Peripheral Artery Disease

Epidemiology and Etiology

Epidemiology

• Affects approximately 10% of the population > 55 years of age in the United States
• Worldwide prevalence is 3%–12%
• Men > women
• Higher prevalence among African Americans and non-Hispanic Whites
• Lower rates in Hispanics and Asians

Etiology

Peripheral artery disease (PAD) usually has the same causative factors as coronary and carotid disease.

• Atherosclerosis:
  • Aging
  • Hypertension
  • Smoking and tobacco use
  • Diabetes mellitus
  • Hypercholesterolemia
  • Hyperhomocysteinemia
  • Obesity
• Arterial embolism:
  • Cholesterol atheroembolism
  • Atrial fibrillation
  • Endocarditis
  • Artificial heart valves
• Functional:
  • Vasospasm
  • Previous injury to the limb
• Risk groups:
  • Age ≥ 70 years
  • Age 50–69 years + smoking or diabetes
  • Age 40–49 + diabetes + 1 other risk factor for atherosclerosis
  • Atherosclerosis at other sites (e.g., coronary, carotid, renal)

Pathophysiology

• Atherosclerosis: endothelial cell dysfunction → macrophage and cholesterol accumulation → foam cell formation → platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) release  → smooth muscle cell migration → proliferation and extracellular matrix deposition → fibrous plaque
• Subintimal accumulation of lipid and fibrous material of the arteries → vessel lumen narrowing → restricted blood flow → chronic ischemia of the affected limb
• Plaque rupture or thrombosis → abrupt occlusion of downstream vessels → acute ischemia of the limb

Clinical Presentation

Patients with PAD may be asymptomatic (20%–25%) or present with evidence of chronic or acute limb ischemia.

Chronic arterial insufficiency

• Symptoms:
  • The lower extremities are most commonly affected.
  • Intermittent claudication: 
    • Reproducible, painful cramping in the buttock, hips, thighs, calf, or foot with exertion 
    • Relieved with rest
  • Atypical limb pain or feeling of “heaviness”
  • Limb numbness or weakness
  • Impotence, erectile dysfunction
• Physical exam findings:
  • Poorly healing wounds
  • Discoloration
    • Pale with limb elevation
    • Redness when limb is lowered
    • Cyanosis
  • Weak or absent pulse below a narrowed area of the artery
  • Bruits over arteries heard on auscultation
  • Decreased blood pressure in the affected limb
  • Severe disease: 
    • Loss of hair follicles, sweat glands, and sebaceous glands 
    • Skin becomes smooth and shiny.
• Fontaine classification:
  • Used to determine the severity of PAD
  • Stages are based on symptoms and exam (see table).

Chronic limb-threatening (critical) ischemia

Any 1 of the following indicates that blood flow no longer meets the metabolic demands of the limb tissues at rest:

• Resting pain
  • Worse distally
  • Aggravated by limb elevation
• Ulcer
• Gangrene

Acute limb ischemia

Acute limb ischemia is most commonly due to an embolism or plaque rupture. Patients will demonstrate acute onset of:

• 6 Ps: 
  1. Pain
  2. Pallor 
  3. Pulseless 
  4. Poikilothermia (cold)
  5. Paresthesia 
  6. Paralysis
• Blue toe syndrome
  • Due to cholesterol atheroembolism to digital arteries
  • Pedal pulses will be normal.
• Ulceration or gangrene
• Ankle blood pressure ≤ 50 mm Hg

Diagnosis

Diagnostic algorithm for PAD

This algorithm demonstrates the diagnostic pathway for a patient presenting with signs or symptoms of PAD:

The diagnosis is usually established through clinical history, exam, and non-invasive testing techniques (ankle-brachial index (ABI), exercise testing).

Note that those with features of limb-threatening ischemia need urgent vascular surgery evaluation. These patients may still undergo imaging studies to locate the area of vascular obstruction or stenosis as part of surgical planning.

Non-invasive techniques

These studies are used to establish the diagnosis:

• Ankle-brachial index
  • Usually the first choice in testing to establish a diagnosis
  • Equals the leg systolic blood pressure divided by the arm systolic blood pressure
    • An ABI < 0.9 indicates PAD (see table below for the severity classification based on ABI).
    • An ABI > 1.3 may indicate noncompressible vessels due to calcification (common in diabetics).
    • If the ABI is > 1.3 and suspicion for PAD is high, consider measuring a BP in the 1st toe or proceed to Doppler ultrasound.
• Treadmill exercise test 
  • Indicated for patients with a classic history suggesting PAD and normal resting ABI (0.91–1.30)
  • ABIs are measured before and after exercise.
    • Normal physiology: ABI should ↑ or stay the same.
    • In PAD: post-exercise ABI ↓ by ≥ 20%

Imaging

These studies are used to evaluate the location and severity of disease:

• Doppler ultrasound
  • Noninvasive, but operator-dependent
  • Can determine blood flow through arteries
  • Measured velocities through diseased portions allow estimation of percent stenosis.
• Computed tomography with angiography (CTA)
  • Quick, but requires contrast administration
  • Becoming more commonly utilized to locate stenotic lesions
• Magnetic resonance imaging with angiography (MRA)
  • Can avoid ionizing radiation
  • High diagnostic accuracy
• Digital subtraction arteriography
  • Reference standard
  • Intravenous contrast is injected imaged with a series of radiographs.
  • Has the highest diagnostic accuracy

Laboratory testing

These studies are not used for the diagnosis of PAD, but can help evaluate risk factors or organ injury:

• Lipid profile → hyperlipidemia
• Hemoglobin A1c → diabetes
• Homocysteine → hyperhomocysteinemia
• Creatinine → renal disease

Screening asymptomatic patients

• Screening is performed in patients who may be asymptomatic but have risk factors or evidence of PAD.
• Important in preventing progression and complications
• Can be used to identify patients at risk for other types of cardiovascular disease
• Again, ABI is the test of choice for establishing the diagnosis.

Management

Lifestyle modification

Lifestyle modification is the 1st line of therapy:

• Smoking cessation
• Diet 
• Exercise therapy program 
  • Increases blood flow
  • Improves endurance and pain tolerance
  • Helps develop collateral circulation
  • Reduces blood cell aggregation and blood viscosity
• Glycemic control

Medications

• Antiplatelet therapy (aspirin, clopidogrel)
• Risk factor modification
  • Statin therapy
  • Antihypertensive treatment
  • Vitamins (folate and vitamin B₁₂) for hyperhomocysteinemia
• Phosphodiesterase inhibitors (cilostazol)
  • Most effective pharmaceutical treatment for improving claudication symptoms
  • Indicated after failure of conservative measures
  • Reduces platelet aggregation and allows arterial vasodilation
• Thrombolysis
  • Used in arterial thrombosis or embolism where tissue salvage is thought to be likely
  • Not for patients with intermittent claudication or where tissue is immediately threatened or irreversibly damaged
  • May be catheter-directed

Revascularization therapy

• Goal is to salvage the limb tissue and prevent amputation.
• Indications:
  • Critical limb ischemia
  • Failure to improve with lifestyle modification and medications
  • Significant disability due to symptoms
• Percutaneous transluminal angioplasty (PTA) 
  • Catheter is inserted into the artery.
  • Balloon is inflated to open an obstruction.
  • Vascular stenting may also be performed.
• Atherectomy
  • Catheter procedure in which plaque is removed from the artery
  • Can be used for in-stent restenosis or in areas where stent placement is not feasible
• Surgical procedures
  • Endarterectomy (direct removal of obstructive plaque)
  • Embolectomy (direct removal of a thrombus)
  • Vascular bypass grafting

Complications

Threatened limb from acute limb ischemia

• Surgical emergency
• Start a heparin drip.
• Surgical embolectomy should be performed in most circumstances.
• Intraoperative angiography follow-up to ensure normal flow

Compartment syndrome

• Increased risk after prolonged ischemia (> 6 hours)
• Occurs due to reperfusion injury → leads to swelling and increased pressure (may result in further ischemia, necrosis, and limb loss)
• Patients will develop severe pain, paresthesias, and muscle weakness. 
• Limb may feel tense.
• Diagnosis is made by measuring compartment pressures.
• Requires 4-compartment fasciotomy

Subclavian steal syndrome

• Retrograde vertebral artery flow due to subclavian artery stenosis or occlusion
• Usually asymptomatic, but upper extremity ischemia and neurologic symptoms (from vetebrobasilar ischemia) indicate severe disease.
• Management is similar to general PAD treatment.

Gangrene or limb loss

Amputation is performed when:

• Revascularization has failed or is not possible
• There is progressive gangrene
• Uncontrolled infection
• Unrelenting pain

Differential Diagnosis

• Arterial aneurysm: abnormal dilation of the arteries due to weakening of the arterial wall. Thrombosis of a popliteal artery aneurysm can result in symptoms of lower extremity ischemia. Patients will have a cold, pale leg with absent distal pulses and paresthesias. Physical exam may reveal a large, pulsatile popliteal artery. Imaging will confirm the diagnosis and differentiate this diagnosis from PAD. Treatment involves surgical repair of the artery.
• Arterial dissection: disruption in the medial layer of the arterial wall, resulting in bleeding into the vessel wall (creating a “false lumen”), which may be due to connective tissue disorders or from vascular interventions. Occlusion of the “true” lumen may result, causing symptoms of ischemia (such as limb-threatening ischemia). Ultrasound or CTA may be used to establish the diagnosis and will differentiate this condition from PAD. Treatment may require surgical repair of the artery.
• Thromboembolic disease: vascular occlusion due to a dislodged thrombus from a more proximal source. The presentation depends on the source, size, and location of the embolism, but includes acute limb ischemia and blue toe syndrome. The clinical history, hypercoagulable workup, and imaging aid in the diagnosis, and a source will typically be suspected or found on workup, which differentiates thromboembolic disease from PAD. Management includes anticoagulation and revascularization.
• Popliteal artery entrapment syndrome: an uncommon condition in which an abnormally positioned, or enlarged, calf muscle compresses the popliteal artery. The compression leads to obstruction of blood flow to the lower extremity, causing distal extremity ischemia, ulceration, or necrosis. The diagnosis is made with imaging, which will differentiate this condition from PAD. Management includes avoiding any inciting exercise and vascular surgery evaluation.
• Spinal stenosis: compression of nerve roots due to narrowing of the spinal canal. Patients may have positional back pain and exertional lower extremity pain. The pain will not be relieved with rest. Other symptoms include weakness, paresthesias, and diminished reflexes. Unlike PAD, pulses will be intact. The diagnosis is made based on clinical exam and MRI imaging of the spine. Treatment includes physical therapy, pain management, and surgery for severe cases.
• Thromboangiitis obliterans (Buerger’s disease): nonatherosclerotic segmental inflammatory disease that affects small to medium-sized vessels of the extremities. Patients are typically young smokers presenting with distal extremity ischemia, ulcers, or gangrene. Diagnosis is based on clinical findings, vascular testing, and angiography. Other potential diagnoses must be ruled out, including PAD. Smoking cessation is an essential part of management and decreases the risk of amputation.
• Vasculitis: a vascular inflammatory disease, often resulting in ischemia, necrosis, and organ damage. Any vessel can be involved. Etiologies include autoimmune disorders, drugs, and infections. Patients present with fever, arthralgias, and arthritis, as well as potential end-organ damage. Diagnosis involves inflammatory markers, autoimmune serology, infectious workup, and biopsy, which will differentiate this disease from PAD. Management depends on the underlying cause.