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Table of Contents

Published May 29, 2002

Felipe
Navarro, MD

Department of
Cardiovascular
Medicine

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Definition

Prevalence

Pathophysiology

Signs and
Symptoms

Diagnosis

Therapy
and Outcomes

References

Peripheral arterial disease (PAD) includes a wide spectrum of entities that manifest in an equally wide spectrum of presentations. PAD is subclassified as either occlusive or aneurysmal. In occlusive diseases, the lumen is narrowed either in a chronic or acute manner. Atherosclerotic involvement of the aorta may be associated with occlusive disease in the carotid, visceral, subclavian, or iliac arteries. In aneurysmal diseases, weakening of the arterial media results in focal dilation of a blood vessel to at least twice its normal diameter. Aneurysmal disease usually affects the aorta; the infrarenal abdominal aorta is the most common site. Whereas aortic aneurysms culminate in rupture, extremity-artery aneurysms tend to thrombose.

Despite the fact that atherosclerotic PAD is a risk factor for premature death, it is vastly under-diagnosed. Estimates of its prevalence depend on which definition of PAD is used. If PAD is identified on the basis of an ankle-brachial index (ABI) of less than 0.90, its prevalence is as high as 29% among patients in primary care practices.¹

Aortic aneurysms usually occur in men over age 50. The estimated prevalence of abdominal aortic aneurysms is 2% to 5% in men over age 60. Ruptured abdominal aortic aneurysms account for at least 15,000 deaths per year.² Peripheral aneurysms occur most frequently in the popliteal arteries. Patients with popliteal artery aneurysms have a 45% to 68% incidence of bilateral involvement.^3,4 As many as 70% of patients with popliteal or femoral artery aneurysms have associated aortic aneurysms or aneurysms in other arteries.⁵

Occlusive Disease
The pathophysiology of arterial occlusive disease is related to the arterial blood supply versus demand of muscles or organs. In both chronic and acute occlusive disease, the degree of ischemia is related to the size and proximity of the occluded artery to the muscle or end organ, the presence of collateral circulation, the rapidity of the occlusion, and the patient's blood pressure (BP).

Chronic occlusive arterial disease is more common than acute. Chronic disease usually is caused by atherosclerosis, a systemic process that affects all vascular beds. Other causes include Buerger's disease (which affects small and medium-sized vessels), giant-cell and Takayasu's arteritis (which affect larger vessels), fibromuscular dysplasia, or chronic and repetitive occupational trauma. External compression syndromes-such as thoracic outlet syndrome, popliteal entrapment syndrome, and adductor tendon compression-also may cause chronic occlusive arterial disease.

Acute arterial occlusions may occur in both normal and diseased arteries. In most cases, a thrombus embolizes from a proximal source (eg, the heart or the wall of an abdominal aortic aneurysm) and acutely occludes a distal peripheral artery. Chronically diseased arteries and peripheral artery aneurysms may thrombose acutely leading to rapid worsening of symptoms.

Aneurysmal Disease
Atherosclerosis is also the primary cause of arterial aneurysmal disease. Severe atherosclerosis in the walls of an aortic aneurysm is thought to cause aneurysmal degeneration. Other important causes of aneurysms include infection (mycotic), trauma, arteritis, cystic medial necrosis, and genetic factors. All of these factors lead to loss of tensile strength in the media of the arterial wall.

Morbidity and Mortality
Because atherosclerosis is a systemic disease, PAD patients have a high prevalence of coronary artery disease and cerebrovascular disease. Patients with symptomatic PAD have a 5-year mortality of almost 30%, which is higher than that of breast cancer.⁶ There is a correlation with PAD severity (as measured by the ABI) and survival. In patients with severe, symptomatic PAD, only 25% survive 10 years.⁷ Most of the morbidity and mortality in patients with PAD is caused by cardiovascular and cerebrovascular events.

Occlusive Disease:

Intermittent Claudication
The most common manifestation of PAD is intermittent claudication. Patients usually describe progressive ache, tightness, fatigue, or pain in a muscle group distal to the arterial obstruction. Symptoms occur predictably after the patient walks a specific distance, provided there is no change in walking speed or surface grade. Relief of symptoms occurs within 2 to 5 minutes of rest. Patients who walk "through the pain" might require significantly more time for their symptoms to resolve. Claudication has a gradual onset and thus might not be noticed initially.

Arterial obstruction in the distal aorta and iliac arteries (aortoiliac disease) typically occurs in patients younger than 40 years of age. Aortoiliac disease is manifested by claudication symptoms in the buttocks, thigh, and calves. Isolated aortoiliac occlusive disease associated with sexual impotence in men is referred to as Leriche's syndrome. Occlusion in the superficial femoral or popliteal arteries usually begins at the level of Hunter's canal (the adductor canal of the thigh), and typically occurs in patients older than 40 years of age. Femoropopliteal disease is manifested by claudication in the calves and occasionally in the arch of the feet. The crucial function of the profunda femoris as the bridge between the aortofemoral segment and the femoropopliteal segment becomes apparent with occlusive disease of the superficial femoral artery. The profunda femoris provides collaterals to keep the lower leg viable and free of severe ischemia. In fact, it is not uncommon that patients with isolated superficial femoral artery occlusion have only mild to moderate, stable intermittent claudication.

Patients with severe, chronic lower extremity ischemia manifest pallor on elevating the leg above the level of the heart and rubor with dependency. In addition, these patients experience ischemic pain at rest, especially in a supine position, and they find often that they must dangle their feet over the side of the bed to obtain relief. Some of these patients sleep in a chair in order to keep their legs in a dependent position.

Among patients with intermittent claudication, 16% will experience a worsening of their claudication symptoms, 7% will require lower-extremity bypass surgery, and fewer than 4% will need primary amputation. Approximately 1.4% of patients with intermittent claudication will progress to ischemic rest pain and/or gangrene. This rate is markedly higher among smokers and diabetics.⁸

Pseudoclaudication
An important differential diagnosis of vascular claudication is pseudoclaudication due to lumbar canal stenosis. Unlike patients who have true vascular claudication, patients with pseudoclaudication experience leg pain with walking or prolonged standing. Calf pain arises while walking variable distances. Relief usually is obtained by sitting or stooping, which decompresses lumbar canal stenosis. Symptoms of pseudoclaudication require at least 20 minutes to abate. These patients often experience associated numbness and tingling in the feet.

The Six Ps
While intermittent claudication is the hallmark of chronic, stable limb ischemia, the six P's herald acute limb ischemia. The absence of compensating collateral circulation in acute arterial occlusive disease is responsible for the development and evolution of the six Ps: pulselessness, pain, pallor, poikilothermy (cold), paresthesia, and paralysis. The evolution to paresthesia and paralysis reflects the presence of severe and potentially irreversible ischemia.

Fibromuscular dysplasia of the right renal artery

Figure 1

Renovascular Symptoms
Clinical clues that suggest underlying renovascular disease include the onset of hypertension before the age of 30 years (from fibromuscular renal artery disease, see Figure 1) or after the age of 55 years (from atherosclerotic renal artery disease), previously well-controlled essential hypertension which becomes difficult to control, accelerated, or even resistant to medical treatment. In elderly patients with atherosclerosis in other vascular beds, the development of azotemia is a clue to the presence of renovascular disease. Patients who develop azotemia while taking an angiotensin-converting enzyme inhibitor might have underlying renovascular disease as well. Finally, a size discrepancy between the two kidneys (eg, atrophy in one) is suggestive of renovascular hypertension. Bilateral renal artery stenosis or renal artery stenosis to a single functioning kidney leads to the release of aldosterone and angiotensin. The resultant volume overload and peripheral vasoconstriction cause an increase in afterload and subsequently leads to increase in filling pressures and increase in myocardial oxygen consumption. Therefore, such patients may also present with recurrent congestive heart failure (despite normal left ventricular function) or recurrent unstable angina. Relief of the renal artery stenosis reverses these adverse neurohormonal and hemodynamic events thereby improving congestive heart failure and unstable angina symptoms (Figure 2).

Mesenteric Ischemia
The classic symptoms of chronic mesenteric ischemia include postprandial abdominal pain that begins 30 to 90 minutes after eating and persists for 2 to 3 hours. Such pain causes some patients to avoid food, which leads to weight loss. Acute mesenteric ischemia is caused by thrombosis of a severely diseased superior mesenteric artery or by an embolic event originating from the heart.

Cerebrovascular Symptoms
Patients with carotid artery stenosis present with ipsilateral transient ischemic attacks, strokes, or amaurosis fugax. Symptomatic carotid ischemia is caused by hemodynamic factors related to (1) the degree of stenosis (usually at least 70%) in the internal carotid artery ipsilateral to the involved hemisphere, (2) the degree of collateral flow, both from the circle of Willis and from the external carotid artery, and (3) the degree of intracranial arterial disease. Embolism from an ulcerated plaque in the internal carotid artery or from the stump of a completely occluded internal carotid artery also may cause a neurologic deficit (Figure 3).

A plaque at the distal common carotid artery extends into the origin of the internal carotid artery.

Figure 3

Aneurysmal Disease:

Factors such as atherosclerosis and genetic defects in connective tissue production may lead to aneurysmal degeneration of the aorta and peripheral arteries. All these factors cause a loss of tensile strength in the media of the arterial wall. Most aneurysms are asymptomatic. When symptoms occur, their manifestations are dependent on the location of the aneurysm. When they are large enough, thoracic aortic aneurysms compress surrounding structures and cause cough, hoarseness, stridor, dysphagia, and back pain. Giant-cell arteritis, Takayasu's arteritis, and annuloaortic ectasia cause aneurysmal dilation of the aortic root and ascending aorta, resulting in aortic valve regurgitation, aortic dissection, and sudden death.

Abdominal Aortic Aneurysms
Approximately 75% of abdominal aortic aneurysms are asymptomatic at the time of diagnosis.⁹ These aneurysms can become symptomatic without rupturing. Symptomatic patients present with abdominal pain or low back pain which may herald the beginning of a rupture. Erosion of an abdominal aortic aneurysm into the duodenum causes gastrointestinal hemorrhage. Upon rupture of an abdominal aortic aneurysm, the classic presenting triad of symptoms are (1) sudden, severe, and constant abdominal or back pain, (2) shock, and (3) a palpable pulsatile abdominal mass.

Peripheral Aneurysms
Aneurysms in the peripheral vessels usually lead to acute thrombosis rather than rupture. As femoral and popliteal artery aneurysms enlarge, they compress the surrounding venous structures and cause unilateral leg edema, venous hypertension, venous thrombosis with occlusion, or pain due to local nerve compression. Ischemia is the most common presentation. The severity of ischemic symptoms ranges from mild claudication to severe limb-threatening ischemia. Urgent reperfusion or revascularization is necessary to avoid limb loss.

History and Physical Examination
The history and physical examination are crucial in evaluating the patient with PAD. Information about the onset of ischemic symptoms, the duration of symptoms, the characteristics of pain, and any alleviating factors is helpful. The quality of pulses should be documented. The absence of pulses in an extremity is probably the most common physical finding. Unlike arterial bruits, which reflect turbulent blood flow due to an atherosclerotic plaque of any severity as well as vessel tortuosity, diastolic bruits reflect high velocity blood flow through a high-grade stenosis. Diastolic bruits, therefore, are a more sensitive clinical sign of significant atherosclerosis. Palpation to detect the presence of abdominal and peripheral aneurysms should be performed. Risk factors, especially smoking and diabetes, should prompt a search for PAD.

The Ankle-brachial Index (ABI)
The ABI is the ratio of (1) the higher systolic blood pressures between the dorsalis pedis and the posterior tibial artery to (2) the higher of the systolic blood pressures in the two brachial arteries. The ABI's sensitivity is 90% and its specificity is 98% for detecting angiographically defined stenoses of 50% or more. Table 1 shows the how ABI values relate to severity of PAD. The ABI also helps to differentiate true claudication from pseudoclaudication. Vascular claudication does not occur without a drop in the ABI. The ABI has limited use in evaluating calcified vessels that are not compressible.

Pulse Volume Recordings (PVR)
The principles of plethysmography are applied to evaluate changes in leg volume (ie, arterial flow) with each pulse. BP cuffs applied to the thigh, upper calf, lower calf, and midfoot help determine the level and severity of arterial disease. The resultant waveform resembles a BP waveform. An abnormal pulse volume recording reflects the presence of disease proximal to the location of the BP cuff. Calcified vessels do not limit the utility of pulse volume recordings.

Duplex Ultrasound Scanning
A combination of two ("duplex") methods of evaluation-B-mode imaging and Doppler measurements-renders both an anatomic and a functional assessment of the patient's condition. As blood flows through a stenotic lesion, its velocity increases. With duplex ultrasound scanning, peak systolic and end-diastolic velocities can be measured and are used to estimate the severity of a focal arterial stenosis. Different velocity criteria apply to different vascular beds. Duplex ultrasonography is an excellent screening tool for abdominal aortic aneurysms and carotid arteries. Limitations to adequate imaging include inability of ultrasound waves to pass through air. Ultrasonography is also limited due to its difficulty in ascertaining neighboring organs, and its reliance on operator experience (Figure 4).

Arteriography
The current arteriographic gold standard is intra-arterial digital subtraction angiography. However, because this is an invasive procedure, it should be reserved for patients who are being considered for endovascular or operative revascularization. Arteriography should not be used to delineate or screen for aneurysms because the mural thrombus, which frequently forms within an aneurysm, will mask the true lumen diameter (Figure 5).

Arteriogram of the abdominal aorta shows all the major branches of the abdominal aorta. There is a high-grade stenosis of the right common iliac artery.

Figure 5

Plain Radiographs
Radiographs are of limited use in the diagnosis of PAD, and not used for diagnostic purposes. On occasion, however, radiographs incidentally may show evidence of PAD. Sometimes the calcified medial layer of an artery will be appreciated. Alternatively, a thin rim of calcium in the wall of an aneurysmal aorta may be detected by a chest or abdominal radiograph.

Computed Tomography (CT)
Contrast-enhanced CT is an excellent tool for obtaining precise information about the aorta and its surrounding anatomic structures. It gives the most accurate measurement of an aneurysm (Figure 6).

1. To improve the functional status of patients with intermittent claudication, which will lead to improvements in quality of life and exercise capacity. The peak oxygen consumption of patients with intermittent claudication is only 15 to 20 ml/kg/min, a value that approximates that of a patient with New York Heart Association class III heart failure symptoms.
   
   To preserve the limb and obviate the need for extremity revascularization with its associated morbidity and mortality.
   
   
2. To prevent coronary and cerebrovascular events, which prove to be fatal in 75% of PAD patients. PAD patients require aggressive risk-factor modification and antiplatelet therapy.¹⁰

Exercise Programs and Pharmacologic Therapies
Patients who participate in 3 to 6 months of supervised walking programs can increase their pain-free walking time by 165% and their peak walking time by 96%.¹¹ They also experience improvement in peak oxygen consumption. Well-supervised exercise programs do not increase the risk of morbidity or mortality. Pharmacologic agents [pentoxifylline (Trental, Pentoxil) and cilostazol (Pletal)] are used in an attempt to increase walking distance, but pentoxifylline has never been shown to provide a statistically significant advantage over placebo.^12,13 Cilostazol, on the other hand, improves exercise performance significantly better than placebo, as well as pentoxifylline.^14,15

Cilostazol is a phosphodiesterase inhibitor and, as such, is contraindicated in patients with congestive heart failure and an ejection fraction of less than 40%.

Risk-factor Modification:

Smoking and Diabetes Mellitus
The two most important risk factors associated with PAD are smoking and diabetes mellitus. One study of intermittent claudication reported that 16% of smokers progressed to ischemic rest pain, compared with 0% of those who had quit smoking.¹⁶ Among diabetic PAD patients, gangrene develops in 31%, compared with only 5% of nondiabetic PAD patients. Rest pain occurs in 40% and 18%, respectively.¹⁷ Finally, patients with PAD and diabetes are reported to have 5-year mortality rates of up to 50%.¹⁸

Cholesterol
Dyslipidemias are common in patients with PAD. Several trials have demonstrated significant reductions in death and myocardial infarctions in patients treated with HMG-CoA reductase inhibitors. The underlying mechanism for the reduction of cardiovascular events is the ability of the HMG-CoA reductase inhibitors to stabilize a fragile atherosclerotic coronary plaque and thereby reduce the likelihood of plaque rupture and thrombosis. In its new guidelines, the National Cholesterol Education Program recommends that patients with PAD target their low-density lipoprotein level to less than 100 mg/dL.¹⁹

Hypertension
High BP not only increases the risk of claudication in patients with PAD, it increases the risks of cardiovascular morbidity and mortality as well. Ideally, systolic BP should be kept lower than 130 mm Hg and diastolic BP less than 85 mm Hg. Keep in mind, however, that lowering BP too much can also lower limb perfusion pressure and worsen claudication symptoms.²⁰

Antiplatelet Therapy
Antiplatelet treatment is the cornerstone of therapy to prevent ischemic events in patients with PAD. Aspirin, which blocks the thromboxane-mediated pathway, has been shown to lower the risk of ischemic cardiovascular events. Aspirin has also been shown to prevent limb loss by preventing occlusions in native arteries and in lower-extremity bypass grafts.^21,22

Thienopyridine derivatives such as ticlopidine (Ticlid) and clopidogrel (Plavix) inhibit platelet aggregation induced by adenosine diphosphate. Ticlopidine has been shown to reduce the composite endpoint of sudden death, myocardial infarction, and stroke and to improve walking distance and lower-extremity venous bypass graft function. However, its use has been severely curtailed because of its significant side effects, including neutropenia and thrombotic thrombocytopenic purpura. Therefore, patients taking ticlopidine require constant blood monitoring.

Clopidogrel was shown in CAPRIE (Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events) trial to be superior to aspirin in reducing cardiovascular and cerebrovascular ischemic events in patients with PAD.²³ The incidence of neutropenia was no higher in patients who received clopidogrel than those who received aspirin.

Because aspirin and the thienopyridine derivatives inhibit platelets via different pathways, their combined use may have an additive effect.

Revascularization:

Occlusive Disease
Among patients with chronic arterial occlusive disease, revascularization is indicated for those who have lifestyle-limiting intermittent claudication, ischemic rest pain, or tissue loss. "Lifestyle-limiting" is a very subjective criterion, but it probably should include an inability to participate in a cardiac rehabilitation program because of claudication. Endovascular revascularization has achieved some popularity because it is associated with lower morbidity and less rehabilitation time than surgical revascularization. Generally speaking, endovascular revascularization [percutaneous transluminal angioplasty (PTA) with or without stenting] is favored for shorter lesions, while surgery is preferred for longer lesions as well as for lesions that fail endovascular revascularization. A general comparison between endovascular and surgical revascularization are outlined below:

• In aortoiliac disease, PTA with stenting has been associated with a 24-month patency rate as high as 84% and a mortality rate as low as 0.2%. Surgery for aortoiliac disease yields 5-year patency rates of 80% to 90% and a mortality rate of 4.4%.^24,25
  
  
• The 5-year patency rate with PTA in femoropopliteal disease ranges from 40% to 60% (depending upon the length of diseased segment), and its mortality rate is lower than that of surgery.²⁶ Surgery has a 2.6% mortality rate and a 5-year patency rate of 70% for above-the-knee femoropopliteal autogenous vein bypass procedures and 40% for below-the-knee procedures. The latter figure drops to 20% when prosthetic graft material is used.²⁷
  
  
• In patients with disabling claudication due to femoropopliteal disease, a comparison study of surgery and angioplasty showed that PTA was the preferred initial treatment.²⁸ Infrapopliteal PTA has been used effectively for limb salvage, although anatomic selection plays an important role in outcomes.
  
  
• PTA for a focal lesion in a tibial vessel with restorable run-off and a complete pedal arch yields a reasonable patency rate (80% at 2 yr).²⁹
  
  
• The 4-year patency rates for infrapopliteal bypass are approximately 50% with autogenous vein grafts and only 12% with prosthetic grafts.³⁰

In patients with acute peripheral arterial occlusive disease, several trials have demonstrated lower mortality and amputation rates when thrombolytic agents are used in the acute setting. In addition, there was a reduction in planned surgical procedures because the unmasked underlying offending lesion could be repaired by endovascular methods.^31,32

Asymptomatic patients with an 80% to 99% internal carotid artery stenosis by duplex ultrasound are at high risk for subsequent ipsilateral neurologic symptoms. These patients benefit from carotid endarterectomy. For patients who are symptomatic, the North American Symptomatic Carotid Endarterectomy Trial (NASCET) guidelines of 1991 recommend carotid endarterectomy for patients with a 70% to 99% stenosis by arteriography (50% to 99% by duplex ultrasound).³³ Surgical benefits are realized provided that the incidence of perioperative stroke is less than 2%. More recently, carotid artery angioplasty with stenting has become an attractive alternative to surgery. Clinical trials are under way to compare endovascular carotid therapy with carotid endarterectomy.

Aneurysmal Disease
The natural history of an aneurysm dictates the type of treatment that should be rendered. Ideally, surgery should be performed before a catastrophic aneurysmal event takes place. With thoracic and abdominal aortic aneurysms, rupture almost always leads to death. With popliteal and femoral artery aneurysms, an acute thrombotic event must be avoided. Once a thoracic aortic aneurysm reaches 5 cm in diameter, becomes symptomatic, or enlarges rapidly, elective surgical resection should be performed. Indications for elective repair of an abdominal aortic aneurysm include 1) an aneurysm larger than 5 cm, 2) rapid aneurysm expansion (> 0.5 cm/6 mo), 3) an atypical or traumatic aneurysm, or 4) a symptomatic aneurysm. Patients who present with a ruptured aneurysm require emergent surgery. Currently, the treatment standard is open surgical repair with either aortobiiliac or aortobifemoral bypass grafting. Recently, endovascular stent grafting has gained popularity, but its long-term outcomes have yet to be determined.

Return to Medicine Index

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