Peripheral Arterial Disease: Causes, Symptoms, and Treatment

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Functional capacity and quality of life are reduced in patients with intermittent claudication, and limited exercise is often a significant symptom in such patients. Pain-free walking ability is a major determinant of quality of life in these individuals and should be a primary focus of both pharmacologic and non-pharmacologic treatment regimens. Although easily assessed in a standard graded treadmill test, there is no consensus in defining meaningful change. Many feel that a change in absolute claudication distance (ACD) is of most value. Others argue that ACD is a crude surrogate for quality of life and advocate the use of patient questionnaires and health-related quality of life (HRQOL) instruments. Improvement in walking ability has also been used as a primary endpoint in many clinical trials. More recently, functional capacity has been assessed by pedometer step counts and has proved to be a simple and sensitive measure of change in walking ability. Despite these advances, there is no widespread agreement on a standard method to assess functional capacity in PAD, and this has hindered comparison of treatment regimens.

Definition and Overview

The term Peripheral Arterial Disease (PAD) refers to a blockage or narrowing of the arteries that supply blood to the extremities, usually caused by atherosclerosis. This risk factor for heart disease is often underdiagnosed and undertreated because of its asymptomatic nature, or atypical leg symptoms that may not immediately be attributed to a narrowing of the peripheral arteries. It is important to study and treat PAD, as it is associated with a high morbidity and mortality; a 5-year cardiovascular mortality rate of 30-40% which is comparable to that of many aggressive cancers. PAD also poses a significant economic burden, with higher costs associated with treating the complications of PAD than with treating coronary artery disease. This is due to the fact that many PAD patients have multiple coexisting disease states, leading to significantly higher rates of both noncardiovascular and cardiovascular-related hospital admissions. The economic impact of PAD is expected to rise as the population grows older and the prevalence of risk factors such as diabetes and obesity increases. An analysis of U.S. national trends in the healthcare burden for PAD has shown that PAD hospital discharges have increased by 34% from 1997 to 2006, with a significantly higher rate of increase and cost seen in patients with a primary or secondary diagnosis of PAD.

Prevalence and Risk Factors

There are over eight million people in the United States with peripheral arterial disease and it is most prevalent in those over 55 years old. It is important to know about the risk factors and prevalence of PAD in order to understand the population most affected by it. Smokers are 8 to 10 times more likely to get PAD than non-smokers or former smokers. Smoking does not have to be current to suffer from the effects. People that smoke in their lifetime, even those that quit in the past, are at risk. “It is important for healthcare providers to be aware of the risk factors for developing PAD and institution nation-wide public health initiatives aimed at primary and secondary prevention of this increasingly prevalent cardiovascular disease,” said Niten Singh, MD, assistant professor of surgery and radiology at the University of Virginia, and the Principal Investigator for the study. “Implementing PAD prevention strategies could have a major impact on reducing future cardiovascular morbidity and mortality.”

Importance of Early Detection

The most common symptom of PAD is claudication, which is ischemic muscle discomfort or pain that is precipitated by exercise and relieved by a few minutes of rest. People with PAD and intermittent claudication become afraid of making the pain worse and often limit their physical activity in an effort to avoid discomfort. They may not report their symptoms of claudication to their healthcare provider because they have heard that the pain will go away on its own and they assume it is not serious. People with PAD often do not perceive themselves as having a disease, and therefore, they do not seek medical care for their PAD symptoms.

Early detection of peripheral arterial disease (PAD) is an important goal because treating the disease in early stages can prevent severe complications. Currently, both patients and healthcare providers fail to recognize the symptoms of PAD. Many people mistake the symptoms of PAD for normal aging. They may feel that it is natural for them to develop arthritis or to become less active. However, leg pain is not a sign of aging and is not something that people should learn to live with.

Causes and Pathophysiology

Atherosclerosis, a buildup of plaque in the inner lining of the artery, is the most common cause of PAD. Progressive narrowing and blockage of the arteries by atherosclerotic plaques reduce blood flow to the lower extremities and cause the symptoms of PAD. A small opening in the artery, and therefore a small amount of plaque, can severely reduce blood flow, while a large plaque and a greater opening can actually increase flow due to the artery functioning as if it were a narrowed artery in which collateral vessels have developed blood will not clot and the arteries will have been blocked, increasing the risk of tissue death and gangrene due to chronic ulceration or injury. Atherosclerosis is an inherent process in aging and develops at an accelerated rate in patients with high levels of damaging lipids and cholesterol. Hypertension promotes atherosclerosis by causing a chronic low level injury to the artery walls and the shifting of the monocyte-macrophage system from debris removal to increased engulfment of lipids and cholesterol, forming foam cells and fatty streaks. High LDL cholesterol and low HDL increase incidence and severity. Diabetes also is a major contributor as hyperglycemia and insulin resistance damage vessel walls and promote atherosclerosis and plaque development. Finally, a genetic predisposition carries a risk that has not yet been quantified.

Atherosclerosis and Plaque Formation

Formation of atherosclerosis is the most common cause of occlusive arterial disease. The term atherosclerosis has been derived from the Greek words athero (gruel) and sclerosis (hardness). The process starts in early adult life and progresses slowly in which the arteries become hardened and narrowed. It is the result of complex interactions between lipids, inflammatory mediators, cellular elements, and the extracellular matrix of the arterial wall. Low-density lipoprotein (LDL) accumulates in the intima layer of the arterial wall where it becomes oxidized. This oxidized LDL is toxic to endothelial cells and attracts monocyte macrophages into the subendothelial space. Ingestion of the oxidized LDL by macrophages turns them into foam cells and is the hallmark pathology of atherosclerosis. Inflammatory mediators play a key role in atherosclerosis and can cause fissuring of the plaque surface, where platelets come into contact with the vessel wall and release growth factors. Smooth muscle cells migrate from the media into the intima and start to proliferate and produce an extracellular matrix, which begins to form a fibrous plaque. This process gradually encroaches on the lumen of the artery and depending on the stability of the plaque, acute events may occur. These can be the result of embolization of the plaque or thrombosis at the site of plaque rupture. A chronic total occlusion may occur from progressive plaque encroachment and/or associated thrombosis. Elevation in plasma homocysteine and complex formation of glycoproteins have also been shown to contribute to atherosclerosis. With progression and in coronary or peripheral arteries, atherosclerosis may be complicated by chronic ischemic symptoms and acute on chronic events.

Other Contributing Factors

Elevated levels of homocysteine are associated with atherosclerosis and are linked to low levels of folic acid. Research in vitamin and mineral deficiencies is limited, but the association of elevated homocysteine and atherosclerosis has led to interest in the role of vitamins and nutrients on artery and lipid metabolism. Randomized trials of folic acid, vitamin B6, and B12 supplementation to reduce homocysteine levels have not shown consistent effects on cardiovascular events, and in fact, one trial suggested an increase in peripheral artery disease. Lp(a) is a low-density lipoprotein particle that is linked with a kringle domain to apo(a). It is highly heritable and has been consistently linked with the risk for cardiovascular events, including peripheral artery disease. High-density lipoprotein is important in reverse cholesterol transport and efflux, and low levels of HDL have been linked to the development of PAD.

Symptoms and Diagnosis

Another symptom of PAD is a change in the color of the legs. The legs may turn pale when elevated and reddish when lowered. People may also notice that their leg hair becomes sparse or stops growing, the toenails become thick, and the skin becomes shiny—even without any scratching or scuffing. These changes in skin color and texture are the result of decreased blood circulation and oxygen to the legs. In severe cases of PAD, patients may develop ulcers (open sores), especially on the toes or feet, that do not heal or that come back. I have to mention that people with PAD often are unaware that they have the disease. For these reasons, all people at age of 70 and even those who are younger and have risk factors for PAD should have a measurement of the ankle brachial index. If this number is less than 0.90, further tests and treatment for PAD should be considered.

Intermittent claudication, or painful walking, is the most common symptom of PAD. The legs may feel heavy, tired, or crampy and the muscles in the calf or thigh may hurt when walking or climbing stairs. Pain may also come from the hips or buttocks. These symptoms often force the patient to stop and rest. Relief comes quickly with rest, because there is less demand for blood flow to muscles. This is a hallmark of claudication. In the early stages of PAD, the pain might come and go, but as the disease gets worse, the pain often becomes constant. Although claudication is the most common symptom of PAD, not all leg discomfort is claudication. It is not unusual for people with diabetes to have pain from peripheral neuropathy (nerve damage) that can mimic claudication. Also, people with arthritis or spinal stenosis (nerve damage in the spine) can have leg pain that is not related to PAD.

Common Symptoms of Peripheral Arterial Disease

Pain in the lower extremities, typically the legs, that occurs at rest, commonly in bed at night. The severity of the pain can range from moderate to severe, and it can be described as sharp, shooting, aching, or burning. It is usually relieved by hanging the leg over the edge of the bed or by walking. A tight, squeezing pain in the calf, thigh or buttocks. Leg numbness or weakness. A person may experience difficulty in finding the right words to express themselves or may become disoriented, especially when they move their legs up, such as with ambulation up a flight of stairs. Coldness in the lower leg or foot, especially when compared with the other side. This can occur from sleeping with the affected extremity dangling off the bed. In addition, in warmer climates, the lack of hair growth on the feet or legs can be an indicator of poor blood flow. Heel or toe pain from an open sore that will not heal. This is a major danger signal of critical limb ischemia (CLI), a severe blockage usually defined as severe pain at rest or a non-healing wound. CLI is a serious form of PAD that can be limb-threatening.

Diagnostic Tests and Procedures

Non-invasive tests are simple to perform and are important in the detection of PAD due to their application to frail, high-risk, and borderline patients. The ankle-brachial index (ABI) is a simple ratio of the systolic blood pressure at the ankle, divided by that in the arm. It is highly sensitive and specific for PAD and has been established as a reliable test with prognostic value. Lower limb arterial Doppler studies are used in combination with ABPI to establish an objective physiological assessment of the severity, site, and extent of arterial disease. It is a rapid and cost-effective test that uses ultrasonic waveform analysis to produce auditory and visual recordings of blood flow. The exercise treadmill test is often used to determine a patient’s functional status and assess the presence of intermittent claudication. It is a very simple and cheap test to perform that uses ABI measurements to predict the likelihood of symptoms and signs of lower limb ischemia during more demanding exercise.

Arteriography is still considered the gold standard and most accurate diagnostic modality for PAD. Conventional x-ray arteriography is expensive, invasive, and has risks related to the use of atherogenic radioactive contrast material and ionizing radiation. Therefore, it is less commonly used. Magnetic resonance angiography (MRA) and CT angiography (CTA) both yield anatomic imaging that is rapid, minimally invasive, and does not entail the morbidity associated with conventional catheter angiography. They are the preferred vascular imaging modalities to evaluate most patients with PAD. Catheter-based angiography presents the highest spatial resolution of any of the imaging tests used for the assessment of PAD. Unfortunately, it is relatively invasive, discomforting, and expensive. Digital subtraction angiography enhances the contrast of angiography images using digital image processing, which decreases radiation dose as well as examination length. DSA of the lower limb has been the most reliable imaging technique for PAD, especially for below-the-knee arterial lesions. However, the development of less invasive angiography imaging tests has warranted a reduction in the use of diagnostic DSA for PAD patients.

Treatment and Management

The goals of supervised exercise programs are to increase pain-free walking time, improve the participant’s walking distance and speed, and improve strength and function, mobility, and overall quality of life. The programs must offer a comprehensive approach to cardiovascular risk reduction and include regular assessment and optimization of the medical treatment, especially as it impacts walking distance. Prompt access to revascularization should be available for those with severe symptoms or those who demonstrate a significant functional decline. Regular surveillance for adverse cardiovascular events is needed in patients who are undergoing intensive exercise therapy, particularly if they are older and have other chronic health conditions. It is important to note that most of the literature surrounding exercise therapy has been in patients with intermittent claudication, although improved function is also an appropriate goal in those with PAD and ataxia or those with mobility impairment. In the absence of specific data relating to the effectiveness of exercise therapy in these patients, exercise program recommendations can be extrapolated from those for patients with claudication.

Treatment of peripheral arterial disease promotes the relief of symptoms and prevention of the progression of the disease to critical limb ischemia. The cornerstone of treatment for PAD is a structured program of therapeutic exercise. For those with intermittent claudication who have associated functional limitation, supervised exercise training provides substantial symptomatic improvement and increased functional capacity. This is recommended as an initial treatment for patients with PAD, at least in a hospital or community-based program.

Lifestyle Modifications and Risk Factor Control

Lifestyle changes that reduce leg ischemia and decrease the progression of atherosclerosis are of paramount importance in PAD. Most patients with PAD are sedentary and unfit and, if they undertake an unsupervised exercise program, are likely to exacerbate leg pain and discontinue exercise. Supervised exercise training is effective for improving walking distances in patients with intermittent claudication. A comprehensive secondary prevention program in patients with PAD has been advocated to modify cardiovascular risk factors and improve leg symptoms. This includes smoking cessation, optimal treatment of hypertension and dyslipidemia, and tight glycemic control in diabetics. Antiplatelet therapy with aspirin is recommended. High doses of antioxidants are not effective for improving ischemic or functional outcomes. In patients with intermittent claudication, the use of cilostazol, a phosphodiesterase III inhibitor, is recommended for improving functional status and increasing the pain-free walking distance. In conclusion, PAD is an atherothrombotic process with a high rate of adverse cardiovascular events. The primary goal in the management of patients with PAD is to reduce cardiovascular morbidity and mortality. The diagnosis of PAD provides a teachable moment for comprehensive risk factor modification and the intensity of risk factor control should be proportionate to the global cardiovascular risk. Long-term, multi-faceted management involving a team of specialists is often required to effectively manage patients with advanced PAD.

Medications for Peripheral Arterial Disease

Epidemiological studies and national registries have documented underuse of these evidence-based therapies in patients with PAD, including antiplatelet and lipid-lowering medications.

Pentoxifylline is another drug that can be used to improve the symptoms of intermittent claudication. Although the way it works is not fully understood, it is believed to widen the blood vessels and therefore increase the blood flow to the extremities.

Cilostazol is a type of medication known as an antiplatelet (platelet aggregation inhibitor) that has been shown to be effective in the treatment of intermittent claudication.

Statins are a type of medication commonly used to lower blood cholesterol levels. Evidence suggests that treatment with statins may have several benefits for people with peripheral arterial disease, as well as those with a history of stroke or TIA. High cholesterol can cause a buildup of fatty deposits in the arteries, known as atherosclerosis. This can further reduce blood flow to the muscles and organs. By reducing cholesterol levels, it is hoped that the progression of atherosclerosis can be slowed down or even reversed. Statins have also been shown to decrease the risk of heart attack, stroke, or death in patients with PAD and help to relieve intermittent claudication.

Antiplatelet drugs are used to prevent the cells in the blood (platelets) from sticking together and forming clots. Aspirin is an antiplatelet drug that has been shown to be beneficial to PAD patients in the prevention of heart attack and stroke. Clopidogrel is also an antiplatelet drug and is often prescribed if aspirin is not tolerated or is ineffective.

Interventional Procedures and Surgical Options

Bypass may be performed to reroute blood flow around a blocked artery. During the procedure, a blood vessel from another part of the body or a synthetic vessel is used to create a path around the blocked area. Bypass can be an effective way to improve blood flow in the legs and lower the pain caused by walking. A bypass may lessen the need for a patient to interrupt physical activity due to leg pain, and though it will not cure the systemic effects of PAD, the symptom relief provided by bypass can significantly improve a patient’s health and quality of life.

Atherectomy may be performed to remove plaque from arteries that have been narrowed by PAD. Though atherectomy can be an effective way to open clogged arteries, it is not as useful for treating long segments of artery as is bypass surgery.

Angioplasty and stenting are often used to open blocked arteries in the legs. During the procedure, a catheter is threaded through the blocked artery, and a small balloon on the tip of the catheter is inflated to open the artery. A stent (a small wire mesh tube) may then be inserted to keep the artery open. Angioplasty and stenting are commonly used to treat arteries that have been narrowed by PAD, but long-term success rates are not as high as with a bypass for complete artery blockages, and the procedures are associated with an increased risk of repeat blockage in the treated area.

Interventional procedures and surgical options for treating PAD include angioplasty and stenting, atherectomy, and bypass surgery. The choice of procedure depends on which arteries are affected and the severity of the disease.

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