found to be universally effective in increasing walking ability in patients with symptomatic PAD. The effects appear to occur primarily as a result of changes in muscle metabolism. Physical therapists can perform or refer to supervised exercise programs for patients with PAD. Currently PAD rehabilitation as described by the literature is conducted in cardiac rehabilitation programs or in physical therapy, however, there are different billing codes and reimbursement levels for these interventions. Work is underway to develop and use a billing code unique to PAD rehabilitation. Early intervention such as increased physical activity may prevent metabolic abnormalities. Other exercise modalities including the use of poles during walking programs (polestriding)52 upper and lower extremity resistance training and combined programs hold promise as alternative exercise modalities. Further investigation is needed to determine optimal training programs for other components of muscle performance and physical function, as well as the role of exercise training in improving quality of life for patients with PAD.

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Susan A. Scherer PT, PhD

Department of Physical Therapy, Regis University, Denver, CO

Address correspondence to: Susan A. Scherer, PT, PhD, Department of Physical Therapy, Regis University, Regia, CO 80221 (sscherer@regis.edu).

Copyright Cardiopulmonary Physical Therapy Journal Mar 2006