Peripheral artery disease

The signs and symptoms of peripheral artery disease are based on the affected body part. About 66% of patients affected by PAD either do not have symptoms or have atypical symptoms. This occurs because during exercise, the muscles require more oxygen. Normally, the arteries would be able to increase the amount of blood flow and therefore increase the amount of oxygen going to the exercised muscle. However, in PAD, the artery cannot respond appropriately to the increased muscular demand for oxygen. Therefore, the muscles are deprived of oxygen, leading to muscle pain that subsides with rest. • Pain, aches, and/or cramps in the buttocks, hip, or thigh • Muscle atrophy (muscle loss) of the affected limb • Hair loss of the affected limb • Skin that is smooth, shiny, or cool to the touch in the affected area • Decreased or absent pulse in the feet • Cold and/or numbness in the toes • Sores/ulcers on the affected limb that do not heal In individuals with severe PAD, complications may arise, including critical limb ischemia and gangrene. Critical limb ischemia occurs when the obstruction of blood flow in the artery is compromised to the point where the blood cannot maintain oxygenation of the tissue at rest. People with diabetes are affected by gangrene of the feet at a rate that is 30 times higher than the unaffected population. Many of these severe complications, such as those leading to amputation, are irreversible. ==Causes==

Risk factors Factors contributing to an increased risk of PAD are the same as those for atherosclerosis. These include age, sex, and ethnicity. PAD is twice as common in males as in females. In terms of ethnicity, PAD is more common in people of color compared to the white population in a 2:1 ratio. Greater than 80%–90% of patients with lower extremity peripheral arterial disease are current or former smokers. The risk of PAD increases with the number of cigarettes smoked per day and the number of years smoked. The risk of developing lower extremity peripheral arterial disease is proportional to the severity and duration of diabetes. • High blood cholesterol – Dyslipidemia is an unhealthy pattern of cholesterol or fat in the blood. • High blood pressure – Hypertension or elevated blood pressure can increase a person's risk of developing PAD. Similarly to PAD, there is a known association between high blood pressure and heart attacks, strokes, and abdominal aortic aneurysms. High blood pressure increases the risk of intermittent claudication, the most common symptom of PAD, by 2.5- to 4-fold in men and women, respectively. • Other risk factors that are being studied include levels of various inflammatory mediators such as C-reactive protein, fibrinogen, homocysteine, and lipoprotein A. Individuals with increased levels of homocysteine in their blood have a 2-fold risk of developing peripheral artery disease. • All people who have leg symptoms with exertion (suggestive of claudication) or ischemic rest pain • All people aged 65 years and over, regardless of risk factor status • All people between 50 and 69 who have a cardiovascular risk factor (particularly diabetes or smoking) • Age less than 50 years, with diabetes and one other atherosclerosis risk factor (smoking, dyslipidemia, hypertension, or hyperhomocysteinemia) • Individuals with an abnormal lower extremity pulse examination • Those with known atherosclerotic coronary, carotid, or renal artery disease • All people with a Framingham risk score of 10%–20% • All people who have previously experienced chest pain == Etiology and pathophysiology ==

Peripheral arterial disease is considered to be a set of chronic or acute syndromes, generally derived from the presence of occlusive arterial disease, which causes inadequate blood flow to the limbs. As previously mentioned, the most common etiology of peripheral artery disease, especially in patients over 40 years old, is atherosclerosis. Additional mechanisms of peripheral artery disease include arterial spasm and fibromuscular dysplasia. The symptoms of claudication ensue when the artery spasms, or clamps down on itself, creating an obstruction. Like atherosclerosis, this leads to decreased blood flow to the tissue downstream of the obstruction. Thrombosis, or the formation of a blood clot, usually occurs due to stasis or trauma. ==Diagnosis==

Diagnosing or identifying peripheral artery disease requires a history of symptoms and a physical exam, followed by confirmatory testing. An ABI range of 0.90 to 1.40 is considered normal. A person is considered to have PAD when the ABI is ≤ 0.90. However, PAD can be further graded as mild to moderate if the ABI is between 0.41 and 0.90, and severe if the ABI is less than 0.40. These categories can provide insight into the disease course. Individuals with noncompressible arteries have an increased risk of cardiovascular mortality within two years. Individuals with suspected PAD with normal ABIs can undergo exercise testing for ABI. A baseline ABI is obtained before exercise. The patient is then asked to exercise (usually patients are made to walk on a treadmill at a constant speed) until claudication pain occurs (for a maximum of 5 minutes), after which the ankle pressure is again measured. A decrease in ABI of 15%–20% would be diagnostic of PAD. As such, CT may be considered as an alternative to invasive angiography. An important distinction between the two is that, unlike invasive angiography, assessment of the arterial system with CT does not allow for vascular intervention. Magnetic resonance angiography (MRA) is a noninvasive diagnostic procedure that uses a combination of a large magnet, radio frequencies, and a computer to produce detailed images of blood vessels inside the body. The advantages of MRA include its safety and ability to provide high-resolution, three-dimensional imaging of the entire abdomen, pelvis, and lower extremities in one sitting. Classification The two most commonly used methods to classify peripheral artery disease are the Fontaine and Rutherford classification systems. The Fontaine stages were introduced by René Fontaine in 1954 to define the severity of chronic limb ischemia: • Stage I: asymptomatic • Stage IIa: intermittent claudication after walking a distance of more than 200 meters • Stage IIb: intermittent claudication after walking a distance of less than 200 meters • Stage III: rest pain • Stage IV: ulcers or gangrene of the limb The Rutherford classification was created by the Society for Vascular Surgery and the International Society of Cardiovascular Surgery, introduced in 1986 and revised in 1997 (and known as the Rutherford classification after the lead author, Robert B. Rutherford). This classification system consists of four grades and seven categories (categories 0–6): • Grade 0, Category 0: asymptomatic • Grade I, Category 1: mild claudication • Grade I, Category 2: moderate claudication • Grade I, Category 3: severe claudication • Grade II, Category 4: rest pain • Grade III, Category 5: minor tissue loss; ischemic ulceration not exceeding the ulcer of the digits of the foot • Grade IV, Category 6: major tissue loss; severe ischemic ulcers or frank gangrene Moderate to severe PAD, classified by Fontaine's stages III to IV or Rutherford's categories 4 to 5, presents a limb threat (risk of limb loss) in the form of critical limb ischemia. Recently, the Society for Vascular Surgery came out with a classification system based on "wound, ischemia and foot infection" (WIfI). This classification system, published in 2013, was created to account for the demographic changes that have occurred over the past forty years, including the increased incidence of high blood sugar and evolving techniques and abilities for revascularization. This system was created on the basis that ischemia and angiographic disease patterns are not the sole determinants of amputation risk. (ABI), although a systematic review of the literature did not support the use of routine ABI screening in asymptomatic patients. Testing for coronary artery disease or carotid artery disease is of unclear benefit. Some studies propose the development of devices measuring oxygen continuously during exercise. This is because resting perfusion and metabolic activity are extremely low, and differences between non-patients and PAD patients are barely measurable. As such, testing of vascular function and energetics requires a physiological challenge. Pulse oximeters can be inconvenient to wear during exercise and only give oxygen values at discrete time points, nor is there sufficient evidence to support any use in identifying PAD. Some publications and studies therefore discuss the use of wearable sensors measuring oxygen levels continuously in PAD patients, such as through transcutaneous means. However, because transcutaneous measurements are affected by movement (such as during exercise) and body temperature, the use of oxygen sensors that are inserted subcutaneously as opposed to transcutaneously may most effectively help monitor a PAD patient's progress and direct therapy decisions. To date, one oxygen sensing system has been approved for use in Europe to measure tissue perfusion in all PAD patients. ==Treatment==

Depending on the severity of the disease, these steps can be taken, according to these guidelines: Cilostazol can improve symptoms in some people. Cilostazol may improve walking distance for people who experience claudication due to peripheral artery disease, but no strong evidence suggests that it improves the quality of life, decreases mortality, or decreases the risk of cardiovascular events. • Angioplasty (or percutaneous transluminal angioplasty) can be done on solitary lesions in large arteries, such as the femoral artery, but may not have sustained benefits. Patency rates following angioplasty are highest for iliac arteries and decrease with arteries towards the toes. Other criteria that affect the outcome following revascularization are the length of the lesion and the number of lesions. There do not appear to be any long-term advantages or sustained benefits to placing a stent following angioplasty in order to hold the narrowing of the subsartorial artery open. • Atherectomy, in which the plaque is scraped off the inside of the vessel wall (albeit with no better results than angioplasty). • Vascular bypass grafting can be performed to circumvent a diseased area of the arterial vasculature. The great saphenous vein is used as a conduit if available, although artificial (Gore-Tex or PTFE) material is often used for long grafts when an adequate venous conduit is unavailable. • When gangrene has set in, amputation may be required to prevent infected tissues from causing sepsis, a life-threatening illness. • Thrombolysis and thrombectomy are used in cases of arterial thrombosis or embolism. • shockwave intravascular lithotripsy, a minimally invasive method that uses ultrasound waves to break up plaque within the artery without the need for penetration. The method was first approved by the US Food and Drug Administration in February 2021, and has been used as a complement to more widely used methods of atherectomy. Guidelines A guideline from the American College of Cardiology and American Heart Association for the diagnosis and treatment of lower extremity, renal, mesenteric, and abdominal aortic PAD was compiled in 2013, combining the 2005 and 2011 guidelines. For chronic limb-threatening ischemia, the ACCF/AHA guidelines recommend balloon angioplasty only for people with a life expectancy of 2 years or less or those who do not have an autogenous vein available. For those with a life expectancy greater than 2 years or who have an autogenous vein, bypass surgery is recommended. ==Prognosis==

Individuals with PAD have an "exceptionally elevated risk for cardiovascular events and the majority will eventually die of a cardiac or cerebrovascular etiology". Prognosis is correlated with the severity of the PAD as measured by an ABI. Of patients with intermittent claudication, only "7% will undergo lower-extremity bypass surgery, 4% major amputations, and 16% worsening claudication", but stroke and heart attack events are elevated, and the "5-year mortality rate is estimated to be 30% (versus 10% in controls)". ==Epidemiology==

The prevalence of PAD in the general population is 3–7%, affecting up to 20% of those over 70; 70%–80% of affected individuals are asymptomatic; only a minority ever require revascularization or amputation. Peripheral artery disease affects one in three diabetics over the age of 50. In the US, it affects 12–20 percent of Americans age 65 and older. Around 10 million Americans have PAD. Despite its prevalence and implications for cardiovascular risk, there are still low levels of awareness of risk factors and symptoms, with 26% of the population in the US reported to have knowledge of PAD. In 2000, among people aged 40 years and older in the United States, rates of PAD were 4.3%. Rates were 14.5% for people aged 70 years or over. Within age groups, rates were generally higher for women than men. Non-Hispanic blacks had a rate of 7.9% compared to 4.4% in Non-Hispanic whites and 3.0% (1.4%–4.6%) in Mexican Americans. The Diabetes Control and Complications Trial and the UK Prospective Diabetes Study trials in people with type 1 and type 2 diabetes, respectively, demonstrated that glycemic control is more strongly associated with microvascular disease than macrovascular disease. Pathologic changes occurring in small vessels may be more sensitive to chronically elevated glucose levels than atherosclerosis occurring in larger arteries. ==Research==

Research is being done on therapies to prevent the progression of PAD. In those who have developed critically poor blood flow to the legs, the benefit of autotransplantation of autologous mononuclear cells is unclear. Only one randomized controlled trial has been conducted comparing vascular bypass to angioplasty for the treatment of severe PAD. The trial found no difference in amputation-free survival between vascular bypass and angioplasty at the planned clinical endpoint, but the trial has been criticized as being underpowered, limiting endovascular options, and comparing inappropriate endpoints. As of 2017, two randomized clinical trials are being conducted to better understand the optimal revascularization technique for severe PAD and critical limb ischemia (CLI), the BEST-CLI (Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia) Trial and the BASIL-2 (Bypass Versus Angioplasty in Severe Ischaemia of the Leg – 2 )Trial. In 2011, pCMV-vegf165 was registered in Russia as the first-in-class gene therapy drug for the treatment of PAD, including the advanced stage of critical limb ischemia. == References ==