Clinical impact of exercise in patients with peripheral arterial disease

Abstract

Increasing prevalence, high morbidity and mortality, and decreased health-related quality of life are hallmarks of peripheral arterial disease. About one-third of peripheral arterial disease patients have intermittent claudication with deleterious effects on everyday activities, such as walking. Exercise training improves peripheral arterial disease symptoms and is recommended as first line therapy for peripheral arterial disease. This review examines the effects of exercise training beyond improvements in walking distance, namely on vascular function, parameters of inflammation, activated hemostasis and oxidative stress, and quality of life. Exercise training not only increases walking distance and physiologic parameters in patients with peripheral arterial disease, but also improves the cardiovascular risk profile by helping patients achieve better control of hypertension, hyperglycemia, obesity and dyslipidemia, thus further reducing cardiovascular risk and the prevalence of coexistent atherosclerotic diseases. American guidelines suggest supervised exercise training, performed for a minimum of 30–45 min, at least three times per week, for at least 12 weeks. Walking is the most studied exercise modality and its efficacy in improving cardiovascular parameters in patients with peripheral arterial disease has been extensively proven. As studies have shown that supervised exercise training improves walking performance, cardiovascular parameters and quality of life in patients with peripheral arterial disease, it should be encouraged and more often prescribed.

Keywords

Peripheral arterial disease intermittent claudication exercise walking rehabilitation cardiovascular risk

Background

Ageing population and increasing prevalence of non-communicable chronic diseases represent a challenging socio-economic burden. Cardiovascular diseases and atherosclerotic vascular disease in particular, are becoming one of the most significant health problems in the elderly.¹ Peripheral arterial disease (PAD) is defined as atherosclerotic occlusion of the body arteries, excluding intracranial and coronary arteries.² Recent research has estimated that prevalence of PAD exceeds 200 million people in the world. PAD is generally perceived as a problem of older adults because the prevalence of PAD increases with age and peaks in the sixth and seventh decades of life.^3,4 In the Slovenian population aged between 50 and 70 years, prevalence of PAD was found to be 18.7%.⁵ In people older than 70 years, estimation ranges from 15% to 20% of the world’s population.⁶ Despite its high prevalence, PAD is still underdiagnosed and undertreated disease.⁷

PAD is associated with significant morbidity and mortality. Mortality in patients with PAD is around two- to three-fold higher than in age-matched controls, with a five-year mortality of about 30%.⁸ In a large longitudinal study of 811 patients with PAD and 788 age- and gender-matched controls, patients with PAD retained a borderline increase in all-cause mortality (3.3 vs. 1.8% at two-year-follow-up, p = 0.059) and a significant increase in non-fatal cardiovascular event rate (20.1 vs. 3.6%, p < 0.001) despite optimal state-of-the-art preventive management.⁹

Clinical manifestations of PAD range from asymptomatic atherosclerotic plaques to intermittent claudication, critical limb ischemia, and limb loss. The most frequent symptom of PAD is intermittent claudication (i.e. exercise-dependent pain in the lower limb muscles that resolves with rest). Symptoms appear due to atherosclerotic plaques in lower limb arteries, causing reduced blood flow and impaired skeletal muscle perfusion resulting in ischemia-induced debilitating pain associated with walking.¹⁰ It is estimated that intermittent claudication affects around one-third of patients with PAD.¹¹

PAD is easily detected by estimating ankle-brachial index (ABI). It is calculated by dividing the systolic pressure on dorsalis pedis or posterior tibial artery (measured by Doppler ultrasound blood flow detector) with the systolic pressure on the brachial artery. An ABI below 0.9 represents a diagnostic criterion for PAD, and also a strong prognostic predictor of adverse cardiovascular events and mortality.^12,13

Exercise training improves cardiovascular performance in both healthy individuals and in patients with different cardiovascular diseases. In the past, it was believed that the benefits of exercise were solely due to improving traditional cardiovascular risk factors (e.g. high blood pressure, increased plasma lipid levels, increased plasma glucose, and obesity).¹⁴ However, epidemiological studies reported that less than one half of the beneficial effects of exercise can be attributed to risk factors modification.¹⁵ The other 50% benefits arise from inducing resistance against currently existing harmful levels of risk factors, as concluded in the study of Santos-Parker et al.¹⁴

Recent in vivo and in vitro studies emphasize the role of endothelial shear stress (ESS) as a key factor in the pathogenesis of atherosclerosis.^16–18 ESS is the tangential stress due to the friction of the flowing blood on the endothelial surface of the arterial wall.¹⁶ In a healthy normal vessel, blood flow is laminar, making the ESS unidirectional. On certain regions in the bloodstream, such as curvatures, arterial branch ostia and bifurcations, blood flow becomes nonlaminar, resulting, among others, in decreased ESS, which further results in reduced nitric oxide synthesis, increased vascular cell-adhesion molecules (VCAM-1) expression, impaired endothelial cell repair and induces endothelial cell apoptosis.^16–18 These entities are defined as endothelial dysfunction. Next pathogenetic steps include subendothelial accumulation of low-density lipoprotein cholesterol, increase in reactive oxygen species (ROS), and smooth muscle cell proliferation.¹⁶ Low ESS is also associated with increased expression of several chemoattractant chemokines and pro-inflammatory cytokines, which induce transmigration of monocytes into the intima. After infiltrating beneath the endothelium, monocytes differentiate to macrophages and evolve to foam cells, which sustain the progression of atherosclerosis, further aggravated by other risk factors, i.e. hypertension, cigarette smoking, hyperlipidemia, hyperhomocysteinemia, and diabetes mellitus.^16,17

Animal models on effects of exercise on atherosclerosis have been extensively studied. Apolipoprotein E knockout (apoEKO) mice were mostly examined, as they have been shown to have similar atherosclerosis pathogenesis and cardiovascular disease progression as in humans.¹⁹ Exercise training has been shown to improve atherosclerotic plaque stability,^20,21 atherosclerosis lesions area, inflammatory²² and antioxidative status in apoEKO mice.²³ Similar to humans, potential mechanism for these effects lies in regulation of nitric oxide synthesis.^23,24

The review focuses on the effects of exercise training on vascular function, parameters of inflammation, walking performance and quality of life in patients with PAD. The effects of exercise on other cardiovascular risk factors and atherosclerotic diseases are further discussed.

Influence of exercise on vascular function

Endothelial dysfunction is the earliest event in the development of atherosclerosis.^16,17,18,25 Patients with PAD have impaired endothelial function in comparison with healthy peers²⁶ that correlates with their walking performance.²⁷ Flow-mediated dilation (FMD), as a widely used method for assessing endothelial function,²⁸ was performed in studies that included patients with PAD and it was confirmed that FMD could serve as a risk marker for symptom severity and impaired physical activity in patients with PAD.²⁷ Improvement of FMD due to exercise training was shown in the majority of the studies,^29–31 but not in all.³² Results on improved FMD might be explained by upregulation of endothelial nitric oxide synthase and consequently enhanced endothelial synthesis and release of nitric oxide, which is stimulated by an increase in blood flow due to exercise. In addition, improved blood perfusion can be at least partially explained by increased collateral flow, as has been suggested in studies that included coronary artery disease (CAD) patients.³³

Besides macrocirculation, microcirculation is also affected in PAD.^34–36 Microcirculation comprises the arterioles, capillaries, venules, initial lymphatic vessels and, in a more wide sense, the endothelium that covers these vascular structures and the circulating cells. It is a system in which components interact with each other and contribute to maintaining circulatory, coagulative and metabolic homeostasis.³⁷ Endothelial dysfunction occurs in microcirculation as well due to impaired synthesis of endothelial vasodilators, such as nitric oxide,³⁸ and impaired microcirculatory vasodilatation, which have been singled out as key elements in the pathogenesis of PAD and CAD.³⁹ Exercise has a beneficial effect on microcirculation, which is confirmed not only in healthy population,⁴⁰ but also in cardiovascular patients.^25,41

Influence of exercise on parameters of inflammation

PAD, as all other forms of atherosclerotic disease, is associated with low-grade inflammation. During repetitive bouts of peripheral ischemia, patients with PAD undergo episodes of low-grade inflammatory response reflected in increased values of plasma markers of inflammation.^42,43 A strong association between markers of inflammation with walking performance^44,45 and with calf musculature oxygen saturation has been reported.⁴⁵ Markers of activated coagulation and fibrinolysis (D-dimer and thrombin-antithrombin III complex), and endothelial stimulation (von Willebrand factor) are also increased in PAD due to endothelial damage and pathologic changes at the atherosclerotic sites.⁴³ As previously stated, exercise leads to reduced production of proinflammatory cytokines, such as interleukin (IL)-1, IL-6⁴⁶ and adhesion molecules,⁴⁷ but in the study of Nowak et al., some cytokines achieved surprisingly higher values after the exercise training program was finished⁴⁸ as compared to pre-exercise levels. Studies have mostly shown that exercise training induced a decrease in the C-reactive protein (CRP) or high sensitive CRP (hs-CRP) values in patients with PAD,^29,49 but there are also studies in which the improvement was not reached.⁵⁰ Fibrinogen, as another marker of inflammation was also examined, but possible effects of exercise on the fibrinogen values are also controversial.^49,50 Apart from its effects on suppression of production of cytokines, exercise induces an increase in endothelial nitric oxide, which decreases the level of ROS formation and inflammation.^25,51 Besides possible methodological issues in detection and measurement of markers of inflammation, and especially markers of activated hemostasis or oxidative stress, basic principles of long-term adaptation to short-term exercise-associated physiologic derangements should be taken into account. For instance, exercise is associated with transient inflammation, spill-over of ROS and activated coagulation and fibrinolysis, while chronic adaptation is associated with a favorable decrease in these biomarkers; the timing of detection (i.e. preexercise, immediately post-exercise, after long-term exercise training or at rest) may therefore significantly influence blood levels of these markers.⁵²

Influence of exercise on walking performance

Numerous studies have shown beneficial effects of exercise training on walking performance in patients with PAD. Outcome measures used as ‘walking parameters’ were pain-free walking distance, maximal walking distance, pain-free walking time and maximal walking time.^{30,42,47,48,53–56}

Although some studies failed to prove a favorable association between exercise training and walking parameters,⁵⁷ various meta-analyses confirmed beneficial effects of exercise training.^58,59 Walking performance has been shown to improve not only during exercise training programs or shortly after them, but even three years after cessation of the exercise program.⁶⁰ However, the effects of exercise training programs persist only if the patient continues to exercise on his/her own for at least 60 min per week.⁶¹

Walking parameters remain the most important outcome measure in studies on exercise programs in patients with PAD. ABI was also a parameter widely used as a measure of disease severity and improvement. ABI is not only a diagnostic tool for diagnosis of asymptomatic PAD, but also a marker of diffuse atherosclerosis associated with CAD and cerebrovascular disease (CVD),⁶² and a strong predictor of cardiovascular mortality.⁸ In a meta-analysis of 30 studies on exercise training in PAD, exercise was associated with an 0.05 increase in ABI as compared to placebo/optimal medical care.⁶³ In some studies, improvement in ABI was correlated with improvement in walking abilities,⁶⁴ while in some the improvement in the walking performance was not followed by the improvement in ABI.⁶⁵

Influence of exercise on quality of life

Numerous authors have shown that, due to positive effects of exercise training programs on walking abilities and vascular function, quality of life of patients with PAD has also improved. Intermittent claudication as the most prominent symptomatic manifestation of PAD is associated with limitations in everyday activities, such as walking. Therefore, improvements in pain-free walking distance are expected to translate in improved health-related quality of life measures. Most studies of exercise in patients with PAD used the Short Form (36) Health Survey (SF-36), a 36-item general health-related quality of life questionnaire comprising physical and mental domains. SF-36 has been shown to have good reliability and has been extensively validated; it is therefore the most widely used research tool for measurement of health-related quality of life in different diseases and conditions. Exercise training also leads to an improvement in the disease-specific quality of life as assessed by other questionnaires, such as walking impairment questionnaire (WIQ), The Peripheral Arterial Occlusive Disease 86 (PAVK-86), The Intermittent Claudication Questionnaire, VascuQol and others. A recent meta-analysis of 15 randomized trials (including data on 1257 participants) showed that along with increasing walking distance, the physical – but not mental – component of the SF-36 also increased significantly.⁶⁶

Supervised vs. non-supervised exercise training programs

In terms of supervision, exercise programs are divided into two subgroups: supervised exercise programs and home-based programs, the latter with two entities where different approaches are examined: different structured home-based exercise programs and “go home and walk” policy.

Supervised exercise programs are organized in the hospitals and health-care clinics⁶⁷ and recommended by all relevant guidelines for the treatment of patients with PAD.^68–70 As professional support and supervision provide early recognition of possible complications, supervised exercise programs are generally safe.⁷¹ Moreover, extremely low complication rates suggest that even cardiovascular screening is superfluous when the exercise program provides necessary supervision.⁷¹ Nonetheless, the American Heart Association/American College of Cardiology (AHA/ACC) guidelines encourage electrocardiographic, heart rate, blood pressure, and blood glucose monitoring.⁷⁰ The most important exclusion criteria, which might be used as contraindications for exercise commencement, are summarized in the study of McDermott et al. and are the following: major amputation, critical limb ischemia, surgery or a myocardial infarction within the past three months, dementia, foot ulcers, inability to walk on a treadmill, and poorly controlled arterial hypertension.⁷²

Comparison between supervised and home-based training programs was performed in several studies and reviews.^73–75 It has been shown that supervised exercise is superior to both entities of home-based exercise (i.e. the “go home and walk” and the structured home-based exercise⁷³) in terms of walking performance.^73,74 In two cost-effectiveness reports,^76,77 supervision was marked as a value for money as compared to unsupervised. It has been shown to stimulate and increase daily physical activity when the supervision was finished.⁷⁸ However, in a study of Gardner et al.,⁷⁹ accurately monitored home-based exercise program was shown to be equally efficacious in terms of walking performance compared to supervised exercise program. Unlike “go home and walk” policy, structured home-based exercise programs seem to be an attractive alternative to supervised exercise programs and should be offered to patients when supervised exercise training is unavailable or impractical.⁶⁷

Low adherence to exercise was mostly emphasized as a main problem in home-based programs in comparison with supervised programs. Obviously, psychosocial aspects play an important role when comparing the two. Supervised programs are often organized for more patients. Thus, patients are given an opportunity to interact with others, which improves adherence to exercise, as reported in one meta-analysis.⁸⁰ Social aspect of the program and positive entertainment associated with it, together with the supportive role played by the supervision are probable answers why supervision programs were superior compared to home-based programs.⁸¹

Exercise modalities

Walking was the most common exercise training modality, applied in thousands of patients participating in numerous studies and has been shown to be an effective treatment modality in patients with PAD. That is why walking is recommended by the AHA/ACC.⁷⁰ However, due to different conditions, such as severe claudication pain, diabetic foot complications, arthritis, osteoporotic vertebral fractures, stroke and severe cardiorespiratory or degenerative neurological diseases, some patients are unable (or unwilling) to take part in the walking programs. Alternative efficient exercise modalities for these patients might be varieties of Nordic walking, cycling, arm-cranking exercise, and progressive resistance training.⁸²

Most often, walking exercise programs in the available studies lasted for three to six months,^{29,30,31,49,83,84} although some programs lasted (and were supervised) for even 12 months.^56,85 Results from the study of Gardner et al.⁸⁶ suggest that the first two months in a longer exercise training program are crucial for improvement of walking performance. After the fourth month, improvement is also significant. On the last follow-up after the sixth months of exercise program, there was no significant improvement as compared to the follow-up after the fourth month.⁸⁶ Therefore, hospitals with limited human and financial resources could still organize qualitative and efficient exercise training program of shorter duration.

As for the frequency, three sessions per week were mostly seen in the programs, although in some reports the frequency was two sessions per week.^50,87 Progressive exercise programs were performed in most of the studies.^30,31,84

Intensities of the training programs were mostly defined as percentage of the maximal workload and ranged from 40–80%.^31,83,86 A less precise way of defining the intensity was the onset of claudication pain or its severity.^{29,30,50,85,88} Results from the study of Gardner et al.⁸³ indicate that more intensive exercise is not associated with superior improvement compared to low intensity exercise in terms of walking performance, tissue oxygen uptake and quality of life.

An optimal treatment modality has not been identified yet. In AHA/ACC guidelines, recommended modality includes supervised exercise training, performed for a minimum of 30–45 minutes, in sessions performed at least three times per week for a minimum of 12 weeks (Table 1).⁷⁰

Table 1.

Exercise training modalities which improve walking performance in patients with peripheral arterial disease.

	Preferred/recommended	Alternative modalities
Exercise training modality	Walking⁷⁰	Nordic walking, cycling, arm-cranking, progressive resistance training⁸²
Program duration	Twelve weeks or more⁷⁰
Frequency	Three times per week or more⁷⁰
Duration of a session	At least 30–45 min⁷⁰
Supervision	Supervised^73,74	Structured home-based^67,79
Definition of intensity	Max workload (40–80%)^31,83,86	Claudication pain onset or pain intensity^29,30,50

Besides from exercise training as an intervention, previous reports provide data about efficacy of other treatment modalities, with or without comparison to exercise training. In one study, exercise training, peripheral artery revascularization with stenting, and optimal medical care were compared. Exercise training mostly showed superior short-term effects as compared to stent vascularization intervention.⁵⁵ Long-term benefits of exercise were equal to benefits of revascularization procedure.⁸⁹ In various meta-analyses on this issue, authors also do not answer the question about superior intervention model, suggesting that exercise training programs should be favored and applied whenever possible.⁹⁰ British guidelines explicitly give priority to exercise training in the treatment hierarchy.⁶⁹

Cost-effectiveness also plays an important role in deciding on appropriate therapy. Results from several cost-effectiveness studies give priority to exercise, as there were no significant differences in the effectiveness between endovascular revascularization compared to exercise, but the costs were significantly higher for revascularization procedures.^91,92 Results from cost-effectiveness studies emphasize exercise as the most cost-effective first line therapy,^92,93 adding that exercise training is even more cost-effective when combined with endovascular revascularization than endovascular revascularization alone.⁹³

Influence of exercise training on cardiovascular risk factors, and coexistence with coronary artery disease, cerebrovascular disease and the metabolic syndrome

Due to their common etiopathogenesis in regard to atherosclerosis, the coexistence of PAD, CAD and CVD is not a surprise and has been proved in many studies. Prevalence of CAD in patients with PAD is estimated to range from 55%⁹⁴ to 62%.⁹⁵ Prevalence of CAD in patients with PAD is around 43%.⁹⁴ Association between complex PAD and complex CAD was shown in a study of Aykan et al.⁹⁶ The coexistence is associated with more severe morbidity profiles – it has been estimated that patients with PAD are three to six times more likely to experience myocardial infarction and stroke than patients without PAD.⁹⁷

Conversely, the prevalence of PAD is also high (36–42%) in patients with established CAD or CVD, and in individuals at high cardiovascular risk (i.e. with two or more risk factors). More importantly, half of the PAD is asymptomatic but nonetheless associated with an increased cardiovascular risk.⁶²

Approximately 50–92% of patients with PAD have arterial hypertension,⁹⁸ 77% have hyperlipidemia,⁹⁹ 20% of symptomatic patients with PAD have diabetes (which is probably underestimated, as there are more asymptomatic than symptomatic PAD patients).¹⁰⁰

Numerous studies have demonstrated beneficial effects of exercise on CAD and CVD.^101–103 Reducing cardiovascular risk factors due to exercise is very well documented.^104,105 Therefore, we strongly believe that exercise training is not helpful only in PAD, but also in conditions associated with it. Exercise training should decrease the incidence and prevalence of other two coexisting atherosclerotic diseases (CAD and CVD) in patients with PAD, as well as other cardiovascular risk factors that worsen prognosis of PAD (hypertension, hyperlipidemia, diabetes) (Figure 1).

Figure 1.

Effects of exercise training on atherosclerotic diseases.

Some of these hypotheses have also been confirmed in the literature. Effects on lipid profiles differed from study to study. In some, exercise had a lowering effect on values of total cholesterol,^49,88 LDL cholesterol^49,88 and triglycerides,⁴⁹ and an increasing effect on the values of HDL⁴⁹ in patients with PAD. On the other hand, these effects of exercise were not shown in the study of Januszek et al.²⁹ The effects of exercise on significant systolic blood pressure reduction were documented in the study of Izquierdo-Porrera et al.⁸⁸

The relationship between tobacco smoking and PAD has been described in numerous studies and meta-analyses.^106,107 It is indicated that the prevalence of patients with PAD, attributed to smoking, is around 50%.¹⁰⁸ In a report of Gardner et al., patients with PAD who were smokers had significant impairments in terms of walking performance, calf muscles blood flow and quality of life, as compared to patients with PAD who were not cigarette smokers. However, exercise training was beneficial almost equally for both groups of patients. That is why smokers are indicated as prime candidates for exercise, due to their low baseline physical performance. It seems that their ability to regain impaired walking performance is not lost due to cigarette smoking and that exercise is an efficient way to regain it.⁸⁴

Usually, patients with PAD have poor nutrition in terms of quality, rich in saturated fats and sodium, and low in fibres, vitamin E and folate intake.⁵⁴ In the study of Leicht et al., supervised exercise training has been successful in improving walking performance in patients with PAD, but this improvement has not been followed with healthier eating habits. Therefore, future studies are needed to examine the impact of combining dietary interventions with supervised exercise in PAD patients.⁸⁵

Sedentary lifestyle is associated with increased risk of PAD.¹⁰⁹ In patients who already have PAD, sedentary lifestyle is more common than in healthy controls¹¹⁰ and is associated with higher mortality rate.¹¹¹ Body mass index also increases the mortality risk in patients with PAD.¹¹¹ Similar result, namely that obesity is associated with cardiovascular events in patients with PAD, was obtained in the study of Golledge et al.¹¹² In their study, only waist circumference was used to define obesity. In the same study, obesity was associated with more impaired walking performance. In several reports, it was indicated that exercise training leads to a decrease in body fat percentage⁸⁶ and body weight.⁴⁹

Metabolic syndrome (MetS) is an entity defined by the USA National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III as having at least three out of the five following components: abdominal obesity, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting glucose.¹¹³ Results from several studies, in which patients exhibiting both PAD and MetS were included, report that prevalence of MetS in patients with PAD range from 52% to 58%.^114,115 Patients with PAD, who have MetS, have increased risk of cardiovascular events,¹¹² limited quality of life¹¹⁶ and walking performance,^112,116 compared to patients with PAD without MetS. Results from the study of Gardner et al. suggest that having more MetS components leads to worsening of walking performance, health-related quality of life and peripheral circulation in patients with PAD. Obesity and elevated fasting glucose are components with highest predictive value.¹¹⁷ However, results from the study of Ambrosetti et al. suggest that MetS is not associated with poor response to exercise in patients with PAD.¹¹⁸ Therefore, due to their increased morbidity from one side and good response to exercise from the other, patients with PAD and MetS should be a target population to commence an exercise training program.

Conclusion

PAD is becoming increasingly important in terms of public health. First, increased morbidity and mortality, and severely impaired quality of life in patients with PAD call for a sustained improvement in the management of patients with PAD. Second, widespread risk factors yielding to PAD represent a potentially modifiable, albeit complex etiopathologic interplay. Exercise training provides an effective management strategy for PAD. Several guidelines have pointed out the supervised exercise training as the first line therapy in patients with PAD. On the one hand, exercise training improves the most common symptomatic manifestation of PAD – intermittent claudication. On the other hand, exercise training helps in the management of cardiovascular risk factors, such as diabetes, dyslipidemia and hypertension, which are important for other two atherosclerotic entities – CAD and CVD. Lastly, exercise training provides an effective vehicle for delivery of lifestyle intervention beyond exercise itself – including a healthy diet and smoking cessation.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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