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 Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • Smoking and tobacco use
  • Diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
  • Hypercholesterolemia
  • Hyperhomocysteinemia
  • Obesity
• Arterial embolism:
  • Cholesterol atheroembolism
  • Atrial fibrillation Atrial fibrillation Atrial fibrillation (AF or Afib) is a supraventricular tachyarrhythmia and the most common kind of arrhythmia. It is caused by rapid, uncontrolled atrial contractions and uncoordinated ventricular responses. Atrial Fibrillation
  • Endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. 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 Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. 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 Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. 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

Management

Lifestyle modification

Lifestyle modification is the 1st line of therapy:

• Smoking cessation
• Diet 
• Exercise therapy program 
  • Increases blood flow
  • Improves endurance and pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of 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 Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 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 Amputation An amputation is the separation of a portion of the limb or the entire limb from the body, along with the bone. Amputations are generally indicated for conditions that compromise the viability of the limb or promote the spread of a local process that could manifest systemically. 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 Acute limb ischemia Acute limb ischemia (ALI) is a major vascular emergency because of the rapid decrease in limb perfusion that causes a potential threat to limb viability. The majority of cases are caused by arterial thrombosis due to plaque progression or embolism, but ALI can also be caused by blockage of the venous drainage. 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 Compartment Syndrome Compartment syndrome is a surgical emergency usually occurring secondary to trauma. The condition is marked by increased pressure within a compartment that compromises the circulation and function of the tissues within that space. 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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, paresthesias, and muscle weakness. 
• Limb may feel tense.
• Diagnosis is made by measuring compartment pressures.
• Requires 4-compartment fasciotomy

Subclavian steal syndrome Subclavian steal syndrome Subclavian steal syndrome occurs when narrowing/occlusion of the subclavian artery proximal to the origin of the vertebral artery causes a reversal of blood flow in the ipsilateral vertebral artery to continue perfusing the ipsilateral arm. The most common cause is atherosclerosis. 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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain

Differential Diagnosis

• Arterial aneurysm Aneurysm An aneurysm is a bulging, weakened area of a blood vessel that causes an abnormal widening of its diameter > 1.5 times the size of the native vessel. Aneurysms occur more often in arteries than in veins and are at risk of dissection and rupture, which can be life-threatening. Extremity and Visceral Aneurysms: abnormal dilation of the arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries due to weakening of the arterial wall. Thrombosis of a popliteal artery aneurysm Aneurysm An aneurysm is a bulging, weakened area of a blood vessel that causes an abnormal widening of its diameter > 1.5 times the size of the native vessel. Aneurysms occur more often in arteries than in veins and are at risk of dissection and rupture, which can be life-threatening. Extremity and Visceral Aneurysms can result in symptoms of lower extremity ischemia. Patients will have a cold, pale leg Leg The lower leg, or just "leg" in anatomical terms, is the part of the lower limb between the knee and the ankle joint. The bony structure is composed of the tibia and fibula bones, and the muscles of the leg are grouped into the anterior, lateral, and posterior compartments by extensions of fascia. 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 Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. 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 Acute limb ischemia Acute limb ischemia (ALI) is a major vascular emergency because of the rapid decrease in limb perfusion that causes a potential threat to limb viability. The majority of cases are caused by arterial thrombosis due to plaque progression or embolism, but ALI can also be caused by blockage of the venous drainage. Acute Limb Ischemia and blue toe syndrome. The clinical history, hypercoagulable Hypercoagulable Hypercoagulable states (also referred to as thrombophilias) are a group of hematologic diseases defined by an increased risk of clot formation (i.e., thrombosis) due to either an increase in procoagulants, a decrease in anticoagulants, or a decrease in fibrinolysis. Hypercoagulable States 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 Vascular surgery Vascular surgery is the specialized field of medicine that focuses on the surgical management of the pathologies of the peripheral circulation. The main goal of most vascular procedures is to restore circulatory function to the affected vessels by relieving occlusions or by redirecting blood flow (e.g., bypass). Vascular Surgery evaluation.
• Spinal stenosis Spinal stenosis Spinal stenosis is the progressive narrowing of the central spinal canal, intervertebral foramen, and lateral recess, leading to compression of the nerve root. Spinal stenosis can occur in the cervical, thoracic, and lumbar spine and is commonly caused by degenerative bone disease (mostly affecting the elderly). Spinal Stenosis: compression of nerve roots due to narrowing of the spinal canal. Patients may have positional back pain Back pain Back pain is a common complaint among the general population and is mostly self-limiting. Back pain can be classified as acute, subacute, or chronic depending on the duration of symptoms. The wide variety of potential etiologies include degenerative, mechanical, malignant, infectious, rheumatologic, and extraspinal causes. Back Pain and exertional lower extremity pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain. The pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of 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 Imaging of the Spine The vertebral column and the spinal cord may be affected by various diseases, in which different imaging methods are important for correct diagnosis and management. Radiographs and CT scans are useful in evaluating bony structures, especially in excluding fractures and checking hardware. Imaging of the Spine and Spinal Cord. Treatment includes physical therapy, pain management Pain Management Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Pain is a subjective experience. Acute pain lasts < 3 months and typically has a specific, identifiable cause. Pain Management, and surgery for severe cases.
• Thromboangiitis obliterans Thromboangiitis Obliterans Thromboangiitis obliterans (TAO), also known as Buerger’s disease, is a rare condition causing inflammatory thrombosis of the small- to medium-sized arteries and veins of the upper and lower extremities. Thromboangiitis Obliterans (Buerger’s Disease) (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 Amputation An amputation is the separation of a portion of the limb or the entire limb from the body, along with the bone. Amputations are generally indicated for conditions that compromise the viability of the limb or promote the spread of a local process that could manifest systemically. 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 Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. 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.