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Patients with peripheral arterial disease (PAD) are often troubled by obstructive sleep apnea (OSA) and excessive daytime sleepiness (EDS), and both features can significantly affect the patients’ quality of life. There are several separate reasons why patients with PAD could be susceptible to disturbed sleep. The presence of ischemia in the lower limbs can cause a reduction in the circulation in the legs, particularly during sleep when the patients lie flat. This can exacerbate symptoms of intermittent claudication or rest pain and can also lead to nocturnal leg cramps. Another probable cause is the presence of coexisting cardiovascular disease. Because many patients with PAD have associated coronary artery disease or cerebrovascular disease, they are likely to have impaired left ventricular function or a previous myocardial infarction or heart failure. The pathophysiological changes which occur in the failing heart can lead to a variety of different breathing disorders during sleep, the most common of which is OSA. This is the first review to our knowledge, to examine the presence of sleep disorders in patients with PAD and their impact.
Sleep Disorders Associated with Peripheral Arterial Disease
2.3 Restless Legs Syndrome (RLS) and Periodic Limb Movements in Sleep (PLMS) RLS is a movement disorder that is associated with discomfort in the legs and an urge to move. Symptoms occur primarily at night, and movement provides temporary relief with subsequent difficulty with sleep onset or maintenance. Prevalence of RLS in the general population is around 10-15%. In those with severe PAD and intermittent or constant ischemic pain, there may be misdiagnosis or dual pathology of severe pain and RLS. This will manifest as increased nocturnal pain due to the increased recumbent time, with difficulties distinguishing from CLAUD based nocturnal pain or rest pain. Treatment of RLS may include addressing iron deficiency, dopaminergic agents, or treatment of associated pathology. An adverse drug effect on ischemic symptoms should be assessed. RLS overlaps with the diagnosis of PLMS with PSG. This is characterized by repetitive cramping or leg movements that cause brief microarousals from sleep. Clinically this can be associated with complaints of nonrestorative sleep and increased daytime sleepiness. PAD patients were found to have a higher frequency of PLMS as compared with control patients. In a study, patients with intermittent claudication had an average PLMS activity index of 17.1 with 23% of patients having moderate to severe PLMS.
2.2 Sleep Apnea Sleep apnea involves repetitive complete or partial cessation of airflow during sleep and is associated with increased risk of cardiovascular events and mortality. The most common form is obstructive sleep apnea (OSA) which is due to repetitive upper airway collapse. PAD patients have been shown to have a high prevalence of OSA. In one study, 60% of patients with PAD had at least moderate OSA. High prevalence of OSA may be related to the common risk factor of obesity, however, is also related to fluid shift from dependent edematous limbs to the neck in the recumbent position. This can precipitate or worsen upper airway collapse. Treatment options for OSA include weight loss, Continuous Positive Airway Pressure (CPAP), or oral appliances. An association between OSA and cardiovascular risk is directly relevant to patients with coexisting cardiovascular disease. The SAVE trial has shown beneficial CPAP therapy on supraortic limb function and exercise performance in patients with OSA and coexisting PAD. This area remains an important area for further research in PAD patients with both limb and systemic cardiovascular morbidity.
2.1 Insomnia Insomnia is defined as difficulty initiating or maintaining sleep, or having the experience of nonrestorative sleep. Daytime symptoms may include fatigue, irritability, or distress, and performance deficits. Insomnia may be comorbid with depression or anxiety, and may be an exacerbating factor for patients with pain. It is known that patients with intermittent claudication have increased difficulty with initiating sleep and have increased disruption of sleep as compared with age-matched controls. In a study, patients with PAD had an average Pittsburgh Sleep Quality Index (PSQI) score of 9.2 as compared with age-matched controls of 4.8. With sleep efficiency < 65%, 29% of PAD patients have evidence of severe sleep disturbance. This study and others suggest that patients with PAD have a form of secondary sleep onset insomnia due to the severe discomfort experienced with ambulatory activities. Patients with chronic limb ischemia may have sleep continuity disturbances due to reduction in limb pain when in the recumbent position, with return of pain and subsequent microarousals on turning to the lateral position. This can be misconstrued as “Prost’s restless leg syndrome” or periodic limb movements. Treatment of insomnia may include hypnotic agents, cognitive-behavioral therapy, or treatment of underlying factors such as pain or depression.
Insomnia
Although not fully understood, atherosclerosis is an inflammatory process which involves the accumulation of lipids and fibrous plaques in the intima of arteries. The process is believed to begin with damage to the arterial wall leading to an inflammatory immune response. Cytokines are integral in communication among cells of the immune system and are involved in the replication of cells in the atherosclerotic lesions. Data from a study conducted by Vgontzas et al. revealed that cytokines have a diurnal rhythm and a shift in the cytokine balance in insomnia can cause an increase in inflammatory immune responses. This particular shift in the cytokine balance leads to an increase in the type-1 helper T cells and activation of monocytes. Increased adhesion of monocytes to the endothelium and migration into the arterial wall leads to the release of more cytokines and perpetuation of the inflammatory process. The end result of these processes is an increased amount of atherosclerotic lesions and narrowing of the arteries which can in turn lead to PAD. This study provides a theoretical model as to how the cytokine shift in insomnia may lead to progression of PAD, but it is ultimately based on a series of inferences and the exact mechanisms are not known.
Insomnia is defined as difficulty falling or staying asleep, and patients with this particular type of sleep disorder have been found to have a higher prevalence of peripheral artery disease (PAD) as compared to those with sleep apnea symptoms. This has been recently demonstrated with data from the National Health and Nutrition Examination Survey III. Patients with insomnia have been found to have a higher amount of comorbid conditions which may predispose them to the development of PAD. Factors such as tobacco use, hypertension, diabetes, and obesity are risk factors for the development of PAD and have been found in greater numbers in patients with insomnia. These comorbid conditions may predispose patients to the development of atherosclerosis or inflammatory processes which lead to PAD. In addition to these comorbid conditions, there is evidence suggesting the pathology of insomnia itself may contribute to the progression of PAD.
Sleep Apnea
An especially pertinent issue in the evaluation and treatment of PAD and its associated sleep disorders is the potential economic impact. The combination of PAD and sleep disorders such as insomnia, sleep apnea, and restless legs syndrome leads to a high burden on the healthcare system and increased morbidity and mortality. The recognition and management of these sleep disorders in the PAD population may lead to improved quality of life and decreased cardiovascular events, but it may be associated with increased healthcare costs. An economic evaluation of the long-term costs and benefits of managing sleep disorders in the PAD population is an important consideration for future health services and outcomes research.
As with insomnia, the relationship between sleep apnea and PAD is bidirectional. Individuals with PAD have a high prevalence of sleep apnea, and individuals with sleep apnea have a high prevalence of PAD. Sleep apnea leads to hypoxemia and fragmented sleep. Hypoxemia may exacerbate the systemic atherosclerotic process, and fragmented sleep is associated with adverse cardiovascular outcomes. Similar to the treatment of insomnia, if sleep apnea is suspected, patients should undergo formal sleep evaluation. Treatment options for sleep apnea include nocturnal nasal continuous positive airway pressure therapy, weight loss in obese individuals, and positional therapy. As with insomnia, the effective treatment of sleep apnea may improve PAD symptoms and cardiovascular outcomes.
Restless Legs Syndrome
Restless legs syndrome (RLS) is a common sleep disturbance in which unpleasant sensations in the legs cause an almost irresistible urge to move them. RLS is one of the most frequent causes of chronic insomnia. Almost 80% of people with RLS have PLMS at night. Because both RLS and PLMS can cause sleep onset and sleep maintenance insomnia, they contribute to increased cardiovascular morbidity and mortality. The symptoms of RLS are often described as a burning or itching in the lower extremities. Symptoms occur during inactivity and are worse in the evening and night. Movement will relieve the discomfort and is often necessary for sleep onset. In a recent study, about one-third of subjects with RLS and frequent sleep disturbance had nocturnal leg ischemia demonstrated by 133 Xe clearance. These patients had low serum ferritin levels and all had a marked improvement in their RLS symptoms and their sleep improvement following the treatment of their anemia. Low serum ferritin levels have been associated with an increase in RLS and the severity of RLS. Psychological symptoms and fatigue are often present in patients with RLS.
Impact of Sleep Disorders on Peripheral Arterial Disease
Given these considerations, it is likely that specific sleep disorders have an adverse impact on cardiovascular events and mortality in PAD and are therefore important targets for therapy in this population. This is an important issue to address in a population where the emphasis of treatment has traditionally been on relief of leg symptoms and prevention of limb loss, rather than the reduction of adverse cardiovascular outcomes.
For example, a substantial body of research has demonstrated that sleep disorders, particularly sleep-disordered breathing and its subtype obstructive sleep apnea, are independent risk factors for the development and progression of heart failure, and are also associated with an increased risk of myocardial infarction and stroke. Although the pathophysiological mechanisms underlying these associations are not entirely understood, it is likely that sleep disorders impact cardiovascular health via mechanisms including sympathetic activation, systemic inflammation, and endothelial dysfunction. These are all mechanisms that are thought to contribute to the poor cardiovascular prognosis of patients with PAD.
Despite the prevalence of sleep disorders among patients with PAD and the proven negative impact of such sleep disorders on patients’ health status, the relationship between sleep disorders and adverse health outcomes in PAD has received little study. To date, no study has estimated the prevalence of specific sleep disorders in a PAD population, and no study has examined the impact of sleep disorders on cardiovascular events or mortality in PAD. This reflects a broader lack of understanding of the impact of sleep disorders on cardiovascular disease compared with understanding of the impact of sleep disorders on other health conditions.
Increased Cardiovascular Risk
Poor sleep quality increases blood viscosity and leads to activation of coagulation and inflammation factors. This can accelerate the progress of atherosclerosis and increase the risk of cerebrovascular or peripheral vascular events. High blood viscosity is a major risk factor for PADA patients and is associated with an increase in cardiovascular morbidity and mortality. An eight-year follow-up of the Edinburgh Artery Study found that PADA patients with high blood viscosity were 2.4 times more likely to have a coronary event than those with low blood viscosity. Sleep-disordered breathing can lead to hypertension, which is another PADA risk factor expressed as a relative risk of 2-4 times higher in patients with sleep apnea.
Poor sleep quality can increase the risk of stroke and heart attack. Activation of the sympathetic nervous system reduces a person’s heart rate variability (HRV). Abnormalities in HRV are associated with an increased risk of developing Coronary Artery Disease (CAD). The Nurses’ Health Study showed that the relative risk of death in women who slept 5 hours per night was 1.5 times higher than that of women sleeping 7 hours per night. This finding was associated with excessive mortality from cardiovascular disease. Similar results were found from the First National Health and Nutrition Examination Survey, a random sample of United States population. Those with a sleeping duration of 5 hours a night were 1.9 times more likely to develop congestive heart failure and had 1.7 times higher relative risk of dying of any cause. The same study found that those sleeping 9 hours per night were more likely to develop CAD than those who slept 7-8 hours a night. This “u-shaped” relationship would suggest that both under and over sleepers are at equal increased risk. This is important to the PADA patient because many PADA patients experience difficulties in sleep due to heart or limb pain during the night. Mediation for relief of leg pain in PADA may cause additional drowsiness during the day, ultimately resulting in sleep disturbances and potential consequences as previously mentioned.
Impaired Quality of Life
Quality of life is a broad, multifaceted concept that has been used in a variety of contexts, including assessing the outcome of therapy. In a 1997 consensus statement, the Society of Vascular Surgery and the International Society for Cardiovascular Surgery outlined quality of life within the particular context of peripheral arterial disease as “a state of well-being that is present when an individual is able to realize his or her potential and to fulfill his or her hope with the ability to participate in a satisfying manner in the roles and activities of his or her choice without symptomatic limitation due to cardiovascular and other chronic medical conditions. Quality of life exists on physical, psychological, and social dimensions. Detection of abnormalities in any of these three dimensions can best be described through findings of impairment in activities of daily living, the most convenient assessment of which is through the Sickness Impact Profile developed by Bergner et al. in 1976.
Reduced Treatment Efficacy
An understanding of sleep-disordered breathing and its effect on these subjective benefits is essential, as this knowledge will critically change the direction of PAD therapy in future years to that of preventing decline in symptomatic status.
Figures specific to surgical bypass are lacking, though there may be considerable reductions in symptom improvement and limb salvage seen with nocturnal ischemic events. Pharmacotherapy for limb symptoms has mainly consisted of antiplatelet agents and cilostazol. While sleep-disordered breathing is not known to affect these medications, their relative benefits may be less apparent in patients with PAD and comorbid sleep disturbances due to the progression of symptoms stemming from intermittent sub-therapeutic oxygen levels.
Revascularization has been the focal point of interventional therapy in PAD for the past decade, producing considerable advancements in minimally invasive surgical techniques, symptomatic improvement, and prevention of limb loss. Angioplasty and stenting have shown substantial promise in reducing physical limitations and improving functional status in patients with intermittent claudication. However, the subjective benefits of these therapies may be greatly reduced in patients with coexisting sleep apnea, as nocturnal desaturation to critical hypoxic levels may effectively nullify symptomatic improvement. Static balloon obstructions have also been shown to have quicker rates of lesion reocclusion and increased restenosis in patients with sleep apnea.
Patients with PAD typically undergo two therapeutic approaches: revascularization and pharmacotherapy. Sleep disturbances have been shown to reduce the efficacy of both treatment modalities.
Managing Sleep Disorders in Peripheral Arterial Disease
The options for treating sleep disorders in PAD are not well studied. In theory, treating the underlying PAD is likely to also help the insomnia. Regular walking has been found to help both RLS and insomnia in elderly individuals, though PAD patients often also have comorbid coronary artery disease, limiting their ability to walk without pain. Cognitive behavioral therapy for insomnia has been shown to be effective in patients with chronic diseases, though no data is available for its use in PAD patients. One study found that a 6-week tai chi program improved both sleep quality and RLS in 20 patients with PAD. Tyron and Price suggest that improving sleep in patients with PAD might require addressing the anxiety that often accompanies fear of limb amputation. Nocturnal oxygen therapy has also been shown to improve sleep quality in patients with comorbid COPD and OSA. A case report by Campbell et al. describes a patient with PAD, OSA, and nocturnal desaturation whose sleep quality improved with CPAP and a marked increase in walking duration. CPAP is often poorly tolerated by patients with PAD due to leg edema and may not be a viable option unless the patient also has significant OSA.
Lifestyle Modifications
Lifestyle modifications are the first step in managing a sleep disorder. Discontinuing caffeine use or reducing the time between quitting caffeine and bedtime is an effective measure. Cognitive behavior therapy to change inappropriate sleep habits and other behaviors also appears to improve sleep quality. Increasing physical activity has been shown to improve sleep quality, duration, and reduce daytime sleepiness. However, increasing physical activity in patients with PAD must be done with caution. Exercise interventions for patients with PAD have focused on improving walking ability and cardiovascular endurance. While improvements in walking ability are important in this patient population, the effects of exercise on sleep in patients with PAD have yet to be studied. Sleep-disordered breathing, specifically apnea, is known to be affected by body position. A recent study has shown improvement in positional dependent sleep apnea for patients who sleep in the lateral position when compared to supine. This simple intervention can significantly improve sleep quality and reduce the severity of sleep apnea in patients who normally sleep in the supine position.
Medications
Patients suffering from PAD and sleep disorder can use a range of medications to help improve their sleep quality. However, the optimal medication treatment for this patient group has not been well defined in the medical literature. Insomnia, which is difficulty initiating or maintaining sleep, affects more than half of PAD patients. The most common choice of drug treatment for PAD patients with insomnia is a benzodiazepine. There are about 12 different benzodiazepine medications and several other hypnotic medications, known as non-benzodiazepine agents, to select from. The benzodiazepine group of drugs all have similar properties and act by enhancing the effect of gamma-aminobutyric acid (GABA) in the brain which causes a sedative, hypnotic, anxiolytic, anticonvulsant and muscle relaxant effect. The non-benzodiazepine hypnotic drugs, zolpidem and zaleplon, have a similar mode of action to the benzodiazepines. These medications can improve total sleep time and sleep quality, but their use should be carefully monitored by the physician in the elderly population. The side effects of these medications for PAD patients can be issues with dizziness and unsteady gait and this could further increase the risk of falls and injury. Anxiety, restless leg syndrome, leg cramping, and insomnia in patients with PAD is related to overactivity of the neurotransmitter dopamine in the brain and central nervous system. These patients may benefit from using dopamine antagonist medications to alleviate these symptoms and improve sleep.
Sleep Therapies
Positive results have been noted following treatment of PAD patients with continuous positive airway pressure (CPAP). In a randomized control trial of 20 PAD patients with OSA, 6 months of CPAP led to a significant increase in walking distance (baseline 344±81 m, 6 months 458±164 m, p=0.007) and decrease in the number of self-reported falls over the trial period. CPAP appeared to be particularly effective in improving walking distance in patients with severe OSA who had a mean compliance to CPAP >10 h/night (baseline 314±104 m, 6 months 547±209 m, p=0.04). CPAP was also noted to reduce plasma concentrations of brain natriuretic peptide (BNP) and improve quality of life in 20 PAD patients with OSA in a separate randomized control trial. At the 3-month follow-up, plasma BNP in the CPAP group was lower than those receiving a placebo treatment (5.3 pmol/L decrease for CPAP vs. 3.5 pmol/L increase for placebo, p=0.02) and there was an improvement in the physical health component summary of the Short Form-36 questionnaire (p=0.007). Nocturnal oxygen therapy may also be beneficial for PAD patients. In a trial of 33 PAD patients with nocturnal hypoxemia, nocturnal oxygen improved the mean nocturnal oxygen saturation from 83±6.8% to 90±3.2% and time spent below 90% saturation from 129±105 to 22±51 minutes. Subsequent patient self-reported data suggested that the improved oxygenation may have had an effect on subjective sleep quality, energy levels or mood.